MX2009000152A - Azaindole derivatives with a combination of partial nicotinic acetylcholine receptor agonism and dopamine reuptake inhibition. - Google Patents

Abstract

The invention concerns azaindole derivatives having the general formula (I) wherein the symbols have the meanings given in the specification. These compounds have a combination of partial nicotinic acetylcholine receptor agonism and dopamine reuptake inhibition. The invention also relates to pharmaceutical compositions containing these compounds, to methods for preparing them, methods for preparing novel intermediates useful for their synthesis, methods for preparing compositions, and uses of such compounds and compositions, particularly their use in administering them to patients to achieve a therapeutic effect in disorders in which nicotinic receptors and/or dopamine transporters are involved, or that can be treated via manipulation of those receptors.

Description

DERIVATIVES OF AZAINDOL WITH A COMBINATION OF AGONISM PARTIAL OF THE NICOTINIC RECEPTOR ACETILCOLINE AND INHIBITION OF THE REOPENATION OF DOPAMINE FIELD OF THE INVENTION The invention relates to azaindole derivatives having a general formula (I): where the symbols have the meanings given in the specification. These compounds have a combination of partial agonism of the nicotinic acetylcholine receptor and inhibition of dopamine reuptake. The invention also relates to pharmaceutical compositions containing these compounds, to methods for preparing them, methods for preparing new intermediates useful for their synthesis, methods for preparing compositions and uses of such compounds and compositions, particularly their use in administration to patients for achieve a therapeutic effect in disorders in which nicotinic receptors and / or dopamine transporters are involved or that can be treated via the manipulation of such receptors.

BACKGROUND OF THE INVENTION It has been proposed that nicotine has several pharmacological effects (Pulían, 1994). Some of these effects may be related to effects on the release of neurotransmitters. The release of acetylcholine, dopamine, norepinephrine, serotonin and glutamate has been reported after nicotine administration (Toth, 1992). Confirmatory reports and recent additional studies included the modulation of glutamate, nitric oxide, GABA, tachykinins, cytokines and peptides in the CNS. { Brioni, 1997). In addition, neuroprotective effects and several other beneficial pharmacological effects of nicotine were proposed (Sjak-shie, 1993; Onaivi, 1994). It was reported that several compounds targeting nAChRs are useful for treating a wide variety of conditions and disorders (Damaj, 1999, Bannon, 1998, Bencherif, 2002, Levin, 2002, O'Neill, 2002, Breining, 2005). Therapeutic indications discussed in the literature cited above include: CNS disorders such as neuroendocrine, neurological and neuropsychiatric disorders, schizophrenia, memory and study disabilities, attention deficit hyperactivity disorder, anxiety disorders, depressive disorders, neurodegenerative disorders , Alzheimer's disease, addiction disorders, nicotine addiction, ***e addiction, addiction to amphetamine, pain due to eating disorders, inflammatory processes, seizure disorders, eye disorders, glaucoma, macular degeneration, diabetic retinopathy, cardiovascular disorders and gastrointestinal and cancer. Nicotinic receptor antagonists have good potential as therapeutic agents, as they offer another means to modulate nicotinic receptor function. Nicotinic agonists rapidly de-sensitize these receptors, essentially inhibiting their function. Therefore, inhibition of nicotinic receptor function may be the action conferring clinical utility, indicating that nicotinic receptor antagonists may also be beneficial in the treatment of diseases for which nicotinic agonists are currently being developed. For example, schizophrenia and drug abuse were both associated with the hyperactivity of CNS dopaminergic systems, and the inhibition of nicotinic receptors may be advantageous in reducing such hyperactivity. CNS disorders, a type of neurological disorders, can be induced by drug; can be attributed to genetic predisposition, infection or trauma or may have an unknown etiology. They include neuropsychiatric disorders, neurological disorders and mental illnesses, and include neurodegenerative diseases, behavioral disorders, cognitive disorders and cognitive affective disorders. There are several CNS disorders whose clinical manifestations were attributed to CNS dysfunction (ie, disorders resulting from unappropriated levels of neurotransmitter release, inappropriate properties of neurotransmitter receptors and / or inappropriate interaction between neurotransmitters and neurotransmitter receptors). Various CNS disorders can be attributed to a deficiency of acetylcholine, dopamine, norepinephrine and / or serotonin. Relatively common CNS disorders include presenile dementia (early onset of Alzheimer's disease), senile dementia (Alzheimer's type dementia), dementia due to microinfarction, AIDS-related dementia, vascular dementia, Creutzfeld-Jakob disease, Pick's disease, parkinsonism including Parkinson's disease, dementia of Lewy bodies, progressive supranuclear palsy, chorea of Hungtinton, tardive dyskinesia, hyperkinesia, epilepsy, mania, attention deficit disorder, anxiety, dyslexia, schizophrenia, depression, obsessive-compulsive disorders and syndrome of Tourette. The action of many neuropharmacological therapeutic agents involves the modulation of the release, absorption and storage of dopamine, norepinephrine and serotonin at their respective terminals in the CNS. Most neurotransmitters are stored in synaptic vesicles, which are prominent organelles of the terminal branches of the nerves. The concentration in the vesicles seems to be responsible for maintaining an immediate supply of a neurotransmitter available for the exocytotic neuronal release in the synaptic cleft. The vesicles also have the function of protecting the neurotransmitter from metabolic depletion. A transport site on the vesicular membrane is the vesicular monoamine transporter 2 (VMAT2) that has the role of transporting the transmitter from the cytosol to the synaptic vesicle. It was used dihydrotetrabenazine, structurally related to methoxytetrabenazine, as a radiolabel to probe the interaction of drugs with VMAT2. Both compounds act in the same place on VATM2. Once released from the terminal into the synaptic space, the neurotransmitter interacts with postsynaptic receptors and is subsequently brought back to the terminal via the plasma membrane transporter (ie, the dopamine transporter and / or the serotonin transporter). Therefore, the transporter proteins modify the concentration of the neurotransmitter in the cytosolic and vesicular storage reservoirs, thus having the capacity to alter the subsequent neurotransmission. Dopamine is a monoamine neurotransmitter that plays a critical role in the function of the hypothalamic-pituitary-adrenal axis and in the integration of information in sensory, limbic and motor systems. The primary mechanism for the termination of neurotransmission by dopamine is the reabsorption of dopamine released by Na + / CI-dependent plasma membrane transporters. Depending on the surrounding ionic conditions, the dopamine transporter can function as a mediator of both the inwardly directed transport of dopamine (ie, "reabsorption") and the outwardly directed transport of dopamine (ie, "release"). The functional significance of the dopamine transporter is the regulation of neurotransmission by dopamine by terminating the action of dopamine in a synapse via resorption.

Dopaminergic stimulation pathways were implicated in disorders resulting from addictive behaviors. Variants of the dopamine D2 receptor gene were associated with alcoholism, obesity, pathological gambling, attention deficit hyperactivity disorder, Tourette syndrome, ***e dependence, nicotine dependence, substance abuse, and other drug dependencies. Since reduced dopaminergic functions were found in individuals with a minor A1 allele of the D2 dopamine receptor, it was suggested that the dopamine D2 receptor may be a booster or reward gene. In addition, several studies suggested that polymorphisms of the dopamine D2 receptor gene are associated with impulsive-addictive-compulsive behavior, ie "Reward Deficiency Syndrome" (Blum)., nineteen ninety five). The dopamine transporter is a presynaptically localized macromolecule that plays an important role in pathophysiological processes in the CNS. The dopamine transporter terminates dopaminergic neurotransmission by reaccumulating dopamine released in the presynaptic neurons. In ***e addiction, the binding of ***e to the dopamine transporter and the consequent blockade of dopamine absorption appear to be related to the drug's reinforcing properties. The concentration of neurotoxic chemicals in dopaminergic neurons, which is implicated in Parkinson's disease, is also associated with the transport function. The transporter macromolecule can be a marker for Parkinson's disease, evidenced by its absence in cuts of putamen tissue of patients with Parkinson's disease. The dopamine transporter also plays a crucial role in the neurotoxic action of 1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine (PTP), which induces idiopathic Parkinson's syndrome in humans. Consequently, potent but selective ligands for the dopamine transporter have a potential to monitored in vivo primary ***e targets in the brain, for the characterization of ***e binding sites, for pharmacotherapeutic agents for the treatment of ***e addiction and for monitoring Parkinson's disease. Many drugs can cause physical and / or psychological addiction.

Those best known drugs include opiates, such as heroin, opium and morphine; sympathomimetics, including ***e and amphetamines; sedative hypnotics, including alcohol, benzodiazepines and barbiturates; and nicotine, which has similar effects to opioids and sympathomimetics. Drug addiction is characterized by an anxiety or compulsion to take the drug and an inability to limit its use. Additionally, drug dependence is associated with drug tolerance, loss of drug effect after repeated administration, and withdrawal syndrome, the appearance of physical and behavioral symptoms when the drug is not consumed. Sensitization occurs when repeated administration of a drug leads to an increased response at each dose. Tolerance, sensitization and withdrawal syndrome are phenomena that show a change in the central nervous system resulting from the use continuous of the drug. This change motivates the individual with addiction to continue with the drug consumption despite serious social, legal, physical and / or professional consequences. Cocaine addiction remains one of the biggest health problems in the United States. Fundamental studies from several laboratories showed that ***e blocks the absorption of dopamine from the synaptic cleft of the dopamine transporter. Nomifensine and bupropion are two compounds used as pharmacological standards for the inhibitors of the dopamine transporter. Both drugs are used clinically as antidepressants, and bupropion is also one of the few compounds used in the therapy of nicotine addiction. The class of compounds "GBR" is known for its unusually high selectivity and potency for the dopamine transporter. Two of these compounds have affinities in the low nanomolar range (DeVries, 1997).

Nupifensin Buppion Vanoxerin (GBR 12909) The radiolabelling of these compounds facilitated the elucidation of the neuropharmacological activity. GBR 12909 (vannoxerin) dissociates very slowly from DAT and attenuates the increase in extracellular levels of dopamine induced by ***e as measured by microdialysis. This compound was non-stimulatory in human volunteers, and was shown to block the self-administration behavior of ***e in rhesus monkeys (Dutta, 1993). These studies increase the possibility that suitable compounds can serve as ***e antagonists without being addictive in turn. One of the effects of nicotine is the release of dopamine. The inhibitors of the dopamine transporter have essentially the same effect, albeit by a completely different mechanism of action. Thus, under conditions where an increase in endogenous dopamine levels is required or desired, a compound having a double action mechanism is more likely to be effective than a compound having only a single mode of action. Compounds with such a double action mechanism are known. The first compound identified was - as so many times in the history of modern medicine - a natural product. A lobeline (lobeline), a non-pyridinic lipophilic, an alkaloidal constituent of tobacco from India, is a major alkaloid of a family of structurally related compounds found in Lobelia inflata. It was reported that lobeline has many effects similar to nicotine, including tachycardia and hypertension, hyperalgesia and improved learning and memory. Lobeline has a high affinity for receptors nicotinic, but no obvious structural similarity between lobeline and nicotine is observed and the functional and structural relationships between S (-) - nicotine and lobeline do not suggest a common pharmacophore. Also, differential effects between lobeline and nicotine suggest that the activity of these drugs may not be due to a common mechanism of the CNS, although lobeline had been considered a mixed agonist / antagonist of nicotine. lobeline nicotine Lobeline evokes the release of dopamine from striated rat cuts. However, the release of dopamine evoked by lobeline neither is dependent on extracellular calcium nor is it sensitive to mecamylamine, a non-competitive nicotinic receptor antagonist. Therefore, the release of dopamine evoked by lobeline occurs via a different mechanism than the release of dopamine evoked by nicotine. In this regard, lobeline also inhibits dopamine uptake by rat striated synaptic vesicles via an interaction with the dihydrotetrabenazide site on VMAT2, thereby increasing the cytosolic dopamine available for reverse transport by the membrane transporter Plasma (DAT) (Teng, 1997, 1998). Therefore, lobeline interacts with receptors nicotinic and blocks the release of dopamine evoked by nicotine, but also interacts with dopamine transport proteins (DAT and VMAT2) to modify the concentration of dopamine in cytosolic and vesicular storage deposits, thereby modifying dopaminergic neurotransmission later. In US 20030100547 and US 20040266824 a series of 2,6-disubstituted piperidine and piperazine derivatives, structural analogues of lobelin, are described: US 20040266824 The compounds were synthesized and analyzed for their activity in nicotinic receptor assays and transporter assays and dopamine release to evaluate the interaction of these compounds with these specific proteins on the presynaptic terminal of monoaminergic neurons in the CNS. Some of these compounds have greater selectivity for the interaction with the DAT than for the interaction with nicotinic receptors, while other compounds interact with both the nicotinic receptors and the DAT, in a more similar way to the lobeline. Other compounds were more selective for the nicotinic receptor than for the DAT. It is considered that these combinations of pharmacological activity they are beneficial for the treatment of abuse and withdrawal symptoms of psychostimulants, eating disorders and diseases and pathologies of the central nervous system. Azaindol-ethylamine derivatives as nicotinic acetylcholine receptor binding agents, useful in the treatment of conditions associated with depletion of nicotine receptors in mammals, particularly nicotine addiction, were described in EP 0 870 768 A1 and EP 1 178 045 A1 . Some of the disclosed compounds are structurally related to the compounds of the present invention. They are powerful displacers of [3H] -nicotine, with IC50 values of less than 2 μ ?, that is, plC50 values of 5.7 or greater. No affinities of specific special compounds were described. The cited applications do not mention the inhibition of dopamine reuptake. With good reason, because the synthesis and testing of several of the claimed compounds described that they have no activity as inhibitors of dopamine reuptake. It was the object of the invention to provide additional compounds with a double action mechanism: (partial) agonism on nicotinic acetylcholine receptors and inhibition of dopamine reuptake.

DETAILED DESCRIPTION OF THE INVENTION It was surprisingly found that compounds of the general formula (I): where -X, Y and Z independently represent N or C, with the understanding that the ring contains at least one N atom, and no more than 2, -myn are independently either 0 (zero) or 1, with the proviso that when Y and Z represent carbon and X represents nitrogen, m is 0 (zero), -R2 and R3 independently represent hydrogen, halogen, alkyl ( Ci-3), alkynyl (C- | .3), NH-alkyl (C1.3), CF3, hydroxyl, alkyl (Ci-3) oxy or a piperidinyl, pyrrolidinyl, tetrahydropyridinyl, morpholinyl, azepanyl group, -aza-bicyclo [2.2.2] octanyl or 1-aza-bicyclo [2.2.2] oct-2-enyl, which group is unsubstituted or substituted by one or more substituents selected from halogen, alkyl (Ci_3), phenyl or benzyl, - R, R5 and R6 independently represent hydrogen, halogen, to uyl ^^), alkynyl (C2-3), CF3, NH-alkyl (Ci.3), hydroxyl or alkyl (Ci-3) oxy, with the condition that R4 exists only when Y = C, and R5 only when Z = C, and tautomers, stereoisomers and N-oxides thereof, as well as pharmacologically acceptable salts, hydrates and solvates of said compounds of formula (I) and their tautomers, stereoisomers and N-oxides, are new and have a combination of partial agonism of the nicotinic acetylcholine receptor and inhibition of dopamine reuptake. The invention particularly relates to compounds of the general formula (I) wherein R 2 and R 3 independently represent hydrogen or a piperidinyl, pyrrolidinyl, tetrahydropyridinyl, morpholinyl, azepanyl, 1-aza-bicyclo [2.2.2] octanyl or 1-aza- bicyclo [2.2.2] oct-2-enyl, which group is unsubstituted or substituted by one or more substituents selected from halogen, alkyl (C- | .3), phenyl or benzyl, R, R5 and R6 independently represent hydrogen , halogen, alkyl (Ci-3) or alkyl (C -3) oxy, with the proviso that R4 only exists when Y = C and that R5 only exists when Z = C, and X, Y, Z, and m have the meanings indicated above. The compounds of the invention of the general formula (I), as well as the pharmacologically acceptable salts thereof, have (partial) agonist activity on nicotinic acetylcholine receptors and inhibit the reuptake of dopamine. They are useful for treating disorders involving the aforementioned receptors or can be treated by manipulation of said receptors. For example, neuroendocrine, neurological and neuropsychiatric disorders, schizophrenia, memory and study disabilities, attention deficit hyperactivity disorder, anxiety disorders, depressive disorders, neurodegenerative disorders, Alzheimer's disease, addiction disorders, nicotine addiction, ***e addiction, addiction to amphetamine, pain due to eating disorders, processes inflammatory, seizure disorders, eye disorders, glaucoma, macular degeneration, diabetic retinopathy, cardiovascular and gastrointestinal disorders and cancer. The invention also encompasses: pharmaceutical compositions for treating, for example, a disorder or condition treatable by activation and / or blocking of the above-mentioned receptors, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier; methods for treating a treatable condition or disorder by activating and / or blocking the above-mentioned receptors, which method comprises administering to a mammal in need of such treatment a compound of formula (I) or a pharmaceutically acceptable salt thereof; pharmaceutical compositions for treating, for example, a disorder or condition selected from the group consisting of neuroendocrine, neurological and neuropsychiatric disorders, schizophrenia, memory and study disabilities, hyperactivity disorder with attention deficit, anxiety disorders, depressive disorders, disorders neurodegenerative diseases, Alzheimer's disease, addiction disorders, nicotine addiction, ***e addiction, addiction to amphetamine, pain due to eating disorders, inflammatory processes, seizure disorders, eye disorders, glaucoma, macular degeneration, diabetic retinopathy, cardiovascular and gastrointestinal disorders and cancer; methods for treating a disorder or condition selected from the group consisting of the disorders listed therein, methods comprising administering to a mammal in need of such treatment a compound of formula (I) or a pharmaceutically acceptable salt thereof; pharmaceutical compositions for treating a disorder or condition selected from the group consisting of the disorders listed therein, compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier; methods for treating a disorder or condition selected from the group consisting of the disorders listed therein, methods comprising administering to a patient in need of such treatment a compound of formula (I) or a pharmaceutically acceptable salt thereof; methods for activating a nicotinic receptor and / or inhibiting the reuptake of dopamine, which method comprises administering to a subject in need thereof an effective amount of a compound of formula (I). The invention also provides the use of a compound or salt according to formula (I) for the manufacture of a medicament. The invention further relates to combination therapies in which a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or formulation comprising a compound of the invention, is administered concurrently or sequentially or as a combined preparation with another agent or therapeutic agents, to treat one or more of the listed conditions. Such other therapeutic agent (s) can be administered before, simultaneously with or after the administration of the compounds of the invention. The invention also provides compounds, pharmaceutical compositions, equipment and methods for treating a disorder or condition selected from the group consisting of the disorders listed therein, which method comprises administering to a patient in need of such treatment a compound of formula (I) or a salt pharmaceutically acceptable thereof. The compounds of the invention possess agonist activity (partial) on nicotinic acetylcholine receptors and inhibit the reabsorption of dopamine. These activities can be easily demonstrated by, for example, the assays described therein or known in the art. The invention also provides methods for preparing the compounds of the invention and the intermediates used in such methods. The compounds of the present invention may contain one or more asymmetric centers and, therefore, may be present as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Depending on the nature of the various substituents, the molecule may have additional asymmetric centers. Each such asymmetric center will independently produce two optical isomers. All optical isomers and possible diastereomers, in mixtures and as pure or partially purified compounds, belong to this invention. The present invention comprises all such isomeric forms of these compounds. Formula (I) shows the structure of the class of compounds without preferred stereochemistry. The independent synthesis of these diastereomers, or their chromatographic separations, can be achieved with methods known in the art by appropriate modifications of the methodology described in the art. Their absolute stereochemistry can be determined by the X-ray crystallography of crystalline products or crystalline intermediates, which are derived, if necessary, with a reagent containing an asymmetric center of known absolute configuration. The racemic mixtures of the compounds can be separated into the individual enantiomers by methods well known in the art, such as coupling a racemic mixture of compounds with an enantiomerically pure compound to form a diastereomeric mixture., followed by the separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography. The coupling often consists of the formation of salts using an enantiomerically pure acid or base, for example (-) - di-p-toluoyl-D-tartaric acid and / or (+) - di-p-toluoyl-L- acid. tartaric Then, the diastereomeric derivatives can be converted to the pure enantiomers by cleavage of the added chiral residue. The racemic mixture of the compounds can also be separated directly by methods Chromatographic using chiral stationary phases: methods well known in the art. Alternatively, any enantiomer of a compound can be obtained by stereoselective synthesis, using optically pure starting materials or reagents of known configuration, by methods well known in the art. Tautomers of the compound of formula (I) or pharmaceutically acceptable salts thereof also belong to the invention. Some of the crystalline forms of the compounds may exist as polymorphic forms: it is intended that such forms belong to the invention. In addition, some of the compounds can form solvates with water (ie, hydrates) or with common organic solvents. Such solvates are also within the scope of this invention. The isotopically-labeled compounds of formula (I) or the pharmaceutically acceptable salts thereof, including the compounds of formula (I) which have been isotopically labeled to be detectable by PET or SPECT, are also within the scope of the invention. The same applies to compounds of formula (I) labeled with [13 C] -, [14 C] -, [3 H] -, [8 F] -, [125 l] - or other isotopically enriched atoms suitable for binding a receptor or for studies of metabolism.

