MXPA01005846A - Non-peptide antagonists of glp-1 receptor and methods of use - Google Patents

Abstract

Non-peptide compounds that act as antagonists of the intestinal hormone glucagon-like peptide 1 (GLP-1) have a 9H-&bgr;-carboline central motif. The compounds exhibit advantageous physical, chemical and biological properties and inhibit GLP-1 peptide binding to the GLP-1 receptor and/or prevent activation of the receptor by bound GLP-1. The invention further relates to a method of inhibiting the binding of GLP-1 to the GLP-1 receptor and a method of inhibiting the activation of the GLP-1 receptor. Intermediate compounds useful for making non-peptide GLP-1 receptor antagonists are also described.

Description

NON-PEPTIDE ANTAGONISTS OF GLUCAGON-LIKE PEPTIDE 1 RECEPTOR (GLP-1), AND METHODS FOR USE TECHNICAL FIELD AND INDUSTRIAL APPLICABILITY OF THE INVENTION The present invention relates generally to compounds that act as antagonists for the intestinal hormone peptide 1 similar to glucagon (GLP-1). More particularly, the invention relates to non-peptide GLP-1 antagonists, which have advantageous physical, chemical and biological properties. The GLP-1 antagonists of the present invention inhibit the binding of the GLP-1 peptide to the GLP-1 receptor or prevent activation of the receptor by bound GLP-1. The invention further relates to a method for inhibiting the binding of GLP-1 to the GLP-1 receptor and a method for inhibiting the activation of the GLP-1 receptor.

BACKGROUND OF THE INVENTION GLP-1 is an intestinal hormone released in minutes within the food intake, which enhances the release of insulin and helps in the regulation of glucose uptake and metabolism.

GLP-1 is derived by post-translational REF-129630 proglucagon procedures and is secreted by intestinal endocrine L cells (Fehman et al., 1995, Endocr Rev. 16: 390-410, Thorens et al., 1995, Di abetes Metab. (Paris) 21: 311-318). The insulin-trophic effects of GLP-1 make it a useful target in the management of diabetes and other management problems to glucose intolerance during the disease. The results of recent studies in 59-year-old non-diabetic women suggest that GLP-1 reduces plasma glucose levels by reducing hepatic glucose production and increasing the rate of metabolic elimination of glucose through indirectly increasing the ratio of insulin to gluclagon in healthy individuals (Larsson et al., 1997, Acta Physi ol. Scand., 160: 413-422). Glucose intolerance is a common feature of the aging process; Aging has been identified as an etiologic factor for Type II diabetes mellitus. In a study designed to characterize abnormalities in beta cells that originate in the aging process, insulin responses were found similar in both age groups studied. GLP-1 in conjunction with IVGTT was found to restore the acute response of insulin to glucose while increasing the elimination of glucose in older animals. The open conclusion is that an insulin response mediated by deleterious glucose is present in older animals even though animals that maintain their insulin response to GLP-1 (Ore et al., 1997, Journal of Geron tol ogy: Bi ol ogi cal Sci ences 52A (5): B245-B249). A GLP-1 agonist refers to a compound or agent that mimics the physiological and pharmacological properties of endogenous GLP-1. A GLP-1 antagonist refers to a compound or agent that attenuates the effects of GLP-1 through the ability of these compounds or agents that inhibit the GLP-1 peptide bond to the GLP-1 receptor and / or prevent the activation of the receptor by the GLP-1 link. The GLP-1 (7-36) -amides and exendin-4- (1-39) glucagon-like peptides have been identified as GLP-1 agonists. The vasoactive intestinal peptide glucagon-secretin exendin (9-39) has been identified as a GLP-1 antagonist (Montrose-Rafizadeh et al., 1997, J Biol. Chem. 272 (34): 21201-21206).

Peptide antagonists of peptide hormones are often quite potent. Without However, the use of peptide antagonists is typically associated with problems due to susceptibility to enzymatic degradation and poor distribution, i.e. the inability to be easily transported from the digestive system into the blood stream. Thus, such antagonists have limited drug effectiveness, since it is difficult to reach the desired blood levels of the peptide antagonists at low dosages. Consequently, there is a need for GLP-1 antagonists, and particularly for non-peptide GLP-1 antagonists. GLP-1 antagonists have the potential to be used therapeutically to increase absorption in alterations characterized by cachexia. For example, papers by Larsen et al., Have shown that central administration of GLP-1 activates neurons containing central CRH of the pituitary adrenocortical axis of the hypothalamus, which may be responsible for dietary behaviors (Larsen et al., 1997, Endocrinol ogy 138 (10): 4445-4455). Many evidences show that GLP-1 agonists inhibit the ingestion of food and water in rats, and these effects are blocked by exepin- (9-39) -amide GLP-1 receptor antagonist (Navarro et al., 1996, J Neurochem 67 (5): 1982-1991, Tang-Christensen, 1996, AMER, J. Physi ol. 271 (4 Part 2): R848-856). Exendin- (9-39) alone, increases feeding in other rat models (Turton et al., 1996, Na ture 379 (6560): 69-72). In addition, GLP-1 receptor antagonists can be employed in post-prandial hypoglycemia and emptying syndrome, where there is an exaggerated release of GLP-1 (Vecht, 1997, Scand. J. Gastroenterol. Supp. 223: 21 -27). Thus, there is a need for a non-peptide GLP-1 antagonist used for the therapeutic regulation of GLP-1 that prevents in vitro degradation and the biodistribution problems presented by peptide GLP-1 antagonists.

BRIEF DESCRIPTION OF THE INVENTION An object of the present invention is to provide non-peptide GLP-1 antagonists used as pharmaceuticals. A further object of the invention is to provide methods for synthesizing compounds and intermediates useful in such syntheses. The compounds of the invention are pharmaceutically superior to peptide compounds, since they provide better biodistribution and tolerance to degradation by physiological enzymes. The invention is directed to GLP-1 antagonist compounds of the general formula: wherein: R1 is a phenyl or pyridyl group, optionally substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, trifluoromethyl, cyano, C6-C6 alkyl, C2-C6 alkenyl and C6-C6 alkoxy groups; Or R is, where R 'is: hydrogen; a hydroxy group; -OR5, wherein R5 is a C6-C6 alkyl or C2-Cd alkenyl group, optionally substituted with a hydroxy group or an amino group, C6-C6 alkoxy, cycloalkyl, thioether, heterocycloalkyl, aryl or heteroaryl, optionally substituted with one or more substituents • independently selected from alkyl, hydroxyalkyl, carboxyl, C?-C6 alkoxycarbonyl, oxygen, halogen and trifluoromethyl groups; or -NR6R7, wherein R6 and R7 are each, independently hydrogen or a C? -C5 alkyl, C2-C6 amino or imino alkenyl, optionally substituted with a hydroxy group, a C? -C6 alkoxy group or an amino group, thioether, heterocycloalkyl, aryl or heteroaryl, Optionally substituted with one or more substituents independently selected from oxygen, halogen, trifluoromethyl and carboxyl, or wherein -NRdR7 form a 5- or 6-membered heterocyclic ring optionally containing, in addition to the nitrogen heteroatom, a heteroatom selected from O, N and S; F - (CH2) r-O-R ", where n is 1 or 2, and R" is Or hydrogen, a C5-C7 heteroaryl group, or "« A 8, wherein R8 is hydrogen, a C? -C6 alkyl group, or a C3-Cd cycloalkyl group, or a 5- or 6-membered heteroaryl group, optionally substituted with one or more substituents independently selected from halogens, methyl and trifluoromethyl.

- (CH2) PN (R ") (R" '), wherein p is 1 or 2, R "is as defined above, and R'" is hydrogen or an alkyl or alkoxy group optionally substituted with a cycloalkyl group C3-C6, optionally substituted with cyano; -CH = N-R "", wherein R "'" is hydrogen, hydroxy or -OR9, wherein R9 is an alkyl, cycloalkyl, aryl or heteroaryl group; or a 5- or 6-membered heterocyclic ring, containing from one to three heteroatoms independently selected from O, N and S, the ring is optionally substituted with one or two substituents independently selected from methyl, methoxymethyl, oxygen and C alco alkoxy groups C5; R3 is hydrogen, or an alkyl group Ci-Ce, C2-C5 alkenyl, or (C? -C3) alkoxyC? -C3 alkyl; or R and RJ together with the atoms to which they are attached, form a ring of 5 or 6 members containing from one to two heteroatoms selected from O, N and S, the ring is optionally substituted with oxygen, hydroxyl or an alkyl group C? -C6, optionally substituted with 5- or 6-membered heterocycloalkyl containing one or two heteroatoms independently selected from O, N and S; and R4 is hydrogen or an amino, halogen, hydroxyl, nitro, trifluoromethyl, cyano, Ci-Ce alkyl or C2-C5 alkenyl group. The invention is also directed to prodrugs, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, and active metabolites of the compounds of formula (I). The GLP-1 antagonists of the present invention inhibit the GLP-1 peptide bond to the GLP-1 receptor and / or prevent activation of the receptor by a GLP-1 bond.

Accordingly, the invention is further directed to a method for inhibiting the binding of GLP-1 to the GLP-1 receptor and a method for inhibiting GLP-1 receptor activation using the inventive compounds.

DETAILED DESCRIPTION AND PREFERRED MODALITIES OF THE INVENTION In accordance with the invention used in the art,. it is used in structural formulas herein to demonstrate the bond that is the point of attachment to the portion or substituent to the core or backbone structure. As used herein, the terms "alkyl group" is intended to mean a straight or branched chain monovalent radical of saturated carbon atoms and hydrogen atoms, such as methyl (Me), ethyl (Et), propyl, isopropyl, butyl, isobutyl, t-butyl and the like. The term "alkenyl group" refers to a straight or branched chain alkene radical containing one or more double bonds, such as ethenyl, pentenyl, butenyl, propenyl, and the like. "Alkynyl group" refers to a straight or branched chain alkyne type radical, which contains at least one triple bond such as ethynyl, butynyl, propynyl, pentynyl, hexynyl and the like. A "cycloalkyl group" is intended to mean a non-aromatic monocyclic, monocyclic, bicyclic or tricyclic radical containing 3 to 14 carbon ring atoms, each of which may be saturated or unsaturated. Illustrative examples of cycloalkyl groups include the following portions: A "heterocycloalkyl group" is intended to mean a non-aromatic, monocyclic, bicyclic or tricyclic monovalent radical, which is saturated or unsaturated, containing from 3 to 18 ring atoms, which includes 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur. Illustrative examples of the heterocycloalkyl groups include the following portions, wherein R is any suitable substituent: An "aryl group" is intended to mean a monovalent, monocyclic, bicyclic or tricyclic aromatic radical, containing from 6 to 18 carbon ring atoms. Illustrative examples of aryl groups include the following portions A "heteroaryl group" is proposed to mean a monovalent, monocyclic, bicyclic or tricyclic aromatic radical, containing from 4 to 18 ring atoms, including 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur. Illustrative examples of heteroaryl groups include the following portions: A "heterocycle" is intended to mean a heteroaryl or heterocycloalkyl group. An "acyl group" is meant to mean a radical -C (0) -R, wherein R is a substituent bonded to a carbon, oxygen nitrogen or sulfur. A "sulfonyl group" is proposed to mean a radical -S02R, wherein R is a substituent attached to a carbon, oxygen or nitrogen. An "amino group" is proposed to mean a radical -NH2 or a primary, secondary or tertiary amine radical (eg, NHRa, where Ra is an alkyl group, and -NRaRb, wherein Ra and Rb are each, independently alkyl group). An "imino" substituent refers to a substituent that contains a carbon-nitrogen double bond, for example, "- ^ = 0 ^ ^ ~ N An" alkoxy group "is proposed to mean a radical -0Ra, where Ra is a group I rent. Exemplary alkoxy groups include methoxy, ethoxy, propoxy and the like. An "alkoxycarbonyl group" is proposed to mean the radical -C (0) 0Ra, wherein Ra is an alkyl group.

The term "thioether" refers to alkylthio, arylthio, and heteroarylthio groups. An "alkylthio group" is proposed to mean the radical -SRa, wherein Ra is an alkyl group. An "arylthio group" is proposed to mean the radical -SRC, wherein Rc is an aryl group. A "heteroarylthio group" is proposed to mean the radical -SRd, wherein Rd is a heteroaryl group. An "aryloxy group" is proposed to mean the radical -0RC, wherein Rc is an aryl group. A "heteroaryloxy" group is proposed to mean the radical -0Rd / wherein Rd is a heteroaryl group. The term "substituent" or "suitable substituent" is intended to mean any chemically suitable substituent that can be recognized or selected, such as through routine testing by those skilled in the art. Illustrative examples of suitable substituents include hydroxy (-OH), halogen, oxo groups; alkyl groups, acyl groups, sulfonyl groups, mercapto groups, alkylthio groups, alkoxy groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, carboxy groups (-C (O) OH), amino groups, carbamoyl groups (-C ( 0) NH2), aryloxy groups, heteroaryloxy groups, arylthio groups, heteroarylthio groups and the like. The term "optionally substituted" is intended to mean that the specified group is substituted or unsubstituted by one or more suitable substituents, unless that the optional substituents are expressly specified, in which case the term indicates that the group is unsubstituted or substituted by the specific substituents. As defined above, several groups • can be substituted or unsubstituted (for example, they are optionally substituted), unless otherwise indicated herein, (for example, by the indication that the specified group is not substituted). A "prodrug" is proposed to mean a compound that is converted under physiological conditions or by solvolysis or metabolically to a specified compound which is pharmaceutically active. A "pharmaceutically active metabolite" is proposed to mean a pharmacologically active product produced through the metabolism in the body of a specified compound. A "solvate" is proposed to mean a pharmaceutically acceptable solvate form that retains the biological effectiveness of such a compound. Examples of solvates include compounds of the invention in combination with water, isopropanol, ethanol, methanol, DMSO, (ethyl acetate, acetic acid or ethanolamine.) A "pharmaceutically acceptable salt" is proposed to mean a salt that retains biological effectiveness of the free acids and bases of the specified compound and which is not biologically or otherwise undesirable Examples of pharmaceutically acceptable salts include sulphates, pyrosulfates, bisulfates, sulphites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexin-1, 6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylene sulphonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates , lactates,? -hydroxybutyrates, glycolates, tartrates, methanesulfonates (mesylates), propansulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates and mandelates. The action of GLP-1 is antagonized by the compounds 9H-β-carboline of the general formula (i; wherein R1, R, R3 and R4 are as defined above. The invention is also directed to prodrugs, pharmaceutically acceptable salts, pharmaceutically acceptable solvates and active metabolites of such compounds. In a preferred embodiment, R1 is a phenyl group substituted with one or more groups selected from halogen, hydroxyl, nitro, trifluoromethyl and cyano. ) Compounds are also preferred where O f ^ is' ^ R ", where R is as defined above and incorporates a hydrogen bond acceptor substituent that can, through normal conformational variations, assume a 3-5A position of the carbonyl group. As used herein, "hydrogen bond acceptor substituent" refers to a substituent that includes a N or O capable of forming a hydrogen bond with a hydrogen bond donor such as OH u = NH. Substituents of the hydrogen bond acceptor B include portions containing a group such as • The exemplary R2 groups of this type • include 10 As is known in the art, the stenographic designation '^ * is used here to demonstrate -CH3. Also preferred are compounds wherein R3 ^ is hydrogen or methoxymethyl. In a further preferred embodiment, R1 is 2,5-dichlorophenyl or 3,5-dinitrophenyl. In another preferred embodiment, R2 and R3 together with the atoms of which are 5 or 6 member lactone linked or lactam rings. In yet another preferred embodiment, R2 is selected from: • In another preferred embodiment, the 5- or 6-membered ring, formed by R2 and R3 and the atoms to which they are attached, are selected from: Especially preferred compounds represented by the above general Formula (I) include • the following: (where R is as defined above) twenty In addition, the present invention is directed to precursors, forming blocks, and intermediates that are useful in the preparation of the compounds of the formula (I). The examples illustrate specific precursors, building blocks, and intermediates within the scope of the present invention. In particular, the following compounds can be used to synthesize certain compounds within the scope of the present invention: The compounds of the present invention include prodrugs, pharmaceutically acceptable salts, solvates pharmaceutically acceptable and active metabolites of the compounds of the formula (I). The salts of the compounds are pharmaceutically acceptable salts derived from inorganic or organic acids as defined above. ^ The invention also includes metabolites active compounds and prodrugs of the compounds of Formula (I). The active metabolites of the present invention have modified their chemical structure resulting from being activated by biotransformation reactions or enzymes that metabolize the drugs in various organs of the body. Prodrugs are compounds that, through these various biotransformation reactions, are metabolically converted in vi v e from a precursor compound to a compound of the Formula (I) Examples of the prodrugs include biohydrolyzable esters and amides. Some compounds of the invention described herein contain one or more centers of asymmetry and can thus originate enantiomers and diastereoisomers and other stereoisomeric forms. The present invention means that it includes all possible stereoisomers as well as its racemic and optically pure forms. The optically active ® and (S) isomers can be prepared using chiral syntheses, chiral reagents or resolved using conventional techniques. When the compounds described herein contain olefinic double bonds, the geometric isomers, both E and Z, are included.