Definitions of chemical terms and other expressions The term "alkyl" refers to saturated, straight or branched hydrocarbon radicals. "Alkyl (Ci-3)", for example, means methyl, ethyl, n-propyl or isopropyl, and "(Ci-4) alkyl" means methyl, ethyl, n-propyl, isopropyl, n-butyl, 2- butyl, isobutyl or 2-methyl-n-propyl '. The term "alkenyl" means straight or branched hydrocarbon radicals having one or more double carbon-carbon bonds, such as vinyl, allyl, butenyl, etc., and preferably represents (C 2-4) alkenyl. In "alkynyl" groups, the straight or branched hydrocarbon radicals have one or more triple carbon-carbon bonds, such as ethynyl, propargyl, 1-butynyl, 2-butynyl, etc., and preferably represent (C 2-4) alkynyl. The term "acyl" means alkyl (Ci.3) carbonyl, arylcarbonyl or aryl-alkyl (Ci-3) carbonyl. "Halo" or "halogen" means chlorine, fluoro, bromo or iodo; "hetero", such as in heteroalkyl, heteroaromatic, etc., means containing one or more N, O or S atoms. "Heteroalkyl" includes alkyl groups with heteroatoms in any position, thereby including N-linked alkyl groups, linked O or linked to S. The terms "oxy", "uncle" and "carbo", as used herein as part of another group, refer respectively to an oxygen atom, a sulfur atom and a carbonyl group ( C = O) which serve as a linker between two groups, such as for example hydroxyl, oxyalkyl, thioalkyl, carboxyalkyl, etc. The term "amino", as used herein only or as part of another group, refers to a nitrogen atom that may be terminal or a linker between two other groups, where the group may be a primary, secondary or tertiary amine (two hydrogen atoms linked to the nitrogen atom, one hydrogen atom linked to the nitrogen atom and no hydrogen atom linked to the nitrogen atom, respectively). The terms "sulfinyl" and "sulfonyl" as used herein as part of another group, refer respectively to an -SO- or -SO2- group. As used herein, unless otherwise indicated, the term "leaving group" shall mean a charged or uncharged atom or group leaving during a substitution or displacement reaction. Suitable examples include, but are not limited to, Br, Cl, I, mesylate, tosylate and the like. The N-oxides of the aforementioned compounds belong to the invention. The tertiary amines may or may not form N-oxide metabolites. The extent to which N-oxidation takes place varies from trace amounts to almost quantitative conversion. The N-oxides may be more active or less active than the corresponding tertiary amines. While the N-oxides can be easily reduced to their corresponding tertiary amines by chemical means, in the human body this occurs in varying degrees. Some N-oxides undergo an almost quantitative reductive conversion to form the corresponding tertiary amines, in other cases the conversion is merely a trace reaction or even completely absent (Bickel, 1969). With reference to substituents, the term "independently" means that when more than one such substituent It is possible, they can be the same or different from each other. To provide a more concise description, some of the quantitative expressions given in this one are not qualified with the term "approximately". It is understood that the term "approximately", whether used explicitly or not, means that any amount indicated therein refers to the actual value given and also to an approximation of such value that could reasonably be inferred by the person skilled in the art, including approximations. due to experimental conditions and / or measurement of such given value. Throughout the description and claims of this specification, the word "understand" and variations thereof, such as "comprising" and "comprising", are not intended to exclude other additives, components, numbers or additional steps. Any compound metabolized in vivo to provide the bioactive agent (ie, the compound of formula (I)) is a pro-drug within the scope and spirit of the application. Pro-drugs are therapeutic agents that are inactive per se, but that are transformed into one or more active metabolites. Therefore, in the methods of treatment of the present invention, the term "administering" will comprise treating the various disorders described with the specifically described compound or with a compound not specifically described, but which is converted in vivo to the specific compound after treatment. administration to the patient. Prodrugs are bio-reversible derivatives of drug molecules, used to overcome some barriers that limit the utility of the drug molecule. mother drug. These barriers include, but are not limited to, solubility, permeability, stability, presystemic metabolism, and limitations in targeting (Bundgaard, 1985, King, 1994, Stella, 2004, Ettmayer, 2004, Járvinen, 2005). The prodrugs, ie the compounds that when administered to humans by any known route are metabolized to compounds having the formula (I), belong to the invention. This relates in particular to compounds with primary or secondary amino groups or hydroxy. Such compounds can be reacted with organic acids to provide compounds having the formula (I) which have an additional group which is easily separated after administration, for example, but not being limited to, an amidine, enamine, a base Mannich, a hydroxyl-methylene derivative, an O- (acyloxymethylenecarbamate) derivative, carbamate, ester, amide or enaminone. The term "composition", as used herein, comprises a product that contains specific ingredients in predetermined amounts or proportions, as well as any product that results, directly or indirectly, from the combination of specific ingredients in specified amounts. In relation to pharmaceutical compositions, this term comprises a product containing one or more active ingredients and an optional carrier comprising inert ingredients, as well as any product that results, directly or indirectly, from the combination, formation of a complex or aggregate of any two or more ingredients, or the dissociation of one or more ingredients, or other types of reaction or interaction of one or more ingredients. In general, pharmaceutical compositions are prepared by uniformly and intimately contacting the active ingredient in association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. The pharmaceutical composition includes a sufficient amount of the active compound object of this invention to produce the desired effect on the progress or condition of diseases. Therefore, the pharmaceutical compositions of the present invention comprise any composition prepared by mixing a compound of the present invention with a pharmaceutically acceptable carrier. "Pharmaceutically acceptable" means that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and must not be harmful to the recipient thereof. Dose. The affinity of the compounds of the invention for nicotine receptors and dopamine reuptake sites was determined as described below. From the measured binding affinity for a given compound of formula (I), a theoretical minimum effective dose can be estimated. At a concentration of the compound equal to twice the K value measured, almost 100% of the receptors will probably be occupied by the compound. Converting this concentration to mg of compound per kg of patient provides a theoretical minimum effective dose, assuming a ideal bioavailability. Pharmacokinetic, pharmacodynamic and other considerations can modify the dose actually administered to a higher or lower value. The dose of the compound to be administered will depend on the relevant indication, age, weight and sex of the patient and can be determined by a physician. The dose will preferably be in the range of 0.01 mg / kg to 10 mg / kg. The typical daily dose of the active ingredients varies within a broad range and will depend on various factors such as the relevant indication, route of administration, age, weight and sex of the patient and can be determined by a physician. Generally, oral and parenteral dosages of the total active ingredients will be in the range of 0.1 to 1,000 mg per day. The term "therapeutically effective amount", as used herein, refers to an amount of a therapeutic agent for treating a treatable condition by administration of a composition of the invention. This amount is sufficient to exhibit a therapeutic response or detectable improvement in an animal or human tissue system. The effect may include, for example, treating the conditions listed therein. The exact effective amount for a subject will depend on the size and health of the subject, the nature and severity of the condition to be treated, the recommendations of the attending physician (researcher, veterinarian, medical doctor or other clinician), and therapeutic products. or the combination of therapeutic products selected for administration. Therefore, it is not useful to specify an exact effective amount in advance.

The term "pharmaceutically acceptable salt" refers to those salts which, within the limits of a sound medical evaluation, are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and that are commensurable with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. They can be prepared in situ during the isolation and final purification of the compounds of the invention, or they can be prepared separately, by reacting the compounds of the invention with non-toxic pharmaceutically acceptable bases or acids, including inorganic or organic bases and inorganic acids or organic The term "treatment", as used herein, refers to any treatment of a condition or disease of a mammal, preferably a human, and includes: (1) inhibiting the disease or condition, i.e., stopping its development, (2) ) relieve the disease or condition, that is, cause the condition to regress, or (3) stop the symptoms of the disease. As used herein, the term "medical therapy" is intended to include prophylactic, diagnostic and therapeutic regimens carried out in vivo or ex vivo with humans or other mammals. The term "subject", as used herein, refers to an animal, preferably a mammal, more preferably a human, which has been the object of treatment, observation or experiment.

Abbreviations APT bound proton test 9-BBN 9-borobicyclo [3.3.1] nonane BOC ferc-butoxycarbonyl n-Buu n-butyl lithium CNS central nervous system CUR curtain gas DA dopamine DAT dopamine transporter DCM dichloromethane DF baffle voltage DHBE dihydro-α-erythroidine DMAP 4-dimethylaminopyridine DMC 2-chloro-1,3-dimethylimidazolinium chloride DME 1, 2-dimethoxyethane DMF?,? '- dimethylformamide DMG targeted metallocation group DMSO dimethylsulfoxide DOM directed ortomethylation EP entry potential EtOAc ethyl acetate EtOH ethanol FAB fast atomic bombardment FP focusing potential g gram (s) h hour (s) HMDS hexamethyldisilazane HPLC high performance liquid chromatography IS ionic spray voltage LDA lithium diisopropylamide mCIPBA metachloroperbenzoic acid Mel methyl iodide MeOH methanol mg milligram (s) min minute (s) my milliliter (s) m.p. melting point, range of melting points EM mass spectrometry NaOEt sodium ethoxide NaOMe sodium methoxide NBS N-bromosuccinimide NEB gas nebulization PE petroleum ether (40-60) PET positron emission tomography QTOF quadrupole-time of flight Rf retention factor (layer chromatography Rt retention time (LC / EM) SEMCI 2- (trimethylsilyl) ethoxymethyl chloride SPECT single-photon emf computed tomography TBAF tetrabutylammonium fluoride TEA triethylamine TEM THF temperature tetrahydrofuran TIPS triisopropylsilyl TIPSCI triisopropylchlorosilane TMEDA tetramethylethylenediamine TMSA ethynyltrimethylsilane VMAT2 vesicular transporter monoamine 2 EXAMPLES EXAMPLE 1 Analytical Methods The nuclear magnetic resonance spectra (1 H NMR and 3 C NMR, APT) were determined in the indicated solvent using a Bruker ARX 400 (1 H: 400 MHz, 13 C: 100 MHz) at 300 K, unless otherwise indicated. The experiments of 19 F NMR and 13 C NMR were carried out with a Vario Inova 500 spectrometer operating at 1.74 T (499.9 MHz for H / 125.7 MHz for 13 C, 50.7 Mhz, 470.4 MHz for 19 F) using a 5 mm SW probe. The spectra were determined in chloroform or deuterated dichloromethane obtained from Cambridge Isotope Laboratories Ltd. The chemical shifts (d) are indicated in ppm downfield of tetramethylsilane (1 H, 13C) or CCI3F (19F). The coupling constants J are given in Hz. The shapes of the peaks in the NMR spectra are indicated by the symbols "q" (quartet), "dq" (double quartet), "t" (triplet), "dt" (double triplet), "d" (doublet), "dd" (double double), "s" (singlet), "bs" (broad singlet) and "m" (multiplet). The NH and OH signals were identified after mixing the sample with a drop of D20. Ultrafast chromatography refers to purification using the indicated eluent and silica gel (either Acros: 0.030-0.075 mm or Merck silica gel 60: 0.040-0.063 mm). Column chromatography was performed using silica gel 60 (0.063-0.200 mm, Merck). The melting points were recorded with a Büchi B-545 melting point apparatus. The mass spectra were recorded with a Micromass QTOF-2 instrument with MassLynx application software for the acquisition and reconstruction of the data. The exact mass of the quasimolecular ion [M + H] + was measured. Exact mass measurements were made with a JEOL JMS-SX / SX 102 A tandem mass spectrometer using atomic bombardment Quick. For high-resolution mass spectrometry with fast atomic bombardment (FAB), a resolution power of 10,000 was used (valley definition 10%). All reactions involving compounds or conditions sensitive to moisture were carried out under an atmosphere of anhydrous nitrogen. The reactions were monitored using thin layer chromatography (TLC) on silica-coated plastic sheets (silica gel precoated 60 F254 from Merck) with the indicated eluent. The spots were visualized by UV light (254 nm) or l2. The extinction coefficients were determined with an HP 8453 UV-Vis spectrometer. Analytical HPLC was performed with a C18 column (Inertsil ODS-3, particle size 3 mm; 4.6 mm, 50 mm) using the following elution gradient: a linear gradient of 5% to 95% aqueous CH3CN containing 0.04% of HC02H for 5 min, then 95% aqueous CH3CN containing 0.04% HC02H for 2 min at 2.0 ml min. "1 The products were detected at? = 254 nm.

Liquid Chromatography - Mass Spectrometry (LC-EM) The LC-EM system consists of 2 Perkin Elmer micropumps of the 200 series. The pumps are connected to each other by means of a 50 μ T-mixer, connected to an automatic device to remove Gilson samples . The method is the next stage total flow time (ml / min) A (%) B (%) 0 0 2000 95 5 1 1 .8 2000 0 100 2 2.5 2000 0 100 3 2.7 2000 95 5 4 3.0 2000 95 5 A = 100% water with 0.025% HCOOH and 10 mmol NH4HCOO, pH = ± 3 B = 100% ACN with 0.025% HCOOH The automatic device for taking samples has an injection loop of 2 μ ?. Said automatic device is connected to a Waters Atlantis C18 30 x 4.6 mm column with 3 mm particles. The column is kept at a constant temperature in a Perkin Elmer series 200 (40 ° C) column heater (thermostat). The column is connected to a Perkin Elmer UV meter with a flow cell of 2.7 μ ?. The wavelength is adjusted to 254 nm. The UV meter is connected to a Sciex API 150EX mass spectrometer. The mass spectrometer has the following parameters: Scanning range: 150-900 a.m.u .; polarity: positive; Sweep mode: profile; Resolution Q1: UNIT; Stage size: 0.10 a.m.u .; Sweep time: 0.500 sec; NEB: 10; CUR: 10 IS: 5200; TEM: 325; DF: 30; FP: 225 and EP: 10. The light scattering detector is connected to the Sciex API 150. The light scattering detector is a Sedere Sedex 55 operating at 50 ° C and 3 bar pressure of N2. The complete system is controlled by a G3 powermac.

EXAMPLE 2 The compounds of general formula (I) are prepared from readily available starting materials. The 1 H-pyrrolo- [2,3-b] pyridines are available from commercial sources or are known from the chemical literature. (Synthesis, 1992; Heterocycles, 1999; US 2002/0061892; Current Organic Chemistry, 2001). In one example of the general procedure (scheme 1), 1 H-pyrrolo- [2,3-b] pyridine (7-azaindole (1)) is reacted with 1-benzyl-piperidin-3-one (2) in the presence of a base to produce compound 3 piperidin-3-ol and not the benzylic analogue of compound 5. (Bioorganic &Medicinal Chemistry Letters, 2002). The separation of the benzyl group can be achieved using well-known methods. The specific conditions are ammonium formate and palladium hydroxide in methanol to produce compound 4, which was dehydrated (5) and reduced to provide 3-piperidin-3-yl-1 H-pyrrolo [2,3-b] -pyridine (6) desired. Some structure-specific compounds can be formed 7 using the procedures illustrated in scheme 1, starting from 1 H-pyrrolo- [2,3-b] pyridine (4, 5 or 6) substituted. In specific examples, R represents lower alkyl, alkyloxy and fluorine.

SCHEME 1 Scheme 2 illustrates an alternative method for preparing compounds of structure 7. More specifically, the synthesis of 6-chloro-3-piperidin-3-yl-1 H -pyrrolo- [2,3-b] pyridine (13). Thus, compound 6 is reacted with di-t-butyl bicarbonate to form compound 9 in a two-step sequence. Greene (1999) provides more information on the aggregate and subsequent separation of protection groups in organic synthesis.

Selective chlorination of the 7-azaindole 9 analog in position 6 was achieved by a Reissert-Henze type reaction (through N-oxide 10 A) according to a known method (Synthesis, 1992). Thus, the N-methoxycarbonyl compound, obtained from this reaction, is converted under basic reactions into compound 12. Separation of the N-t-Boc group provides compound 13.

SCHEME 2 In yet another example of the general procedure (scheme 3), 7- Azaindole (1) is reacted with 1-aza-bicyclo [2.2.2] octane-3-one (14) to produce the dehydrated product which is reduced to provide the 3- (1H-pyrrolo [2]). , 3-b] pyridin-3-yl) -1-aza-bicyclo [2,2,2] -octane (16) desired.

SCHEME 3 The generation of anions in the ortho position of the aromatic systems used in the scientific methods described in this application is included in a general synthetic strategy known to those skilled in the art as Directed Ortometalation (DOM). For this purpose, several functional groups known as Direct Metalation Groups have been studied within this area. The 1-phenylsulfonyl group as a DMG in position 1 of azaindol analogues allows the introduction of lithium in position 2 and, therefore, its functionalization (Synthesis, 20052; Tetrahedron, 1997). The 2-lithioderived from 17, prepared in a scale of several grams by metametal (1.1 equiv of LDA, THF, -10 ° C to 0 ° C) was trapped with 14 leading to compound 18, which was unprotected to produce a mixture of the anticipated alcohol 19 and an enamine 20. The reduction of 20 gave 3- (1 H -pyrolo [2,3-b] pyridin-2-yl) -1-aza-bicyclo [2,2,2] octane (twenty-one ).

SCHEME 4 With reference to scheme 3, starting material 17 is converted to compound 22 (scheme 4). After the basic hydrolysis of the N-phenylsulfonyl group (23), the preferred sequence was the separation of the benzyl group (24), followed by the dehydration (25). The reduction generates the desired compound 26 (2-piperidin-3-yl-1 H -pyrrolo [2,3-b] -pyridine). With reference to scheme 2, the reduction of 27 with a strong reducing agent, for example LiAIH4, is the preferred method for generating the compound with the group N-CH3 (28). In addition, by the sequence described in scheme 2, the starting material 27 was converted into a separable mixture of 30 and 31 (scheme 4). The lack of selectivity of this specific reaction of the Reissert-Henze type (through the N-oxide 29A) will be understood by those skilled in the art. The basic hydrolysis, followed by the separation of the Nt-Boc protection group provides the corresponding 6- (or 4) -chloro-2-p-per-din-3-1-1 H-pyrrolo [2,3-b] ] pyridines (32 and 33).

SCHEME 5 In another aspect, 5- (R) - [3,3,0] -1-aza-2-thia-3-oxabicyclooctane-2,2-dioxide (compound 35, scheme 5) or its analog 5- (S ) (compound 36, Tetrahedron Asymmetry, 1990) are used as starting materials for the compounds of the present invention illustrated by the formula I. The 2-lithioderived from 17 was reacted with the (R) -sulfamidate to produce the sulfonate of lithium 37, which was subsequently hydrolyzed to generate 38A. The separation of the N-phenylsulfonyl group can be achieved using well-known methods, for example, optionally, by making reacting compound 38A with potassium hydroxide in diethylene glycol in the presence of hydrazine, generates (R) -2-pyrrolidin-2-ylmethyl-1-H-pyrrolo [2,3-b] pyridine (39A). The derivative (S) 39B was obtained from the (S) -sulfamidate 36. The reductive alkylation of 39A to form the compound 41A (scheme 5) can be achieved using different methods. Alternatively to the conversion from 26 to 28 (scheme 4), the reductive methylation of 38A and the subsequent separation of the N-phenylsulfonyl group from compound 40A generates the (R) -2- (1-methyl-pyrrolidin-2-ylmethyl) -1- H-pyrrolo [2,3-b] pyridine (41 A).

SCHEME 6 50 R = = Br 52AB R = Br 51 R * = CH3 53?.? : R = = CH3 Scheme 6 illustrates the preparation of compounds of formula I wherein R5 and R6 represent halogen, (Ci-3) alkyl or alkyloxy. The above procedure (using the chiral sulfamidates 35 and 36) is used to convert 42 and 43 (Synthesis, 1992), AA (scheme 7), 50 (Heterocycles, 1999) and 51 (Current Organic Chemistry, 2001) to compounds 45A / B, 46A / B, 47A / B, 52A / B and 53A / B corresponding. An example of the functionalization of the 7-azaindole system in position 6 is illustrated by the conversion catalyzed by Cu (l) bromide of 48 (and the subsequent removal of the t-Boc protecting group) to provide (R) -6-methoxy -2-pyrrolidin-2-ylmethyl-1-H-pyrrolo [2,3-b] -pyridine (49). It should be emphasized that the synthesis of 6-fluoro-7-azaindole (44) has not yet been reported. Thus, the present invention provides a method for generating compound 44, although based on synthesis strategies known to those skilled in the art and illustrated in scheme 7.

SCHEME 7 The commercially available 2,6-difluoropyridine (54) was converted to 2-amino-6-fluoro-pihdine (55, Tetrahedron, 2002). Different DMG groups were examined (for example the 2,2-dimethyl-propanamide group, (Heterocycles, 1999, WO 2003/053970) It was found, however, that a carbamate such as DMG (Chem. Pharm. Bull., 1987) is essential for the selective iodination of compound 56 to generate compound 57 (6-fluoro-3-iodo-pyridin-2-yl) -carbamic acid ethyl ester.A Sonogashira reaction, followed by ring closure in the presence of Cu (l) iodide (Synthesis, 20051) provided compound 59. Cleavage of carbamate generates 6-fluoro-1 H-pyrrolo [2,3-b] pyridine (44) Synthesis of compounds 47 A / B is illustrated in scheme 6 according to the procedure illustrated by scheme 5. Another illustration of compounds of the present invention of formula I is shown in scheme 8.

SCHEME 8 The softness and selectivity of 9-BBN is demonstrated by its ability to selectively reduce the lactam functional group of the commercially available tertiary lactam 61 (Tetrahedron Letters, 1999) to form the cyclic amine 62, which was converted to the Weinreb amide 63 (Tetrahedron Letters, 1997). With reference to scheme 5, the 2-lithioderivative of 17 was reacted with the Weinreb amide 63 to generate compound 64. In the general method for carrying out the reaction with the 2-lithioderivative 17 and the appropriate electrophile (see the preceding schemes ), the optimum conditions are a temperature from about -50 ° C to -10 ° C, preferably from -30 ° C to -20 ° C for about 2 hours. Compound 64 is subjected to a reduction of Huang-Minlon with concomitant cleavage of the N-phenylsulfonyl group to generate compound 65. Subsequent reductive cleavage of the benzyl group can be achieved under the conditions previously described (scheme 4) to generate 2-pyrrolidin-3. -ylmethyl-1 H-pyrrolo [2,3-b] pyridine (66) The conversion of 66 to 67, using the methodology described in scheme 4 and the subsequent reduction provide compound 68.

SCHEME 9 74: Y = C. X = N 76 Y = C X 75 Y = N. X = C 77: Y = N. X Separation of the isomers (chiral column) 78 Y = C. X = N 79 | Y = N. X = C In yet another example of the general procedure (scheme 9), the 2-lithioderivative of 17 (or 70) is reacted with Ce (lll) chloride (J. Med. Chem., 2002) and subsequently trapped with the tertiary ester. -butyl of 3-oxo-pyrrolidin-1-carboxylic acid (71) to provide the corresponding tertiary alcohols (72, 73). Referring to scheme 5, the Ni cleavage of the phenylsulfonyl group generates the compounds 74, 75. The separation of the Nt-Boc protective group catalyzed by acid medium (preferably 6 M HCl) and the subsequent dehydration generate the compounds 76, 77, which were reduced to the 2-pyrrolidin-3-yl-1 H -pyrrolo [2,3-b] pyridine (78) and 2-pyrrolidin-3-yl-1 H -pyrrolo [3,2-b] pyridine (79 ) desired. The separation of the isomers could be achieved using a chiral column. For the preparation of 83 (scheme 10, European Journal of Medicinal Chemistry, 2004).

SCHEME 10 The 2-valent variant of 70 and / or 83 (preferably obtained with t-BuLi / TMEDA in THF) is reacted with 35 or 36 to provide the corresponding compounds 80 A / B and 84. The conversion of 80 A / B and 84 to 81 A / B and 85 could be performed using the methodology described in scheme 5. The bromination at position 3 of the different isomeric azaindoles can be achieved by known methods (Heterocycles, 1999, 2000; Tetrahedron Letters, 1969; WO2004 / 078757). It was surprisingly found that the preferred conditions were NBS / DMF, allowing the bromination (from 69 to 86) to be produced with an almost quantitative yield. The selection Suitable for the protective group, in particular the triisopropylsilyl group (TIPS), allows the exchange of the 3-bromoderivative by the 3-lithioderivative of 87, which was subsequently trapped with the (R) -sulfamidate (compound 35). The separation in acid medium of TIPS followed by hydrolysis of the sulfonate group (referring to scheme 5) generates (R) -3-pyrolidin-2-yl-methyl-1 H -pyrrolo [3,2-b] pyridine (88) desired. Another illustration of compounds of the present invention of formula I is shown in scheme 1 1. Commercially available 4-chloro-7H-pyrrolo [2,3-d] pyrimidine (89) is reductively converted to 7H-pyrrolo [2] , 3-d] pyrimidine (90). The 2- (trimethylsilyl) ethoxy-methyl group as DMG in position 1 of the indole derivatives enables the lithiation of position 2 (Helvetica Chimica Acta, 1993).

SCHEME 11 Using this well-known methodology, the 2-lithioderivative of 91 was trapped with (for example) compound 35. To avoid the problems associated with the use of alkyl lithium or lithium dialkylamides, the appropriate selection was lithium-tetramethylpiperidine (92). Thus, the 2-lithioderived from 91 was reacted with (R) -sulfamidate (35) to generate compound 93, with subsequent removal of the SEM protecting group (94). Hydrolysis of the sulfonate group under standard conditions, as described above, provides the desired (R) -6-pyrrolidin-2-ylmethyl-7-H-pyrrolo [2,3-dyrpyrimidine (95). Pharmaceutically acceptable salts can be obtained by standard procedures well known in the art, for example by mixing a compound of the present invention with a suitable acid, for example an inorganic acid or an organic acid.

EXAMPLE 3 Synthesis of specific compounds The specific compounds whose synthesis is described below are intended to further illustrate the invention in greater detail, and therefore should not be construed as limiting the scope of the invention in any way. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the description and practice of the invention described herein. Therefore, the description and examples should be considered only by way of example. 1-Benzyl-3- (1 H -pyrrolo [2,3-b1pyridin-3-yl) -piperidin-3-ol. (compound 3] A 60% dispersion of NaH in mineral oil (9.5 g, 179 mmol) was added slowly to 150 mL of EtOH (0 ° C). This solution was added to 7-azaindole (5.3 g, 44.9 mmol) and 1.25 g (44.9 mmol) of 1-benzyl-piperidin-3-one (as the HCI salt). The resulting mixture was stirred for 72 hours at room temperature. Ethyl acetate was added to the mixture, and the organic layer was washed three times with saturated NaHCO3 solution, dried (Na2SO4), filtered and concentrated. The resulting residue was purified by flash chromatography (gradient of diethyl ether / ethyl acetate (1: 1 to pure ethyl acetate)) to provide compound 3 in the form of an oil (10.3 g, 74.7%). 1 H-NMR (400 MHz, CDCl 3): d 10.0 (bs, 1 H), 8.27 (dd, J = 5 Hz, 2 Hz, 1 H), 8.14 (dd, J = 8 Hz, 2 Hz, 1 H), 7.35-7.24 (m, 6H), 7.03 (dd, J = 5 Hz, 8 Hz, 1 H), 3.96-3.88 (bs, 1 H), 3.60 (dd, J gem = 13 Hz, 2H), 3.07-3.01 (m, 1 H), 2.95-2.89 (m, 1 H), 2.39 (d, J = 10 Hz, 1 H), 2.16-1.96 (m, 2H), 1.92-1.78 (m, 2H), 1.72-1.65 (m, 1 H). (TLC EtOAc Rf 0.09). 3- (1-HProlo [2,3-b1-pyridin-3-yO-piperidin-3-ol. (Compound 4) Compound 3 (2.4 g, 7.8 mmol), 1.5 g of ammonium formate (23.8 mmol) ) and 20% Pd (OH) 2 / C (240 mg) were combined in MeOH (50 ml) and they were heated at reflux for 2 hours. The mixture was cooled, filtered, concentrated and redissolved in MeOH. Filtration over 25 g of SCX-2 (MeOH followed by NH 3 / MeOH 1 N) afforded the title compound (1.5 g, 6.9 mmol, 88%) in the form of an amorphous material. H-NMR (400 MHz, D6DMSO): d 11.3 (bs, 1 H), 8.17-8.13 (m, 2H), 7.24 (s, 1 H), 7.0-6.95 (m, 1 H), 3.0-2.89 (m, 2H), 2.85 (d, J = 13 Hz, 1 H), 2.6-2.51 (m, 1 H), 2.06-1.8 (m, 3H), 1.5-1.42 (m, 1 H). (TLC MeOH / triethylamine (97/3 Rf 0.16). 3- (1,2,5,6-tetrahydro-pyridin-3-yl) -1 H -pyrroloyl 2,3-bpyridine. (compound 5) 10 ml of acetyl chloride were added slowly to 200 ml of EtOH (-10 ° C). After 15 minutes, this solution was added to the compound 4 (5 g, 16.3 mmol) and heated to reflux for 1 hour. The mixture was cooled, concentrated and redissolved in MeOH. Filtration over 25 g of SCX-2 (MeOH followed by 1 N NH 3 / MeOH) gave the title compound (1.43 g, 7.18 mmol, 44.1%) in the form of an amorphous material. H-NMR (400 MHz, CDCl 3): d 1 1.4-10.8 (bs, 1 H), 8.32 (dd, J = 5 Hz, 2 Hz, 1 H), 8.2 (dd, J = 8 Hz, 2 Hz, 1 H), 7.15 (dd, J = 8 Hz, J = 5 Hz, 1 H), 6. 32-6.27 (m, 1 H), 3.76-3.72 (m, 2H), 3.10-3.04 (m, 2H), 2.36-2.29 (m, 2H).

(TLC MeOH / triethylamine (97/3 R, 0.25). 3-Piperidin-3-yl-H-pyrrolo [2l3-b1pyridine. (compound 6) 10 ml of acetyl chloride were added slowly to 200 ml of MeOH (-10 ° C). After 5 minutes, this solution was added to compound 5 (1.43 g, 7.18 mmol) and to 20% Pd (OH) 2 / C (130 mg). The mixture was hydrogenated at 3.4 atmospheres for 1 hour. The mixture was filtered and concentrated. A subsequent filtration over SCX-2, followed by flash chromatography (MeOH / triethylamine (97/3)) gave compound 6 (0.81 g, 4.02 mmol, 55%) which was reacted with 1 equivalent of fumaric acid in EtOH and concentrated Recrystallization from EtOH / ethyl acetate gave a solid (free base / fumaric acid (2: 1)), mp> 225 ° C (decomposition). 1 H-NMR (400 MHz, D20): d 8.04 ( bd, J = 5 Hz, 1 H), 7.93 (bd, J = 8 Hz, 1 H), 7.13 (bs, 1 H), 7.01 (dd, J = 8 Hz, 5 Hz, 1 H), 6.36 ( s, 1 H), 3.46-3.40 (m, 1 H), 3.37-3.31 (m, 1 H), 3.14-3.04 (m, 1 H), 2.92-2.82 (m, 2H), 2.0-1.87 (m , 2H), 1.8-1.54 (m, 2H). 3- (1 H -pyrrolo [2,3-blpyridin-3-yl) -piperidine-1-carboxylic acid tert-butyl ester. (compound 9) Compound 6 (0.3 g, 1.5 mmol), 1.0 g of di-t-butyl dicarbonate (4.58 mmol) and 0.5 ml of triethylamine were combined in dichloromethane (20 ml) and heated to reflux for 15 minutes. . The mixture was cooled and concentrated in vacuo. The resulting residue was taken up in ethyl acetate, washed with brine, dried (Na 2 SO 4), filtered and concentrated in vacuo to provide compound 8 in the form of an oily residue, which was used in the next stage (without needing additional purification). 1 H NMR (400 MHz, CDCl 3): d 8.5 (dd, J = 5 Hz, 2 Hz, 1 H), 7.98-7.91 (bd, J = 8 Hz, 1 H), 7.39 (s, 1 H), 7.18 (dd, J = 8 Hz, 5 Hz, 1 H), 4.48-4.04 (m, 2H), 2.97-2.75 (m, 3H), 2.2-2.14 (m, 1 H), 1.84-1.63 (m, 3H), 1.67 (s, 9H), 1.49 (s, 9H). (TLC diethyl ether Rf 0.39). This material (8) was dissolved in 10 ml of MeOH and 3 ml of 2 N NaOH. The reaction mixture was stirred for 0.5 hour at room temperature. Ethyl acetate was added to the mixture, and the organic layer was washed three times with 2N NaOH solution, dried (Na2SO4), filtered and concentrated. The resulting residue was purified by flash chromatography (diethyl ether) to provide compound 9 in the form of an oil (0.25 g, 0.83 mmol, 55% (total)). 1 H-NMR (400 MHz, CDCl 3): d 9.8 (bs, 1 H), 8.3 (bd, J = 5 Hz, 1 H), 8.04-7.98 (bd, J = 8 Hz, 1 H), 7.13 (bs) , 1 H), 7.07 (dd, J = 8 Hz, 5 Hz, 1 H), 4.45-4.02 (m, 2H), 3.04-2.76 (m, 3H), 2.2-2.14 (m, 1 H), 1.83 -1 .60 (m, 3H), 1.49 (s, 9H). (TLC diethyl ether Rf 0.13). 3- (7-Oxy-1 H -pyrrolof2,3-b] pyridin-3-yl) -piperidine-1-carboxylic acid tert-butyl ester. (compound 10 A) Compound 9 (0.23g, 0.76 mmol) and 0.23 g of meta-chlorobenzoic acid (1.4 eq., 1.07 mmol) were combined in dimethoxyethane (10 mL) and stirred for 10 minutes at room temperature. The mixture was concentrated on SiO2 and purified by flash chromatography (ethyl acetate followed by ethyl acetate / MeOH / triethylamine (90/10/1) to provide compound 10A (amorphous, 0.23 g, 0.72 mmol, 95%). 1 H-NMR (400 MHz, CDCl 3): d 8.2 (bd, J = 5 Hz, 1 H), 7.8-7.5 (bs, 1 H), 7.22 (s, 1 H), 7.04 (dd, J = 8 Hz , 5 Hz, 1 H), 4.44-4.02 (m, 2H), 2.99-2.78 (m, 3H), 2.2-2.12 (m, 1 H), 1.81-1.60 (m, 3H), 1.48 (s, 9H ). 3-Piperidin-3-yl-1 H-pyrrolof2,3-b1pyridine-7-oxide. (compound 10B) 0.4 ml of acetyl chloride were added slowly to 10 ml of EtOH (-10 ° C). After 15 minutes, this solution in HCl / EtOH was added to compound 10A (0.27 g, 0.85 mmol) and heated to reflux for 1 hour. The mixture was cooled and partially concentrated, ethyl acetate was added and the resulting precipitate was collected by filtration and washed with diisopropyl ether. The title compound (10B, as the salt with HCl) was obtained in the form of a solid (220 mg, 100%). P.f. > 145 ° C (decomposition). 1 H-NMR (400 MHz, D 20): d N H was invisible, 8.21 -8.18 (m, 1 H), 8. 15-8.12 (m, 1 H), 7.40 (bs, 1 H), 7.25-7.0 (m, 1 H), 3.56-3.49 (m, 1 H), 3.41-3.34 (m, 1 H), 3.31- 3.22 (m, 1 H), 3.04-2.90 (m, 2H), 2.14-2.06 (m, 1 H), 2.05-1.94 (m, 1 H), 1.86-1.66 (m, 2H). 6-Chloro-3-piperidin-3-yl-1 H-pyrrolo [2,3-blpyridine. (compound 13) Compound 10A (0.22 g, 0.69 mmol) and 0.15 ml of 1,1,1,3,3-hexamethyldisilazane (0.72 mmol) were combined in 10 ml of THF. To this solution was added 0.14 ml (1.8 mmol) of methyl chloroformate and the The reaction mixture was stirred for 30 minutes at room temperature. The reaction was concentrated in vacuo. The resulting residue was taken up in ethyl acetate, washed with 5% NaHCO 3 solution followed by brine, dried (Na 2 SO 4), filtered and concentrated in vacuo. Purification by flash chromatography (diethyl ether / PA: 1/1) afforded compound 1 1 in the form of an oil (0.16 g, 58.6%). 1 H-NMR (400 MHz, CDCl 3) d 7.95-7.84 (bd, J = 8 Hz, 1 H), 7.53 (s, 1 H), 7.24 (d, J = 8, 1 H), 4.42-4.20 (m, 1 H), 4.10-4.01 (m, 1 H), 4.09 (s, 3H), 3.14-2.84 (m, 2H), 2.84-2.68 (m, 1 H) , 2.19-2.1 1 (m, 1 H), 1.82-1.60 (m, 3H), 1.49 (s, 9H). (TLC diethyl ether / PE (1/1) R, 0.19). Compound 11 (0.16 g) was dissolved in 25 ml of MeOH containing 3 ml of 2N NaOH and stirred for 18 hours at room temperature. The reaction mass was concentrated in vacuo. The resulting residue was taken up in dichloromethane, washed with 5% NaHCO3 solution followed by brine, dried (Na2SO4), filtered and concentrated in vacuo to provide compound 12 (0.13 g, 95%). H-NMR (400 MHz, CDCl 3) d 7.99-7.91 (bd, J = 8 Hz, 1 H), 7.12-7.07 (m, 2H), 4.42-4.20 (m, 1 H), 4.16-4.02 (m, 1 H), 3.02-2.75 (m, 3H), 2.20-2.12 (m, 1 H), 1.82-1.60 (m, 3H), 1.49 (s, 9H). (TLC diethyl ether / PE (1/1) R, 0.17). 0.2 ml of acetyl chloride were slowly added to 10 ml of EtOH (-10 ° C). After 15 minutes, this solution was added to compound 12 (0.13 g, 0.39 mmol) and heated to reflux for 1.5 hours.