• The chemical formulas referred to here can be present the phenomenon of tautomerism. As the formulas are designed within this specification, they can only represent one of the possible tautomeric forms, it should be understood that the invention encompasses any tautomeric form which can be generated by the use of tools described and is not limited to (any taturomeric form used within the designed formulas.

Pharmaceutical Compositions and Treatment Methods: The pharmaceutical compositions of this invention comprise an effective amount of a compound of Formula (I) and an inert pharmaceutically acceptable carrier or diluent. An "effective amount" of a compound of Formula (I) is determined to be an antagonistic amount GLP-1, which is a concentration of the compound wherein the binding and / or activation of the GLP-1 receptor is inhibited. Such amount provides 5 therapeutic benefits for the regulation of the trophic effects of insulin, associated with the GLP-1 bond. The inventive pharmaceutical compositions are prepared in appropriate unit dosage forms • for administration to a patient in need of treatment or a condition or condition mediated by the inhibition of GLP-1. Appropriate forms of administration include (but are not limited to) oral, parenteral, intravenous, intramuscular and transdermal methods, known in a manner general in the art. The compositions can be prepared by the effective combination of an amount of the compound of the Formula (I) with known pharmaceutical carriers or diluents, in accordance with the procedures conventional. These procedures may involve mixing, granulating, compressing or dissolving the ingredients as appropriate, for the desired preparation.

The pharmaceutical carrier used can be, for example, either solid or liquid. Examples of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Examples of liquid carriers are syrups, peanut oil, olive oil, water and the like. Similarly, the carrier or diluent may include material released by time • known in the art, such as monostearate glyceryl, or glyceryl distearate, alone or with a wax, ethylcellulose, hydroxypropylmethylcellulose, methylmethacrylate or the like. A variety of pharmaceutical forms can be exemplified. Thus, if a solid carrier is used, the preparation can be formed into tablets, placed in A) Hard gelatine capsules in the form of powder or pellet or in the form of troches or pellets. The amount of solid carrier can vary, and will preferably be from about 25 mg to about 1 g. If used In a liquid carrier, the preparation may be in the form of syrup, emulsion, soft gelatin capsule, sterile injectable solution or suspension in a vial or vial or non-aqueous liquid suspension.

To obtain a stable water-soluble dosage form, the pharmaceutically acceptable salt of a compound of Formula (I) is dissolved in an aqueous solution of an organic or inorganic acid, such as a 0.3 M solution of succinic acid, or preferably citric acid. . If a soluble salt form is not available, the compound of formula (I) is dissolved in one or more suitable cosolvents. Examples of suitable co-solvents include (but are not limited to) alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin and the like, in concentrations ranging from 0-60% of the total volume. The composition may also be in the form of a solution of a salt form of the active ingredient in an appropriate aqueous vehicle, such as isotonic water or saline or dextrose solution. It will be appreciated that the current dosages of the compounds of Formula (I) used in the compositions of this invention will be selected according to the particular complex to be used, the particular composition formulated, the mode of administration and the particular site, and the host and condition to be treated. Optimal dosages to give a number of conditions can be assessed by those skilled in the art using standard dosage determination tests. For oral administration, the dose generally employed is from about 0.001 to about 1000 mg / kg of body weight, with courses of treatment repeated at appropriate intervals. Synthesis Methods: • The following synthesis protocols refer to to preferred intermediates and final products identified in the synthesis schemes or also in the specification. The preparation of the compounds of the present invention is described in detail using the following specific and general examples.

Occasionally, the reaction can not be applicable as described for each compound included within the described scope of the invention; the compounds for which this occurs will be readily recognized by those skilled in the art. In such cases, the reactions can be successfully performed by routine modifications, within the level of ordinary ordinarily skilled in the art (for example, with reference to the teachings in the art, including those cited herein), such as by appropriate protection of interference groups, by the change to other conventional reagents, or by w? changes from routine to reaction conditions. Alternatively, other reactions described here or from In another conventional manner, they will be applicable for the preparation of the corresponding compounds of the invention. In the preparative methods described below: all the initiating materials, available or • easily prepared from starting materials known; all temperatures are exposed in degrees Celsius; and, unless otherwise indicated, all parts and percentages are by weight. The reagents are purchased from commercial suppliers such as Aldrich Chemical Company or Lancaster Synthesis Ltd. and were used without further purification unless otherwise indicated. Tetrahydrofuran (THF) and N, -dimethylformamide (DMF) were purchased from Aldrich in closed bottles and used as received. All the solvents were purified using standard methods known to those skilled in the art, unless otherwise indicated. Biological Assays: In general, the activity of the non-peptide antagonists of the present invention can be determined using a variety of assays and techniques. The M GLP-1 antagonists of the present invention, inhibit the binding of GLP-1 to its receptor and / or inhibit activation of the receptor by the GLP-1 link. Thus, binding affinity studies are useful to assess the antagonistic activity of the compounds of the present invention. The binding affinity can be determined, for example, by ^^ the displacement of a ligand binding to the receptor, in Wherein the ligand is labeled with a detectable label. In particular, one of ordinary skill in the art will be able to conduct a binding study in vi tro, to calculate the specific binding affinity of the compounds of the present invention to GLP-1 receptor through the cells pretreated with the Ak compounds and then exposure of cells pretreated with GLP-1 radioactively labeled. Additionally, one of ordinary skill in the art could appreciate that the activation of the GLP-1 receptor can be measured by the determination of the intracellular cAMP levels measured in the cells treated with the compounds of the present invention. See, for example, Montrose-Rafizadeh et al., 1997, J Bi ol. Chem. 272 (34) .21201-21206. After treatment with the compounds of the present invention, the 4m% cells are stimulated with GLP-1 and the intracellular cAMP levels are determined. Antagonistic activity could be represented by the decreased levels of cAMP relative to an untreated control. In addition to these biological assays, other peripheral assays are also suitable for determining the • Antagonistic activity of the compounds of the formula (I). For example, known assays for determining GLP-1 activity include ingestion bioassays and assays of ANG II-stimulated thistles (Tang-Christensen et al., 1996, Amer J. Physiol. 271 (4 Pt2): R848-R856 ), and lipolysis assays (Montrose-Rafizadeh et al., 1997, J.

Cell. Phys. 172 (3): 275-283). ^ m Based on the above assays, one of ordinary skill in the art could determine the effectiveness of the compounds of the present invention to inhibit the activation and / or binding of the GLP-1 receptor. for GLP-1. In addition, such studies could be determined to be useful in the assessment of the effective amounts of the compounds of the present invention to inhibit the activity of GLP-1.

GENERAL EXAMPLES mk Method A: General N-alkylation procedures • In the compounds discussed above, R1, R4, and R5 are as defined above. To a solution of alkyl halides in DMF (1 equivalent), a DMF solution of methyl 9H-β-carbolin-3-carboxylate (1 equivalent) is added and a suspension of sodium hydride in the mixture is added to the mixture.

DMF (~ 1 equivalent of 60% NaOH in oil). Mix • cover, briefly shake and shake briefly every 15 minutes for approximately 1 hour. The DMF is removed in vacuo.

Method B: N-alkylation In the above compounds, Z represents m) -CH2R1, which is as defined above. A mixture of a 5-methyl-9-ß-carboline-3-carboxylate or derivative (5.0 mmol) and sodium hydride (0.20 g of 60% in oil, 5.0 mmol) is treated with dry DMF (11 mL) under nitrogen. After stirring for 15 minutes, the evolution of the gas is essentially complete, providing an almost clear, slightly brown solution of the ß-carboline sodium salt (~0.40 M), with traces of solid material still permanent. This solution is prepared in a similar manner by the addition of solid β-carboline to a suspension of sodium hydride in DMF, or by the addition of sodium hydride to a suspension / solution of the β-carboline in DMF. Cooling to 0 ° C is necessary when the reaction is carried out on a large scale (40-80 mmol). To the solution of the sodium salt is added a solution of the alkyl halide in DMF (5 mL of 1.0 M, 5.0 mmol, 1 equiv), resulting in a slight exotherm. After stirring at room temperature for 2-24 hours, the DMF is removed in vacuo, and the residue is partitioned between water and ethyl acetate. The ethyl acetate phase is separated, dried over NaSOa, filtered, concentrated in vacuo, and • The residue is crystallized from ethyl ether, ethyl acetate / ethyl ether, or ethyl acetate / petroleum ether. Alternatively, the products are purified by chromatography on silica gel using 95: 5 diethyl ether / 8M NH3-CH3-OH or a gradient elution of 90:10 of trichloromethane (CHCl3) / 2M NH3-CH3-OH in CHC13 or Reverse phase preparative HPLC, followed by recrystallization of ethyl ether or ethyl acetate / petroleum ether.

Method C: Esterification of imidazolide carboxylic acid: In the compounds set forth above, R5 is as defined above. The esterification of acids via 3- (l-imidazolylcarbonyl) -9- (2, 5-dichlorobenzyl) -9H-β-carboline can be conducted by the following method (Staab, H.A., ACIEE 1962, 1: 351). To a solution of one alcohol (125 -μl of 0.40 M, 0.050 mmol) in DMF is added (1,2-dimethoxyethane) to a solution of 3- (1-imidazolylcarbonyl) -9- (2,5-dichlorobenzyl) - 9H-ß-carboline (125 μL of 0.40 M, 0.050 mmol, 1 equivalent) in DMF, followed by a solution of imidazolyl sodium (25 μL of 0.1 M, 0.0025 mmol, 5 mol%) in DMF. The latter is recently prepared from imidazole and sodium hydride. The resulting mixture is briefly stirred and heated at 50 ° C for 18-24 hours. The solvents are removed in vacuo and the product is isolated from the residue by preparative HPLC.

Method D: Esterification of an Alcohol In the compounds set forth above, R8 is as defined above.

The esterification of an alcohol such as [9- (2,5-dichlorobenzyl) -9H-β-carbolin-3-yl] methanol (see above), can be conducted by the following method. A solution of [9- (2, 5-dichlorobenzyl) -9H-β-carbolin-3-yl-methanol (100 μL of 0.5 M, 0.05 mmol) in DME is treated with an acid chloride solution (100 μL of 0.5M, 0.05 mmol) in DCE (1,2-dichloroethane), and the mixture is stirred briefly. A solution of triethylamine (100 μL of 1.0M, 0.1 mmol, 2 equivalents) in DMF is added, and the mixture is stirred again and allowed to stand at room temperature overnight. The volatiles are removed in vacuo, and the product is isolated from the residue by preparative HPLC.

Method E: Esterification of a Carboxylic Acid • A carboxylic acid such as 9H-β-carboline-3-carboxylic acid (see above), can be esterified according to the present invention as follows. The 9H-β-carboline-3-carboxylic acid is stirred with an excess of S0C12 at room temperature overnight. The excess of S0C1; stir in vacuo and the crude acid chloride dissolves in CHC13. To this solution, Et3N (3 equivalents) and an alcohol (5 equivalents) are added, and the resulting mixture is stirred at room temperature overnight. The reaction mixture is subjected to an aqueous treatment, and the residue of the organic phase is chromatographed on silica gel (CH2C12) to give the ester.

SPECIFIC EXAMPLES Example 1 Preparation of methyl 9H-ß-carbolin-3-carboxylate This compound was prepared by a modification of a known process (Couts et al., Heterocycles 1984: 22: 131). To a mixture of the methyl ester of L-tryptophan (161 g, 0.738 mol) and paraformaldehyde (22 g, 0.733 mol), toluene (ΔL) was added. The mixture was refluxed with efficient mechanical agitation, and the water was removed using a Barrett trap. After 1 hour, almost the theoretical amount of water was collected (13 mL). Trifluoroacetic acid (5 mL, 0.065 mol, 8.8 mol%) was added through the top of the condenser (exothermic) and the mixture was refluxed for another 1.5 hours. The solvent was evaporated and 10% palladium carbon was added to the container (44 g of wet material recovered from a previous run: dry weight = 38 g based on the water removed in the subsequent stage: ~ 0.036 mol Pd, or 4.8 mol%). Xylene (800 mL) was added, and the mixture was stirred vigorously (mechanical agitator) and refluxed overnight with a Barret trap to remove water from the Pd / C.

The reaction mixture was then cooled in an ice bath, then in a freezer at -20 ° C overnight. The resulting slurry was filtered, providing mother liquors containing impurities, including a compound consisting of methyl 2-methyl-1,2,3,4-tetrahydro-9H-β-carbolin-3-carboxylate, and a gray filter cake which contains a mixture of the product and Pd / C. The filter cake was transferred to a thin paper and extracted in a Soxhlet apparatus with methanol (800 mL, in a 2 L recovery flask) in several batches. As product 5 crystallized in the package, the suspension was filtered, the slightly yellow solid was washed with methanol and dried, and the filtrate was returned to the package. Three batches of the product were collected, providing a total of 76 g of the • product (46% yield from methyl ester 10 of tryptophan).

Example 2 Preparation of ethyl 9- (2, 5-dichlorobenzyl) -9H-β-carbolin-3-carboxylate 15 A suspension of ethyl 9H-ß-carboline-3-carboxylate (2.40 g, 10 mmol) in anhydrous DMF (20 mL) was cooled in an ice bath under nitrogen. Sodium hydride (420 mg of 60% NaH in mineral oil, 10.5 mmol) was added at the beginning, and the mixture was stirred until most of the solids dissolved and the hydrogen evolution stopped (approximately 10 minutes). The cold mixture was treated with 2, 5-dichlorobenzyl chloride (2.15 g, 1.0 mmol) slowly with stirring, then allowed to warm to room temperature for two hours. The resulting cloudy solution was neutralized with acetic acid, then the • solvent was removed in vacuo, giving a tan solid (3.94 g). The crude material was chromatographed on silica gel using a mixture of chloroform and ethyl acetate to give the title product (1.96 g, 49%), X-NMR (300 MHz, DMSO-d6) d 9.06 (s, ÍH), 8.96 (s, HH), 8.48 (d, J = 8.0 HH), 7.55-7.64 (, 3H), 7.35-7.42 (m, 15 2H), 6.60 (d, J = 2.3 HH), 5.89 (s, 2H) ), 4.36 (c, J = 6.9, fH), 1.35 (t, J = 7.2, 3H); EMBR calculated for C2? H? 6Cl2N2? 2 (M + H) 399, found 399.0.

Example 3 Preparation of 9- (2, 5-dichlorobenzyl) -9H-β-carboline-3-carboxylic acid • 9- (2, 5-Dichlorobenzyl) -9H-β-10-carbolin-3-carboxylic acid was prepared as described for the compound 9-unsubstituted corresponding (Hagen et al., Heterocycles 1986, 24: 2845). A mixture of methyl 9- (2,5-dichlorobenzyl) -9H-ß-carbolin-3-carboxylate (15.0, 0.0389 mol), sodium hydroxide (2.0 g, 0.05 mol), water (75 mL) and 95% ethanol (200 mL) was refluxed • for 1 hour. The mixture was concentrated in vacuo, and the residue was dissolved in hot water (500 mL), and the pH was adjusted to 3 using dilute HCl with vigorous stirring, resulting in the precipitation of a solid. The fine suspension is filtered, washed vigorously with water, and dried in vacuo overnight at 70 ° C, and on another day at 85 ° C, providing 12.60 g (87%) of the product. In another run, the product was isolated in 82% yield after recrystallization from hot acetic acid. The product had the following properties: X-NMR (300 MHz, DMSO-d6) d 9.16 (s, HH), 9.08 (s, HH), 8.59 (d, J = 8.0, HH), 7.60-7.69 (, 3H) , 7.39-7.44 (m, 2H), 5 6.705 (d, J = 2.3 HH), 5.93 (s, 2H), 1.93 (s, 3H); LRMS calculated for C? 9H? OCl; N2? 2 (M + H) 371, found 371.0.