The mixture was cooled and partially concentrated, ethyl acetate was added and the resulting precipitate was collected by filtration and washed with diisopropyl ether. The title compound, 6-chloro-3-piperidin-3-yl-1 H-pyrrolo [2,3-b] pyridine 13 was obtained in the form of a solid (80 mg, 76%). P.f. > 279 ° C (decomposition). 1 H NMR (400 MHz, D 20): d 7.60 (d, J = 8 Hz, 1 H), 7.14 (s, 1 H), 6.99 (d, J = 8 Hz, 1 H), 3.52-3.44 (m , 1 H), 3.40-3.32 (m, 1 H), 3.19-3.09 (m, 1 H), 2.97-2.87 (m, 2H), 2.08-1.91 (m, 2H), 1.84-1.60 (m, 2H) ). 3- (1 H-Pyrroloyl 2,3-b1-pyridin-3-ylV1-aza-bicyclo | 2.2.21octane. (Comp. 16) A 60% dispersion of NaH in mineral oil (4 g, 75 mmol) was added slowly to 75 ml of EtOH (0 ° C). This solution was added to 7-azaindole (2 g, 16.9 mmol) and 3.4 g (21 mmol) of 1-aza-bicyclo [2.2.2] octane-3-one (14) (as the HCI salt). The resulting mixture was stirred for 24 hours at 60 ° C. The solution was allowed to come to room temperature. 0.5 ml of H2O and 25 g of S02 were added to the reaction mixture and then it was concentrated in vacuo. The resulting residue was purified by flash chromatography (dichloromethane / MeOH / NH3 / MeOH 7N (960/35/5 to 910/100/10)) to provide compound 15 in the form of a solid (2.5 g, 69%). P.f. 180 ° C. 1 H-NMR (400 MHz, D 6 DMSO): d 1 1.8 (bs, 1 H), 8.24 (dd, J = 5 Hz, 2 Hz, 1 H), 8.12 (dd, J = 8 Hz, 2 Hz, 1 H), 7.61 (s, 1 H), 7.08 (dd, J = 5 Hz, 8 Hz, 1 H), 6.87 (d, J = 2 Hz, 1 H), 3.14-3.09 (m, 1 H), 3.01-2.91 (m, 2H), 2.64-2.54 (m, 2H), 1.78-1.69 (m, 2H), 1.59 -1.49 (m, 2H). Compound 15 (1.9 g, 7.11 mmol) and 20% Pd (OH) 2 / C (190 mg) were combined in MeOH (100 mL). The mixture was hydrogenated at 3.4 atmospheres for 72 hours. The mixture was filtered and concentrated on 25 g of SiO2. The resulting residue was purified by flash chromatography (dichloromethane / MeOH / NH3 / MeOH 7N (960/35/5 to 910/100/10)) to provide compound 16 in the form of a solid (1.55 g, 57%). P.f. 180 ° C. 1 H NMR (400 MHz, D6DMSO): d 11.35 (bs, 1 H), 8.17 (dd, J = 5 Hz, 2 Hz, 1 H), 7.85 (dd, J = 8 Hz, 2 Hz, 1 H) , 7.31 (d, J = 2 Hz, 1 H), 6.98 (dd, J = 5 Hz, 8 Hz, 1 H), 3.32-3.24 (m, 1 H), 3.22-2.95 (m, 1 H), 3.0-2.83 (m, 4H), 2.78-2.68 (m, 1 H), 1 .95-1.91 (m, 1 H), 1.84-1.54 (m, 3H), 1.35-1.24 (m, 1 H). 3- (1-Benzenesulfonyl-1 H -pyrrolo [2,3-b1pyridin-2-yl) -1-aza-bicyclo [2.2.21octan-3-ol. (comp.18) LDA (2.0 M in THF / heptane) (5.5 ml, 11 mmol) was added to 100 ml of anhydrous THF at -10 ° C under N2. A solution of anhydrous THF (10 ml) containing compound 17 (Tetrahedron, 1997) (2.58 g, 10 mmol) was added dropwise. After the addition, the resulting solution was stirred for 30 minutes at -10 ° C-0 ° C. Then, the temperature was lowered to -70 ° C. At this temperature, a solution of 14 (1.25 g, 10 mmol) was added dropwise. ml of THF. The free base of the HCI salt of commercially available 1-aza-bicyclo [2.2.2] octan-3-one (14) was obtained after filtration over SCX-2 (MeOH followed by NH 3 / MeOH 1 N) and subsequent evaporation. After the addition of 14, the temperature was raised to -30 ° C-25 ° C and the resulting solution was stirred for 60 minutes. The solution was allowed to come to room temperature. To the reaction mixture, 5 ml of H 2 O and 50 g of SiO 2 were added and subsequently concentrated in vacuo. The resulting residue was purified by flash chromatography (dichloromethane / MeOH / NH 3 / MeOH 7 N (960/35/5)) to provide compound 18 in the form of an oil (1.4 g, 37%). 1 H-NMR (200 MHz, CDCl 3): d 8.30 (dd, J = 5 Hz, 2 Hz, 1 H), 8.15-8.05 (m, 2H), 7.75 (dd, J = 8 Hz, 2 Hz, 1 H ), 7.60-7.38 (m, 3H), 7.12 (dd, J = 5 Hz, 8 Hz, 1 H), 6.71 (s, 1H), 5.10-4.85 (bs, 1 H), 3.20-2.74 (m, 6H), 2.45-2.25 (m, 1 H), 2.08-1.92 (m, 2H), 1.74-1.44 (m, 2H). (TLC dichloromethane / MeOH / NH3 / MeOH 7 N (960/35/5)) Rf 0.33). 3- (1 H-Pirrolor2.3-blpyridin-2-yl) -1-aza-bicyclo [2.2.21octane. (comp. 21. #} Compound 18 (2.4 g, 6.26 mmol) and 31 ml of 2N NaOH were combined in EtOH (310 ml) and heated to reflux for 2 hours. The mixture was cooled and concentrated. To the residue were added 50 g of SiO2 and 100 ml of MeOH. This mixture was concentrated in vacuo and subsequently purified by flash chromatography (dichloromethane / MeOH / NHS / MeOH 7 N). (960/35/5)) to provide compound 20 in the form of an oil (0.54 g, 38.3%). 1 H-NMR (200 MHz, CDCl 3): d 1 1.3 (bs, 1 H), 8.33 (dd, J = 5 Hz, 2 Hz, 1 H), 7.87 (dd, J = 8 Hz, 2 Hz, 1 H ), 7.14-7.02 (m, 2H), 6.52 (bs, 1 H), 3.25-2.65 (m, 5H), 1.95-1.40 (m, 4H). (TLC dichloromethane / MeOH / NHa / MeOH 7 N (960/35/5)) Rf 0.20). The second compound obtained during this chromatography (19) was obtained in the form of a solid (0.71 g, 46.6%). P.f. 272 ° C. 1 H-NMR (400 MHz, D6DMSO): d 11.38 (s, 1 H), 8.17 dd, J = 5 Hz, 2 Hz, 1 H), 7.87 ((dd, J = 8 Hz, 2 Hz , 1 H), 7.02 (dd, J = 8 Hz, 5 Hz, 1 H), 6.43 (d, J = 2 Hz, 1 H), 5.32-5.28 (bs, 1 H), 3.5-3.43 (m, 1 H), 2.97-2.88 (m, 2H), 2.84-2.64 (m, 3H), 2.24-2.12 (m, 2H), 1.48-1.37 (m, 2H), 1.33-1.24 (m, 1 H) (TLC dichloromethane / MeOH / NH3 / MeOH 7 N (960/35/5)) R, 0. 09). Compound 20 (0.54 g, 2.4 mmol), 0.76 g of ammonium formate (12 mmol) and 20% Pd (OH) 2 / C (54 mg) were combined in MeOH (50 mL) and heated to reflux for 2 hours. The mixture was cooled, filtered, concentrated and redissolved in MeOH, followed by subsequent filtration over 5 g of SCX-2 (MeOH followed by NH 3 / MeOH 1 N). Purification by flash chromatography (dichloromethane / MeOH / NH 3 / MeOH 7 N (960/35/5)) afforded compound 21 in the form of a solid (0.25 g, 46%). P.f. 190 ° C. 1 H-NMR (400 MHz, CDCl 3): d 1 1.65 (bs, 1 H), 8.21 (dd, J = 5 Hz, 2 Hz, 1 H), 7.88 (dd, J = 8 Hz, 2 Hz, 1 H), 7.06 (dd, J = 8 Hz, 5 Hz, 1 H), 6.34 (s, 1 H), 3.46-3.37 (m, 1 H), 3.29-3.20 (m, 2H), 3.03-2.93 (m, 3H), 2.91-2.80 (m, 1 H), 2.27-2.21 (m, 1 H), 1.90-1.78 (m , 2H), 1.70-1.60 (m, 1 H), 1 .43-1.33 (m, 1 H). 1-Benzyl-3- (H-pyrrolo [2,3-b1-pyridin-2-yl) -piperidin-3-ol. (compound 23) LDA (2.0 M in THF / heptane) (28 mL, 56 mmol) was added to 200 mL of anhydrous THF at -10 ° C under N2. A solution of anhydrous THF (20 ml) containing compound 17 (14.54 g, 56 mmol) was added dropwise. After the addition, the resulting solution was stirred for 30 minutes at -10 ° C -0 ° C. Then, the temperature was lowered to -70 ° C. At this temperature, a solution of 2 (.5 g, 60.8 mmol) in 25 ml of THF (10 minutes) was added dropwise. The free base of the salt with commercially available 1-benzyl-piperidin-3-one (2) HCl was obtained after filtration over SCX-2 (MeOH followed by NH 3 / MeOH 1 N) and subsequent evaporation. After the addition of 2, the temperature was raised to -35 ° C, -30 ° C and the resulting solution was stirred for 2 hours. The mixture was allowed to warm to room temperature and poured into a solution of NH 4 Cl (10 g / 50 ml of H 2 O). Ethyl acetate was added and the organic layer was washed with a 5% NaHC03 solution, dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (gradient of diethyl ether / PA 1: 2 to pure diethyl ether) to provide compound 22 in the form of an oil (5.8 g, 23%). 1 H-NMR (400 MHz, CDCl 3): d 8.31 (dd, J = 5 Hz, 2 Hz, 1 H), 8.10-8.05 (m, 2H), 7.55 (dd, J = 8 Hz, 2 Hz, 1 H ), 7.51-7.45 (m, 1 H), 7.41-7.24 (m, 7H), 7.09 (dd, J = 5 Hz, 8 Hz, 1 H), 6.80 (s, 1 H), 4.97-4.86 (bs) , 1 H), 3.69 and 3.59 (2xd, J gem = 13 Hz, 2H), 3.12-2.87 (m, 2H), 2.58-2.38 (m, 2H), 2.14-2.04 (m, 1 H), 1.96- 1.83 (m, 1 H), 1.68- .44 (m, 2H). (TLC diethyl ether R, 0.2). Compound 22 (1.49 g, 3.3 mmol) and 31 mL of 2N NaOH were combined in MeOH (31 mL) and heated to reflux for 2 hours. The mixture was cooled and concentrated. Ethyl acetate was added and the organic layer was washed with a 5% NaHCO3 solution, dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (ethyl acetate) to give the title compound (23) in the form of a solid. Recrystallization from ethyl acetate / diisopropyl ether. Yield: 0.68 g, 66.5%. P.f. 122- 126 ° C. 1 H-NMR (400 MHz, CDCl 3): d 10.9 (bs, 1 H), 8.26 (dd, J = 5 Hz, 2 Hz, 1 H), 7.84 (dd, J = 8 Hz, 2 Hz, 1 H), 7.34-7.22 (m, 5H) 7.02 (dd, J = 5 Hz, 8 Hz, 1 H), 6.28 (d, J = 2 Hz, 1 H), 3.98-3.86 (bs, 1 H), 3.59 (dd, J gem = 13 Hz, 2H), 2.93-2.83 (m, 2H), 2.45-2.39 (m, 1 H) , 2.25-1.95 (m, 1 H), 2.04-1.80 (m, 3H), 1.75-1.66 (m, 1 H) (TLC diethyl ether Rf 0.2). 3- (1 H-Pyrroloyl-2,3-b1-pyridin-2-yl) -piperidin-3-ol. (compound 24) Compound 23 (3.07 g, 10 mmol), 3.5 g of ammonium formate (58.3 mmol) and 20% Pd (OH) 2 / C (340 mg) were combined in MeOH (100 ml) and they were heated to reflux for 1 hour. The mixture was cooled, filtered, concentrated and redissolved in MeOH. Filtration over 40 g of SCX-2 (MeOH followed by NH 3 / MeOH 1 N) and subsequent purification by flash chromatography (MeOH / triethylamine (90/3)) afforded the title compound 24 (amorphous, 1.73 g, 80% ). 1 H-NMR (400 MHz, D 6 DMSO): d 1.4 (bs, 1 H), 8.15 (dd, J = 5 Hz, 2 Hz, 1 H), 7.84 (dd, J = 8 Hz, 2 Hz, 1 H ), 7.01 (dd, J = 8 Hz, J = 5 Hz, 1 H), 6.32 (bs, 1 H), 5.24-5.0 (bs, 1 H), 2.99-2.85 (m, 3H), 2.63-2.56 (m, 1 H), 2.12-2.02 (m, 1 H), 1.97-1.75 (m, 2H), 1.51 -1.42 (m, 1 H). (TLC MeOH / triethylamine (97/3 R, 0.26). 2-Piperidin-3-yl-1 H-pyrrolof2,3-blpyridine (compound 26) Compound 24 (1.73 g, 7.97 mmol) dissolved in 75 ml of 6N HCl was refluxed for 18 hours. The mixture was cooled and concentrated. Crystallization from ethyl acetate / EtOH afforded compound 25 (1.99 g, 92% (as di-HCl salt)). P.f. > 275 ° C (decomposition). H NMR (400 MHz, D6DMSO): d 12.75 (bs, 1 H), 8.33 (dd, J = 5 Hz, 2 Hz, 1 H), 8.24 (dd, J = 8 Hz, 2 Hz, 1 H) , 7.30 (dd, J = 8 Hz, J = 5 Hz, 1 H), 6.89-6.85 (m, 1 H), 6.42 (bs, 1 H), 4.10-4.04 (m, 2H), 3.34-3.27 ( m, 2H), 2.65-2.58 (m, 2H). (TLC MeOH / triethylamine (97/3 Rf 0.25) Compound 25 (1.71 g, 6.3 mmol) and 20% Pd (OH) 2 / C (210 mg) were combined in 100 ml of MeOH and hydrogenated at 3.4 atmospheres for 1 hour, the mixture was filtered and concentrated. on 30 g of SCX-2 (MeOH followed by 1 N NH 3 / MeOH) provided the title compound 26 (1.06 g, 84%) which was reacted with 1 equivalent of fumaric acid in EtOH and concentrated. Recrystallization from EtOH / ethyl acetate gave a solid (free base / fumaric acid (1: 1)), P. > 211 ° C (decomposition). H-NMR (400 MHz, D6DMSO): d 12.75 (bs, 1 H), 8.33 (dd, J = 5 Hz, 2 Hz, 1 H), 8.24 (dd, J = 8 Hz, 2 Hz, 1 H) , 7.30 (dd, J = 8 Hz, J = 5 Hz, 1 H), 6.89-6.85 (m, 1 H), 6.42 (bs, 1 H), 4.10-4.04 (m, 2H), 3.34-3.27 ( m, 2H), 2.65-2.58 (m, 2H). (TLC MeOH / triethylamine (97/3) R, 0.14). Separation of the enantiopure isomers was achieved using a chiral column (Chiralpak AD 20 μ ?, 250 x 4.6, MeOH / EtOH 1/1, 2 ml / min, d = 220 nm, Rt: 5.6 min (26 A), ([ a] D25 +4 (c 1, toluene) and Rt: 8.3 min (26B), ([a] D 5 -4 (c 1, toluene). 2- (1 H -pyrrolo [2,3-b] pyridin-3-yl) -piperidine-1-carboxylic acid tert-butyl ester (compound 27) Compound 26 (8.3 g, 41.29 mmol) was converted to the compound of title (27) by the method described for compound 9. Yield: 10.9 g (36.21 mmol, 87.7%). P.f. 144-145 ° C. (TLC diethyl ether R, 0.20). 2- (1-methyl-piperidin-3-yl) -1 H-Pirrolof2,3-blpyridine. (compound 28) Compound 27 (0.54 g, 1.8 mmol) was dissolved in 5 ml of anhydrous THF. The resulting solution was added slowly to a stirred solution of LiAIH4 (0.2 g, 5.2 mmol) in 25 ml of anhydrous THF (60 ° C under N2). After stirring for 1.5 hours, the mixture was cooled. To the resulting mixture were added 0.2 ml of H2O, 0.4 ml of 2N NaOH and 0.2 ml of H20 and heated to 60 ° C under N2. The mixture was cooled, filtered, and washed with MeOH, followed by subsequent filtration over 5 g of SCX-2 (MeOH followed by NH 3 / MeOH 1 N). Purification by flash chromatography (MeOH / triethylamine (97/3)) afforded the title compound 28 in the form of a solid (0.32 g, 83%), which was reacted with one equivalent of fumaric acid in EtOH and concentrated . Recrystallization from EtOH / ethyl acetate gave a solid (0.47 g, free base / fumaric acid (1: 1)), m.p. > 218 ° C (decomposition). H-NMR (400 MHz, D6DMSO): d 1 1.58 (bs, 1 H), 8.13 (dd, J = 5 Hz, 2 Hz, 1 H), 7.83 (dd, J = 8 Hz, 2 Hz, 1 H), 7.00 (dd, J = 8 Hz, 5 Hz, 1 H), 6.56 (s, 2H), 6.20 ( bs, 1 H), 3.36-3.30 (m, 1 H), 3.18-3.04 (m, 2H), 2.56-2.50 (m, 1 H), 2.47 (s, 3H), 2.41-2.32 (m, 1 H), 2.1 1-2.03 (m, 1 H), 1.86-1.67 (m, 2H), 1. 58-1.45 (m, 1 H). 2-Piperidin-3-yl-1 H-pyrrolof2,3-b] pyridine-7-oxide (compound 29B) Compound 27 (5.95 g, 19.7 mmol) and 5 g of meta-chlorobenzoic acid (23.2 mmol) were combined in dimethoxyethane (60 ml) and stirred for 10 minutes at room temperature. The reaction mass was concentrated in vacuo. The resulting residue was taken up in ethyl acetate, washed with 2N NaOH, dried (Na2SO4), filtered and concentrated in vacuo. The mixture was concentrated over S1O2 and purified by flash chromatography (ethyl acetate / MeOH / triethylamine (90/10/1) to give compound 29A (amorphous, 5.48 g, 87.5%), LCEM, R ,. 50 min, ([M + H] + = 318), (TLC MeOH / ethyl acetate / triethylamine (10/90/1 Rf 0.46). Compound 29A (0.44 g, 1.38 mmol) was converted to the title compound ( 29B) by the method described for compound 10 B. The title compound (29B, as the salt with HCl) was obtained in the form of a solid (0.33 g, 95%), Mp 245 ° C (decomposition), LCEM, Rt. : 0.63 min, ([M + H] + = 218), 1 H-NMR (400 MHz, D 20): d NH is invisible, 8.20-8.16 (m, 1 H), 8.10-8.05 (m, 1 H), 7.25-7.20 (m, 1 H), 6.53 (bs, 1 H), 3.64-3.57 (m, 1 H), 3.40-3.33 (m, 1 H), 3.31-3.22 (m, 1 H), 3.10 ( bt, J = 10 Hz, 1 H), 2.99-2.90 (m, 1 H), 2.19-2.12 (m, 1 H), 2.01 -1.94 (m, 1 H), 1.85-1.66 (m, 2H) ). 6-Chloro-2-piperidin-3-yl-1 H-pyrrolo [2,3-b] pyridine (compound 32) and 4-chloro-2-piperidin-3-yl-1 H-pyrrolo [ 2,3-b1pyridine (compound 33) Compound 29A (4.87 g, 15.36 mmol) and 3.4 ml of 1.1, 1, 3,3,3-hexamethyldisilazane (16.30 mmol) were combined in 100 ml of THF. To this solution was added 3.2 ml (41.4 mmol) of methyl chloroformate and the reaction mixture was stirred for 1.5 hours at reflux. The reaction mixture was cooled and concentrated in vacuo. The resulting residue was taken in acetate from ethyl, washed with 5% NaHCO3 solution followed by brine, dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash chromatography (diethyl ether / PA: 1/2, followed by ether) provided compound 30A (amorphous, 2.08 g, 34.4%). (TLC diethyl ether / PE (1/1) Rf 0.17). The second compound obtained during this chromatography (31 A) was obtained in the form of an oil (2.7 g, 44.6%) (TLC diethyl ether / PE (1/1) Rf 0.08). The basic cleavage of the N1-carbamate group was carried out according to the method described for compound 12. Thus, compound 30A (2.08 g, 5.29 mmol) was dissolved in 75 ml of MeOH containing 20 ml of 2N NaOH and stirred for 18 hours at room temperature. The reaction mixture was concentrated in vacuo. The resulting residue was taken up in dichloromethane, washed with 5% NaHCO3 solution followed by brine, dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash chromatography (diethyl ether / PE: 1/1) provided compound 30B (amorphous, 1.74 g, 98%). (TLC diethyl ether / PE (1/1) R, 0.21). LCEM; R ,: 2.33 min, ([M + H] + = 336). Compound 31 A (0.35 g, 0.89 mmol) was dissolved in 8 ml of MeOH containing 2 ml of 2 N NaOH and stirred for 18 hours at room temperature. The reaction mass was concentrated in vacuo. The resulting residue was taken up in dichloromethane, washed with 5% NaHCO3 solution followed by brine, dried (Na2SO4), filtered and concentrated in vacuo. Repeated purification by flash chromatography (diethyl ether / PE: 1/1) provided compound 31 B (amorphous, 0.1 g, 33%). (TLC diethyl ether Rf 0.3). LCEM; Rt: 2.27 min, ([M + H] + = 336). 2 ml of acetyl chloride were added slowly to 40 ml of EtOH (-10 ° C). After 15 minutes, this solution was added to compound 30B (1.67 g, 5 mmol) and heated to reflux for 1.5 hours. The mixture was cooled and partially concentrated, ethyl acetate was added and the resulting precipitate was collected by filtration and washed with diisopropyl ether. The title compound, 6-chloro-2-piperidin-3-yl-1 H-pyrrolo [2,3-b] pyridine 32 (as salt with HCl) was obtained in the form of a solid (1.29 g, 100% ). P.f. >; 290 ° C (decomposition). 1 H-NMR (400 MHz, D 6 DMSO): d 12.0 (bs, 1 H), 7.93 (d, J = 8 Hz, 1 H), 7.08 (d, J = 8 Hz, 1 H), 6.31 (d, J = 2 Hz, 1 H), 3.58-3.49 (m, 1 H), 3.34-3.24 (m, 2H), 3.15-3.02 (m, 1 H), 2.92-2.79 (m, 1 H), 2.18-2.10 (m, 1 H), 1.94-1.80 (m, 2H), 1.78-1.64 (m, 1 H). The separation of the enantiopure isomers was achieved using a chiral column (Chiralpak AD-H 5 μ? T ?, 250 x 4.6, 100% EtOH + 0.1% diethylamine, 0.5 ml / min, d = 220 nm, R ,: 18.4 min (32A), ([a] D25 -10 (c 1, toluene) and R ,: 25.2 min (32B), ([a] D25 +10 (c 1, toluene) Both isomers were reacted with 1 EtOAc / EtOAc afforded a solid (free base / fumaric acid (1: 1)), mp; 206 ° C (decomposition). 0.22 ml of acetyl chloride were added slowly to 5 ml of EtOH (-10 ° C). After 15 minutes, this solution was added to compound 31 B (0.1 g, 0.3 mmol) and heated to reflux for 1.5 hours. The mixture was cooled and partially concentrated, ethyl acetate was added and the resulting precipitate was collected by filtration and washed with diisopropyl ether to provide the compound 33: 4-chloro-2-piperidin-3-yl-1 H-pyrrolo [2,3-b] pyridine (as salt with HCl), (52 mg, 64%). P.f. > 250 ° C (decomposition). 1 H-NMR (400 MHz, D 2 O): d N H was invisible, 8.30 (bd, J = 8 Hz, 1 H), 7.39 (bd, J = 8 Hz, 1 H), 6.63 (bs, 1 H), 3.66-3.58 (m, 1 H), 3.42-3.23 (m, 2H), 3.16-3.06 (m, 1 H), 3.0-2.90 (m, 1 H), 2.23-2.14 (m, 1 H), 2.04-1.92 (m, 1 H), 1.86-1.67 (m, 2H).

(R) -2-pyrrolidin-2-ylmethyl-1 H-pyrrolo [2,3-blpyridine. (compound 39A) and (S) -2-pyrrolidin-2-ylmethyl-1 H-pyrrolof2,3-b1pyridine. (compound 39 B) To a solution of anhydrous THF (75 ml) containing compound 17 (6.2 g, 24 mmol) was added dropwise 12 ml (24 mmol) of LDA (2.0 M in THF / heptane) to -10. ° C under N2. After the addition, the resulting solution was stirred for 30 minutes at -10 ° C-0 ° C. Then, the temperature was lowered to -70 ° C. At this temperature, a solution of 35 (4 g, 24.5 mmol) in 25 ml of THF (10 minutes) was added dropwise. After the addition of 35, the temperature was raised to -20 ° C and the resulting solution was stirred for 2 hours. hours. The mixture was allowed to warm to room temperature and was stirred for another 2 hours. The reaction mixture was concentrated and the residue was dissolved in 40 ml of 1 N HCl, 40 ml of EtOH and 40 ml of THF. The mixture was stirred at 80 ° C for 18 hours. The reaction mixture was concentrated in vacuo. The resulting residue was taken up in ethyl acetate, washed with 2N NaOH, dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash chromatography (MeOH / triethylamine 97/3) provided compound 38A (amorphous, 3.63 g, 44%). 1 H-NMR (400 MHz, CDCl 3): d 8.35 (bd, J = 5 Hz, 1 H), 8.09 (bd, J = 8 Hz, 2H), 7.67 (bd, J = 8 Hz, 1 H), 7.57-7.41 (m, 3H), 7.12 (dd, J = 8 Hz, 5 Hz, 1 H), 6.46 (s, 1 H), 3.70-3.58 (m, 1 H), 3.39-3.31 (m, 1 H), 3.23-3.15 (m, 1 H), 3.13-3.03 (m, 1 H), 2.98-2.86 (m, 1 H), 2.10-1.70 (m, 3H), 1.57-1.44 (m, 1 H). (TLC MeOH / triethylamine (97/3 R, 0.18) LCEM; R ,: 1.27 min, ([M + H] + = 342) Compound 38 A (3.63 g, 10.6 mmol), 1 1 g KOH and 22 ml of hydrazine monohydrate were combined in 2- (2-hydroxy-ethoxy) -ethanol (100 ml) and stirred for 1 hour at 100 ° C. To the cooled reaction mixture was added ethyl acetate and the organic layer. The resulting mixture was washed with 2N NaOH, dried (a2SO4), filtered and concentrated in vacuo.The mixture was dissolved in MeOH and filtered over 40 g of SCX-2 (MeOH followed by 1 N NH3 / MeOH). by flash chromatography (MeOH / triethylamine (98/2)) gave the title compound 39 A, LCEM; Rt: 0.91 min, ([M + H] + = 202), (amorphous, 1.42 g, 66%), ([a] D25 -50 (c 1, toluene), which was reacted with 1 equivalent of fumaric acid in EtOH and concentrated. of EtOH / ethyl acetate gave a solid (free base / fumaric acid (1: 1)), mp> 163 ° C (decomposition). 1 H-NMR (400 MHz, D6DMSO): d 1 1.7 (bs, 1 H ), 8.13 (dd, J = 5 Hz, 2 Hz, 1 H), 7.84 (dd, J = 8 Hz, 2 Hz, 1 H), 7.0 (dd, J = 8 Hz, 5 Hz, 1 H), 6.51 (s, 2H), 6.32 ( s, 1 H), 3.85-3.77 (m, 1 H), 3.26-3.04 (m, 4H), 2.09-1.80 (m, 3H), 1.71-1.61 (m, 1 H). (S) -2-pyrrolidin-2-ylmethyl-1 H -pyrrolo [2,3-b] pyridine (compound 39B) was obtained using the methodology described for compound 39 A, using sulfamidate 36. ([a] D25 +50 (c 1, toluene).

(R) -2- (1-methyl-pyrrolidn-2-ylmethyl) -1 H -pyrrolor2,3-b] pyridine. (compound 41A) and (S) -2- (1-methyl-pyrrolidin-2-ylmethyl) -1 H -pyrrolo [2,3-blpyridine. (compound 41 B) Compound 38 A (0.39 g, 1.14 mmol), 0.5 g of NaBH (OAc) 3 and 0.2 ml of formaldehyde (37)% were combined in dichloroethane (15 ml) and stirred for 1 hour at room temperature . The reaction mass was concentrated in vacuo. The resulting residue was taken up in ethyl acetate, washed with 2 N NaOH, dried (Na 2 SO 4), filtered and concentrated in vacuo, which gave 40 A (amorphous, 0.40 g, 98%). 1 H-NMR (400 MHz, CDCl 3): d 8.35 (dd, J = 5 Hz, 2 Hz, 1 H), 8.12-8.07 (m, 2 H), 7.69 (dd, J = 8 Hz, 2 Hz, 1 H ), 7.56-7.41 (m, 3H), 7.12 (dd, J = 8 Hz, 5 Hz, 1 H), 6.40 (s, 1 H), 3.73-3.67 (m, 1 H), 3.16-3.10 (m, 1 H), 2.87-2.73 (m, 2H), 2.47 (s, 3H), 2.33-2.25 (m, 1 H), 1 .95-1.50 (m, 4H). Compound 40A (0.4 g, 1.2 mmol), 1.1 g of KOH and 2.2 ml of hydrazine monohydrate were combined in 2- (2-hydroxy-ethoxy) -ethanol (10 ml) and stirred for 1 hour at 100 °. C. To the cooled reaction mixture was added ethyl acetate and the resulting organic layer was washed with 2N NaOH, dried (Na2SO4), filtered and concentrated in vacuo. The mixture was dissolved in MeOH and filtered over 40 g of SCX-2 (MeOH followed by NH 3 / MeOH 1 N). Subsequent purification by flash chromatography (MeOH / triethylamine (99/1)) gave the title compound 41 A (solid, 0.19 g, 76%). ([α] D 25 +44 (c 1, toluene). 1 H-NMR (400 MHz, CDCl 3): d 10.4 (bs, 1 H), 8.18 (dd, J = 5 Hz, 2 Hz, 1 H), 7.79 (dd, J = 8 Hz, 2 Hz, 1 H), 6.99 (dd, J = 8 Hz, 5 Hz, 1 H), 6.18 (bs, 1 H), 3.18-3.07 (m, 2H), 2.90- 2.83 (m, 1 H), 2.61-2.53 (m, 1 H), 2.45 (s, 3H), 2.25-2.17 (m, 1 H), 1.89-1.79 (m, 1 H), 1.69-1.43 (m , 3H). (S) -2- (1-methyl-pyrrolidin-2-ylmethyl) -1 H -pyrrolo [2,3-b] pyridine (compound 41 B) was obtained using the methodology described for compound 41 A. ([a] D25 -42 (c 1, toluene). MP: 130-131 ° C.

(R) -6-chloro-2-pyrrolidin-2-ylmethyl-1 H-pyrroloyl-2,3-blpyridine (compound 45A) and (S) -6-chloro-2-pyrrolidin-2-ylmethyl-1 H-pyrrolo [2,3-blpyridine (compound 45 B) 6-chloro-7-azaindole (9.3 g, 61 .1 mmol), prepared as described (Synthesis, 1992), was dissolved in 100 ml of anhydrous THF under N2. At 0 ° C, a 60% dispersion of 3.5 g of NaH (65.9 mmol) in mineral oil was added. After stirring for 1 hour at room temperature, the mixture was cooled (0 ° C) and 8.7 ml (67.2 mmol) of benzenesulfonyl chloride dissolved in 20 ml of anhydrous THF were added. The reaction mixture was stirred at room temperature for 1 hour. Ethyl acetate was added to the mixture, and the organic layer was washed three times with saturated NaHCO3 solution, dried (Na2SO4), filtered and concentrated. The resulting residue was purified by flash chromatography (diethyl ether / PE gradient (from 1: 4 to pure diethyl ether) to give 1-benzenesulfonyl-6-chloro-1 H -pyrrolo [2,3-b] pyridine (amorphous, 14.4 g, 80.7%) (TLC diethyl ether / PE (1/1) Rf 0.37) LCEM, Rt: 1.98 min, ([M + H] + = 293) To an anhydrous THF solution (100 ml) containing the compound 1-benzenesulfonyl-6-chloro-1 H -pyrrolo [2,3-b] pyridine (2.52 g, 8.6 mmol) were added dropwise 4.3 ml (24 mmol) of LDA (2.0 M in THF / heptane) at -78 ° C under N2.After the addition, the resulting solution was stirred for 60 minutes at -78 ° C. At this temperature, a solution of 35 (1.4 g, 8.6 mmol) was added dropwise. 10 mL of THF (5 minutes) After the addition of 35, the temperature was raised to -20 ° C and the resulting solution was stirred for 2 hours.The mixture was allowed to warm to room temperature and stirred for another 2 hours. The reaction mixture was concentrated and the residue was dissolved in 40 ml of HCl 1 N, 40 ml of EtOH and 40 ml of THF. The mixture was stirred at 80 ° C for 18 hours. The reaction mixture was concentrated in vacuo. The resulting residue was taken up in ethyl acetate, washed with 2N NaOH, dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash chromatography (MeOH / triethylamine 98/2) provided (R) -1-benzenesulfonyl-6-chloro-2-pyrrolidin-2-ylmethyl-1 H -pyrolo [2,3-b] pyridine (amorphous, 1.01 g, 31%) (TLC MeOH / triethylamine 98/2 Rf 0.32). (R) -1-Benzenesulfonyl-6-chloro-2-pyrrolidin-2-ylmethyl-1 H -pyrrolo [2,3-b] pyridine (1.01 g, 2.69 mmol), 20 mL of 2N NaOH and 30 mL of isopropanol were combined and stirred for 3 hours at 100 ° C. To the cooled reaction mixture was added ethyl acetate and the resulting organic layer was washed with 2N NaOH, dried (Na2SO4), filtered and concentrated in vacuo. The mixture was dissolved in MeOH and filtered over 10 g of SCX-2 (MeOH followed by NH 3 / MeOH 1 N). Subsequent purification by flash chromatography (MeOH / triethylamine (98/2)) gave the title compound 45A (solid366 mg, 58%). ([a] D25 -48 (c 1, toluene). 1 H-NMR (400 MHz, CDCl 3): d 1 1.0-10.0 (bs, 1 H), 7.52 (d, J = 8 Hz, 1 H), 7.01 (d, J = 8 Hz, 1 H), 6.16 (s, 1 H), 3.50-3.42 (m, 1 H), 3.02-2.90 (m, 3H), 2.81 -2.73 (m, 1 H), 1.95 -1.85 (m, 1 H), 1.82-1.64 (m, 2H), 1.43-1.33 (m, 1 H) Compound 45A was reacted with 1 equivalent of fumaric acid in EtOH and concentrated. of EtOH / ethyl acetate gave a solid (free base / fumaric acid (2: 1)), Pf >; 222 ° C (decomposition). (S) -6-chloro-2-pyrrolidin-2-ylmethyl-1 H -pyrrolo [2,3-b] pyridine (compound 45B) was obtained (from 36) using the methodology described for compound 45 A ([a] D25 +44 (c 1, toluene) Compound 45 B was reacted with 1 equivalent of fumaric acid in EtOH and concentrated.Recrystallization from EtOH / ethyl acetate gave a solid (free base). / fumaric acid (1: 1)), mp 189-190 ° C.

(R) -6-bromo-2-pyrrolidin-2-ylmethyl-1 H-pyrrolo [2,3-blpyridine. (compound 46A) and (S) -6-bromo-2-pyrrolidin-2-ylmethyl-1 H-pyrrolo [2,3-blpyridine. (compound 46 B) 6-bromo-7-azaindole (4.65 g, 23.6 mmol), prepared as described (Synthesis, 1992), was converted to 1-benzenesulfonyl-6-bromo-H-pyrrolo [2,3-b ] pyridine using the methodology described above (solid, mp 121-124 ° C). (7.57 g, 95%) 1 H-NMR (400 MHz, CDCl 3): d 8.28-8.22 (m, 2 H), 7.70-7.50 (m, 5 H), 7.32 (d, J = 8 Hz, 1 H), 6.56 (d, J = 4 Hz, 1 H). (TLC diethyl ether R, 0.55). 1-Benzenesulfonyl-6-bromo-1 H -pyrrolo [2,3-b] pyridine (2.07 g, 6.1 mmol) was converted to (R) -1-benzenesulfonyl-6-bromo-2-pyrrolidin-2-ylmethyl -1 H -pyrrolo [2,3-b] pyridine using the methodology previously described (amorphous, 1.24 g, 48%) H-NMR (400 MHz, CDCl 3): d 8.21-7.97 (m, 2H), 7.61-7.47 (m, 5H), 7.25 (d, J = 8 Hz, 1 H), 6.46 (s, 1 H), 3.65-3.57 (m, 1 H), 3.37-3.31 (m, 1 H), 3. 09-3.03 (m, 1 H), 2.96-2.89 (m, 1 H), 2.06-1.73 (m, 3H), 1.54-1.45 (m, 1 H). (TLC MeOH / triethylamine (97/3 R, 0.22). (R) -1-Benzenesulfonyl-6-bromo-2-pyrrolidin-2-methyl-1H-pyrrolo [2,3 -b] pyridine (1.24 g, 2.95 mmol), 30 mL of 2N NaOH and 50 mL of MeOH were combined and stirred for 30 minutes at 60 [deg.] C. To the cooled reaction mixture was added ethyl acetate and the organic layer The resulting mixture was washed with 2N NaOH, dried (Na2SO4), filtered and concentrated in vacuo.The mixture was dissolved in MeOH and filtered over 10 g of SCX-2 (MeOH followed by 1 N NH3 / MeOH). Subsequent by flash chromatography (MeOH / triethylamine (97/3)) gave the title compound 46A (amorphous, 630 mg, 76%), ([a] D25 -50 (c 1, toluene), which became its salt (free base / fumaric acid (1: 1)), 1 H-NMR (400 MHz, D6DMSO): invisible d NH, 7.82 (d, J = 8 Hz, 1 H), 7.18 (d, J = 8 Hz, 1 H), 6.49 (s, 2H), 6.38 (s, 1 H), 3.82-3.72 (m, 1 H), 3.27-3.05 (m, 4H), 2.09-1.80 (m, 3H), 1.70-1.60 (m, 1 H). (S) -6-Bromo-2-pyrrolidin-2-ylmethyl-1 H-pyrrolo [2,3-b] pyridine (compound 46B) was obtained (from 36) using the methodology described for compound 46 A. ([a] D25 + 50 (c 1, toluene).

(R) -6-fluoro-2-pyrrolidin-2-ylmethyl-1 H-pyrrolo [2,3-blpyridine. (compound 47A) and (S) -6-fluoro-2-pyrrolidin-2-methylmethyl-1 H-pyrrolo [2,3-blpyridine] (Compound 47 B) Compound 55 (18 g, 161 mmol), 70 g of K2CO3 (506 mmol) and 15. 4 ml (161 mmol) of ethyl chloroformate were combined in CH3CN (400 ml) and stirred for 4 days at 40 ° C. The TLC showed a moderate conversion. An additional 15.4 ml of ethyl chloroformate was added and stirring was continued for 2 days. The mixture was cooled. Ethyl acetate was added to the mixture, and the organic layer was washed with saturated NaHCO 3 solution, dried (Na 2 SO 4), filtered and concentrated. The resulting residue was purified by flash chromatography (diethyl ether / PE (1: 3)) and the ethyl ester of (6-fluoro-pyridin-2-yl) -carbamic acid (56) (amorphous, 19.68 g, 66.5%) was provided. . 1 H-NMR (400 MHz, CDCl 3): d 7.83 (dd, J = 8 Hz, 2 Hz, 1 H), 7.80-7.73 (m, 1 H), 7.50-7.40 (bs, 1 H), 6.61 -6.57 (m, 1 H), 4.25 (q, J = 8 Hz, 2H), 1.32 (t, J = 8 Hz, 3H). (TLC diethyl ether / PE (1/1) R, 0.5). 28.6 ml (0.18 mmol) of TMEDA were added to a solution of compound 56 (13.41 g, 72.9 mmol) dissolved in 300 ml of anhydrous THF. The mixture was cooled to -78 ° C (under N2). To the stirred reaction mass was added 76 ml (n-BuLi 2.5 M) and the mixture was stirred for 2 hours at -78 ° C. After the addition of 12 (48 g, 0.17 mol), the mixture was stirred for 1 hour at -78 ° C. The reaction mixture was then quenched with a saturated solution of Na2S2O3 and allowed to warm to room temperature. Ethyl acetate was added to the mixture, and the organic layer was washed with saturated NaHCO3 solution, dried (Na2SO4), filtered and concentrated. The resulting residue was purified by flash chromatography (diethyl ether / PE 1/3 to 1/1) and the ethyl ester of (6-fluoro-3-iodo-pyridin-2-yl) - carbamic (57) (amorphous, 15.86 g, 70%). 1 H-NMR (400 MHz, CDCl 3): d 8.07 (bt, J = 8 Hz, 1 H), 7.24-7.14 (bs, 1 H), 6.49 (dd, J = 8 Hz, 3 Hz, 1 H), 4.29 (q, J = 8 Hz, 2H), 1.35 (t, J = 8 Hz, 3H). (TLC diethyl ether / PE (1/1) Rf 0.27). A mixture of compound 57 (4 g, 12.9 mmol), 3.3 ml (23.4 mmol) of TMSA (ethynyl-thmethylsilane), 246 mg (1.29 mmol) of Cu (l) iodide, 454 mg (0.65 mmol) of PdCI2 ( PPh3) 2 (454 mg, 0.64 mmol) and triethylamine (6.3 ml) was stirred and degassed (N2). The resulting reaction mixture was stirred for 10 hours at 100 ° C (closed vessel), cooled and poured into ethyl acetate and H2O. The organic layer was washed with H2O, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (diethyl ether / PE (1/3)) to give the ethyl ester of (6-fluoro-3-trimethylsilanylethynyl-pyridin-2-yl) -carbamic acid (58) (oil, 1.5 g, 42 %). 1 H-NMR (200 MHz, CDCl 3): d 7.76 (bt, J = 8 Hz, 1 H), 7.68-7.60 (bs, 1 H), 6.56 (dd, J = 8 Hz, 3 Hz, 1 H), 4.29 (q, J = 8 Hz, 2H), 1.34 (t, J = 8 Hz, 3H), 0.3 (s, 9H). (TLC diethyl ether / PE (1/1) R, 0.39). A mixture of compound 58 (6 g, 21.4 mmol) and 8.2 g (43 mmol) of Cu (I) iodide was dissolved in 100 ml of DMF and degassed for 0.5 hour. The reaction mixture was stirred at 150 ° C (preheated oil bath) for 30 minutes. The mixture was cooled and diluted with ethyl acetate and filtered. The residue was washed with H20, dried (Na2SO4), filtered and concentrated. Subsequent purification by flash chromatography (diethyl ether / PE (1/1)) gave compound 59 (amorphous, 2.58 g, 12.4 mmol, 57. 9%), H-NMR (200 MHz, CDCl 3): d 7.95 (bt, J = 8 Hz, 1 H), 7.69 (d, J = 4 Hz, 1 H), 6.87 (dd, J = 8 Hz, 2 Hz, 1 H), 6.57 (d, J = 4 Hz, 1 H), 4.55 (q, J = 8 Hz, 2 H), 1.49 (t, J = 8 Hz, 3 H). (TLC diethyl ether / PE (1/1) Rf 0.42). Compound 59 (2.58 g, 12.4 mmol) was dissolved in 50 ml of MeOH and 20 ml of 2 N NaOH. The reaction mixture was stirred for 30 minutes at room temperature. Ethyl acetate was added to the mixture and the organic layer was washed with an aqueous 5% NaHCO 3 solution, dried (Na 2 SO 4), filtered and concentrated to give 6-fluoro-1 H-pyrrolo [2,3- bjpyridine (6-fluoro-7-azaindole, compound 44) in the form of a semi-solid (1.68 g, 12.3 mmol, 99%). H-NMR (400 MHz, CDCl 3): d 9.6 (bs, 1 H), 7.95 (bt, J = 8 Hz, 1 H), 7.31-7.27 (m, 1 H), 6.75 (dd, J = 8 Hz , 2 Hz, 1 H), 6.55-6.50 (m, 1 H). (TLC diethyl ether / PE (1/1) R, 0.34). LCEM; Rt: 1.39 min, ([M + H] + = 137). The 6-fluoro-7-azaindole (compound 44, 1.72 g, 12.6 mmol) was reacted with benzenesulfonyl chloride as described for the synthesis of 45 AB to provide 1-benzenesulfonyl-6-fluoro-1 H-pyrrolo [2 , 3-b] pyridine (compound 60), (solid, 3.03 g, 86.6%), mp 130-132 ° C. (TLC diethyl ether / PE (1/1) Rf 0.29). LCEM; R ,: 1.79 min, ([M + H] + = 277). 1-Benzenesulfonyl-6-fluoro-1 H -pyrrolo [2,3-b] pyridine (0.8 g, 2.9 mmol) was converted to (R) -1-benzenesulfonyl-6-fluoro-2-pyrrolidin-2 -ylmethyl-1 H- pyrrolo [2,3-b] pyridine using the methodology described for 45 A / B (amorphous, 0.31 g, 30%). (TLC MeOH / triethylamine (97/3) Rf 0.28). (R) -1-Benzenesulfonyl-6-fluoro-2-pyrrolidin-2-ylmethyl-1 H -pyrrolo [2,3-b] pyridine (0.26 g, 0.72 mmol) was converted to (R) -6-fluoro -2-pyrrolidin-2-ylmethyl-1 H -pyrrolo [2,3-b] pyridine (compound 47A, 90 mg, 57%) using the conditions described for 45 A / B. The title compound 47 A (amorphous), ([a] D25-38 (c 1, toluene), was converted to its (amorphous) salt (free base / fumaric acid (1: 1)), 1 H-NMR (400 MHz, D6DMSO): d 12.2-1 1.7 (bs, 1 H), 8.0 (bt, J = 8 Hz, 1 H), 6.76 (bd, J = 8 Hz, 1 H), 6.51 (s, 2H), 6.37 (s, 1 H), 3.83-3.74 (m, 1 H), 3.26-3.03 (m, 4H), 2.10-1.79 (m, 3H), 1.71-1.61 (m, 1 H). (TLC MeOH / triethylamine (97/3) R, 0.22). (S) -6-Fluoro-2-pyrrolidin-2-ylmethyl-1 H-pyrrolo [2,3-b] pyridine (compound 47B) was obtained (from 36) using the methodology described for compound 47 A. ([a] D25 +38 (c 1, toluene).

(R) -6-methoxy-2-pyrrolidin-2-ylmethyl-1 H-pyrrolo [2,3-b-pyridine. (compound 49) (R) -6-bromo-2-pyrrolidin-2-ylmethyl-1 H -pyrrolo [2,3-b] pyridine. (46A, 0.67 g, 2.39 mmol) was converted to pyrrolidine analogous to 48 (protected with Boc) (amorphous, 0.72 g, total 79%), using the methodology described for compound 9. H-NMR (400 MHz, CDCl 3 ): d 9.4 (bs, 1 H), 7.66 (bd, J = 8 Hz, 1 H), 7.18 (bd, J = 8 Hz, 1 H), 6.19 (bs, 1 H), 4.10-4.03 (m, 1 H), 3.42-3.25 (m, 2H), 3.16-3.07 (m, 1 H), 3.04-2.88 (m, 1 H), 2.0-1.89 (m, 1 H), 1.8-1.63 (m, 3H). Compound 48 (0.34 g, 0.89 mmol) was dissolved in DMF and 2.5 ml of MeOH (under N2). To this mixture was added 1.6 g (29.6 mmol) of NaOMe and 0.25 g (1.74 mmol) of Cu (l) bromide and the mixture was stirred for 1 hour at room temperature. Ethyl acetate was added and the organic layer was washed with a 5% NaHC03 solution, dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (diethyl ether) to provide the pyrrolidine (protected with Boc) precursor of 49 in the form of an oil (0.32 g, 56%). (TLC diethyl ether R, 0.8). 1 H-NMR (400 MHz, CDCl 3): d 8.7 (bs, 1 H), 7.68 (bd, J = 8 Hz, 1 H), 6.52 (bd, J = 8 Hz, 1 H), 6.1 (bs, 1 H), 4.1 1-4.01 (m, 1 H), 3.94 (s, 3 H), 3.46-3.23 (m, 2 H), 3.18-2.96 (m, 1 H), 2.93-2.78 (m, 1 H), 1.97-1.84 (m, 1 H), 1.83-1.71 (m, 3H), 1.51 (s, 9H), which is deprotected (HCl / EtOH as described above) to generate the title compound (49) as a salt HCI (amorphous, hygroscopic). Yield 0.180 mg (80%), ([a] D25 -12 (c 1, MeOH) LCEM; Rt: 1.17 min, ([M + H] + = 232), Compound 49 (the free base obtained after filtration of the salt with HCI on SCX-2) it was converted into its salt (using the methodology previously described) (free base / fumaric acid (1: 1), amorphous), H-NMR (400 MHz, D6DMSO) : d 1 1.61 (bs, 1 H), 7.75 (d, J = 8 Hz, 1 H), 6.49 (s, 2H), 6.47 (d, J = 8 Hz, 1 H), 6.21 (s, 1 H) ), 3.84 (s, 3H), 3.78- 3. 71 (m, 1 H), 3.23-3.18 (m, 1 H), 3.14-3.08 (m, 1 H), 3.01-2.95 (m, 1 H), 2.05-1.80 (m, 3H), 1 .67 -1.59 (m, 1 H).

(R) -5-bromo-2-pyrrolidin-2-ylmethyl-1 H-pyrrolo [2,3-b1pyridine (compound 52A) and (S) -5-bromo-2-pyrrolidin-2-ylmethyl-1 H- pyrrolo [2,3-b1pyridine. (compound 52 B) 5-bromo-7-azaindole (5.19 g, 26.3 mmol), commercially available, was converted to 1-benzenesulfonyl-5-bromo-1 H-pyrrolo [2,3-b] pyridine using the methodology described for 45 A / B, solid, mp 141-142 ° C. (6.9 g, 78%) 1 H-NMR (400 MHz, CDCl 3): d 8.45 (d, J = 2 Hz, 1 H), 8.19-8.15 (m, 2H), 7.98 (d, J = 2 Hz, 1 H), 7.74 (d, J = 4 Hz, 1 H), 7.62-7.47 (m, 3H), 6.55 (d, J = 4 Hz, 1 H). LCEM; Rt: 1.92 min, ([M + H] + = 337). 1-Benzenesulfonyl-5-bromo-1 H -pyrrolo [2,3-b] pyridine (5.52 g, 16. 3 mmol) was converted to (R) -1-benzenesulfonyl-5-bromo-2-pyrrolidin-2-ylmethyl-1 H-pyrrolo [2,3-b] pyridine using the methodology described for 45 A / B (amorphous, 3.02 g, mixture of compounds containing about 70% of the anticipated C2 regioisomer). (TLC MeOH / triethylamine (97/3) Rf 0.3). LCEM; R ,::44 min, ([M + H] + = 420, 422). The aforementioned mixture, containing (R) -l-benzenesulfonyl-5-bromo-2-pyrrolidin-2-ylmethyl-1 H-pyrrolo [2,3-b] pyridine (3.02 g, ca. became the title compound 52 A using the methodology described for 45 A / B (repeated flash chromatography), (amorphous, 0.5 g, about 25%), which was converted into its salt (free base / fumaric acid (1: 1)), 1 H-NMR (400 MHz, D6DMSO): invisible dH NH, 8.16 (d, J = 2 Hz, 1 H), 8.06 (d, J = 2 Hz, 1 H), 6.46 (s, 2H), 6.30 (s, 1 H), 3.80- 3.72 (m, 1 H), 3.23-3.03 (m, 4H), 2.06-1.77 (m, 3H), 1.67-1.57 (m, 1 H). (S) -5-Bromo-2-pyrrolidin-2-ylmethyl-1 H -pyrrolo [2,3-b] pyridine (compound 52B) was obtained (from 36) using the methodology described for compound 52 A LCEM; R ,: 1.27 min, ([M + Hf = 280), ([a] D25 + 38 (c 1, toluene).

(R) -5-methyl-2-pyrrolidin-2-ylmethyl-1 H-pyrrolo [2,3-b1pyridine. (compound 53 A) 5-methyl-7-azaindole (4.15 g, 31.4 mmol), was converted to 1-benzenesulfonyl-5-methyl-1 H-pyrrolo [2,3-b] pyridine using the methodology described for 45 A / B, (amorphous, 7.07 g, 82%). H-NMR (400 MHz, CDCl 3): d 8.25 (bd, J = 2 Hz, 1 H), 8.19-8.15 (m, 2H), 7.66 (d, J = 4 Hz, 1 H), 7.62 (bd, J = 2 Hz, 1 H), 7.58-7.43 (m, 3H), 6.51 (d, J = 2 Hz, 1 H), 2.38 (s, 3H). (TLC diethyl ether Rf 0.52). LCEM; Rt: 1.75 min, ([M + Hf = 273). 1-Benzenesulfonyl-5-methyl-1 H -pyrrolo [2,3-b] pyridine (3.15 g, 1 1.5 mmol) was converted to (R) -1-benzenesulfonyl-5-methyl-2-pyrroline-2- ilmethyl-1 H-pyrrolo [2,3-b] pyridine using the methodology described for 45 A / B (amorphous, 7.04 g, 61%).