Example 4 • Preparation of 3- (1-imidazolylcarbonyl) -9- (2,5-dichlorobenzyl) -9H-β-carboline To a suspension of 9- (2, 5-dichlorobenzyl) -9H-β-carboline-3-carboxylic acid (4.55 g, 0.0123 mol) in dry DMF (100 mL), was added 1,1-carbonyldiimidazole (3.77 g, 20 0.0233 mol), resulting in the formation of an opaque yellow solution. The reaction was stirred at room temperature under nitrogen for 5 hours. Cold water (800 mL) was added, and the resulting precipitate was filtered, washed with cold water, and dried in vacuo giving 4.85 g (94%) of the product as a white solid.

• NMR X (CDC13) d 9.13 (s, ÍH), 9.12 (s, ÍH), 8.87 (s, ÍH), 8.33 (d, J = 7.9 Hz, ÍH), 8.08 (s, ÍH), 7.71 (t , J = 7.7 Hz, 5 HI), 7.52-7.45 (m, 3H), 7.28-7.25 (m, ÍH), 7.16 (s, ÍH), 6.56 (d, J = 2.2 Hz, ÍH), 5.74 (s) , 2H). MS (APCl; (M + H) m / z 421.

• Example 5 Preparation of 9- (2, 5-dichlorobenzyl) -9H-β-carbolin-3-isopropyl carboxylate A mixture of the 9- (2,5-dichlorobenzyl) -9H-β-carboline-3-carboxylic acid acetate salt (1.30 g, 3.02 mmol) and thionyl chloride (2.2 mL, 30 mmol) was stirred and refluxed for 2 hours. The reaction mixture was concentrated in vacuo and the resulting dark oil was used without further purification. The oil was dissolved in 15 mL of DMF (0.2M theory). One portion (2.5 mL, 0.5 mmol) of • this solution was added to a large excess of isopropanol and triethylamine and the resulting mixture was stirred at 60 ° C overnight. After cooling to room temperature, the mixture was stirred with methylene chloride, and the mixture was washed with water and brine. The organic phase was dried with anhydrous sodium sulfate and the solvent was removed • in vacuo. Purification by flash chromatography on silica gel provided the product as an oil (144 mg, 70%). NMR X (300 MHz, DMSO-d6) d 8.80 (s, HH), 8.75 (s, HH), 8.13-8.16 (m HH), 7.50-7.56 (m, HH), 7.20-7.33 (m, 3H) , 7.08 (dd, J = 2.6, 8.7 HH), 6.48 (d, J = 2.3, HH), 5.48 (s, 15 2H), 5.37 (septet.J = 6.4 HH), 1.43 (d, J = 6.4, 6H).

• Example 6 Preparation of 9H-β-carbolin-3-ylmethyl acetate A suspension of 9H-β-carbolin-3-methanol (99 mg, 0.50 mmol) in acetic anhydride (10 L) was stirred for 4 hours at room temperature, during which time the initiating material was dissolved. Removal of acetic anhydride in vacuo gave a brown solid (122 mg). Purification by flash chromatography on silica gel with ethyl acetate as the eluent afforded 82 mg (68%) of the title compound. NMR X (300 MHz, DMSO-d6) d 9.49 (s, HH), 8.99 (s, HH), 8.13 (d, J = 8.0, HH), 8.07 (s, HH), 7.56-7.61 (m, 2H) ), 7.26- 10 7.34 (m, ÍH), 5.43 (s, 2H), 2.15 (s, 3H). LRMS calculated for C? 4H? 2N202 (M + H) 241, found 241.0.

Example 7 15 Preparation of [9- (2, 5-dichlorobenzyl) -9H-β-carbolin-3-yl] methyl acetate [9- (2, 5-Dichlorobenzyl) -9H-β-carbolin-3-yl] methyl acetate, was prepared from 3-acetoxymethyl-9H-pyrido [3,4-b] indole, using Method A Purification by flash chromatography on silica gel with chloroform / ethyl acetate as eluent provided the product in 89% yield. NMR X (300 MHz, DMS0-d6) d 8.72 (s, HH), 8.19 (d, J = 7.9, HH), 8.09 (s, HH), 7.55-7.61 (m, HH), 7.28-7.39 (m , 3H), 7.18 (dd, J = 2.3, 8.7, ÍH), 6.51 (d, J = 2.3IH), 5.54 (s, • 2H), 5.42 (s, 2H), 2.19 (s, 3H). Example 8 Preparation of methyl 9- (2, 5-dichlorobenzyl) -9H-ß-carbolin-3-carboxylate To a suspension of sodium hydride (1.60 g, 60% dispersion in oil, 0.04 mol) in dry DMF (60 mL) was added methyl 9H-ß-carbolin-3-carboxylate (8.7 g, 0.0385 mol) at -20 ° C with stirring. The mixture was allowed to warm to room temperature with stirring under nitrogen. After stirring for 10 minutes, at room temperature, the formation of the sodium salt of the β-carboline appeared to be complete, resulting in a clear brown solution. The reaction mixture was cooled in an ice bath, 2, 5-dichlorobenzyl chloride (7.82 g, 0.040 mol) was added, and the mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with water (200 mL), filtered and the cake was washed with water, ethyl acetate, ether and dried, yielding 13.05 g (88%) of the title product. NMR X (CDC13) d 8.88 (s, ÍH), 8.78 (s, ÍH), 8.20 (d, J = 7.8 Hz, ÍH), 7.61 (t, J = 7.8 Hz, ÍH), 7.45-7.35 (m, 3H), 7.18 (dd, J = 8.2, 1.7 Hz, ÍH), 6.52 (s, ÍH), 5.56 (s, 2H), 4.06 (s, 3H); MS (APCl: (M + H) +) m / z 385. EXAMPLE 9 Preparation of [9- (2, 5-dichlorobenzyl) -9H-β-carbolin-3-yl] methanol A mixture of methyl 9- (2, 5-dichlorobenzyl) -9H-β-carboline-3-carboxylate (13.05 g, 0.0339 mol), and sodium borohydride (3 g, 0.079 mol), was stirred and subjected to reflux in anhydrous ethanol (200 mL) for 15 hours. The ethanol was evaporated and the residue was partitioned between 10% aqueous Na 2 CO 3 (100 mL) and methylene chloride (100 L). The organic phase was dried over MgSO4 and evaporated, and the residue was recrystallized from ether, yielding the title product as an ivory solid (11 g, 91%). In an alternative synthesis, a solution of [9- (2, 5-dichlorobenzyl) -9H-β-carbolin-3-yl] methyl acetate (53.4 mg, 0.13 mmol) in methanol (2 mL) was treated with sodium hydroxide. potassium (54 mg, 0.96 mmol) and stirred, resulting in almost immediate hydrolysis, as evidenced by TLC and EM flow injection. The product was isolated by flash chromatography on silica gel using 10: 1 chloroform / methanol, yielding 35 mg (75%) of the pure product. NMR X (CDC13) d 8.58 (s, ÍH), 8.10 (d, J = 9.0 Hz, ÍH), 7.91 (s, ÍH), 7.50 (td, J = 7.7 Hz, ÍH), 7.23-7.32 (6 miltiplete line, 2H), 7.10 (dd, J = 8.5 Hz, 2.4 Hz, ÍH), 6.41 (d, J = 2.4 Hz, ÍH), 5.48 (s, 2H), 4.87 (s, 2H), 3.62-3.77 (br, s, ÍH); MS monoisotopic mass (calculated) 355.9, MH + (observed) 357.0.

Example 10 5 Preparation of 2- (2, 5-dichlorobenzyl) -9H-β-carbolin-3-carboxylic acid 2- (dimethylamino) ethyl ester 9- (2, 5-Dichlorobenzyl) -9H-β-carbolin-3-carboxylic acid 2- (dimethylamino) ethyl ester was prepared in accordance with • method D. NMR X (CDC13) d 8.96 (s, ÍH), 8.82 (s, ÍH), 8.26 (d, J = 8.2 Hz, ÍH), 7.62 (m, ÍH), 7.59-7.66 (m, 3H), 7.19 (d, J = 6.2 Hz, ÍH), 6.52 (s, ÍH), 5.61 (d, J = 8.4 Hz, 2H), 4.58 (t, 20 J = 6.0 Hz, 2H), 2.81 (t , J = 6.1 Hz, 2H), 2.37 (s, 6H); MS (APCl; (M + H) +) m / z 441.

Example 11 Preparation of 2-methoxyethyl 9- (2, 5-dichlorobenzyl) -9H-β-carboline-3-carboxylate 9- (2, 5-dichlorobenzyl) 9H-β-carboline-3-carboxylic acid 2-methoxyethyl ester was prepared according to Method D. X-NMR (CDC13) d 8.95 (s, 1H), 8.85 (s, ÍH) , 8.27 (d, J = 7.8 Hz, ÍH), 7.62 (t, J = 7.4 Hz, ÍH), 7.41 (m, 3H), 7.21 (t, J = 2.4 Hz, ÍH), 6.54 (s, ÍH) , 5.67 (s, 2H), 4.64 (t, J = 5.0 Hz, 2H), 3.83 (t, J = 3.7 Hz, 2H), 3.46 (s, 3H); MS (APCl; (M + H) +) m / z 429.

Example 12 Preparation of 9- (2, 5-dichlorobenzyl) -9H-β-carboline-3-carboxylate 2-hydroxyethyl 9- (2, 5-dichlorobenzyl) 9H-β-carboline-3-carboxylic acid 2-hydroxyethyl ester was prepared in accordance with Method D. X-NMR (CDC13) d 8.83 (s, ÍH), 8.82 (s, ÍH) , 8.15 (d, J = 7.8 Hz, ÍH), 7.62 (t, J = 7.2Hz, ÍH), 7.41 (m, 3H), 7.21 (d, J = 6.1 Hz, ÍH), 6.49 (s, ÍH) , 5.54 (s, 2H), 4.61 (t, J = 4.7 Hz, 2H), 4.26 (broad s, HI), 4.08 (t, J = 3.5 Hz, 2H); MS (APCl; (M + H) +) m / z 415.

Example 13 Preparation of 9- (2, 5-dichlorobenzyl) -3- (3-methyl-1,2,4-oxadiazol-5-yl) -9H-β-carboline A suspension of sodium hydride (40 mg, 60% by weight in mineral oil, 1.0 mmol), acetamidoxime (74 mg, 1.0 mmol), and 3Á molecular sieves in powder (200 mg) in THF (3 mL) were added. stirred and refluxed for 30 minutes. To this was added methyl 9- (2, 5-dichlorobenzyl) -9H-β-carboline-3-carboxylate (193 mg, 0.50 mmol), using an additional 2 mL of THF to transfer it quantitatively to the flask. The resulting suspension is • stirred and refluxed until the reaction was completed by TLC (1.5 hours or less). The reaction mixture was filtered through 10 cc of silica gel in a fritted glass funnel, using THF as the eluent, yielding 193 mg of the crude oxadiazole after evaporation of the solvent. The product is purified by preparative TLC using 1: 1 • ethyl / petroleum ether, affording 79 mg (39%) of the pure title compound. NMR X (CDC13) d 8.96 (s, ÍH), 8.92 (s, ÍH), 8.28 (d, J = 7.5 Hz, ÍH), 7.66 (t, J = 7.5 Hz, ÍH), 7.47-7.41 (m, 3H), 7.23 20 (dd, J = 8.5, 2.3 Hz, ÍH), 6.57 (d, J = 2.3 Hz, 1H), 5.70 (s, 2H), 2.54 (s, 3H); MS (APCl; (M + H) +) m / z 409.

Example 14 Preparation of Butyl 9- (2, 5-dichlorobenzyl) -9H-β-carboline-3-carboxylate 9- (2, 5-dichlorobenzyl) 9H-ß-carboline-3-carboxylic acid methyl ester (195 mg, 0.5 mmol), was heated with n-butanol (15 L) and concentrated sulfuric acid; the mixture was slowly distilled for 45 minutes, after which time, the reaction seems to be completed by TLC. The reaction mixture was partitioned between aqueous sodium carbonate and ethyl acetate, the organic phase was dried over sodium sulfate, filtered and evaporated, the residue was recrystallized from ethyl acetate / petroleum ether. From this, 318 mg of the white solid was isolated, whose γ NMR was consistent with sodium butylsulfate. The filtrate was filtered through silica gel using ethyl acetate / petroleum ether 1: 1, and the filtrate was recrystallized from a minimum amount of ethyl acetate and petroleum ether, affording the product as an ivory solid ( 119 mg, 56%). NMR X (CDCI3) d 8.93 (s, ÍH), 8.85 (s, ÍH), 8.28 (d, J = 8.3 Hz, ÍH), 7.64 (ddd, J = 8.3, 7.2, 1.1 Hz, ÍH), 7.45- 7.39 5 (m, 3H), 7.21 (dd, J = 8.5, 2.4 Hz, ÍH), 6.54 (d, J = 2.3 Hz, ÍH), 4.49 (t, J = l Hz, 2H), 1.87 (m, 2H), 1.51 (m, 2H), 1.01 (t, J = 7 Hz, 3H); MS (APCl; (M + H) +) m / z 427.

• Example 15 10 Preparation of propyl 9- (2, 5-dichlorobenzyl) -9H-ß-carbolin-3-carboxylate Methyl 9- (2, 5-dichlorobenzyl) 9H-ß-carboline-3-carboxylate (195 mg, 0.5 mmol) was refluxed with n-propanol (15 mL) and concentrated sulfuric acid (1.5 L), as it is described for the synthesis of butyl 9- (2, 5-dichlorobenzyl) -9H-β-carboline-3-carboxylate, yielding an ivory solid (152 mg, 74%). NMR X (CDC13) d 8.94 (s, ÍH), 8.85 (s, ÍH), 8.28 (d, J) 8.3 Hz, ÍH), 7.64 (t J = 7.5 Hz, ÍH), 7.45-7.40 (m, 3H), 7.22 (dd, J = 8.5 2.3 Hz, ÍH), 6.55 (s, ÍH), 5.66 (s, 2H), 4.45 (t, J = 7 Hz, 2H), 1.93 (, 2H), 1.07 ( t, J = 7 Hz, 3 H); MS (APCl; (M + H) +) m / z 413.

Example 16 Preparation of ethyl 9- [(5,6-dichloro-3-pyridyl) methyl] -9H-β-carboline-3-carboxylate 9- [(5,6-dichloro-3-pyridyl) methyl] -9H-β-carboline-3-carboxylic acid ethyl ester was prepared by Method A, and purified by preparative thin layer chromatography (TLC). NMR X (300 MHz, DMSO-d6) d 8.91 (s, 2H), 8.23-8.26 (m, 2H), 7.59-7.68 (m, ÍH), 7.39-7.45 (m, 3H), 5.62 (s, 2H) ), 4.53 (c, J = 7.2 2H), 1.49 (t, J = 7.2, 3H); LRMS calculated f for C20Hi5Cl2 3? 2 (M + C1-) 434, found 433.9.

Example 17 Preparation of ethyl 9- (3, 5-dinitrobenzyl) -9H-β-carbolin-3-carboxylate 9- (3, 5-Dinitrobenzyl) -9H-β-carbolin-3-carboxylic acid ethyl ester was prepared according to Method A, and purified by preparative thin layer chromatography (66% yield). NMR X (300 MHz, DMSO-d6) d 8.95 (s, 2H), 8.90 (s, ÍH), 8.31 (s, 3H), 7.65-7.67 (m, ÍH), 7.41-7.49 (m, 2H), 5.86 (s, 2H), 4.54 (c, J = 7.1, 2H), 1.50 (t, J = 7.1, 3H); LRMS calculated for C2iH? 6N406 (M-H) 419, found 419.0 Example 18 Preparation of ethyl 9- (3-nitrobenzyl) -9H-ß-carbolin-3-carboxylate 9- (3-Nitrobenzyl) -9H-β-carboline-3-carboxylic acid ethyl ester was prepared by Method A, and purified by preparative thin layer chromatography (yield: 39%). NMR X (300 MHz, DMSO-d6) d 8.90 (s, ÍH): s, 1H), 8. 24 (d, J = 7.9, ÍH), 8.08-8.13 (m, 2H), 7.61-7.66 (m, ÍH), 7.35-7.46 (m, 4H), 5.72 (s, 2H), 4.52 (c, J) = 7.1, 2H), 1.49 (t, J = 7.1, 3H); LRMS calculated for C2iH? 7N304 (M-H) 374, found 374.0.