LCEM; Rt: 1.41 min, ([M + H] + = 356). (R) -1-Benzenesulfonyl-5-methyl-2-pyrrolidin-2-ylmethyl-1 H -pyrrolo [2,3-b] pyridine (1.5 g, 4.22 mmol), 3.5 g of KOH and 1 ml of hydrazine Monohydrate were combined in 2- (2-hydroxy-ethoxy) -ethanol (25 ml) and stirred for 1 hour at 100 ° C. To the cooled reaction mass was added MeOH and the reaction mixture was filtered over 60 g of SCX-2 (MeOH followed by NH 3 / MeOH 1 N). Subsequent purification by flash chromatography (MeOH / triethylamine (90/2)) gave the title compound 53 A (amorphous, 0.46 g, 50%), ([a] o 25 -10 (c 1, dioxane), which was made react with an equivalent of fumaric acid in MeOH and concentrate to provide the title compound 53 A (amorphous) (free base / fumaric acid (1: 1)). H NMR (400 MHz, D6DMSO): d 1.6 ( bs, 1 H), 7.97 (bs, 1 H), 7.63 (bs, 1 H), 6.51 (s, 2H), 6.22 (s, 1 H), 3.84-3.77 (m, 1 H), 3.26-3.03 (m, 4H), 2.33 (s, 3H), 2.07-1.81 (m, 3H), 1.69-1.61 (m, 1 H). 2-Pyrrolidin-3-ylmethyl-1 H -pyrrolo [2,3-b1pyridine. (compound 66). 8.83 g (91 mmol) of methoxymethylamine (salt with HCl) were stirred in 200 ml of anhydrous benzene (0 ° C, under N2). 46.2 ml of trimethylaluminum / toluene (2.5 M) was added and the mixture was stirred for 2.5 hours at 0 ° C. Compound 62 (6.73 g, 30.7 mmol) dissolved in 100 ml of benzene was added and the resulting mixture was stirred for 1 hour at room temperature. Saturated NaHCO3 (0 ° C) and ethyl acetate were subsequently added to the mixture. The organic layer was washed three times with a 5% solution NaHCO3, dried (Na2SO4), filtered and concentrated. The resulting residue was purified by flash chromatography (MeOH / ethyl acetate (1/9)) to give the methoxymethylamide of 1-benzyl-pyrrolidine-3-carboxylic acid (compound 63, 6.76 g, 88.7%). H-NMR (400 MHz, CDCl 3): d 7.38-7.22 (m, 5H), 3.69-3.62 (m, 5H), 3.45-3.35 (m, 1 H), 3.19-3.18 (2 xs, 3H), 3.06-2.99 (m, 1 H), 2.88-2.81 (m, 1 H), 2.56-2.41 (m, 2H) ), 2.14-2.03 (m, 2H). To a solution of anhydrous THF (75 ml) containing compound 17 (7.2 g, 27.1 mmol) was added dropwise 13.6 ml of LDA (2.0 M in THF / heptane) at -10 ° C under N2. After the addition, the resulting solution was stirred for 30 minutes at -10 ° C-0 ° C. Then, the temperature was lowered to -70 ° C. At this temperature, a solution of 63 (6.72 g, 27 mmol) in 25 ml of THF (10 minutes) was added dropwise. After the addition of 63, the temperature was raised to -30 ° C (0.5 hours) and the resulting solution was stirred for 1 hour at -30 ° C. Then, the mixture was warmed with a saturated solution of NH 4 Cl at -30 ° C and allowed to warm to room temperature. Ethyl acetate was added and the organic layer was washed with a 5% NaHCO 3 solution, dried (Na 2 SO 4), filtered and concentrated in vacuo. Purification by flash chromatography (diethyl ether followed by ethyl acetate) gave compound 64 (amorphous, 5.38 g, 44.6%) LCEM; Rt: 1.27 min, ([M + H] + = 342). Compound 64 (1.05 g, 2.35 mmol), 2 g of KOH and 3.56 ml of hydrazine monohydrate were combined in 2- (2-hydroxy-ethoxy) -ethanol (20 ml) and they were stirred for 30 minutes at 100 ° C (under N2), followed subsequently by stirring for 45 minutes at 200 ° C. To the cooled reaction mixture was added ethyl acetate and the resulting organic layer was washed with 2N NaOH, dried (Na2SO4), filtered and concentrated in vacuo. The mixture was dissolved in MeOH and filtered over 80 g of SCX-2 (MeOH followed by NH 3 / MeOH 1 N). Subsequent purification by flash chromatography (MeOH / ethyl acetate) provided compound 65 (amorphous, 0.6 g, 83%). 1 H-NMR (400 MHz, CDCl 3): d 10.65 (bs, 1 H), 8.20 (dd, J = 5 Hz, 2 Hz, 1 H), 7.80 (dd, J = 8 Hz, 2 Hz, 1 H) , 7.37-7.20 (m, 5H), 7.02 (dd, J = 8 Hz, 5 Hz, 1 H), 6.17 (s, 2H), 3.63 (dd, J gem = 13 Hz, 2H), 2.95-2.90 ( m, 2H), 2.77-2.54 (m, 4H), 2.43-2.38 (m, 1 H), 2.12-2.02 (m, 1 H), 1.65-1.55 (m, 1 H). LCEM; R ,: 1.46 min, ([M + H] + = 292). Compound 65 (0.52 g, 1.8 mmol), 0.3 g of ammonium formate (4.7 mmol) and 20% Pd (OH) 2 / C (50 mg) were combined in MeOH (10 mL) and heated to reflux for 1 hour. The mixture cooled, filtered, concentrated and dissolved in MeOH. Subsequent filtration over 25 g of SCX-2 (MeOH followed by 1 N NH 3 / MeOH) afforded the title compound: 2-Pyrrolidin-3-ylmethyl-1 H -pyrrolo [2,3-b] pyridine (compound 66, 0.34 g, 94%) which was reacted with one equivalent of fumaric acid in MeOH and concentrated to give the title compound 66 (amorphous) (free base / fumaric acid (1: 1)). 1 H-NMR (400 MHz, D 6 DMSO): d 1 1.6 (bs, 1 H), 8.1 1 (dd, J = 5 Hz, 2 Hz, 1 H), 7.81 (dd, J = 8 Hz, 2 Hz, 1 H), 6.99 (dd, J = 8 Hz, 5 Hz, 1 H), 6.5 (s, 2H), 6.21 (bs, 1 H), 3.29-3.22 (m, 2H), 3.17-3.09 (m, 1 H), 2.90-2.76 (m, 3H), 2.72-2.61 (m, 1 H) ), 2.06-1.97 (m, 1 H), 1.69-1.59 (m, 1 H). (TLC MeOH / triethylamine (97/3) Rf 0.08). 2- (1-Methyl-pyrrolidin-3-ylmethyl) -1 H -pyrrolo [2,3-blpyridine. (compound 68). Compound 66 (0.3 g, 1.49 mmol) was converted to compound 67, using the methodology described for compound 9, yield 0.362 g (80.7%), (TLC ether Rf 0.1 1), which was used as such for generate the title compound (68) using the methodology described for compound 28. (Yield 0.17 g, 65%), mp 96-97 ° C. 1 H-NMR (400 MHz, CDCl 3): invisible d NH, 8.16 (dd, J = 5 Hz, 2 Hz, 1 H), 7.77 (dd, J = 8 Hz, 2 Hz, 1 H), 6.98 (dd, J = 8 Hz, 5 Hz, 1 H), 6.16 (bs, 1 H), 2.92-2.84 (m, 2H), 2.76-2.64 (m, 2H), 2.62-2.50 (m, 2H), 2.34 (s) , 3H), 2.40-2.31 (m, 1 H), 2.1 1-2.01 (m, 1 H), 1.63-1.53 (m, 1 H). (TLC MeOH / triethylamine (97/3) R, 0.2). 2-Pyrrolidin-3-yl-1 H-pyrrolo [2,3-b1pyridine. (compound 78). To a solution of anhydrous THF (75 ml) containing compound 17 (6.0 g, 23.2 mmol) was added dropwise 12.5 ml (24 mmol) of LDA (2.0 M in THF / heptane) at -10 ° C under N2. After the addition, the resulting solution was stirred for 30 minutes at -10 ° C-0 ° C and subsequently the temperature was lowered to -70 ° C.

Anhydrous CeCl3 (6 g, 24.3 mmol) was added to 50 ml of anhydrous THF and the resulting mixture was stirred for 0.5 hour at 30 ° C (under N2). This mixture was added to the 2-lithioderived from 17, maintaining the temperature at -70 ° C. The temperature was raised to -10 ° C and stirred for 10 minutes. Subsequently, the temperature was lowered to -50 ° C. To the reaction mixture was added compound 71 (5 g, 28.5 mmol) dissolved in 50 ml of THF and the resulting mixture was stirred for 2 hours at -30 ° C. The mixture was allowed to warm to room temperature and was stirred for another 2 hours. The mixture was concentrated in vacuo, ethyl acetate was added and the organic layer was washed with a 5% NaHC03 solution, dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (gradient of diethyl ether / PE 1: 1 to pure diethyl ether) to ide compound 72: 3- (1-Benzenesulfonyl-1 H -pyrrolo [3] -3-t-butyl ester -b] pyridin-2-yl) -3-hydroxy-pyrrolidine-1-carboxylic acid, (amorphous, 6.0 g, 58%). 1 H-NMR (400 MHz, CDCl 3): d 8.38-8.32 (m, 1 H), 8.17-8.12 (m, 2H), 7.80-7.50 (m, 1 H), 7.60-7.43 (m, 3H), 7.17-7.12 (m, 1 H), 6.55 (s, 1 H), 4.90 and 4.85 (2 x bs, 1 H) ), 4.24-4.13 (m, 1 H), 3.92-3.79 (m, 1 H), 3.75-3.48 (m, 2H), 2.68-2.47 (m, 2H), 1.49 (s, 9H). LCEM; Rt: 1.83 min, ([M + H] + = 444). Compound 72 (8.6 g, 19.4 mmol), 12 g of KOH and 20 ml of hydrazine monohydrate were combined in 2- (2-hydroxy-ethoxy) -ethanol (150 ml) and stirred for 30 minutes at 100 ° C ( under N2). To the cooled reaction mixture was added ethyl acetate and the resulting organic layer was washed several times with 2N NaOH, dried (Na2SO4), filtered and concentrated in vacuo. The Subsequent purification by flash chromatography (diethyl ether followed by ethyl acetate) ided compound 74 (oil, 4.97 g, 84%). 1 H NMR (400 MHz, D6DMSO): d 1 1.6 (bs, 1 H), 8.15 (dd, J = 5 Hz, 2 Hz, 1 H), 7.87 (dd, J = 8 Hz, 2 Hz, 1 H ), 7.01 (dd, J = 8 Hz, 5 Hz, 1 H), 6.38 (d, J = 2 Hz, 1 H), 5.67 (bs, 1 H), 3.61 -3.41 (m, 4H), 2.37- 2.28 (m, 1 H), 2.16-2.07 (m, 1 H), 1.43 and 1.41 (2 xs, 9H). LCEM; R ,: 1.48 min, ([M + Hf = 304). Compound 74 (4.92 g, 16.23 mmol), 100 mL of H2O and 100 mL of 38% HCl were combined and refluxed for 12 hours. The mixture was cooled, concentrated and dissolved in MeOH. Filtration over 50 g of SCX-2 (MeOH followed by 1 N NH 3 / MeOH), followed by flash chromatography (MeOH / triethylamine (99/1)) afforded compound 76 (oil, 1.75 g, 58%). H-NMR (400 MHz, D6DMSO): d 12.1 (bs, 1 H), 8.22 (dd, J = 5 Hz, 2 Hz, 1 H), 7.92 (dd, J = 8 Hz, 2 Hz, 1 H), 7.05 (dd, J = 8 Hz, 5 Hz, 1 H), 6.55-650 (m, 1 H) , 6.49 (s, 1 H), 4.23-4.17 (m, 2H), 4.07-4.02 (m, 2H). LCEM; R ,: 0.91 min, ([M + H] + = 186). Compound 76 (1.8 g, 9.73 mmol) and 20% Pd (OH) 2 / C (180 mg) were combined in MeOH (100 mL). The mixture was hydrogenated at 3.4 atmospheres for 2 hours. The mixture was filtered, concentrated, redissolved in MeOH and filtered over 50 g of SCX-2 (MeOH followed by NH 3 / MeOH 1 N), followed by flash chromatography (MeOH / triethylamine (98/2)) to to provide the title compound: 2-pyrrolidin-3-yl-1 H -pyrrolo [2,3-b] pyridine. (compound 78). (amorphous, 1.09 g, 59%), LCEM; Rt: 0.75 min, ([M + H] + = 188). Separation of the enantiopure isomers was achieved using a chiral column (Chiralpak AD 20μG ?, 250 x 4.6, 20% MeOH, 20% EtOH, 60% heptane, 2 ml / min, d = 220 nm, R ,: 6.0 min (78A), ([a] D25 -10 (c 1, MeOH) and R ,: 7.9 min (78B), ([a] D25 +12 (c 1, MeOH) Both isomers were reacted with 1 equivalent of fumaric acid in MeOH and concentrated to provide the salt of the title compound, mp 130-133 ° C, (free base / fumaric acid (1: 1 .5)). 1 H-NMR (400 MHz, D6DMSO) : d 1 1.7 (bs, 1 H), 8.08 (dd, J = 5 Hz, 2 Hz, 1 H), 7.78 (dd, J = 8 Hz, 2 Hz, 1 H), 6.95 (dd, J = 8 Hz, 5 Hz, 1 H), 6.4 (s, 3H), 6.27 (bs, 1 H), 3.63-3.53 (m, 2H), 3.33-3.15 (m, 3H), 2.36-2.25 (m, 1 H ), 2.08-1.97 (m, 1 H). 2-Pyrrolidin-3-yl-1 H-pyrrolo [3,2-blpyridine. (compound 79). Compound 69 (commercially available) was reacted with benzenesulfonyl chloride as described for 45 A / B or as described in Eur. J. of Med. Chem (2004). Performance 80-90%. Compound 70 was obtained in the form of an oil that crystallized on standing. 1 H-NMR (400 MHz, CDCl 3): d 8.54 (dd, J = 5 Hz, 2 Hz, 1 H), 8.27 (bd, J = 8 Hz, 1 H), 8.0-7.85 (m, 2H), 7.81 (d, J = 4 Hz, 1 H), 7.60-7.54 (m, 1 H), 7.49-7.43 (m, 2H), 7.24 (dd, J = 8 Hz, 5 Hz, H), 6.88 (bd, J = 4 Hz, 1 H).

Compound 70 (2.58 g, 10 mmol) was reacted with compound 71 using the methodology described for the synthesis of the above-mentioned compound 72 to generate compound 73. Compound 73: 3- (1-Benzenesulfonyl) t-butyl ester -1 H -pyrrolo [3,2-b] pyridin-2-yl) -3-hydroxy-pyrrolidine-1-carboxylic acid, (amorphous, 1.23 g, 28%). H-NMR (400 MHz, CDCl 3): d 8.52-8.48 (m, 1 H), 8.28-8.21 (m, 2 H), 7.82-7.78 (m, 2 H), 7.58-7.51 (m, 1 H), 7.45 -7.39 (m, 2H), 7.23-7.17 (m, 1 H), 6.93 (bs, 1 H), 4.58 and 4.53 (2 x bs, 1 H), 4.14-4.08 (m, 1 H), 3.81- 3.50 (m, 3H), 2.64-2.45 (m, 2H), 1.49 (s, 9H). Compound 75: The 3-hydroxy-3- (1 H -pyrrolo [3,2-b] pyridin-2-yl) -3-hydroxy-pyrrolidine-1-carboxylic acid t-butyl ester was obtained from of compound 73 (1.2 g, 2.7 mmol) using the methodology described for the synthesis of compound 74 mentioned above. Compound 75 (amorphous, 0.42 g, 51%): 1 H-NMR (400 MHz, CDCl 3) showed rotation isomers (the important ones described): d 9.02 in 9.0 (2 xs, 1 H), 8.40-8.32 (m, 1 H), 7.66-7.59 (m, 1 H), 7.08-7.02 (bdd, J = 8 Hz, 5 Hz, 1 H), 6.41 and 6.33 (2 x bs, 1 H). Compound 77: 2- (2,5-dihydro-1 H -pyrrol-3-yl) -1 H -pyrrolo [3,2] pyridine was obtained from compound 75 (0.42 g, 1.38 mmol) using the methodology described for the synthesis of compound 76 mentioned above. Compound 77, (amorphous, 0.2 g, 78%): 1 H NMR (400 MHz, D 6 DMSO): d 1 1.4 (bs, 1 H), 8.19 (bd, J = 5 Hz, 1 H), 7.61 (bd, J = 8 Hz, 1 H), 7.0 (dd, J = 8 Hz, 5 Hz, 1 H), 6.43-6.38 (m, 2H), 3.93-3.88 (m, 2H), 3.77-3.72 (m, 2H). The title compound: 2-pyrrolidin-3-yl-1 H-pyrrolo [3,2-b] pyridine (compound 79) was obtained from compound 77 (0.19 g, 1.02 mmol). ) using the methodology described for the synthesis of compound 78 mentioned above. Compound 79 (amorphous, 0.16 g, 83%) was reacted with 1 equivalent of fumaric acid in MeOH and concentrated to provide the salt of the title compound. (Amorphous, free base / fumaric acid (1: 1.5)). 1 H NMR (400 MHz, D 6 DMSO): d 1 1.6 (bs, 1 H), 8.26 (bd, J = 5 Hz, 1 H), 7.69 (bd, J = 8 Hz, 1 H), 7.05 (bdd, J = 8 Hz, 5 Hz, 1 H), 6.54 (s, 3H), 6.48 (bs, 1 H), 3.74-3.62 (m, 2H), 3.40-3.25 (m, 2H), 2.44-2.37 (m , 1 H), 2.09-1.97 (m, 1 H).

(R) -2-pyrrolidin-2-ylmethyl-1 H-pyrrolo [3,2-blpyridine. (compound 81 A) and (S) -2-pyrrolidin-2-ylmethyl-1 H-pyrrolof3,2-blpyridine. (compound 81 B) The lithiation (LDA) of compound 70 (1.42 g, 5.05 mmol) and the subsequent reaction with 35 was performed using the methodology described for the synthesis (first step) of compound 39 A. Compound 80A: (R) -1-Benzenesulfonyl-2-pyrrolidin-2-ylmethyl-1 H -pyrrolo [3,2-b] pyridine. (1.32 g, 70%). 1 H-NMR (400 MHz, CDCl 3): d 8.48 (dd, J = 5 Hz, 2 Hz, 1 H), 8.40 (bd, J = 8 Hz, 1 H), 7.73-7.70 (m, 2H), 7.57. -7.53 (m, 1 H), 7.44-7.40 (m, 2H), 7. 18 (dd, J = 8 Hz, 5 Hz, 1 H), 3.62-3.55 (m, 1 H), 3.23-3.13 (m, 2H), 3.08-3.02 (m, 1 H), 2.95-2.88 (m , 1 H), 2.0-1.95 (m, 1 H), 1 .90-1.75 (m, 1 H), 1.51-1 .42 (m, 1 H). A solution of 247 mg of KOr-Bu (1.1 equiv.) In 40 ml of MeOH was prepared and stirred for 30 min under N2. Compound 80A (683 mg, 2 mmol) was added and the mixture was stirred for 20 hours at 50 ° C. The mixture was cooled, filtered, concentrated and redissolved in MeOH. Filtration over 25 g of SCX-2 (MeOH followed by 1 N NH 3 / MeOH) followed by flash chromatography (MeOH / triethylamine (97/3)) afforded the title compound: (R) -2-pyrrolidin-2-ylmethyl -1 H-pyrrolo [3,2-b] pyridine. (compound 81 A). ([α] D 25 -74 (c 1, toluene). 1 H-NMR (400 MHz, D 6 DMSO): d 1 1.0 (bs, 1 H), 8.20 (bd, J = 5 Hz, 1 H), 7.62 (bd) , J = 8 Hz, 1 H), 6.98 (dd, J = 8 Hz, 5 Hz, 1 H), 6.30 (bs, 1 H), 3.37-3.28 (m, 1 H), 2.90-2.70 (m, 4H), 1.82-1.55 (m, 3H), 1.37-1.28 (m, 1 H). (S) -2-pyrrolidin-2-ylmethyl-1 H -pyrrolo [3,2-b] pyridine (compound 8 B) was obtained using the methodology described for compound 81 A, using sulfamidate 36. ([a] D25 +74 (c 1, toluene).

(R) -5-methoxy-2-pyrrolidin-2-methylmethyl-1 H-pyrrolo [3,2-blpyridine. (compound 85) To a solution of 9.5 ml (59 mmol) of TMEDA in anhydrous THF (60 ml) were added 10.5 ml of t-butyllithium (1.5 M in pentane) dropwise at -70 ° C under N2. After the addition, the resulting solution was stirred during 15 minutes at -70 ° C. At this temperature, a solution of 83 (3.7 g, 14.3 mmol) in 25 ml of THF (10 minutes) was added dropwise. The mixture was stirred for 60 minutes at -70 ° C. At this temperature a solution of 35 (2.33 g, 14.3 mmol) in 30 ml of anhydrous THF was added and the mixture was stirred for 30 minutes at -70 ° C and the temperature was subsequently raised to -20 ° C. The mixture was allowed to warm to room temperature and stirred for another 20 hours. The reaction mixture was concentrated and the residue was dissolved in 100 ml of 1 N HCl and 100 ml of THF. The mixture was stirred at 70 ° C for 20 hours. The reaction mixture was concentrated in vacuo. The resulting residue was taken up in ethyl acetate, washed with 2N NaOH, dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash chromatography (MeOH / triethylamine (97/3)) provided compound 84 (solid, 2.83 g, 53%). P.f. 101-103 ° C. 1 H-NMR (400 MHz, CDCl 3): d 8.30 (d, J = 9 Hz, 1 H), 7.71-7.65 (m, 2H), 7.57-7.50 (m, 1 H), 7.45-7.35 (m, 2H ), 6.65 (d, J = 9 Hz, 1 H), 6.54 (s, 1 H), 3.94 (s, 3H), 3.56-3.47 (m, 1 H), 3.15-2.98 (m, 4H), 2.05 -1.65 (m, 3H), 1.48-1.37 (m, 1 H). Compound 84 was converted to the title compound (85) using the methodology used for the synthesis of 39A. The title compound: (R) -5-methoxy-2-pyrrolidin-2-ylmethyl-1 H -pyrrolo [3,2-b) pyridine was obtained in the form of a syrup (1.18 g, 68%), [ a] D25 -42 (c 1, CHCl3), which was reacted with 1 equivalent of fumaric acid in MeOH and concentrated to provide the title compound 95 (amorphous) (free base / fumaric acid (eleven )). P.f.180-182 ° C.

(P -3-Pyrrolidin-2-ylmethyl-1 H -pyrrolo [3,2-blpyridine (compound 88) 4.6 g (25.8 mmol) of NBS was added to 3.05 g (25.8 mmol) of 4-azaindole in 40 ml of DMF (0 ° C) The mixture was stirred for 30 minutes at 0 ° C. MeOH was added and the mixture was filtered over SCX-2, followed by flash chromatography (ethyl acetate followed by MeOH) and provided 3-bromo- 1 H- [3,2-b] pyridine (86) in the form of a solid Mp 241 ° C (4.52 g, 89%) H-NMR (400 MHz, D6DMSO): d 1 1.7 (bs, 1 H), 8.39 (dd, J = 5 Hz, 2 Hz, 1 H), 7.85 (s, 1 H), 7.82 (dd, J = 8 Hz, 2 Hz, 1 H), 7.19 (dd J = 8 Hz, 5 Hz, 1 H). To a solution of anhydrous THF (75 ml) containing compound 86 (2.28 g, 1.6 mmol) was added 4.6 ml of n-Buli (2.5 M in hexane) at -78 ° C under N2. After the addition, the resulting solution was stirred for 45 minutes at -78 ° C. At this temperature, a solution of TIPS-CI (2.73 ml) in 10 ml of THF was added dropwise. After the addition, the resulting solution was stirred for 1 hour at -78 ° C. Then, the mixture was allowed to warm to room temperature. The reaction mixture was concentrated and the resulting residue was taken up in ethyl acetate, washed with 5% NaHCO3, dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash chromatography (diethyl ether / PE (1/1)) afforded 3-bromo-1-tri- tert-butylsilyl-1 H -pyrrolo [3,2-b] pyridine (87) in the form of a solid. P.f. 79- 80 ° C (3.52 g, 86%). 1 H-NMR (400 MHz, CDCl 3): d 8.55 (dd, J = 5 Hz, 2 Hz, 1 H), 7.76 (dd, J = 8 Hz, 2 Hz, 1 H), 7.49 (s, 1 H) , 7.13 (dd, J = 8 Hz, 5 Hz, 1 H), 1.73-1.60 (m, 3H), 1.15 and 1.13 (2 xs, 18H). To an anhydrous THF solution (100 ml) containing compound 87 (3.42 g, 9.69 mmol) were added drop by drop 3.9 ml of n-Buli (2.5 M in hexane) (-78 ° C under N2). After the addition, the resulting solution was stirred for 60 minutes at -78 ° C. At this temperature, a solution of 35 (1.58 g, 9.69 mmol) in 10 ml of THF (5 minutes) was added dropwise. After the addition of 35, the temperature was raised to -20 ° C and the resulting solution was stirred for 2 hours. The mixture was allowed to warm to room temperature and was stirred for another 2 hours. The reaction mixture was concentrated and the residue was dissolved in 40 ml of 1 N HCl, 40 ml of EtOH and 40 ml of THF. The mixture was stirred at 80 ° C for 18 hours. The reaction mixture was concentrated in vacuo. MeOH (25 mL) was added and the mixture was concentrated on 25 g of SiO2. Subsequent flash chromatography (MeOH / triethylamine (98/2)) afforded the title compound: (R) -3-pyrrolidin-2-ylmethyl-1 H -pyrrolo [3,2-b] pyridine. (compound 88), (amorphous, 0.32 g, 0.72 mmol, 9.3%). H-NMR (400 MHz, CDCl 3): d 9.1 (bs, 1 H), 8.42 (dd, J = 5 Hz, 2 Hz, 1 H), 7.58 (dd, J = 8 Hz, 2 Hz, 1 H), 7.20 (s, 1 H), 7.06 (dd, J = 8 Hz, 5 Hz, 1 H), 3.59-3.51 ( m, 1 H), 3.14-3.02 (m, 2H), 2.97-2.85 (m, 2H), 2.0-1.90 (m, 1 H), 1.86-1.71 (m, 2H), 1.54-1.43 (m , 1 HOUR). LCEM: Rt; 0.64 min, ([M + H] + = 202). ([a] D25 -10 (c 1, dioxane).

(R) -6-Pyrrolidin-2-ylmethyl-7H-pyrrolo [2,3-b1pyrimidine. (compound 95) 6-Chloro-7-deazapurine (1.58 g, 10.3 mmol) commercially available, 3.25 g of ammonium formate (51.6 mmol) and 20% Pd (OH) 2 / C (140 mg) were combined in MeOH (50 mi) and heated to reflux for 2 hours. The mixture was cooled, filtered, concentrated and redissolved in MeOH. Filtration over 25 g of SCX-2 (MeOH followed by 1 N NH 3 / MeOH), followed by flash chromatography (ethyl acetate / MeOH (9/1)) afforded compound 90 (1.2 g, 4.02 mmol, 97 %), amorphous material. 1 H-NMR (400 MHz, CDCl 3): d 1 1.1 (bs, 1 H), 9.1 (bs, 1 H), 9.0 (bs, 1 H), 7.45-7.40 (m, 1 H), 6.68-6.62 ( m, 1 H). 7H-Pyrrolo [2,3-d] pyrimidine (1.16 g, 9.74 mmol) was dissolved in 100 ml of anhydrous THF under N2. At 0 ° C, a 60% dispersion of 0.51 g of NaH in mineral oil was added. The mixture was stirred at room temperature and 2.93 ml (9.8 mmol) of (2-chloromethoxy-ethyl) -trimethyl-silane dissolved in 15 ml of anhydrous THF were added. The reaction mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. Ethyl acetate was added to the mixture, and the organic layer was washed three times with saturated NaHCO3 solution, dried (Na2SO4), filtered and concentrated. The resulting residue was purified by flash chromatography (diethyl ether) to provide 7- (2-trimethylalanyl-ethoxymethyl-7H-pyrrolo [2,3-d] pyrimidine. (compound 91), (amorphous, 0.84 g, 35%). H-NMR (400 MHz, CDCl 3): d 9.1 (bs, 1 H), 9.0 (bs, 1 H), 7.43 (bd, J = 4 Hz, 1 H), 6.68 (bd, J = 4 Hz, 1 H), 5.73 (s, 1 H), 3.6 (t, J = 8 Hz, 2H), 0.97 (t, J = 8 Hz, 2H), 0.1 (s, 9H). Under nitrogen, 0.62 ml (3.7 mmol) of 2,2,6,6-tetramethylpiperidine was added to 20 ml of anhydrous THF (-78 ° C). 1.3 ml of n-Buli (2.5 M, 3.33 mmol) was added and the reaction mixture was stirred for 30 minutes. Compound 91 (0.83 g, 2.16 mmol) dissolved in 10 ml of THF was added and the mixture was stirred for 30 minutes. Compound 35 (557 mg, 2.16 mmol) dissolved in 5 ml of THF was added. After the addition of 35, the temperature was raised to -30 ° C and the resulting solution was stirred for 2 hours. The mixture was allowed to warm to room temperature and was stirred for another 2 hours. To the reaction mixture was added a saturated solution of NH 4 Cl (5 ml) followed by 25 g of S 1 O 2 and subsequently the mixture was concentrated in vacuo. The resulting residue was purified by flash chromatography (dichloromethane / MeOH / NH4OH) (90/10/1) to provide compound 93 (0.4 g, 44.9%). LCEM; Rt: 1.38 min, ([M + H] + = 413). Compound 93 (0.63 g, 1.53 mmol), 1.4 ml of tetrabutylammonium fluoride (1 M in THF) and 25 ml of THF were combined and the mixture was heated to reflux (36 hours). The mixture was cooled, 25 g of S1O2 were added and subsequently concentrated in vacuo. The resulting residue was purified by flash chromatography (dichloromethane / eOH / NH4OH) (90/10 / 0.5) to give compound 94 (0.35 g, 81%). 1 H-RN (400 MHz, CDCl 3): d 1 1.3 (bs, 1 H), 8.80 (bs, 1 H), 8.65 (bs, 1 H), 6.2 (bs, 1 H), 3.95-3.88 (m, 1 H), 3.65-3.58 (m, 1 H), 3.24-3.17 (m, 2H), 2.89-2.82 (m, 1 H), 2.05-1.96 (m, 2H), 1.74-1.6 (m, 2H) . Compound 94 (0.35 g, 1.24 mmol), 10 mL of 1 N HCl and 10 mL of EtOH were combined and heated to reflux for 18 hours. The reaction mixture was cooled and concentrated in vacuo. The resulting residue was taken up in ethyl acetate, washed with a 2N NaOH solution, dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash chromatography (MeOH / triethylamine (97/3)) afforded the title compound: (R) -6-pyrrolidin-2-ylmethyl-7H-pyrrolo [2,3-b] pyrimidine. (compound 95), (amorphous, 70 mg, 27.9%), LCEM; Rt: 0.68 min, ([M + H] + = 203), which was reacted with one equivalent of fumaric acid in MeOH and concentrated to provide the title compound 95 (amorphous) (free base / fumaric acid (1: 2)). 1 H-NMR (400 MHz, D6DMSO): d 12.8- .8 (bs, 1 H), 8.86 (s, 1 H), 8.68 (s, 1 H), 6.54 (s, 4 H), 6.45 (s, 1 H), 3.85-3.79 (m, 1 H), 3.25-3.19 (m, 2H), 3.17-3.09 (m, 2H), 2.10-2.03 (m, 1 H), 2.00-1.92 (m, 1 H) ), 1.90-1.82 (m, 1 H), 1.69-1.62 (m, 1 H). The structures of the compounds of the invention whose syntheses are described above are given in the following table.

(I) 81 B C N C 1 0 H H H H (S) H 47A N C C 1 0 H H H F (R) H 45A N C C 1 0 H H H Cl (R) H 46A N C C 1 0 H H H Br (R) H 49 N C C 1 0 H H H OCH3 (R) H 39B N C C 1 0 H H H H (S) H 52B N C C 1 0 H H Br H (S) H 41B N C C 1 0 H H H H 47B N C C 1 0 H H H F 45B N C C 1 0 H H H Cl (S) 46B N C C 1 0 I H H H Br 41A N C C 1 0 H H H H (R) I The names of the compounds are listed in the table following: Compound Name 6 3-piperidin-3-yl-1 H -pyrrolo [2,3-b] pyridine 10A 3- (1 H -pyrrolo [2,3-b] pyridin-3-yl) -piperidin-3-ol 10B 3-piperidin-3-yl-1 H -pyrrolo [2,3-b] pyridine-7-oxide 13 6-chloro-3-piperidin-3-yl-1 H -pyrrolo [2,3-b] pyridine 16 3- (1 H -pyrrolo [2,3-b] pyridin-3-yl) -1-aza-bicyclo [2.2.2] octane 19 3- (1 H -pyrrolo [2,3-b] pyridine-3 -il) -1-aza-bicyclo [2.2.2] octan-3-ol 20 3- (1 H -pyrrolo [2,3-b] pyridin-3-yl) -1-aza-bicyclo [2.2.2] oct-2-ene 21 3- (1 H-pyrrolo [2,3- b] pyridin-2-yl) -1-aza-bicyclo [2.2.2] octane 24 3- (1 H -pyrrolo [2,3-b] pyridin-2-yl) -piperidin-3-ol 25 2- (1, 2,5,6-tetrahydro-pyridin-3-yl) -1 H -pyrrolo [2,3-b] pyridine 26 2-piperidin-3-yl-1 H -pyrrolo [2,3-b] pyridine 26A (S) -2-piperidin-3-yl-1 H -pyrrolo [2,3-b] pyridine 26B (R) -2-piperidin-3-yl-1 H -pyrrolo [2,3-b] pyridine 28 2- (1-methyl-piperidin-3-yl) -1H-pyrrolo [2,3-b] pyridine 29B 2-piperidin-3-yl-H-pyrrolo [2,3-b] pyridine- 7-Oxide 32 6-chloro-2-piperidin-3-yl-1 H -pyrrolo [2,3-b] pyridine 32A (S) -6-chloro-2-piperidin-3-yl-1 H-pyrrolo [ 2,3-b] pyridine 32B (R) -6-chloro-2-piperidin-3-yl-1H-pyrrolo [2,3-b] pyridine 33 4-chloro-2-piperidin-3-yl- H- pyrrolo [2,3-b] pyridine 39 2-pyrrolidin-2-ylmethyl-1 H -pyrrolo [2,3-b] pyridine 39A (R) -2-pyrrolidin-2-ylmethyl-1 H-pyrrolo [2, 3-b] pyridine 39B (S) -2-pyrrolidin-2-ylmethyl-1 H -pyrrolo [2,3-b] pyridine 41A (S) -2- (1-methy1-pyrrolidin-2-methyl-1) - H-pyrrolo [2,3-b] pyridine 41 B (R) -2- (1-methyl-2- pyrrolidin-2-ylmethyl) -1 H -pyrrolo [2,3-b] p'iridine 45A (R) -6-chloro-2-pyrrolidin-2-ylmethyl-1 H -pyrrolo [2,3-b] pyridine 45B (S) -6-chloro-2-pyrrolidin-2-ylmethyl-1 H-pyrrolo [2,3-b] pyridin 46A (R) -6-bromo-2-pyrrolid n-2-methyl-1-H-pyrrolo [2,3-b] pyridine 46B (S) -6-bromo-2-pyrrolidin-2-ylmethyl-1 H-pyrrolo [2,3-b] pyridine 47A (R) -6-fluoro-2-pyrrolidn-2-ylmethyl-1 H-pyrrolo [2,3-b] pyridine 47B (S) -6-fluoro-2 -pyrrolidin-2-methylmet-1 H -pyrrolo [2,3-b] pyridin 49 (R) -6-methoxy-2-pyrrolidot-2-ylmethyl -1 Hyrrolo [2,3-b] pyridine 52A (R) -5-bromo-2-pyrrolidn-2-ylmethyl-H-pyrrolo [2,3-b] pyridine 52B (S) -5-bromo-2-pyrrolidin-2-methyl-1H-pyrrolo [2,3-b] pyridine 53A (R) -5-methyl-2-pyrrolidin- 2-ylmethyl-1 H-pyrrolo [2, 3-b] pyridine 65 2- (1-benzyl-3-pyrrolidin-3-ylmethyl) - Hyrrolo [2,3-b] pyridine 66 2-pyrrolid N-3-ylmethyl-1 H -pyrrolo [2,3-b] pyridine 68 2- (1-methyl-pyrrolidin-3-ylmethyl) -1 H -pyrrolo [2,3 -b) pyridine 78 2-pyrrolidn-3-yl-1 Hyrrolo [2,3-b] pyridine 78A (S) -2-pyrrolidin-3-yl- 1 H-pyrrolo [2,3-b] pyridine 78B (R) -2-pyrrolidin-3-1-1 H-pyrrolo [2,3-b] pyridine 79 2-pyrrolidin-3 -il-1 H -pyrrolo [3,2-b] pyridine 81A (R) -2-pyrrolidin-2-ylmethyl-1 H -pyrrolo [3,2-b] pyridine 81 B (S) -2-pyrrolidin-2-ylmethyl-1 H-pyrrolo [3,2-b] pyridine 85 (R) -5-methoxy-2-pyrrolidin-2-methylmethyl- 1 Hyrrolo [3,2-b] pyridine 88 (R) -3-pyrrolidin-2-ylmethyl-H-pyrrolo [3,2-b] pyridine 95 (R) -6-pyrrolidin-2 -ylmethyl-7 H-pyrrolo [2,3-b] pyrimidine EXAMPLE 4 Synthesis of compounds described in EP 1178045 (R) -3-PA-pyrrolidin-2-ylmethyl-1 H-pyrrolo [2,3-blpyridine. (compound 96) and (S) -3-pyrrolidin-2-ylmethyl-1 H-pyrrolo [2,3-b1pyridine. (comp.97).

The metallation of 3-bromo-7-azaindole with 2.2 equivalents of n-Buli (J. Heterocyclic Chem., 1984) provided the dilithioderivative that trapped the sulfamidate 35 (-30 ° C under N2). The elaboration with the described methodology for 39A provided the title compound 96: (R) -3-pyrrolidin-2-ylmethyl-H-pyrrolo [2,3-b] pyridine (46%), LCEM; R,; 0.91 min, ([M + H] + = 202), ([a] D25 -8 (c 1, MeOH), which was converted to its salt (free base / fumaric acid (1: 1)), (amorphous) 1 H- NMR (400 MHz, D6DMSO): d 1.5 (bs, 1 H), 8.21 (dd, J = 5 Hz, 2 Hz, 1 H), 8.02 (dd, J = 8 Hz, 2 Hz, 1 H), 7.42 (s, 1 H), 7.05 (dd, J = 8 Hz, 2 Hz, 1 H), 3.79 -3.71 (m, 1 H), 3.27-3.21 (m, 1 H), 3.19-3.09 (m, 2H), 3.05-2.99 (m, 1 H), 2.03-1.79 (m, 3H), 1.69-1.61 (m, 1 H). (S) -3-pyrrolidin-2-ylmethyl-1 H -pyrrolo [2,3-b] pyridine was obtained. (compound 97) (from 36) using the methodology described for compound 96. ([a] D25 +8 (c 1, MeOH).

(R) -3- (1-Methyl-pyrrolidin-2-ylmethyl) -1 H -pyrrolor2,3-b1pyridine. (compound 98) and (S) -3- (1-methy1-pyrrolidin-2-ylmethyl) -1 H -pyrrolo [2,3-b1pyridine. (compound 99) Compounds 96 and 97 were converted to the title compounds 98 and 99 as described in EP 1178045. Compound 98: LCEM; R ,; 0.94 min, ([M + H] + = 216), ([a] D25 +68 (c 1, dioxane) Compound 99: ([α] D25 -68 (c 1, dioxane) .The structures of the four The compounds described above are indicated in the following table: Com Structure Name EP 1178045 (R) -3-pyrrolidin-2-ylmethyl-Ex. 1 1 (rac) 96 1 H-pyrrolo [2,3-b] pyridine (S) -3-pyrrolidin-2-ylmethyl) - Ex. 1 1 (rac) 97 1 H-pyrrolo [2,3-b] pyridine (R) -3- (1-methyl-2- Ex. 13 (rac) 98 pyrrolidin-2-ylmethyl-1 H- pyrrolo [2,3-b] pyridine (S) -3- (1 -methyl-pyrrolidine- Ex. 13 (rac) 99 2-ylmethyl) -1 H -pyrrolo [2,3- b] pyridine Ex. 1 1 (rae) means: example number 11 in EP 1 178045, described as racemate.

EXAMPLE 5 Pharmacological methods In vitro affinity for rat nicotinic cholinergic receptors The affinity of the compounds for nicotinic receptors in rat brain receptors was determined by CEREP (Celle lÉvescault, France), using a known assay. { Pabreza, 1991).

In vitro affinity for human nicotinic cholinergic receptors The affinity of the compounds for human nicotinic receptors cloned in SK-N-F1 neuroblastoma cells was determined by Novascreen (Hanover, MD, U.S.A.), using a known assay (Perry, 1995).

Release of [3H1-Dopamine in vitro The release of dopamine was measured using striated rat sections, as described (Stoof, 1980). Male rats (Wistar Hsd / Cpb: WU, 175-200 g) were decapitated and the striatum rapidly separated from the brain. Cuttings were prepared (0.3 x 0.3 x 2.00 mm) using a Mcllwain blade. The striated sections of 6 rats were pooled and incubated for 15 minutes in 5 ml of Krebs-Ringer bicarbonate medium containing 0.37 MBq of [3H] -DA. After labeling, the sections were transferred to each of the 24 chambers (10 mg of tissue per chamber, volume 0.20 ml) of a superfusion apparatus and then superfusion (0.20 ml / min) was performed with the medium. All the superfusion experiments were performed in a Krebs bicarbonate pH buffer of the following composition: 18 mM NaCl, 2.4 mM KCI, 2.4 mM CaCl2.2H2O, 1.2 mM MgSO4.7H20, 1.2 mM KH2P04, 25 mM NaHC03 and 10 mM glucose taken to pH 7.4, saturated with 95% 02/5% C02. After a pre-superfusion period of 45 minutes, thirteen 10-minute fractions were collected (starting with t = 0).

During the superfusion the liberation of the calcium dependent neurotransmitter at = 10 (S1), t = 50 (S2) and t = 90 min (S3) was induced during 5 min, exposing the cuts to the medium in which the K + concentration had elevated at 10 mM; NaCl concentration was correspondingly decreased to maintain osmolarity. The test compounds or epibatidine were added to the medium in conjunction with the K + pulse at t = 50 (10 8 M) and t = 90 min (10 6 M) for 5 min. In parallel, the responses of the test compound in the presence of the nonspecific antagonist of the nicotinic receptor mecamylamine (10 ~ 5 M) or of the specific antagonist of the n-acetylcholine receptor a4ß2 DHBE (10 ~ 6 M) were determined. At the end of the experiment, the remaining radioactivity of the tissue was extracted with 0.1 M HCl. The radioactivity in the superfusion fractions and the tissue extract was determined by liquid scintillation counting. The radioactivity efflux during each collection period was expressed as the percentage of the amount of radioactivity in the cuts at the beginning of the respective collection period. To calculate the induced release of [3H] -dopamine, the spontaneous efflux of radioactivity from the total shedding of radioactivity was subtracted during the stimulation and the next 15 min. The spontaneous release of radioactivity was calculated assuming a linear decline from the 10 min interval before to the 20-30 min interval after the start of stimulation. The connections S2 / S1 and S3 / S1 were used as an index for stimulated release. The effects of the test compounds were calculated as percentages of the control group. The release responsive to mecamylamine or DHBE was expressed as a percentage inhibition of the release of [3 H] -dopamine evoked in response to the test compound. Within each test, a repeat was made with each test compound using 2-3 cameras, averaging the repeats.

Absorption of [3H] -Dopamine in vitro Male rats (Wistar Hsd / Cpb: WU, 175-200 g) were decapitated; the striatum separated rapidly and the crude synaptosomal fraction (P2) was prepared by homogenization and centrifugation. The synaptosomes were preincubated in the absence or presence of the test compound for 15 min at 37 ° C, in a medium containing the parmagillin monoamine oxidase inhibitor (7x10"6 M) (Coyle, 1969). [3H] -dopamine (final concentration 2x10"7 M) and incubation continued for 10 min. Absorption of [3 H] -dopamine was interrupted by filtration and the synaptosomes were washed four times with phosphate buffered saline. The amount of [3 H] -dopamine in the synaptosomes was determined by liquid scintillation counting in Betaplate. The compounds were tested in a concentration range of 10 ~ 9 to 0"5 M. The inhibitory effects on [3H] -dopamine absorption were expressed using the plC50 value (the negative logarithm of the concentration at which the drug caused). an inhibition of 50% absorption). The inhibition of DA absorption is performed in duplicate.

EXAMPLE 6 Results of pharmacological tests The results of in vitro pharmacological tests were obtained according to the protocols indicated above and shown in the table following: In vitro pharmacology Receptor linkage Functional activity displacement release reabsorption [JH] -cytisine [JH] - lJH] - l3H] - epibatidine dopamine dopamine references pK¡ pK¡% p! C5o nicotine control 8.2 7.3 180 < * cytisine 8.7 7.5 136 < nomifensin 6.6 bupropion 124 5.4 GBR 12909 7.0 Compound 96 5.6 124 < 97 5.2 122 < 98 < 132 < 99 5.9 1 12 < Comp. 6 5.5 < 139 5.4 13 5.5 < 174 5.8 16 5.4 6.8 21 5.3 6.8 26A < < 139 5.6 26B 5.3 6.0 121 6.2 32 < 173 32B 5.3 < 170 6.4 39A 6.9 6.1 151 5.1 39B 5.5 < 133 41A 5.4 < 100 45A 6.9 6.0 1 15 45B 5.4 6.0 153 5.6 46A 6.1 5.9 92 46B < 5.9 123 47A 6.3 137 47B 6.0 128 5.4 49 < < 160 5.2 52A 5.0 < 135 5.4 78 7.7 7.8 154 5.7 78A 6.6 6.4 109 5.4 78B 7.9 8.0 187 5.8 79 6.9 6.3 1 19 5.2 81A 5.8 < 153 5.0 81 B 5.2 < 120 5.2 85 131 5.1 88 < 1 10 5.1 < * means: < 5.0 (inactive at 10-5 M) From the data given in the preceding table, it is evident that the compounds of the invention, ie, the compounds of general formula (I), combine high affinity for nicotinic acetylcholine receptors, a affinity comparable to that of nicotine or cytosine, with an activity inhibitor of dopamine reuptake comparable to that of inhibitors of standard dopamine resorption nomifensin and bupropion. This is in contrast with the structurally closest compounds: those described in EP 1 178045, which are inactive as inhibitors of dopamine reuptake. When comparing enantiomeric pairs (the preceding table in combination with the table with structural data), it is evident that the (R) enantiomers are more potent than the (S) enantiomers.