Example 19 Preparation of [9- (2,5-dichlorobenzyl) -9H-β-carbolin-3-yl] -cyclopropanecarboxylate A solution of [9- (2, 5-dichlorobenzyl) -9H-β-carbolin-3-yl] methanol (357 mg, 1.0 mmol) and cyclopropylcarbonyl chloride (133 mg, 1.27 mmol) in methylene chloride (5 mL) ), was allowed to remain for 10 minutes. The solvent was evaporated, and the residue was partitioned between aqueous Na 2 CO 3 and methylene chloride. The extract was dried over NaSO4, filtered and evaporated to yield a resin. This was dissolved in ether and filtered through a plug of silica gel, treated with ethereal hydrogen chloride, evaporated and the residue was recrystallized from ethanol / ethyl acetate / ether, yielding 270 mg (58%), compound of the title as a yellow solid. NMR * H (CDC13) d 8.85 (s, ÍH), 8.44 (s, ÍH), 8.25 (d, J = 7.9 Hz, ÍH), 7.58 (t J = 7.5 Hz, ÍH), 7.35-7.28 (m , 3H), 7. 10 (dd, J = 8, 2.3 Hz, ÍH), 6.37 (d, J = 2.3 Hz, ÍH), 5.-62 (s, 2H), 5.46 (s, 2H), 1.74 (m, 2H), 1.56 (m, ÍH), 0.84-0.71 (m, 4H); MS (APCl; (M + H) +) m / z 425.

Example 20 Preparation of isopropyl 9- (2, 5-dichlorobenzyl) -4- (methoxymethyl) -9H-β-carbolin-3-carboxylate A mixture of 4- (methoxymethyl) -9H-β-carboline-3-carboxylic acid isopropyl ester (100 mg, 0.33 mmol), NaH (0.36 mmol), 15 mg of a suspension 60% by weight in mineral oil) and 2,5-dichlorobenzyl (80 mg, 0.41 mmol) in DMF (2 L) was treated according to method A. Purification of the crude product by column chromatography on silica with hexane / ether (1: 1) as eluent provided the desired product (90 mg, 60% yield) as a pale yellow solid. NMR X (CDC13) d 8.64 (s, ÍH), 8.25 (d, J = 7.5 Hz, ÍH), 7.49 (t, J = 7.7 Hz, 1H) .7.18-7.31 (m, 2H), 7.05-7.11 ( m.2H) .6.38 (s, 1H), 5.52 (s.2H), 5.23 (s, 2H), 5.20-5.23 (m.1H), 3.40 (s, 3H), 1.33 (, J = 6.3 Hz, 6H); MS (APCl, (M + H) * nz 457.

Example 21 • Preparation of ethyl 6-amino-9- (2, 5-dichlorobenzyl) -9H-β-10 carbolin-3-carboxylate A mixture of ethyl 6-amino-9H-ß-carbolin-3-carboxylate (100 mg, 0.39 mmol), NaH (0.58 mmol, 24 mg of a suspension at 60% by weight of mineral oil) and chloride of 2,5-dichlorobenzyl (115 mg, 0.59 mmol) in DMF (2 mL) was treated according to Method A. Purification of the crude product by column chromatography on silica gel with hexane / ethyl acetate ( 7: 3) as eluent provided the desired product (87 mg, 54% yield) as a yellow solid. NMR X (DMSO-d6) d 8.96 (s, ÍH), 8.74 (s, 1 H), 7.60 (d, J = 8.6 Hz, ÍH), 7.48 (d, ÍH), 7.41 (dd, J = 8.4 Hz , 2.1 Hz, 1 H), 7.35 (d, J = 8.8 Hz, 1 H), 7.01 (d, J = 8.6 Hz, 1 H), 6.51 (d, J = 1.8 Hz, 1 H), 5.80 (s, 2H), 5.10 (s broad, ÍH), 4.37 (c, J = 7.0 Hz, 2 H), 1.37 (t, J = 7.0 Hz, 3H); MS (APCl; (M + H) *) m / z 414.

Example 22 Preparation of 6- (2, 5-dichlorobenzyl) -1-methyl-l, 6-dihydro-3H-furo [3 ', 4': 5,6] pyrido [3,4-b] indole-3- ona 6- (2, 5-Dichlorobenzyl) -1-methyl-1, 6-dihydro-3H-furo [3 ',': 5,6] pyrido [3,4-b] indol-3-one was prepared using Method A of 1-methyl-l, 6-dihydro-3H-furo [3 ', 4': 5,6] pyrido [3,4-b] indol-3-one (9 mg, 0.038 mmol), NaH (0.046 mmol), 2 mg of a suspension at 60% by weight in mineral oil) and 2, 5-dichlorobenzyl chloride (9 mg, 0.046 mmol) in DMF (1 L). Purification of the crude product by preparative thin layer chromatography with hexane / ether (2: 1) as eluent afforded the desired product (5 mg, 33% yield) as a yellow solid. XH NMR (CDC13) d 8.93 (s, 1 H), 8.09 (d, J = 8.0 Hz, ÍH), 7.65 (t, J = 7.8 Hz, 1 H), 7.37-7.46 (m, 3 H), • 7.16 (d, J = 2.2 Hz, 1 H), 6.42 (d, J = 2.2 Hz, 1 H), 6.05 (c, J = 6.6 Hz, 1 H), 5.70 (s, 2H), 1.92 (d, J = 6.6 Hz, 3 H); MS (APCl; (M + H) +) m / z 397.

EXAMPLE 23 Preparation of 2- (4-morpholinyl) ethyl 9- (3, 5-dinitrobenzyl) -9H-β-carbolin-3- 15-carboxylate • 9- (3, 5-Dinitrobenzyl) -9H-β-carboline-3-carboxylate 2- (4-morpholinyl) ethyl was prepared according to Method A. X-NMR (CDC13) d 8.93 (m, 2H), 8.86 (s, 1 H), 8.28 (m, 3H), 7.68 (t, 1 H), 7.47-7.34 (m, 2 H), 5.80 (s, 2 H), 4.53 (t, 2 H), 3.69 (m, 4H), 2.81 (t, 2 H), 2.53 (m, 4H); MS (APCl; (M + H) *) m / z 506.

Example 24 Preparation of 2- (4-morpholinyl) ethyl 9- (2, 5-dichlorobenzyl) -9H-β-carbolin-3-carboxylate • 9- (2, 5-dichlorobenzyl) -9H-ß- • carbolin-3-carboxylate 2- (4-morpholinyl) ethyl was prepared according to Method D. Followed by purification in chromatography, the free base was treated with ethereal hydrogen chloride, and the product was isolated as the dihydrochloride salt in 11% yield was then recrystallized from ethanol / ether. X-NMR (DMSO-dβ) d 11.7 (broad s, ÍH), 9.63 (s, 1 H), 9.42 (s, 1H), 8.75 (d, J = 7.9Hz, 1 H), 7.81-7.70 (m, 2 H), 7.63 (d, J = 8.5 Hz, 1 H), 7.53 (t, J - 7.4 Hz, 1 H), 7.44 (dd, J = 8.5, 2.4 Hz, 1 H), 6.68 (d, J = 2.4 Hz, 1 H), 6. 05 (s, 2 H), 4.75 (broad s, 2H, overlap with the water peak), 4.00 (s broad, 4H), 3.60 (s broad, 4H), 3. 22 (broad s, 2H); MS (APCl; (M + H) *) m / z 484.

Example 25 Preparation of ethyl 9- (2-methoxy-5-nitrobenzyl) -9H-β-carboiin-3-carboxylate fifteen • Ethyl 9- (2-methoxy-5-nitrobenzyl) -9H-β-carboline-3-carboxylate was prepared according to Method A. The product was purified by reverse phase HPLC. NMR XH (CDC13) d 8.94 (s, ÍH), 8.91 (s, ÍH), 8.23-8.13 (m, 2H), 7.66 (s, ÍH), 7.63 (m, ÍH), 7.44 (d, J = 7.5 Hz, ÍH), 7.32 (t, J = 7.5 Hz, ÍH), 6.96 (d, J = 8.5 Hz, ÍH) , 5.60 (s, 2H), 4.52 (c, J = 6.7 Hz, 2H), 3.93 (s, 3H), 1.51 (t, J = 6.7 Hz, 3H); MS (APCl; (M + H) +) m / z 406.

Example 26 Preparation of [9- (2, 5-dichlorobenzyl-9H-β-carbolin-3-yl] methyl 2-chloronicotinate] The 2-chloronicotinate of [9- (2, 5-dichlorobenzyl-9H-β-carbolin-3-yl] methyl was prepared according to Method C, and purified by reverse phase HPLC.The product was isolated as the base free, XH NMR (CDC13) d 8.77 (s, 2H), 8.51 (dd, J = 4.6, 2.0 Hz, ÍH), 8.29-8.21 (m, s, • overlap, 3H), 7.60 (t, J = 7.8 Hz, ÍH), 7.42-7.29 (m, overlapped, 3H), 7.21 (dd, J = 8.5, 2.3 Hz, ÍH), 6.50 (s, ÍH), 5.63 (s, 2H), 5.59 (s, 2H); MS (APCl; (M + H) +) m / z 496. EXAMPLE 27 Preparation of nicotinate of [9- (2, 5-dichlorobenzyl) -9H-β-carbolin-3-yl] methyl The nicotinate of [9- (2, 5-dichlorobenzyl) -9H-β-carbolin-3-yl] methyl was prepared according to Method C, and purified by preparative TLC. The product was isolated as the hydrochloride salt after treatment of the free base with ethereal hydrogen chloride, followed by recrystallization from ethanol / ether (total yield: 43%). NMR X (DMSO-d6) d 9.61 (s, ÍH), 9.40 (s, ÍH), 9.18 (s, ÍH), 9.02 (d, ÍH), 8.75 (m, 2H), 7.8-7.39 (m, 6H ), 6.70 (s, ÍH), 6.03 (s, 2H), 5.89 (s, 2H) (note: acidic hydrogens, which include water in the solvent, are not observed, presumably due to severe dilation); MS (APCl; (M + H) +) m / z 462.

Example 28 Preparation of isopropyl 9- (3, 5-dinitrobenzyl) -4- (methoxymethyl) -9H-β-carbolin-3-carboxylate The isopropyl 9- (3, 5-dinitrobenzyl) -4- (methoxymethyl) -9H-β-carboline-3-carboxylate was prepared from 4- (methoxymethyl) -9H-β-carboline-3-carboxylate of isopropyl according to method A, in 44% yield. The free base was treated with ethereal hydrogen chloride, and the product was isolated as the hydrochloride salt. NMR XH (DMSO-de) d 9.38 (s, ÍH), 8.72 (t, J = 2 Hz, ÍH), 8.48 (d, J = 2 Hz, 2H), 8.37 (d, J = 7.5 Hz, ÍH) , 7.3 (s broad, (H), 6.24 (s, 2H), 5.31-5.23 (s, m, overlap, 3H), 3.41 (s, 3H), 1.41 (d, J = 6.3 Hz, 6H); MS (APCl; (M + H) +) m / z 479.

Example 29 Preparation of 2- (4-morpholinyl) ethyl 9H-β-carboline-3-carboxylate A suspension of β-carboline-3-carboxylic acid, methyl ester (5.3 g, 23.4 mmol), 4- (2-hydroxyethyl) morpholine (4.62 g, 35 mmol), 4-dimethylaminopyridine (1.2 g, 9.8 mmol), sieves Molecular 4Á (5 g) and xylene (250 mL), was heated to reflux for 48 hours. The reaction mixture was cooled to room temperature, concentrated in vacuo, and the resulting suspension was partitioned with CH2C12 (250 mL). The mixture was filtered under vacuum and the residue was washed with CH2C12 (2x25 mL). The combined organic layers were washed several times with water, dried over Na 2 SO 4, and concentrated. Purification of the crude product by column chromatography on silica gel with 2M of 8% NH3-CH30H in CH2Cl2 as eluent afforded the desired product (4.8 g, 64%) as a pale yellow solid. NMR X (CDC13) d 9.09 (s, ÍH) ÍH) 21 (d, J 7.9 Hz, ÍH), 7.63 (d, J = 8.1 Hz, ÍH), 7.63 (d, J = 8.1 Hz, ÍH), 7.62 (t, J = 7.4 Hz, ÍH), 7.38 (t, J = 7.4 Hz, 2H), 4.63 (t, J = 6.1 Hz, 2H), 3.73 (t, J = 4.6 Hz, 4H), 2.87 (t, J = 6.1 Hz, 2H), 2.59 (t, J = 4.6 Hz, 4H); MS (APCl; (M + H) +) m / z 326.

Example 30 10 Preparation of 9- (3, 5-dinitrobenzyl) -3- [3- (methoxymethyl) -1,2,4-oxadiazol-5-yl] -9H-β-carboline The 9- (3, 5-dinitrobenzyl) -3- [3- (methoxymethyl) -1,2,4-oxadiazol-5-yl] -9H-β-carboline was prepared according to the modification of a process of the literature for the synthesis of oxadiazoles from esters (Swain et al., J. Med. Chem. 1991, 34: 140). A suspension of hydroxylamine hydrochloride (2.02 g, 29.2 mmol), potassium carbonate (5.48 g, 39.6 mmol), and 2-methoxyacetonitrile (1.42 g, 20 mmol) in absolute ethanol (160 mL) was heated to reflux for 15 hours . The reaction mixture was cooled, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel with an elution gradient of 2M NH3-CH3OH 10-30% in CH2Cl2 affording 2-methoxyacetamidoxime (1.35 g, 65%) as a white solid. X-NMR (DMSO-dβ) d 9.25 (br, s, ÍH), 5.40 (br, s, 2H), 3.76 (s, 2H), 3.25 (s, 3H); MS (APCl; (M + H) +) m / z 105. A suspension of methyl 9H-β-carboline-3-carboxylate (2.26 g, 10 mmol), sodium hydride (11 mmol, 440 mg dispersion 60% mineral oil) and 3,5-dinitrobenzyl chloride (2.17 g, 10 mmol) in DMF (25 mL) was treated as described in Method B. Recrystallization of the crude material from ethyl acetate / hexane providing methyl 9- (3, 5-dinitrobenzyl) -9H-β-carboline-3-carboxylate (2.85 g, at 70%) as a yellow solid. NMR X (CDCl 3) d 8.95 (s, 2H), 8.94 (s, ÍH), 8.37 (s, 2H), 8.30 (d, J = 7.7 Hz, ÍH), 7.67 (t, J = 7.4 Hz, ÍH) , 7.39-7.50 (5-line multiplet, 2H), 5.94 (s, 2H), 4.06 (s, 3H); MS (APCl; (M + H) +) m / z 406.

A suspension of 2-methoxyacetamidoxime (260 mg, 2.5 mmol) and 4Á molecular sieves (1 g) in anhydrous tetrahydrofuran (15 mL) was stirred at room temperature for 0.5 hours, then treated with sodium hydride (2.75 mmol, 110 mL). mg of a 60% mineral oil suspension). The mixture was heated to reflux for 1 hour. After it was cooled to room temperature, a suspension of methyl 9- (3, 5-dinitrobenzyl) -9H-β-carbolin-3-carboxylate (205 mg, 0.5 mmol) was added. anhydrous tetrahydrofuran (10 mL). The resulting mixture was refluxed for 15 hours, cooled, filtered, and the filtrate was concentrated in vacuo. The residue was purified by preparative thin layer chromatography with 2M of 4% NH3-CH30H in CH2Cl2 as eluent to provide the desired product (86 mg, 38% yield) as a • white solid. NMR X (DMS0-d6) d 9.41 (s, 1H), 9.24 (s, ÍH), 8.72 (t, J = 1.9 Hz, ÍH), 8.59 (d, J = 7.8, ÍH), 8.49 (d, J) = 1.9 Hz, 2H), 7.94 (d, J = 8.3 Hz, ÍH), 7.73 (t, J = 7.8 Hz, ÍH), 7.45 (t, J = 7.5 H, ÍH), 6.20 (s, 2H), 4.67 (s, 2H), 3.42 (s, 3H); MS (APCl; (M + H) +) m / z 461.

Example 31 Preparation of ethyl 9- (2-cyanobenzyl) -9H-β-carbolin-3-carboxylate The 9- (2-cyanobenzyl) -9H-β-carbolin-3-carboxylate ethyl was prepared according to Method A. The compound was purified by RP-HPLC using as eluent acetonitrile / water / trifluoroacetic acid, and isolated as the trifluoroacetate salt. X H NMR (300 MHz, DMSO-d 6) d 9.23 (s, ÍH), 9.11 (s, ÍH), 8.57 (d, J = 7.9, ÍH), 7.95-7.98 (m, 1H), 7.67-7.71 (m , 2H), 6.40-6.53 (m, 3H), 6.72-6.78 (m, ÍH), 6.13 (s, 2H), 4.42 (c, J = 7.2, 2H), 1.39 (t, J = 7.2, • 3H); LRMS calculated for C 22 H 17 N 3 O 2 (M + H) 356, found 356.1.

Example 32 Preparation of ethyl 9- (4-methyl-3-nitrobenzyl) -9H-β-carbolin-3-carboxylate 9- (4-Methyl-3-nitrobenzyl) -9H-ß- • carbolin-3-carboxylate ethyl was prepared by Method A.

The product was purified by RP-HPLC using eluent of acetonitrile / water / trifluoroacetic acid, and isolated as the trifluoroacetate salt. NMR X (300 MHz, DMS0-d6) d 9.21 (s, ÍH), 8.93 (s, ÍH), 8.45 (d, J = 8.0, ÍH), 7.88 (s, ÍH), 7.78-7.83 (m, ÍH) ), 7.58-7.68 (m, ÍH), 7.30-7.45 (m, 3H), 5.89 (s, 2H), 4.31 (c, J = 7.2, 2H), 2.35 (s, • 3H), 1.30 (t, J = 7.2, 3H); LRMS calculated for C22H? 9N304 (M + H) 390, found 390.1.

Example 33 20 Preparation of 2- (-morpholinyl) ethyl 9- (2-methoxy-5-nitrobenzyl) -9H-β-carboline-3-carboxylate The 2- (4-morpholinyl) ethyl 9- (2-methoxy-5-nitrobenzyl) -9H-β-carboline-3-carboxylate was prepared by the Method A. NMR X (CDC13) d 8.95 (s, ÍH), 8.94 (s, ÍH), 8.28 (d, J = 7.9 Hz, ÍH), 8.23 (dd, J = 9.1 Hz, 2.8 Hz, 2H), 7. 73 (d, J = 2.6 Hz, ÍH), 7.66 (t, J = 7.7 Hz, ÍH), 7.51 (d, J = 8.2 Hz, HH), 7.43 (t, J = 7.5 Hz, ÍH), 7.03 (d, J = 9.1 Hz, HH), 5.66 (s, 2H), 4.63 (t, J = 6.1 Hz , 2H), 4. 02 (s, 3H), 3.76 (t, J = 4.6 Hz, 4H), 2.89 (t, J = 6.0 Hz, 2H), 2.63 (t, J = 4.4 Hz, 4H); MS (APCl; (M + H) +) m / z 491.

EXAMPLE 34 Preparation of 2- (4-morpholinyl) ethyl 9- (2, 4-dichlorobenzyl) -9H-β-carboline-3-carboxylate 9- (2,4-Dichlorobenzyl) -9H-ß- • carbolin-3-carboxylate 2- (4-morpholinyl) ethyl was prepared by the Method A. NMR X (CDC13) d 8.95 (s, ÍH), 8.86 (s, ÍH), 8.23 (d, J = 8.1 Hz, ÍH), 7.65 (dd, J = 8.0 Hz, 7.5 Hz, 2H), 7. 56 (d, J = 1.8 Hz, ÍH), 7.44 (dd, J = 8.3 Hz, 4.8 Hz, 2H), 7.02 (dd, J = 8.3 Hz, 1.2 Hz, ÍH), 6.48 (d, J = 8.3 Hz, ÍH), 5.70 (s, 2H), 4.62 (t, J = 6.0 Hz, 2H), 3.76 (t, J = 4.5 Hz, 4H), 2.88 (t, J = 6.0 Hz, 2H), 2.63 (t, J = • 4.4 Hz, 4H); MS (APCl; (M + H) +) m / z 484.

Example 35 Preparation of 2- (4-morpholinyl) ethyl 9- (3,4-dichlorobenzyl) -9H-β-carbolin-3-carboxylate 3-carboxylate • The 9- (3,4-dichlorobenzyl) -9H-β-carbolin-3-carboxylate of 2- (4-morpholinyl) ethyl was prepared by the Method A. NMR XH (CDC13) d 8.93 (s, ÍH), 8.90 (s, ÍH), 8.27 (d, J = 5.8 Hz, ÍH), 7.66 (t, J = 7.7 Hz, ÍH), 7.35-7.48 (7-line multiplet, 3H), 7.27 (s, ÍH), 6.96 (d, J = 8.3 Hz, ÍH), 5.60 (s, 2H), 4.62 (t, J = 6.2 Hz, 2H), 3.76 (t, • J = 4.4 Hz, 4H), 2.88 (t, J = 6.1 Hz, 2H), 2.63 (t, J = 4.0 Hz, 4H); MS (APCl: (M + H) +) m / z 484.

Example 36 Preparation of 9- [3-fluoro-5- (trifluoromethyl) benzyl] -9H-β-carbolin-3-carboxylate 2- (4-morpholinyl) ethyl 9- [3-Fluoro-5- (trifluoromethyl) benzyl] -9H-β-carboline-3-carboxylate 2-10 (4-morpholinyl) ethyl was prepared by Method A. XH NMR (CDC13) d 8.96 (s, ÍH), 8.89 (s, ÍH), 8.30 (d, J = 8.1 Hz, ÍH), 7.68 (t, J = 7.7 Hz, ÍH), 7.43-7.48 (multiplet, 2H), 7.34 (s, ÍH), 7.28 (s, ÍH), 6.88 (d, J = 8.7 Hz, ÍH), 5.70 (s, 2H), 4.63 (t, J = 6.1 Hz, 2H), 3.76 (t, J = 4.5 Hz, 4H), 2.89 (t, J = 6.1 Hz, 2H), 2.63 (t, J = 4.0 Hz, 4H); MS (APCl; (M + H) +) • m / z 502.

Example 37 Preparation of 2- (4-morpholinyl) ethyl 9- (4-fluoro-3- (trifluoromethyl) benzyl] -9H-β- 20 carbolin-3-carboxylate 9- (4-Fluoro-3- (trifluoromethyl) benzyl) -9H-β-carboline-3-carboxylate 2-10 (4-morpholinyl) ethyl was prepared by Method A. NMR (CDC13) d 8.95 (s, 1 H), 8.90 (s, ÍH), 8.29 (d, J = 7.8 Hz, ÍH), 7.68 (t, J = 7.7 Hz, ÍH), 7.42-7.53 (7-multiplet line, 3H), 7.20- 7.25 (multiplet, ÍH), 7.12 (t, J = 9.2Hz, ÍH), 5.67 (s, 2H), 4.62 (t, J = 6.0 Hz, 2H), 3.76 (t, J = 4.0 Hz, 4H ), 2.89 (t, J = 6.1 Hz, 2H), 2.60 (t, J = 4.0 Hz, 4H); EM • (APCl; (M + H) +) m / z 502.

Example 38 Preparation of 2- (2, 3, 4-trifluorobenzyl) -9H-β-carbolin-3-carboxylate of 2- (-morpholinyl) ethyl 9- (2,3-Trifluorobenzyl) -9H-β-carboline-3-carboxylic acid 2- (4-morpholinyl) ethyl ester was prepared by Method A. X-NMR (CDC13) d 8.97 (s, ÍH) , 8.93 (s, ÍH), 8.26 (d, J = 7.8 Hz, ÍH), 7.68 (td, J = 7.2Hz, 1.0 Hz, ÍH), 7. 53 (d, J = 8.3 Hz, HH), 7.44 (t, J = 7.4 Hz, HH), 6.78-6.87 (10-multiplet lines, HH), 6.57-6.65 (multiplet, ÍH), 5.68 (s, 2H), 4.62 (t, J = 6.1 Hz, 2H), 3.76 (t, J = 4.5 Hz, 4H), 2.89 (t, J = 6.1 Hz, 2H), 2.63 (t, J = 4.5 Hz, 4H); MS (APCl; (M + H) +) m / z 470. EXAMPLE 39 Preparation of 2- (4-morpholinyl) ethyl 9- (2-bromo-5-fluoromethylbenzyl) -9H-β-carbolin-3-carboxylate • 9- (2-Bromo-5-fluoromethylbenzyl) -9H-5β-carboline-3-carboxylate 2- (4-morpholinyl) ethyl was prepared by the Method A. NMR X (CDC13) d 8.94 (s, ÍH), 8.83 (s, ÍH), 8.28 (d, J = 7.8 Hz, ÍH), 7.61-7.68 (5-lines multiplet, 2H), 7. 40-7.46 (5-line multiplet, 2H), 6.90 (td, J = 8.2 Hz, • 2.9 Hz, ÍH), 6.16 (dd, J = 9.0 Hz, 2.9 Hz, ÍH), 5.64 (s, 2H), 4.62 (t, J = 6.1 Hz, 2H), 3.76 (t, J = 4.6 Hz, 4H), 2. 88 (t, J = 6.1 Hz, 2H), 2.62 (t, J = 4.5 Hz, 4H); EM (APCl; (M + H) +) m / z 514. EXAMPLE 40 Preparation of 2- (4-morpholinyl) ethyl 9- (2-cyanobenzyl) -9H-β-carbolin-3-carboxylate It is prepared 2- (4-morpholinyl) ethyl 9- (2-cyanobenzyl) -9H-β-carbolin-3-carboxylate from 2- (4-morpholinyl) ethyl 9H-β-carbolin-3-carboxylate , according to method A. The free base is treated with ethereal hydrogen chloride and the product is isolated as the dihydrochloride salt in a yield of 25% after crystallization from acetone / ether-NMR E (DMSO-d6 ) d 11.8 (s broad, ÍH), 9.61 (s, ÍH), 9.40 (S, ÍH), 8.71 (d, J 0 8 Hz, ÍH), 7.93 (d, J = 8 Hz, • HH), 7.72 (s, 2H), 7.54-7.47 (m, 3H), 6.78 (d, J = 7.3 Hz, HH), 10 6.22 (s, 2H), 4.79 (broad s, 2H, overlap with peak of water), 4.00 (s broad, 4H), 3.66 (s broad, 4H), 3.27 (s broad, 2H); MS (APCl; (M + H) +) m / z 441.

Example 41 15 Preparation of 9- 2 .4-bis- (trifluoromethyl) encyl -9H-β-fl | 2- (4-morpholinyl) ethyl carboline-3-carboxylate 2 - (4-Morpholinyl) ethyl-9- [2,4-bis- (trifluoromethyl) benzyl] -9H-ß-carbolin-3-carboxylate is prepared from 9H-ß-carboline-3-carboxylate 2 - (4-morpholinyl) ethyl using the alkylation method A at a scale of 0.2 mmol (yield: 45%). NMR'H (CDC13) d 8.97 (s, ÍH), 8.83 (s, ÍH), 8.31 (d, J = 8 Hz, ÍH), 8.07 (s, ÍH), 7.66 (t, J = 7.5 Hz, ÍH) ), 7.54 (d, J = 7.9 Hz, ÍH), 7.47 (t, J = 7.5 Hz, ÍH), 7.38 (d, J = 8 Hz, ÍH), 6.79 (d, J = 7.9 Hz, ÍH), 5.9 (s, 2H), 4.63 (t, • J = 6 Hz, 2H), 3.75 (m, 4H), 2.88 (t, J = 6 Hz, 2H), 2.62 m, 10 4H); MS (APCl; (M + H) +) m / z 552.

Example 42 Preparation of 6- (2,5-dichlorobenzyl) -l-hydroxy-2- {2- (4- morpholinyl) ethyl] -l, 6-dihydropyrrolor3 ', 4': 5,61pyrid3,4 15 indole bl -3 (2H) -one 6- (2,5-Dichlorobenzyl) -l-hydroxy-2- [2- (4-morpholinyl) ethyl] -1,6-dihydropyrrolo [3 ', 4': 5,6] -pyrido [3, 4- • b] indole-3 (2H) -one by a slight modification of a reported procedure (Dodd et al., J. Org. Chem. 1993, 5 58: 7587): A solution of 9- (2, 5 -dichlorobenzyl) -N- [2- (4-morpholinyl) ethyl] -9H-β-carbolin-3-carboxamide (400 mg, 0.83 mmol) in 12 ml of anhydrous THF is stirred and cooled to -78 ° C under nitrogen . When an internal temperature has been reached • from -78 ° C, 1.0 M methyllithium is added by means of a syringe; in a solution of diethyl ether / cumene (4.2 ml, 4.2 mmol) over a period of 0.3 hours. The reaction mixture develops a very dark blue color after the complete addition of methyllithium. The solution is stirred at -78 ° C for 2 hours and the dry-acetone ice bath is then replaced. with an ice-water bath. After 0.5 h, DMF (3070 mg, 4.2 mmol) is added dropwise and the reaction mixture is stirred at room temperature for another 15 hours. The solution is cooled to 0 ° C and distilled water is added slowly while maintaining the internal temperature of the reaction mixture at 0-5 ° C. The solution is concentrated to approximately 10 ml under reduced pressure, excess CH2C12 is added and the mixture is washed with water. The organic phase is dried (Na2SO4), and the solvents are removed in vacuo. The resulting crude residue is washed several times with ether. The purification of the raw material by Column chromatography on silica with 2M MH3-CH3OH 4% in CH2C12 as eluent afforded the lactam (106 mg, 25%) as a light yellow solid. A portion of 241 mg (60%) of initial material that has not reacted is recovered by evaporation of the combined ether layers and the chromatography fractions. 5 XH NMR (CDC13) d 8.76 (s, HH), 8.48 (d, J = 7.6 Hz, ÍH), 7.66 (td, J = 8.2 Hz, 0.91 Hz, HH), 7.46 (t, J = 7.4 Hz, ÍH), 7.35- 7.40 (multiplet of 4 lines, 2H), 7.18 (dd, J = 8.5 Hz, 2.4 Hz, ÍH), 6.42 (d, J = 2.3 Hz, ÍH), 6.17 (s, ÍH), 5.56 (s, 2H),• 4.46 (dt, J = 9.6, 2.7 Hz, ÍH), 3.83 (t, J = 4.3 Hz, 4H), 3.47 10 (td, J = 9.8, 1.5 Hz, ÍH), 2.78-2.86 (m, 3H) , 2.51-2.64 (m, 3H), 1.50-2.30 (v. S broad, ÍH); EM APCl; (M + H) +) m / z 511.

Example 43 Preparation of 3- (3-pyridyl) propyl 9- (2, 5-dichlorobenzyl) -9H-carbol 3- 3- carboxylate • A "suspension of 3- (1-imidazolylcarbonyl) -9- (2,5-dichlorobenzyl) -9H-β-carboline (505 mg, 1.20 mmol) and 3- pyridinopropanol (8.2 g, 60 mmol) is heated to 80 ° C in 15 ml of toluene for 22 hours The resulting solution is cooled to room temperature and extracted several times with water before drying the organic phase with Na 2 SO 4 The evaporation of the solvent followed by preparative thin layer chromatography of the material resulting crude with hexane / ethyl acetate (6: 4) as eluent afforded the desired product (470 mg, 80% yield) as a light yellow solid. XH NMR (CDC13) d 8.91 (s, ÍH), 8.88 (s, ÍH), 8.56 (s, ÍH), 8.48 (s, ÍH), 8.31 (d, J = 8.0 Hz, ÍH), 7.67 (AB c , J = 7.4 Hz, HH), 7.60 (d, J = 7.8 Hz, ÍH), 7.42-7.48 (m, 3H), 7.22-7.28 (m, 2H), 6.60 (s, HH), 5.70 (S, 2H), 4.53 (t, J = 6.5 Hz, 3H), 2.87 () t, J = 7.7 Hz, 3H), 2.26 (t, J = 7.3 Hz, 3H), EM (ACPI; (M + H) +) m / z 490.

Example 44 • Preparation of 9- (2, 5-dichlorobenzyl) -9Hß-carbolin-3-carboxylate tetrahydro-3-furanylmethyl ester 9- (2, 5-dichlorobenzyl) -9H-β-carbolin-3-carboxylate of tetrahydro-3-furanylmethyl is prepared in accordance with ; Method B. The compound is purified by RP-HPLC using acetonitrile / water / trifluoroacetic acid as eluent, and the The product is isolated as the trifluoroacetate salt. NMR 'H (300 MHz, DMSO-d6) d 9.12 (s, ÍH), 9.02 (s, ÍH), 8.54 (d, J = 4.72 f hz, ÍH), 7.65-7.68 (m, 2H), 7.61 (d, J = 5.28 Hz, ÍH), 7.39-7.45 (m, 2H, 6.65 (d, J = 1.6 Hz, ÍH), 5.94 (s, ÍH), 4.35 (dd, J = 4.05, 6.48 Hz, ÍH), 4.27 (dd, J = 4.75 Hz, 6.48, ÍH), 3.77- j 20 3.85 (m, 2H), 3.65-3.71 (m, 2H), 3.57-3.62 (, ÍH) ), 2.69-2.74 i (m, ÍH), 2.03-2.09 (m, ÍH), 1.68-1.75 (m, ÍH); Calculated EMBR I for C 24 H 20 Cl 2 N 2 O 3 (M + H) 455, found 455.1.

Example 45 • Preparation of 9- (2,5-dichlorobenzyl) -N- \ 2 - (4-morpholinyl) ethyl] 9H-β-carboline-3-carboxylate fifteen 9- (2, 5-Dichlorobenzyl) -N- [2 - (4-morpholinyl) ethyl] -9Hβ-carbolin-3-carboxylate is prepared by a modification of a known procedure (Dodd et al., J. "Org. Chem., 1993, 58: 7587). To a solution of trimethylaluminum (2 ml of a 2M solution in hexane, 4 mmoles) in 12.5 ml of anhydrous CH2C12 cooled to -10 ° C is added a solution of 4- (2- aminoethyl) morpholinyl (261 mg, 2 mmol) in 2.5 ml of anhydrous CH2C12 dropwise The reaction mixture is stirred for 0.5-25 hours at -10 ° C and then allowed to warm to room temperature for 0.5 hours. Solution of methyl 9- (2, 5-dichlorobenzyl) -9H-ß-carbolin-3-carboxylate (800 mg, 2 mmol) in 5 ml of anhydrous CH2C12 is added to the reaction mixture, and the latter is heated to reflux for 15 hours.The solution is cooled to room temperature, suspended slowly with 5 ml of 1.8M aqueous hydrochloric acid and basified to pH 9.0-9.5 with aqueous sodium bicarbonate for p Roporcionar a white solid. The suspension is filtered through a pad of Celite and the residue is washed with CH2C12 (2 x 5 ml). Evaporation of the dried filtrate (over Na 2 SO 4) gives a yellow solid which, by recrystallization from ethyl acetate, gives the desired carboxamide in an isolated yield of 80% (774 mg). XH NMR (CDC13) d 9.00 (s, ÍH), 8.68 (s, ÍH), 8.43 (t, J = 3.9 Hz, ÍH), 8.30 (dd, J = 7.5, 1.1 Hz, ÍH), 7.64 (dt, J = 7.7, 1.1 Hz, ÍH), 7.42 (t, J = 7.9 Hz, 2H), 7.23 (dd, J 8.5, 2.4 Hz, ÍH), 6.54 (s, ÍH), 5.67 (s, 2H), 3.77 (t, J = 4.6 Hz, 4H), 3.68 (c, J = 5.8, 3.9 Hz, 2H), 2.67 (t, J = 6.2 Hz, 2H), 2.56 (t, J = 5.1 Hz, 4H); MS (APCl; (M + h) +) m / z 483.

Example 46 • Preparation of 9- (2,5-dichlorobenzyl) -9Hß-carbol in 3 carbohydrazide 5 A mixture of methyl 9- (2, 5-dichlorobenzyl) -9H-ß-carbolin-3-carboxylic acid (4.8 g, 12.5 mmol), 6 ml of hydrazine and 50 ml of methanol is refluxed for 5 hours. The reaction mixture is cooled to room temperature and the precipitate is collected by filtration. The solid is treated with 50 ml of methanol and the suspension is stirred for 10 minutes, filtered and dried, yielding 4.6 grams (98%) of the title compound. XH NMR (DMSO-d6) d 9.5 (s, HH), 8.8 (s, HH), 8.7 (s, HH), 8.25 (d, HH), 7.6-7.4 (m, 3H), 7.2-7.1 (m , 2H), 6.5 (S, ÍH), 5.7 (s, 2H), 4.3 (s, 2H); MS (APCl; (M + H) +) m / z 385. 25 Example 47 Preparation of 9- (2,5-dichlorobenzyl) -9H-β-carbonyl-3-carbaldehyde O-methyloxime A mixture of O-methyloxime of 9H-β-carboline-3-carbaldehyde (46 mg, 0.20 mmol), NaH (0.22 mmol, 9 mg of a suspension 60% by weight in mineral oil) and chloride of 2.5 - dichlorobenzyl (43 mg, 0.22 mmol) in 1.5 ml of DMF is treated according to method A. Purification of the crude product by preparative thin layer chromatography with hexane / ethyl acetate (7: 3) as eluent gives the desired product (37 mg, 48% yield) as a white solid. XH NMR (DMSO-d6) d 9.00 (s, ÍH), 8.64 (s, ÍH), 8.45 (d, J = 7.8 Hz, ÍH), 8.32 (s, ÍH), 7.64-7.59 (m, 2H), 7.61 (d, J = 8.6 Hz, ÍH), 7.41 (dd, J = 8.6, 1.5 Hz, 1 H), 7.36 (m, ÍH), 6.60 (d, J = 275 Hz, ÍH), 5.86 (S, 2H), 3.97 (s, 3H); MS (APCl; (M + H) +) m / z 384. • Example 48 5 Preparation of 4- \ 2 - acid. { \ 9 - (2,5-dichlorobenzyl) -9H-β-carbolin-3-ip carbonyl} hydrazone) benzoic methylate • A mixture of 9- (2, 5-dichlorobenzyl) -9H- ß-carbolin-3. - carbohydrazide (77 mg, 0.2 mmol), 4-formylbenzoic acid (30 mg, 0.2 mmol), 5 ml of DMSO and one drop of acetic acid Glacial is stirred at room temperature for 12 hours. 50 ml of ethyl acetate are added to the flask. The mixture is extracted with water and brine. The product which crystallizes from the organic phase is filtered, which provides 80 mg (78%) of the title compound. NMR XH (DMS0-d6) d 9.0 (s, 2H), 8.5 (s, ÍH), 8.3 (s, ÍH), 8.0 (d, 2H), 7.8 (d, 2H), 7.5-7.7 (m, 4H) 7.3-7.4 (m ~ 2H), 6.8 (s, ÍH), 5.9 (s, 2H); MS (APCl; (M + H) +) m / z 517.

Example 49 Preparation of 4-fl- (2 { \ 9 - (2, 5-dichlorobenzyl) -9H-β-carbolin-3-ill carbonyl} -hydrazono) etyl benzoic acid A mixture of 9- (2, 5-dichlorobenzyl) -9H-β-carbonyl-3-carbohydrazide (100 mg, 0.25 mmol), 4-acetylbenzoic acid (50 mg, 0.3 mmol), 5 ml of DMSO and one drop of Glacial acetic acid is stirred at room temperature for 12 hours. 50 ml of ethyl acetate are added to the flask. The mixture is extracted with water and brine. The product that crystallizes from the organic phase is filtered, which gives 97 mg (73%) of the title compound. NMR XH (DMSO-d6) d 9.0 (s, 2H), 8.5 (d, ÍH), 8.25 (sAlH), 8.0-7.9 (m, 4H), 7.6-7.5 (m, 3H), 7.4-7.3 (m , 2H), 6.6 (s, ÍH), 5.9 (s, 2H), 2.4 (s, 3H); MS (APCl; (M + H) +) m / z 531.

Preparation 50 Preparation of 2- (4-morpholinyl) ethyl 9- (3,5-dinitrobenzyl) -4-methoxymethyl) -9H-β-carboline-3-carboxylate • • A suspension of 4- (methoxymethyl) -9H-β-carboline-3-isopropyl carboxylate (522 mg, 1.75 mmol), 4- (2-hydroxyethyl) morpholinyl (6.7 g, 51 mmol), 4-dimethylaminopyridine ( 130 mg, 1.05 mmol), 500 mg of 4Á molecular sieves and 25 ml of xylene are refluxed for 48 hours. The reaction mixture is cooled to room temperature, concentrated under vacuum and the resulting suspension is partitioned with 50 ml of CH2C12. The mixture is filtered and the residue is washed with CH2C12 (2 x 5 ml). The combined organic layers are washed several times with water, dried over Na 2 SO 4 and concentrated. The crude product, 2- (4-morpholinyl) ethyl 4- (methoxymethyl) -9H-β-carboline-3-carboxylate is approximately 95% pure by γ NMR and is used in the next step without further purification. The title compound is prepared according to method A using 2- (4-morpholinyl) ethyl 4- (methoxymethyl) -9H-β-carboline-3-carboxylate (100 mg, 0.27 mmol), sodium hydride (0.30 mmol, 12 mg of a 60% mineral oil suspension) and 3,5-dinitrobenzyl chloride (65 mg, 0.30 mmol) in 2 ml of DMF. Purification of the crude material by preparative thin layer chromatography with ethyl acetate / hexane (7: 3) gives the 9- (3,5-dinitrobenzyl) -4- (methymethyl) -9-beta-carbolic 3-carboxylate of 2- (4-morpholinyl) ethyl (107 mg, 72%). RMN'H (CDC13) d 8.98 (s, ÍH), 8. 81 (s, ÍH), 8.44 (d, J = 8.0 Hz, ÍH), 8.31 (d, J = 1.9 Hz, 2H), 7.68 (t, J = 7.3 Hz, ÍH), 7.49 (t, J = 7.6 Hz, ÍH), 7.42 (d, J = 8.3 Hz, 2H), 8.53 (s, 2H), 5.44 (s, 2H), 4.59 (t, J = 5.8 Hz, 2H), 3.76 (t, J = 4.5 Hz, 4H), 3.56 (s, 3H), 2.85 (t, J = 5.8 Hz, 2H), 2.63 (t, J = 4.5 Hz, 4H), MS (APCl; (M + H) +) m / z 550.

Example 51 • Preparation of 3- (4-pyridinyl) propyl 9- (2,5-dichlorobenzyl) -9Hß-carbol 3- 3-carboxylate Prepare 9- (2,5-dichlorobenzyl) -9H-β-carbolin-3-f} 3- (4-pyridinyl) ropyl carboxylate according to method B. XH NMR (300 MHz, DMSO-d6) 6 9.10 (s, ÍH), 8.94 (s, ÍH), 8.53 (d, J = 7.9, ÍH), 8.47 (d, J = 5.3, 2H), 7.59-7.68 (m, 3H), 20 7.40-7.45 (m, 2H), 7.32 (d, J = 5.6, 2H), 6.64 (d, J = 2.3, ÍH), 5.93 (S, 2H), 2.77-2.85 (, 4H), 2.08-2.16 (m, 2H); LRMS calculated for C27H21C12N302 (M + H) 490, found 490.1.

Example 52 • Preparation of 3- (2-oxo-l-pyrrolidinyl) propyl 9- (2,5-dichlorobenzyl) -9Hß-carbol 3- 3-carboxylate Prepare 3- (2-oxo-l-pyrrolidinyl) propyl 9- (2, 5-dichlorobenzyl) -9H-β-carbolin-3-p-carboxylate according to Method B. NMR * H (300 MHz, DMSO-d6) 6 9.17 (s, ÍH), 9.07 (s, ÍH), 9.17 (s, ÍH), 9.07 (s, ÍH), 8.52 (d, J = 7.93 Hz, ÍH), 20 7.56-7.69 ( m, 3H), 7.37-7.44 (m, 2H), 6.64 (d, J = 2.3 Hz, ÍH), 5.92 (s, 2H), 4.32 (t, J = 6.2 Hz, 2H), 3.33-3.40 (m , 4H), 2.16 (t, J = 7.9 Hz, 2H), 1.82-2.00 (m, 4H); LRMS calculated for C 26 H 23 C 12 N 303 (M + H) 496, found 496.1.

Example 53 Preparation of 3- (2-pyridinyl) propyl 9- (2,5-dichlorobenzyl) -9H-carbol in 3- (3-carboxylic acid) 9- (2, 5-Dichlorobenzyl) -9H-b-carbolin-3-carboxylate 3- (2-pyridinyl) ropyls are prepared according to the method B. NMR XH (300 MHz, DMSO-d6) d 9.14 (s, HH), 8.97 (s, HH), 8.56 f (d, J = 4.5 Hz, HH), 8.50 (d, J = 7.9 Hz, HH ), 7.60-7.75 (m, 5H), 7.39-7.46 (m, 2H), 7.34 (d, J = 7.6 Hz, ÍH), 7.20-7.25 (m, ÍH), 6.69 (d, J = 2.3 Hz, ÍH), 5.90 (s, ÍH), 4.46 (t, J = 6.4 Hz, 2H), 3.00 (t, J = 7.4 Hz), 2.22-2.32 (m, 2H). LRMS calculated for C27H21C12N302 (M + H) 490, found 490.

Example 54 • Preparation of 2- (2, 5-dichlorobenzyl) -9Hß-carbol 3-carboxylic acid 2- F4- (ethoxycarbonyl) -l-piperazinyl] ethyl ester 9- (2, 5-Dichlorobenzyl) -9H-β-carboline-3-carboxylic acid 2- [4- (ethoxycarbonyl) -l-piperazinyl] ethyl ester is prepared according to Method B. NMR 'H (300 MHz, DMS0-d6) d 9.11 (s, ÍH), 8.99 (s, ÍH), 8.50 (d, J 7.9 Hz, ÍH), 7.59-7.67 (m, 3H), 7. 38-7.44 (m, 2H), 6.65 (d, J = 2.3 Hz, ÍH), 5.90 (s, 2H), 4.46-4.52 (m, 2H), 4.05 (c, J = 7.2 Hz, 2H), 3.35-3.45 (m, 4H), 2.75-2.87 (m, 2H), 2.45-2.60 (m, 4H), 1.18 (t, J = 7.2 Hz, 3H); LRMS calculated for C28H28C12N404 (M + H) 555, found 555.1. Example 55 • Preparation of 9 - (2,5-dichlorobenzyl) - 9Hß - carbol in 3 carbaldehyde A 250 ml round bottom flask is charged with [9-15 (2, 5-dichlorobenzyl) -9H-β-carbolin-3-yl] methanol (1.84 g, 5.1 mmol), manganese (IV) oxide (1.14). g, 13.1 mmoles) and 60 ml of dichloromethane. The reaction mixture is stirred at • room temperature for 12 hours. The mixture is filtered, concentrated in vacuo and the residue is subjected to chromatography (hexane: ethyl acetate = 10: 1), to give the title compound (1.6 g, 87% yield). XH NMR (CDC13) d 10.3 (s, ÍH), 8.9 (s, ÍH), 8.8 (s, ÍH), 8.3 (d, ÍH), 7.7 (t, ÍH), 7.5-7.4 (m, 3H), 7.2 (s, ÍH), 6.6 (s, ÍH), 5.7 (s, 2H); MS (Cl): 355, 357, 359. Example 56 Preparation of T9-2.5-dichlorobenzyl) -9Hß-carbolin-3-yl] methylamine A solution of [9- (2, 5-dichlorobenzyl) -9H-β-carbolin-3-yl] methanol (7.14 g, 20 mmol) in 100 ml of CH, anhydrous C12 is cooled to 0 ° C under an atmosphere of nitrogen and it is added to drops with thionyl chloride stirring (2.5 g, 20.8 mmol). The solution is allowed to warm to room temperature • and stirred for another 15 hours. The reaction mixture is diluted with 50 ml of anhydrous ethanol and concentrated in a rotary evaporator to give a colored solid. light yellow. The crude material crystallizes by the addition of anhydrous ether, which gives 6.92 grams (84%) of 3-chloromethyl-9- (2, 5-dichlorobenzyl) -9H-β-carboline hydrochloride. This salt is converted to the free base by addition of aqueous Na 2 CO 3 and then extraction of the resulting mixture with CH2C12. The organic layer is dried with Na2SO4 and concentrated in vacuo to provide 0.30 g (100%) of the free base as a light yellow solid. XH NMR (CDC13) d 8.72 (s, • HH), 8.20 (d, J = 7.9, 2.3 Hz, HH), 8.18 (s, HH), 7.60 (t, J = 7 Hz, HH), 7.38 (m, 3H), 7.20 (dd, J = 8.3, 2.3 Hz, ÍH), 6.55 (s, ÍH), 5.65 (s, 2H), 4.92 (s, 2H): MS of the monoisotopic mass (calculated) 374.0, MH + (observed) 375.2 (MH + - HC1) 339.1 .

• A suspension of 3-chloromethyl-9- (2,5-10 dichlorobenzyl) -9H-β-carboline hydrochloride (5.64 g, 15 mmol) and sodium azide (2.0 g, 30 mmol) in 60 ml of anhydrous ethanol it is refluxed under nitrogen for 15 hours. The resulting suspension is cooled to room temperature, diluted with an equal volume of CH2C12 and washed with water (2 x 50 ml) and 2.5 ml. of brine, respectively. The organic extract is dried over anhydrous Na2SO4 and concentrated to give 5.70 grams (100% 3-azidomethyl-9- (2,5-dichlorobenzyl) -9H-β-carboline as a light yellow solid. XH NMR (CDC13) d 8.75 (S, ÍH), 8.20 (d, J 0 7.4 Hz, ÍH), 8.04 (s, ÍH), 7.58 (t, J = 7.5 Hz, HI), 7.32-7.40 (m, 3H), 7.20 (dd, J = 9.6, 2.5 Hz, ÍH), 6. 53 (d, J = 2.3 Hz, ÍH), 5.52 (s, 2H), 4.20 (s, 2H); MS of monoisotopic mass (calculated) 381. 1, MH + (observed) 382. 0, (MH + -N2) 354. 2 .

The reduction of this azide to the corresponding amine is carried out according to the published procedure of Gartiser et al., Tetrahedron Lett. , 1983, 24: 1609. A suspension of 3-azidomethyl-9- (2, 5-dichlorobenzyl) -9H-β-carboline (4.60 g, 12 mmol), ammonium formate (3.90 g, 61.7 mmol) and Pd in carbon 10% (2.0 g, 20 mmol)%) in 200 ml of ethanol is stirred at room temperature under nitrogen for 15 hours. The reaction mixture is filtered to remove the solids and the filtrate is concentrated and diluted with 100 ml of CH2C12. The resulting solution is washed with water (2 x 25 ml) and 25 ml of brine, dried over anhydrous Na 2 SO 4 and concentrated. The crude product is recrystallized from ethyl acetate which provides 3.0 grams (65%) of N-formyl- [9- (2, 5-dichlorobenzyl) -9H-β-carbolin-3-yl] methylamine as a solid. light yellow. NMR XH (CDC13) d 8.65 (s, ÍH), 8.30 (s, ÍH), 8.24 (d, ÍH), 7.95 (s, ÍH), 7.58 (t, ÍH), 7.30-7.40 (m, 3H), 7.20 (dd, ÍH), 6.51 (S, ÍH), 5.60 (s, 2H), 4.78 (d, ÍH); MS monoisotopic mass (calculated) 383.1, MH + (observed) 384.9.

This formamide (2.90 g, 7.5 mmol) is treated with potassium hydroxide (5.40 g, 9.4 mmol) in ethanol / water (5: 1, 48 ml) at reflux for 6 hours. The resulting suspension is cooled to room temperature, concentrated and diluted with 50 ml of CH2C12. The organic phase is washed with water (2 x 25 ml), dried over Na 2 SO 4, filtered and concentrated to give [9- (2, 5-dichlorobenzyl) -9H-β-carbolin-3-yl] methylamine as a solid yellow. The crude material is recrystallized from ethyl acetate / hexane to provide 1.48 grams (55%) of • a light yellow solid. XH NMR (CDC13) d 8.70 (s, ÍH), 8.18 (d, J = 7.9 Hz, ÍH), 8.03 (s, ÍH), 7.58 (td, J = 7.2, 1.1 Hz, 5 ÍH), 7.32-7.42 (line 6 m, 3H), 7.20 (dd, J = 9.6, 2.6 hz, ÍH), 6.55 (d, J = 2.6 Hz, ÍH), 6.55 (d, J = 2.6 Hz, ÍH), 5.60 (s, 2H), 4.28 (d, ÍH), 1.96 (broad s, 2H); MS of monoisotopic mass (calculated) 355.1, MH + (observed) 356.7.

Example 57 Preparation of N-. { f9- (2, 5-dichlorobenzyl) -9H-ß-carbolin-3-ill methyl} -5-methyl-3-isoxazolecarboxamide fifteen A solution of 5-methylisoxazole-3-carbonyl chloride in DCE (0.25M) is treated with a solution of [9- (2,5-dichlorobenzyl) -9H-β-carbolin-3-yl] methylamine in DME ( 0.25M, 1 equivalent) "followed by a solution of triethylamine in DME (l.OM, l equivalent). The mixture is stirred and allowed to • rest during the night. The solvent is evaporated and the residue is purified by preparative HPLC. NMR? U (300 MHz, DMSO-d6) d 9.5 (broad t, ÍH), 9.40 (s, ÍH), 8.74 (s, ÍH), 8.60 (d, J 7.8 Hz, ÍH), 7.78 (m, ÍH) ), 7.66-7.60 (m, superposition, 2H), 7.50- 7.41 (m, superposition, 2H), 6.69 (s, ÍH), 6.65 (s, ÍH), 5.97 (s, ÍH), 4.96 (d, J = 5.4 Hz, 2H), 2.49 (s, overlap with • a peak of DMSO). A peak at 13.7 ppm in the 13 C NMR spectrum is consistent with the methyl group, which probably overlaps with the solvent in the γU NMR spectrum. Monoisotopic mass calculated for C24H18C12N402: 464.1, (M + H) found 465.4.

Example 58 fl Preparation of N { 9- (2,5-dichlorobenzyl) -9H-β-ill methyl-2- (trifluoromethyl)} benzamide twenty The title compound is prepared using the procedure described for N-. { [9- (2,5-dichlorobenzyl) -9H-ß- • carbolin-3-yl] methyl} -5-methyl-3-isoxazolecarboxamide. NMR'H (300 MHz, DMS0-d6) d 9.41 (t, J = 5.6 Hz, ÍH), 9.35 (s, ÍH), 8.59 5 (s, ÍH), 8.43 (d, J 0 7.9 Hz, ÍH) , 7.84-7.60 (m, superposition, 7H), 7.50-7.33 (m, superposition, 2H), 6.66 (d, J = 2.4 Hz, ÍH), 5.94 (s, 2H), 4.87 (d, J = 5.6 Hz , 2H), monoisotopic mass calculated for C27H18C122F3N30: 527.1, (M + H) found 528.5 • Example 59 Preparation of 9- (2,5-Dichlorobenzyl) -9H-carbol in 2- (2, 5-dioxo-l-pyrrolidinyl) ethyl 3-carboxylate fifteen 9- (2,5-Dichlorobenzyl) -9H-β-carboline-3- carboxylic acid 2- (2,5-dioxo-l-pyrrolidinyl) ethyl is prepared by the general method C. NMR'H (300 MHz, CDC13 ) d 8.95 (s, ÍH), 8.85 (s, ÍH), 8.30 (d, J = 7.8 Hz, ÍH), 7.65 (m, ÍH), 7.47-7.42 (m, superposition, "3H), 7.23 (dd, J = 8.5, 2.4 Hz, ÍH), 6.59 (d, J = 2.4 Hz, HH), 5.68 (s, 2H), 4.65 (t, J = 5 Hz, 2H), 4.05 (t, • J = 5 Hz, 2H), 2.75 (s, 4H), monoisotopic mass calculated for C25H19C12N304: 495.1 (M + H) found 495.8.

Example 60 Preparation of 6- (2,5-dichlorobenzyl) -1-hydroxy-l.6-dihydrol-3H- • furor3 ', 4': 5.61 -pyrid-3, 4-bl-indol-3-one 10 6- (2, 5-Dichlorobenzyl) -1-hydroxy-l, 6-dihydrol-3H-furo [3 ', 4': 5,6] -pyrido [3,4-b] indole-3- is prepared ona by a literature procedure (Narasimhan et al., Synthesis, 1975, 797) with some modifications, as follows. A solution of 6- (2, 5-dichlorobenzyl) -l-hydroxy-2- [2- [2- (4-morpholinyl) ethyl] -25 l, 6-dihydrol-3H-furo [3 ', 4': 5, 6] -pyrido [3,4-b] indole-3 -one (2.51 g, 4.91 mmol) in concentrated hydrochloric acid (35 ml, 406 mmol) is refluxed (using a temperature of • 140 ° C bath) for 48 hours. The solution changes from a brown solution to a gray-yellow color in the course of about 24 hours. The solution is cooled, made basic to pH ~ 9 with saturated NaHCO 3 and extracted twice with CH 2 C 12 (2 x 25 ml). The aqueous layer is acidified to pH ~6 with 10% aqueous hydrochloric acid. The light brown precipitate • the resultant is filtered, washed with CH2C12 and ether, respectively, and dried in vacuo at 80 ° C for 15 hours. The weakly acidic filtrate precipitates an additional quantity of solid by allowing it to stand overnight. This is filtered and treated as above, which provides a combined yield of 1.6 grams (82%). NMR 'H (DMSO-d6) d 9.25 (s, ÍH), 8.52 (d, J = 1.7 Hz, ÍH), exchange with D20), 8.30 (d, J 0 7.8 Hz, ÍH), 7.67 (m, 2H), 7.55 (d, J 0 8.5 Hz, ÍH), 7.42 (t, J = 5.8 Hz, ÍH), 7.36 (dd, J = 8.4, 1.6 Hz, ÍH), 7.13 (s, ÍH), 6.52 (d, J = 1.7 Hz, ÍH) 5.94 (s, 2H); 13 C NMR (DMSO-d6) d 166.1, 140.1, 136.4, 135.3, 135.0, 134.8, 133.5, 130.8, 130.4, 129.6, 128.5, 128.1, 125.8, 123.1, 121.1, 120.5, 117.6, 109.9, 94.4, 43.5; MS of monoisotopic mass (calculated) 398.0, MH + (observed) 399.0. 61 • Preparation of acetate 2 -) r (4-cyanocyclohexyl) metip. { 9- (2,5-dichlorobenzyl) -9H- ß-carbolin-3-methyl} amino) -2 -oxoethyl 5 N The first stage of the sequence used to Making this compound is a modification of a reported procedure for reductive amination (Abdel-Magid et al., J. "Org. Chem., 1996, 61: 3849) A solution of 9- (2, 5-dichlorobenzyl) - 9H-ß-carbolin-3-carbaldehyde in 0.10M methanol is treated with 1 equivalent of 4-cyanocyclohexanmethylamine (as a mixture of diastereomers) in 0.10M methanol). The mixture is stirred briefly and allowed to stand at room temperature overnight. The solution is treated with two equivalents of a freshly prepared solution of sodium borohydride in 0.50M non-denatured anhydrous ethanol, stirred and allowed to stand at room temperature for 2 hours. The solution is diluted to half its volume with water, stirred (gas production is present) and the volatile fractions are removed in vacuo. To the solid residue is added 1 equivalent of an O.lM solution of acetoxyacetyl chloride in DCE, 1.5 equivalent of a 0.2M solution of triethylamine in methylene chloride and the mixture is stirred for 2 hours. The solvent is evaporated and the residue is subjected to preparative HPLC chromatography. Approximately 50 mg of this residue is dissolved • in 15 ml of 15% DMSO, 30% isopropanol and 55% hexanes. This is elute on a Kromasil 100-5 Sil column (250 x 22 mm), using a gradient of hexanes (A) and isopropanol (B) at 12 ml / min, while monitoring at 238 mm. The column is eluted with a mixture of 95% A and 5% B for 15 minutes, followed by an increase in the amount of B by 2% every 10 minutes until the peaks of the cis and trans isomers elute (approximately 60-80 minutes). The column is washed with a ff mixture of 80% B and 20% A for 20 minutes, for a total running time of 120 minutes.

Cis isomer: The compound appears as a set of rotamers around the tertiary amide bond: NMR 'H (DMSO-d6) d 8.92, 8.86 (s, ÍH), 8.30 (m, ÍH), 8.17, 7.98 (s, ÍH ), 7.59 (m, superposition, 3H), 7.40-7.31 (m, 2H), 6.45 (s broad, ÍH), 5.82 (s, 2H), 5.01, 4.87 (s, 2H), 4.69 (s broad, 2H), 3.17 (m, 2H), 2.55 (m, Wh / 2 = 29 Hz, ÍH), 2.08, 2.04 (s, 3H), 2.00-1.89"(m, 2H), 1.75-1.52 (m, 3H), 1.45-1.20 (m, 2H), 1.30-0.82 (m, 2H); LRMS calculated for C31H30C12N403: 567.2; MH + (observed) 577.2. trans isomer. The compound appears as a set of rotamers around the tertiary amide bond. NMR? (DMSO-d6) d 8.92, 8.85 (s, ÍH), 8.30 (m, ÍH), 8.19, 7.98 (s, ÍH), 7.60 (m, superposition, 3H), 7.38 (dd, J = 8.6, 2.4 Hz , ÍH), 7.30 (m, ÍH), 6.51 (d, J 0 2.6 Hz, ÍH), 8.51 (s broad, 2H), 5.03, 4.90 (s, 2H), 4.71 (s broad, 2H), 3.25, 3.20 (d, J 0 6.4 Hz, 7.2 Hz, respectively, 2H), 3.09, 3.03 (m, Wh / e = 8.7 Hz, 10.5 Hz, respectively, ÍH), 2.08, 2.04 (s, 3H), 1.85-1.2 (m, superposition, 9H): LRMS calculated for C31H30C12N403: 576.2, MH + (observed) 577.2.

Example 62 Preparation of N-. { f (4-cyanocyclohexyl) methyl] -N-9- (2,5-dichlorobenzyl) -9H- ß-carbol in -3,5-methyl} cyclopropanecarboxamide They are getting ready- . { [(4-Cyanocyclohexyl) methyl] -N-9- (2,5-dichlorobenzyl) -9H- ß-carbolin-3-yl] methyl} cyclopropanecarboxamide • in a manner similar to the procedure described above for 2 - ([(4-cyanocyclohexyl) methyl] { [9- (2, 5 dichlorobenzyl) -9H-β-carbolin-3-yl) ] methyl.}. amino) -2-oxoethyl. This compound appears as a mixture of rotamers around the tertiary amide bond. NMR 'H (DMSO-d6) d 8.92, 8.87 (s, ÍH), 8.31 (m, superposition, ÍH), 8.09, 7.96 (s, ÍH), 7.60 (m, • superposition, 3H), 7.38 (dd, J = 8.7, 2.6 Hz, HH), 7.30 (m, 10 HH), 6.52, 6.50 (d, J 0 2.3 Hz, HH), 5.82, 5.80 (s, 2H), 4.93, 4.73 (S, 5H), 3.44, 3.27 (d, J 0 7.2, 6.8 Hz, 2H), 2.58 (m, ÍH), 1.95 (m, 2H), 1.72-1.56 (m, 2H), 1.48-0.55 (m, superposition, 10H), - LRMS calculated for C31H30C12N403: 576.2, MH + (observed) 545.2. 15 Example 63 • Preparation of 7- (2, 5-dichlorobenzyl) -3- (2-hydroxyethyl) -3,7-dihydro-4H-pyrazidino T4 ', 5': 5.61 pyrido f3, 4-bl indol-4-one 20 The ring system is prepared by a modification of a reported procedure (Mylari et al., J. "Org Chem., 1991, 56: 2587) A solution of 6- (2, 5-dichlorobenzyl) -1 - hydroxy-1,6-dihydro-3H-furo [3 ', 3': 5,6] irido [3,4-b] indol-3-one 5 and 1 equivalent of 2-hydroxyethylhydrazine in 0.033M ethanol is subjected at reflux for 15 hours The solvent is evaporated and the product is purified by preparative HPLC, H-NMR (DMSO-d6) d 9.48 (s, ÍH), 9.29 (s, ÍH), 8.78 (d, J = 8 Hz , ÍH), 7.68 (m, • 2H), 7.57 (d, J = 8.5 Hz, ÍH), 7.48 (m, ÍH), 7.37 (dd, J = 8.5, 10 2.5 Hz, ÍH), 6.55 (d, J = 2.5 Hz, ÍH), 6.01 (s, 2H), 4.82 (broad s, ÍH), 4.28 (t, J = 6 Hz, 2H), 3.78 (t, J = 6 Hz, 2H); LRMS calculated for C22H16C12N4: (M + H) found 439.1.

PROOF OF COMPOUNDS TO DETERMINE ACTIVITY 15 BIOCHEMISTRY The following tests are carried out to determine the activity of GLP-1 when the cells are pretreated with the compounds of the present invention: Test 1: GLP-1 Binding Assays An assay is performed for receptor binding using cloned human GLP-1 receptor expressed in a line of baby hamster kidney cells (BHK). The clones are selected in the presence of 0.5 mg / ml of G-418 and are shown to be stable for more than 40 passages.The plasma membranes are prepared by growing cells at confluence, separating them from surface 5 and resuspending the cells. cells in cold buffer (10 mM Tris / HCl), pH 7.4 containing 30 mM NaCl, 1 mM dithiothreitol, 5 mg / ml leupeptin, 5 mg / ml pepstatin, 100 mg / l bacitrecin and 15 mg / l of recombinant aprotinin. • homogenized by two 10-second discharges using a Polytron PT 10-35 homogenizer (Kinematica) and centrifuge. The precipitate containing the plasma membranes is suspended in buffer and stored at -80 ° C until required. Duplication assays are carried out in polypropylene tubes with 96-well plates. The buffer used in this assay is 25 mM HEPES, pH 7.4 containing 0.1% bovine serum albumin (Sigma) and 0.01% bacitracin. Typically, 100 μl of sample (GLP-1 or test compound) is added to each tube. Tracer is diluted (radioiodinated GLP-1, -20 20,000 cpm) in buffer and 100 μl is added to each tube. An amount of 0.5 μg of freshly re-heated plasma membrane protein diluted in buffer is then added in 100 μl aliquots to each tube. The tubes are incubated at 37 ° C for 1 hour. The non-specific binding is determined in presence of 100 nM GLP-1. The attached and unbound tracer is then vacuum filtered. The tubes are washed twice with 3 ml of buffer per tube. The filters are counted in a gamma scintillation counter. Because radio-iodinated GLP-I is available with high activity, the assays must be carried out under conditions such that the radioiodinated GLP-1 used in the assays represents only 5-10% of the LPG dissociation constant. -l for the GLP-1 receptor, and therefore the measured IC50 values of the antagonists closely approximate their K values.

Test 2: Functional Test of GLP-l The functional assay determines the ability of the compounds to perform a shift to the right in the dose-response curve of GLP-1 in a full-cell cAMP assay or its ability to stimulate cAMP accumulation in these cells. The test is carried out in 12 x 75 borosilicate glass tubes. The concentrations of buffer in the assay is 10 mM HEPES, 1 mM EGTA, 1.4 mM MgCl 2, 0.1 mM IBMX, 30 mM NaCl, 4.7 mM KCl, NaH , 2.5 mM P04, 3 mM glucose and 0.2% BSA. The pH is adjusted to 7.4. In determining the ability of the compounds to antagonize the accumulation of cAMP-l mediated AMPc, cells (typically 0.5 ml, 10 6 / ml) are pretreated with various concentrations of the compounds, for 10 minutes at 37 ° C, and then exposed with increasing concentrations of GLP-1 for 20 minutes. In determining the ability of the compounds to behave as agonists, the cells are treated with varying concentrations of the compounds alone. The reactions terminate by centrifugation, followed by cell lysis with the addition of 500 μl of 0.1% HCl. The cellular debris is pelleted and the cAMP-containing supernatant is evaporated to dryness. CAMP is measured by the use of a RIA (New England Nuclear) equipment. Preferred compounds of the invention show IC50 binding affinities of less than 1 μM in the GLP-1 binding assay described above, and most preferred compounds have IC50 binding affinities of less than 100 nM. Because the concentration of iodinated GLP-l used in the assays represents only 5-10% of the dissociation constant of GLP-1 for the GLP-1 receptor, the IC 50 values of the antagonists closely approximate their values K ^. -None of the tested compounds shows agonist activity in the GLP-I functional assay.

PHARMACEUTICAL COMPOSITIONS Pharmaceutical compositions comprising the compounds of the present invention can be manufactured in one way using known techniques, by means of mixing, dissolving, granulating, dragee-making, levigating, k-emulsifying, encapsulating, trapping or conventional lyophilization processes. The pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate the processing of the active compounds into preparations which can be used pharmaceutically. A suitable formulation • depends on the route of administration chosen. For injection, the agents of the invention are formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks' solution, Ringer's solution or physiological saline buffer. For transmucosal administration, they are used in the formulation penetrants appropriate for the barrier to be permeated. Such penetrants are generally known in the art. For oral administration, the compounds are easily formulated by combining the active compounds with carriers Pharmaceutically acceptable compounds known in the art. Such carriers allow the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion for a patient to be treated. The Pharmaceutical preparations for oral use are obtained as a solid excipient optionally by grinding a resulting mixture, adding suitable auxiliaries, if desired and processing the mixture of granules to obtain tablets or dragee cores. Suitable excipients include fillers such as sugars including lactose, sucrose, mannitol or sorbitol and cell preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose or polyvinylpyrrolidone (PVP). If desired, disintegrating agents such as cross-linked polyvinylpyrrolidone, agar or alginic acid or a salt thereof such as sodium alginate can be added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions are used which optionally may contain gum arabic, polyvinylpyrrolidone, Carbopol gel, polyethylene glycol or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. The dyes or pigments are optionally added to the tablets or dragee coatings for identification or to characterize the different combinations of active compound doses. Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin as well as sealed soft capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.Possing and placing capsules contain the active ingredients in optional mixture with filler material 5 such as lactose, binders such as starches or lubricants such as talc or magnesium stearate and, optionally, stabilizers In soft capsules, the active compounds are dissolved or suspended in suitable liquids such as fatty oils, In addition, stabilizers are optionally added.All formulations for oral administration are in dosages suitable for such administration.For buccal administration, the compositions take the form of tablets or dragees formulated in conventional manner. In the case of inhalation, the compounds for use according to the present invention are conveniently supplied in the form of an aerosol spray presentation from pressurized packages or a nebulizer with the use of a suitable propellant, for example 20 dichlorodifluoromethane, trichlorofluorome dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit is determined by providing a valve to supply a measured quantity. Capsules and gelatin cartridges, for example, for use in an inhaler or insufflator are formulated to contain a pulverized mixture of the compound fc and a suitable powdered base such as lactose or starch. The compounds are formulated for parenteral administration by injection, for example by bolus injection or continuous infusion. Formulations for injection are represented in unit dosage form, for example, in ampoules or in multi-dose containers, with an added preservative. The compositions take forms such as • suspensions, solutions or emulsions in oily vehicles or aqueous, and optionally contain formulation agents such as suspension improving agents, stabilizers or dispersants. Pharmaceutical formulations for parenteral administration include aqueous solutions of the compounds active in a water soluble form. Additionally, suspensions of the active compounds are prepared as • suspensions for appropriate oily injection. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil or synthetic fatty acid esters Such as ethyl oleate, triglycerides or liposomes. Suspensions for aqueous injection optionally contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspension also contains Suitable stabilizers or agents which increase the solubility of the compounds to allow the preparation of highly concentrated solutions Alternatively, the active ingredient is provided in powder form for constitution with a suitable vehicle, for example free water sterile pyrogens, before use The compounds are also formulated in rectal compositions such as suppositories or retention edema, for example containing conventional suppository bases • such as cocoa butter or other glycerides. In addition to the formulations described previously, the compounds are also formulated as a preparation for deposition. Such long-acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. So by For example, the compounds are formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or in ion exchange resins, or as sparingly soluble derivatives, for example as a sparingly soluble salt. A pharmaceutical carrier for the hydrophobic compounds of the invention is a cosolvent system comprising benzyl alcohol, a polar surfactant, an organic water miscible polymer and an aqueous phase. The cosolvent system desirably is a VPD cosolvent system.

VPD is a solution of 3% w / v benzyl alcohol, 8% w / v surfactant ño polar polysorbate 80 and 65% w / v polyethylene glycol 300, brought up to a volume in absolute ethanol. The VPD cosolvent system (VPD: 5W) contains VPD diluted 1: 1 with 5% dextrose in aqueous solution. This co-solvent system 5 dissolves hydrophobic compounds well, and in itself produces low toxicity before systemic administration. The proportions of a desirable cosolvent system are varied considerably without destroying its solubility and toxicity characteristics. In addition, the identity of the 10 cosolvent components may vary. For example, other non-polar surfactants with low toxicity can be used instead of polysorbate 80; the reaction size of polyethylene glycol can vary, - polyethylene glycol can be replaced by other biocompatible polymers, for example polyvinyl pyrrolidone; or the dextrose can be replaced by other sugars or polysaccharides. ^ Alternatively, other delivery systems for hydrophobic pharmaceutical compounds are used. Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethyl sulfoxide are also used, although usually at the expense of greater toxicity. Additionally, the compounds are delivered using a sustained release system such as semi-permeable matrices of solid hydrophobic polymers containing the therapeutic agent. Several sustained release materials have been established and are well known to those skilled in the art. Sustained-release capsules can release, based on their chemical nature, the compounds for a period from a few weeks to more than 100 days. The pharmaceutical compositions also comprise a solid phase or gene suitable for carriers or excipients. Examples of such carriers or excipients include (but are not limited to) calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin and polymers such as polyethylene glycols. Some of the compounds of the invention are provided as salts with pharmaceutically compatible counterions. The pharmaceutically compatible salts can be formed with many acids including, but not limited to, hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. The salts tend to be more soluble in aqueous solvents or other protonic solvents as compared to their corresponding free base forms. Pharmaceutical compositions suitable for use in the compounds provided in the present invention include compositions wherein the active ingredients are contained in an effective amount to achieve their intended purpose, i.e., to prevent development or to alleviate the existing symptoms of the subject what is being treated The determination of the optimum amount to carry out the desired biological, chemical or other effects is within the ability of those skilled in the art For example, a parenteral pharmaceutical composition suitable for administration by injection includes 10 mg of a salt water soluble of a compound of formula (I) mixed with 10 ml of sterile 0.9% saline, which is subsequently incorporated into a unit dosage form suitable for administration by injection.Also, an oral pharmaceutical composition suitable for administration may include 10 mg of a compound of formula (I) mixed with 750 mg of lactose, which is subsequently incorporated into the unit dosage form such as a hard gelatin capsule, for oral administration, although the invention has been illustrated with reference to examples specific and preferred embodiments, it will be apparent to those skilled in the art that they can make various modifications and variations without departing from the spirit of the invention. Therefore, the invention is intended not to be limited by the foregoing description, but to be defined by the following claims and their equivalents.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (19)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: I. A compound of the formula: wherein: R1 is a phenyl or pyridyl group, optionally substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, trifluoromethyl, cyano, C6-6 alkyl, C2-C6 alkenyl and C6-6 alkoxy groups; Or R is where R 'is: hydrogen; a hydroxy group; -OR, wherein R is a C?-C6 alkyl or C2-C5 alkenyl group, optionally substituted with a hydroxy group or an amino group, Ci-Cß alkoxy, cycloalkyl, thioether, heterocycloalkyl, aryl or heteroaryl, optionally substituted with one or more substituents independently selected from alkyl, hydroxyalkyl, carboxyl, C 1 -C 5 alkoxycarbonyl, oxygen, halogen and trifluoromethyl groups; or -NRdR7, wherein R6 and R7 are each, independently hydrogen or a C?-C6 alkyl, C-C6 alkenyl / amino or imino, optionally substituted with a hydroxy group, a Ci-Cß alkoxy group or an amino group, thioether, heterocycloalkyl, aryl or heteroaryl, optionally substituted with one or more substituents independently selected from oxygen, halogen, trifluoromethyl and carboxyl, or wherein -NR6R7 form a 5- or 6-membered heterocyclic ring optionally containing, in addition to the nitrogen heteroatom, a heteroatom selected from 0, N and S; - (CH2) n-0-R ", where n is 1 or 2, and R" is hydrogen, a C5-C7 heteroaryl group, or -JLR8 wherein R8 is hydrogen, a C? -C6 alkyl group, or a C3-C6 cycloalkyl group, or a 5- or 6-membered heteroaryl group, optionally substituted with one or more substituents independently selected from halogens, methyl and trifluoromethyl. - (CH2) PN (R ") (R" '), wherein p is 1 or 2, R "is as defined above, and R'" is hydrogen or an alkyl or alkoxy group optionally substituted with a group C3-C6 cycloalkyl, optionally substituted with cyano; -CH = N-R "", wherein R "'" is hydrogen, hydroxy or -OR9, wherein R9 is an alkyl, cycloalkyl, aryl or heteroaryl group; or a 5- or 6-membered heterocyclic ring containing from one to three heteroatoms independently selected from O, N and S, the ring is optionally substituted with one or two substituents independently selected from methyl, methoxymethyl, oxygen and C alco alkoxy groups C6; R 3 is hydrogen, or a C 1 -C 6 alkyl, C 2 -C 5 alkenyl, or C 1 -C 3 alkoxy C 1 -C 3 alkyl group; or R2 and R3 together with the atoms to which they are attached, form a ring of 5 or 6 members containing from one to two heteroatoms selected from O, N and S, the ring is optionally substituted with oxygen, hydroxyl or an alkyl group C? -C6, optionally substituted with 5- or 6-membered heterocycloalkyl containing one or two heteroatoms independently selected from 0, N and S; and R 4 is hydrogen or an amino, halogen, hydroxyl, nitro, trifluoromethyl, cyano, C 1 -C 6 alkyl or C 2 -C 6 alkenyl group, or a precursor, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or active metabolite of such a compound.
2. 2. A compound, precursor, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or active metabolite according to claim 1, characterized in that: R1 is a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, nitro, trifluoromethyl and cyano groups; Or R2es ^ s * »R ', wherein R is as defined above and incorporates a hydrogen bond acceptor substituent that can, through the
3. 3. A compound, precursor, pharmaceutically acceptable salt, pharmaceutically solvate Acceptable, or active metabolite according to claim 1, characterized in that R1 is 2,5-dichlorophenyloyl or 3, 5-dinitrophenyl.
4. 4. A compound, precursor, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or active metabolite according to claim 1, characterized in that R2 and R3 together with the atoms to which they are attached form a ring of 5 or 6 members which It is a lactone or lactam. 15.
5. A compound, precursor, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or active metabolite according to claim 1, characterized in that R2 is selected 20 of the group consisting of: fifteen
6. 6. A compound, precursor, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or active metabolite according to claim 1, characterized in that R2 and R3, and the atoms to which they are attached together form a ring of 5 or 6 members which is selected of the group consisting of:
7. 7. A compound, precursor, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or active metabolite according to claim 1, characterized in that the compound is of the formula: where R is as defined above
8. 8. A compound, precursor, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or active metabolite according to claim 1, characterized in that the compound is selected from the group consisting of twenty twenty
9. 9. A pharmaceutical composition, characterized in that it comprises an effective amount of a compound, • precursor, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or active metabolite, 5 according to claim 1, and a pharmaceutically acceptable carrier.
10. 10. A method to regulate insulin secretion • in mammals, characterized in that it comprises administering to A mammal is an effective amount of a compound, precursor, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or active metabolite, according to claim 1.
11. 11. A method to inhibit the activity of GLP-1, • characterized in that it comprises administering to a patient an effective amount of a compound, precursor, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or active metabolite, in accordance with 20 claim 1.
12. 12. A method for inhibiting the binding of GLP-1 to the GLP-1 receptor, characterized in that it comprises administering to a patient an effective amount of a compound, precursor, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or active metabolite, according to claim 1 .
13. 13. A method for inhibiting the activation of the GLP-1 receptor, characterized in that it comprises administering to a patient an effective amount of a compound, precursor, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or active metabolite, according to claim 1.
14. 14. A method for regulating insulin secretion in mammals, characterized in that it comprises administering to a mammal an effective amount of a compound, precursor, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or active metabolite, according to claim 1.
15. 15. The compound, precursor, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or active metabolite, according to claim 1, characterized in that it is a GLP-1 receptor antagonist having an IC50 binding affinity of less than 1 uM.
16. 16. A pharmaceutical composition, characterized in that it comprises an effective amount of a GLP-1 receptor antagonist, according to claim 15, and a pharmaceutically acceptable carrier.
17. 17. A method for inhibiting the activation of the GLP-1 receptor, characterized in that it comprises administering to a patient an effective amount of a GLP-1 receptor antagonist, according to claim 15.
18. 18. A compound useful for preparing a non-peptide GLP-1 receptor antagonist having a central 9H-B-carboline motif, the compound is characterized in that it has the formula where • R4 is hydrogen or an amino, halogen, hydroxyl, nitro, trifluoromethyl, cyano, alkyl of 1 to 6 carbon atoms, or an alkenyl group of 2 to 6 carbon atoms; and R5 is hydrogen or an alkyl of 1 to 6 carbon atoms or alkenyl group optionally substituted with • hydroxy or an amino, alkoxy of 1 to 6 carbon atoms, thioether, aryl or heteroaryl group optionally substituted with one or more selected substituents from the group consisting of oxygen, halogen and trifluoromethyl.
19. 19. A compound, characterized in that 15 is selected from the group consisting of: • twenty