EXAMPLE 7 Pharmaceutical preparations The compounds of formula (I) are formulated in pharmaceutical compositions for clinical use, which are important and novel embodiments of the invention because they contain the compounds, more particularly specific compounds, described herein. Types of pharmaceutical compositions that can be used include, but are not limited to, tablets, chewable tablets, capsules (including microcapsules), solutions, parenteral solutions, ointments (creams and gels), suppositories, suspensions and other types described therein or apparent to a person skilled in the art from the description and a general knowledge of the art. The compositions are used orally, intravenously, subcutaneously, tracheally, bronchially, intranasally, pulmonarily, transdermally, buccally, rectally, parenterally or by other routes of administration. The pharmaceutical formulation contains at least one compound of formula (I) mixed with a adjuvant, diluent and / or pharmaceutically acceptable carrier. The total amount of active ingredients is suitably in the range of from about 0.1% (w / w) of the formulation, suitably from 0.5% to 50% (w / w) and preferably from 1% to 25% (w / w) ). The compounds of the invention can be brought into forms suitable for administration by usual methods using auxiliary substances such as liquid or powdered solid ingredients, such as customary liquid or solid pharmaceutically charged solvents and diluents, solvents, emulsifiers, lubricants, flavors, colorants and solvents. the pH regulating substances. Frequently used auxiliary substances include magnesium carbonate, titanium dioxide, lactose, sucrose, sorbitol, mannitol and other sugars or sugar alcohols, talc, lactoprotein, gelatin, starch, amylopectin, cellulose and its derivatives, animal and vegetable oils such as oil of fish liver, sunflower oil, peanut or sesame, polyethylene glycol and solvents such as, for example, sterile water and mono- or polyhydric alcohols such as glycerol, as well as disintegrating agents and lubricating agents such as magnesium stearate, calcium, sodium stearyl fumarate and polyethylene glycol waxes. The mixture can then be processed into pellets or compressed into tablets. The active ingredients can be premixed separately with the other non-active ingredients, before preparing the final mixture to form a formulation. The active ingredients can also be mixed together, before mixing them with the non-active ingredients to form a formulation. Soft gelatin capsules can be prepared with capsules containing a mixture of the active ingredients of the invention, vegetable oil, fat or other suitable vehicle for soft gelatine capsules. Hard gelatin capsules may contain granules of the active ingredients. The hard gelatin capsules may also contain the active ingredients in conjunction with powdered solid ingredients such as lactose, sucrose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatin. Dosage units for rectal administration can be prepared (i) in the form of suppositories containing the active substance mixed with a neutral fat base; (ii) in the form of a rectal gelatin capsule containing the active substance in a mixture with a vegetable oil, paraffin oil or other suitable vehicle for rectal gelatin capsules; (iii) in the form of a microenema prepared for use; or (iv) in the form of a dry microenema formulation that must be reconstituted in a suitable solvent immediately prior to administration. The liquid preparations can be prepared in the form of syrups, elixirs, drops or concentrated suspensions, for example solutions or suspensions containing the active ingredients, the remainder consisting of, for example, sugar or sugar alcohols and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations may contain coloring agents, agents saborizant.es, preservatives, saccharin and carboxymethylcellulose or other thickening agents. Liquid preparations can also be prepared in the form of a dry powder, reconstituted with a suitable solvent prior to use. Solutions for parenteral administration can be prepared in the form of a solution containing a formulation of the invention in a pharmaceutically acceptable solvent. These solutions may also contain stabilizing ingredients, preservatives and / or pH regulating ingredients. Solutions for parenteral administration can also be prepared in the form of a dry preparation, reconstituted with a suitable solvent before use. The present invention also provides formulations and "parts kits" comprising one or more containers filled with one or more of the ingredients of a pharmaceutical composition of the invention, for use in medical therapy. Such containers may be associated with various written materials, such as instructions for use or a note in the form required by a governmental agency that regulates the manufacture, use or sale of pharmaceutical products, note that reflects the approval by the agency of the manufacture, use or sale for human or veterinary administration. The use of formulations of the present invention in the manufacture of medicaments to be used to treat a condition in which the activation of dopamine receptors and / or the inhibition of dopamine absorption, and methods of medical treatment are required or desired. which comprise the administration of a therapeutically effective total amount of at least one compound of formula (I) to a patient suffering from, or susceptible to, a condition in which the activation of dopamine receptors and / or the inhibition of dopamine absorption is required or desired.

References Bannon et al., Science 279: 77 (1998). Bencherif and Schmitt, Current Drug Targets: CNS and Neurological Disorders, 1, 349-57, 2002. Bickel, MH, "The pharmacology and Biochemistry of N-oxides", Pharmacoloqical Reviews, 21 (4), 325-355. 1969. Bioorganic & Medicinal Chemistry Letters, 12, 307-310, 2002. Blum et al., Pharmacogenetics 5: 121-141, 1995. Breining et al., "Neuronal nicotinic acetylcholine receptor modulators: recent advances and therapeutic potentia." Annual reports in medicinal chemistry, 40, 3-16, 2005. Brioni et al., Adv. Pharmacol., 37, 153, 1997. Bundgaard, H. (editor), "Design of Prodrugs", Elsevier, 1985. Chem. Pharm. Bull., 35, 1823-1828, 1987. Coyle and Snyder, Catecholamine uptake by synaptosomes in homogenates of rat brain, stereospecificity in different areas, J Current Organic Chemistry, 5, 471-506, 2001. Damaj et al., J. Pharmacol. 291: 390- 1999. DeVries et al., "Heteroaromatic analogs of 1- [2- (diphenylmethoxy) ethyl] - and 1- [2- [bis (4-fluorophenyl) metho-xy] ethyl] -4- (3-phenyl-propyl) piperazines (GBR 12935 and 12909) as High-Affinity Dopamine Reuptake Inhibitors " , J. Med. Chem., 40, 705-716, 1997. Dutta, K. et al., "Positional Importance of the Nitrogen Atom in Novel Piperidine Analogs of GBR 12909: Affinity and Selectivity for the Dopamine Transpose, MED. CHEM. RES., 3, 209-222, 1993. Ettmayer, P. et al., "Lessons learned from marketed and research prodrugs", J. Med. Chem., 47, 2393-2404, 2004. European Journal of Medicinal Chemistry, 39, 2004, 515-526. Greene, T.W. and P.G.M. Wuts, "Protective Groups in Organic Synthesis ", third edition, John Wiley &Sons, Inc., New York, 1999. Helvética Chimica Acta, 76, 2356-2366, 1993. Heterocycles, 50, 1065-1080, 1999. Heterocycles, 50, 1 165-1080 , 1999. Heterocycles, 50, 1 145-1 150, 2000. Járvinen, T. et al., "Design and Pharmaceutical applications of prodrugs", pages 733-796 in: SC Gad (editor): "Drug Discovery Handbook", John Wiley &Sons Inc., New Jersey, USA, 2005. J. Heterocyclic Chem., 21, 421, 1984. J. Med. Chem. 2002, 45, 3972-3983. King, FD, (editor), page 215 in: "Medicinal Chemistry: Principles and Practice", 1994, ISBN 0-85186-494-5 Levin and Rezvani, Current Drug Targets: CNS and Neurological Disorders 1, 423-431, 2002. Onaivi et al., Life Sci. 54 (3): 193, 1994. O'Neill, et al., Current Drug Targets: CNS and Neurological Disorders 1 (4): 399-41. , 2002. Pabreza et al .: "[3H] -Cytosine binding to nicotinic cholinergic receptors in brain", Mol. Pharmacol, 39, 9-12, 1991. Perry and Kellar: "[3H] -Epibatidine labels nicotinic receptors in rat brain: an autoradiographic study", J. Pharmacol. Exp. Ther., 275, 1030-1034, 1995. Pulian et al., N. Engl. J. Med. 330, 81-1-815, 1994. Sjak-shie et al., Brain Res. 624: 295.1993. Stella, J., "Prodrugs as therapeutics", Expert Opin. Ther. Patents. 14 (3), 277-280, 2004. Stoof et al., Brain Research 196: 276-28, 1980. Synthesis, 7, 661-663, 1992. Synthesis, 15, 2503-2506, 20051. Synthesis, 20, 3581-3588, 20052. Teng. et al., "Lobeline and nicotine evoke [3H] -overflow from rat striatal slices preloaded with [3H] dopamine: differential inhibition of synaptosomal and vesicular [3 HJdopamine uptake" J. Pharmacol. Exp. Therap., 80: 1432-1444, 1997. Teng et al, "Lobeline displaces [3 HJdihydrotetrabenazine binding and releases3 HJdopamine from rat sriatal synaptic vesicles," J. Neurochem., 71, 258-265, 1998. Tetrahedron, 53, 3637-3648, 1997. Tetrahedron, 58, 489-493, 2002. Tetrahedron Asymmetry, 1, 885-894, 1990. Tetrahedron Letters, 1909-1912, 1969. Tetrahedron Letters , 38, 751 1-7514, 1997. Tetrahedron Letters, 40, 3673-3676, 1999. Toth et al., Neurochem Res. 17, 265, 1992.

Patents and patent applications cited EP 0 870 768, EP 1 178 045 US 2002/0061892, US 2003/0100547, US 2004/0266824 WO 2003/053970, WO 2004/078757

Claims (6)

NOVELTY OF THE INVENTION
2. Compounds of the formula (I): or a tautomer, stereoisomer, N-oxide, or a pharmaceutically acceptable salt, hydrate or solvate of any of the foregoing, wherein - X, Y and Z independently represent N or C, with the proviso that the ring contains at least one N atom, and not more than 2, - m and n are independently either 0 (zero) or 1, with the proviso that when Y and Z represent carbon and X represents nitrogen, m is 0 (zero), - R2 and R3 independently represent hydrogen, halogen, alkyl (Ci.3), alkynyl (C -3), NH-alkyl (Ci-3), CF3, hydroxyl, alkyl (C1-3) oxy or a piperidinyl group, pyrrolidinyl, tetrahydropyridinyl, morpholinyl , azepanyl, 1-aza-bicyclo [2.2.2] octanyl or 1-aza-bicyclo [2.2.2] oct-2-enyl, which group is unsubstituted or substituted by one or more substituents selected from halogen, alkyl ( Ci.3), phenyl or benzyl, - R4, R5 and R6 independently represent hydrogen, halogen, alkyl (Ci-3), alkynyl (C2-3), NH-alkyl (Ci-3), hydroxyl or alkyl (Ci-3) ox, with the proviso that R exists only when Y = C, and R5 only when Z = C, with the proviso that when X and Z are N, Y is C, R4 is Cl, R5 and R6 are H, myn are zero (0), and R2 is H , R3 is not iodo or 1, 2,3,6-tetrahydropyridin-4-yl; with the proviso that when X is N, Y and Z are C, R4 is Cl, R5 is Br, R6 is H, m and n are zero (0), and R3 is H, R2 is not iodine or H; with the proviso that when X and Z are C, Y is N, R5 is hydroxy, R2, R4 and R6 are H, myn are zero (0), R3 is not 1, 2,3,6-tetrahydropyridin-4- ilo with the proviso that when X is N, Y and Z are C, m and n are zero (0), R2 > R3, R4 and R5 are H, R6 is not chloro or fluoro. 2.- Compounds of the formula (I): or a tautomer, stereoisomer, N-oxide, or a pharmaceutically acceptable salt, hydrate or solvate of any of the foregoing, wherein: - X, Y and Z independently represent N or C, with the proviso that the ring contains at least an atom of N, and not more than 2, - myn are independently either 0 (zero) or 1, with the proviso that when Y and Z represent carbon and X represents nitrogen, m is 0 (zero), - R2 and R3 independently represent hydrogen, halogen, alkyl (Ci-3), alkynyl (Ci-3), NH-alkyl (d-3), CF3, hydroxyl, alkyl (C1-3) oxy or a piperidinyl group, pyrrolidinyl, tetrahydropyridinyl, morpholinyl, azepanyl, 1-aza-bicyclo [2.2.2] octanyl or 1-aza-bicyclo [2.2.2] oct-2-enyl, which group is or is not substituted or substituted with one or more substituents selected from halogen, (Ci-3) alkyl, phenyl or benzyl, - R 4, R 5 and R 6 independently represent hydrogen, halogen, alkyl (Ci.3), alkynyl (C2-3) , CF3, NH-alkyl (Ci-3), hydroxyl or alkyl (C -3) oxy, with the proviso that R exists only when Y = C, and R5 only when Z = C, with the proviso that when X and Z are N, Y is C, R is Cl, R5 and R6 are H, m and n are zero (0), and R2 is H, R3 is not iodine or 1, 2,3,6-tetrahydropyridin-4-yl; with the proviso that when X is N, Y and Z are C, R is Cl, R5 is Br, R6 is H, m and n are zero (0), and R3 is H, R2 is not iodine or H; with the proviso that when X and Z are C, Y is N, R5 is hydroxy, R2, R4 and R6 are H, myn are zero (0), R3 is not 1, 2,3,6-tetrahydropyridin-4- ilo with the proviso that when X is N, Y and Z are C, myn are zero (0), R2, R3, R4 and R5 are H, R6 is not chlorine or fluoro, with the proviso that when X is N , Y and Z are C, myn are zero (0), R2, R3, R4 and R6 are H, R6 are H, R2 is not bromine, chlorine or fluoro, with the proviso that when X is N, Y and Z are C, m is 1, n is zero (0), R2, R4, R5 and R6 are H, R3 is not ethyl or morpholin-1-yl, with the proviso that when X is N, Y and Z are C , myn are zero (0), R2, R4, R5 and R6 are H, R3 is not bromine, with the proviso that when X is N, Y and Z are C, myn are zero (0), R2) R3, R5 and R6 are H, R4 is not chlorine, with the proviso that when X is N, Y and Z are C, m is zero (0), n is 1, R3, R4, R5 and R6 are H, R2 is not is hydrogen or pyridin-1-yl, with the proviso that when X is N, Y and Z are C, m is zero (0), n is 1, R, R5 and R6 are H, R3 is bromine, R2 is not pyridin-1-yl, 2-methylpyridinyl-1-yl, 2-ethyl-pyridinyl-1-yl or morpholin-1-yl.
3. 3 - . 3 - The compounds according to claim 1 of general formula (I), further characterized in that R 2 and R 3 independently represent hydrogen or a piperidinyl, pyrrolidinyl, tetrahydropyridinyl, morpholinyl, azepanyl, 1-aza-bicyclo [2.2.2] octanyl group or 1-aza-bicyclo [2.2.2] oct-2-enyl, which group is unsubstituted or substituted by one or more substituents selected from halogen, alkyl (Ci-3), phenyl or benzyl, R, 5 and 6 independently represent hydrogen, halogen, alkyl (C. 3) or alkyl (Ci-3) oxy, with the proviso that R4 only exists when Y = C and that R5 only exists when Z = C, and X, Y, Z, m and n have the meanings indicated in claim 1, with the proviso that when X and Z are N, Y is C, R4 is Cl, R5 and R6 are H, myn are zero (0), and R2 is H, R3 is not is 1, 2,3,6-tetrahydropyridin-
4. 4-yl; with the proviso that when X is N, Y and Z are C, R4 is Cl, R5 is Br, R6 is H, m and n are zero (0), and R3 is H, R2 is not H; with the proviso that when X and Z are C, Y is N, R5 is hydroxy, R2, R4 and R6 are H, myn are zero (0), R3 is not 1, 2,3,6-tetrahydropyridin-4- ilo with the proviso that when X is N, Y and Z are C, m and n are zero (0), R2, R3, R4 and R5 are H, R6 is not chlorine or fluoro. 4 - The compounds according to claim 1 of general formula (I), further characterized in that R2 and R3 independently represent hydrogen or a piperidinyl, pyrrolidinyl, tetrahydropyridinyl, morpholinyl, azepanyl, 1-aza-bicyclo [2.2.2] octanyl group or -aza-bicyclo [2.2.2] oct-2-enyl, which group is unsubstituted or substituted by one or more substituents selected from halogen, alkyl (Ci-3), phenyl or benzyl, R4, R5 and R6 independently represent hydrogen, halogen, alkyl (d.3) or alkyl (Ci.3) oxy, with the proviso that R4 only exists when Y = C and that R5 only exists when Z = C, and X , Y, Z, m and n have the meanings indicated in claim 1, with the proviso that when X and Z are N, Y is C, R4 is Cl, R5 and R6 are H, m and n are zero (0), and R2 is H, R3 is not 1, 2,3,6-tetrahydropyridin-4-yl; with the proviso that when X is N, Y and Z are C, R4 is Cl, R5 is Br, R6 is H, m and n are zero (0), and R3 is H, R2 is not H; with the proviso that when X and Z are C, Y is N, R5 is hydroxy, R2, R4 and R6 are H, myn are zero (0), R3 is not 1, 2,3,6-tetrahydropyridin-4- ilo with the proviso that when X is N, Y and Z are C, myn are zero (0), R2, R3, R and R5 are H, R6 is not chlorine or fluoro, with the proviso that when X is N , Y and Z are C, m is 1 and n is zero (0), R2, R4 R5 and R5 are H, R3 is not ethyl or morpholin-1-yl, with the proviso that when X is N, Y and Z are C, m and n are zero (0), R2, R4 > R5 and R6 are H, R3 is not bromine, with the proviso that when X is N, Y and Z are C, myn are zero (0), R2, R3, R5 and R6 are H, R4 is not chlorine, with the condition that when X is N, Y and Z are C, m is zero (0), n is 1, R3, R4, R5 and R6 are H, R2 is not hydrogen or pyridin-1-yl, with the condition that when X is N, Y and Z are C, m is zero (0), n is 1, R, R5 and R6 are H, R3 is bromine, R2 is not pyridin-1-yl, 2-methylpyridinyl-1 -yl, 2-ethyl-pyridinyl-1-yl or morpholin-1-yl. 5. The compound according to claim 1, further characterized in that it is: 2-pyrrolidin-3-yl-1 H-pyrrolo [3,2-b] pyridine; 2-pyrrolidin-3-yl-1 H -pyrrolo [2,3-b] pyridine; (S) -2-pyrrolidin-3-yl-1 H -pyrrolo [2,3-b] pyridine (R) -2-pyrrolidin-3-yl-1 H-pyrrolo [2,3-b] pyridine; 2-piperidin-3-yl-1 H- pyrrolo [2,3-b] pyridine; 2-piperidin-3-1-1 H-pyrrolo [2,3-b] pyridine-7-oxido; (S) -2-pipendin-3-yl-1 H-pyrrolo [2,3-b] pyridine; (R) -2-piperidin-3-yl-1 H-pyrrolo [2,3-b] pyridine; 3-piperidin-3-yl-1 H -pyrrolo [2,3-b] pyridine-3-piperidn-3-yl-1 H -pyrrolo [2,3-b] pyridine 7-oxid; 4-chloro-2-piperdin-3-1-1 H-pyrrolo [2,3-b] pyridine; 6-chloro-2-piperidin-3-yl-1 H-pyrrolo [2,3-b] pyridin; (S) -6-chloro-2-piperidin-3-yl-1 H-pyrrolo [2,3-b] pyridinium (R) -6-chloro-2-pperidin-3 -l-1 H-pyrrolo [2,3-b] pyridine-6-chloro-3-piperidin-3-yl-H-pyrrolo [2,3-b] pyridine; 2- (1-methyl-piperdin-3-yl) -1 H -pyrrolo [2,3-b] pyridine; 2- (1, 2,5,6-tetrahydro-pyridin-3-yl) -1 H -pyrrolo [2,3-b] pyridine-3- (1 H -pyrrolo [2, 3-b] pyridin-2-yl) -piperidn-3-oll 3- (1 H -pyrrolo [2,3-b] pyridin-3-yl) -1-aza -bicyclo [2.2.2] octan-3-ol; 3- (1 H -pyrrolo [2,3-b] pyridin-2-yl) -1-aza-bicyclo [2.2.2] octane; 3- (1 H-pyrrolo [2,3-b] pyridn-3-yl) -piperidin-3-ol- 3- (1 H -pyrrolo [2,3-b] pyra Din-3-yl) -1-aza-bicyclo [2.2.2] octane; 3- (1 H -pyrrolo [2,3-b] pyridin-3-yl) -1-aza-b-cyclo [2.2.2] oct-2-ene-2-pyrrolidin-2-ylmethyl- 1 Hr¡rrolo [2,3-b] pyridine; (R) -2-pyrrolidin-2-methylmethyl-1 H-pyrrolo [2,3-b] pyridn (R) -6-pyrrolidin-2-methyl-7H -pyrrolo [2,3-b] pyrimidine (R) -6-fluoro-2-pyrrolidin-2-ylmethyl-1 H -pyrrolo [2,3-b] pyridine; (R) -6-chloro-2-pyrrolidin-2-ylmethyl-1 H -pyrrolo [2,3-b] pyridin; (R) -6-bromo-2-pyrrolidin-2-ylmethyl-H-pyrrolo [2,3-b] pindin; (R) -6-methoxy-2-pyrrolidin-2-ylmethyl-H-pyrrolo [2,3-b] pyridine; (R) -
5. 5-bromo-2-pyrrolidin-2-methyl-1 H-pyrrolo [2,3-b-pyridine; (R) -5-methyl-2-pyrrolidin-2-ylmethyl-1 H-pyrrolo [2,3-b] pyridin; (R) -5-methoxy-2-pyrrolidin-2-ylmethyl-1 H -pyrrolo [3,2-b] pyridine; (R) -2-pyrrolidin-2-ylmethyl-1 H-pyrrolo [3,2-b] pyridine; (R) -3-pyrrolidin-2-ylmethyl-1 H-pyrrolo [3,2-b] pyridine; (S) -2-pyrrolidin-2-ylmethyl-1 H -pyrrolo [3,2-b] pyridine; (S) -2-pyrrolidin-2-ylmethyl-1 H-pyrrolo [2,3-b] pyridine; (S) -
6. 6-fluoro-2-pyrrolidin-2-methyl-1-pyrrolo [2,3-b] pyridin; (S) -6-chloro-2-pyrrolidin-2-ylmethyl-1 H -pyrrolo [2,3-b] pyridine; (S) -6-bromo-2-pyrrolidin-2-methyl-1H-pyrrolo [2,3-b] pyridine; (S) -5-bromo-2-pyrrolidin-2-ylmethyl-1 H-pyrrolo [2,3-b] pyridine; (S) -2- (1-methyl-pyrrolidin-2-ylmethyl) -1 H -pyrrolo [2,3-bjpyridine; (R) -2- (1-methylene-2-pyrrolidin-2-ylmethyl) -1 H-pyrrolo [2,3-b] pyridine; 2-pyrrolidn-3-methyl-1H-pyrrolo [2,3-b] pyridine; 2- (1-methy1-pyrrolidin-3-methyl) -1 H-pyrrolo [2,3-b] pyridine; 2- (1-benzyl-3-pyrrolidin-3-ylmethyl) -1 H -pyrrolo [2,3-b] pyridine. 6. - (R) -enantiomers of compounds according to claim 1 of the formula (I) wherein R2 or R3 independently represent a piperidinyl, pyrrolidinyl, tetrahydropyridinyl, morpholinyl, azepanyl, 1-aza-bicyclo [2.2 .2] octanyl or 1-aza-bicyclo [2.2.2] oct-2-enyl, which group is unsubstituted or substituted by one or more substituents selected from halogen, alkyl (Ci-3), phenyl or benzyl, and whose ring contains an asymmetric carbon bonded either directly to the azaindol core (when m and n are 0) or via a methylene bridge (when m or m are 1), and where all other symbols have the meanings of claim 1. 7. - A pharmaceutical composition comprising, in addition to a pharmaceutically acceptable carrier and / or at least one pharmaceutically acceptable auxiliary substance, a pharmacologically active amount of at least one compound of one of claims 1-6, or a salt thereof, as an active ingredient. 8. - A method for preparing pharmaceutical compositions according to claim 7, characterized in that a compound of one of claims 1-6 is brought to a suitable form for the administration. 9. The compound according to any of the cations 1-6, or a salt thereof, for use as a medicament. 10. - A compound of the general formula (P) where Q represents the protective group: - X, Y and Z independently represent N or C, with the proviso that the ring contains at least one atom of N, and no more than 2, - myn are independently either 0 (zero) or 1, with the proviso that that when Y and Z represent carbon and X represents nitrogen, m is 0 (zero), - R2 and R3 independently represent a piperidinyl, pyrrolidinyl, tetrahydropyridinyl, morpholinyl, azepanyl, 1-aza-bicyclo [2.2.2] octanyl group or -aza-bicyclo [2.2.2] oct-2-enyl, which group is unsubstituted or substituted by one or more substituents selected from halogen, alkyl (Ci-3), phenyl or benzyl, in whose ring, when it contains a nitrogen atom, said nitrogen atom is substituted with a hydrogen atom, a benzyl group, a r-BOC group or a group S02-OH, - R4, R5 and R6 independently represent hydrogen, halogen, alkyl-a), alkynyl (C2-3), CF3, NH-alkyl (Ci-3), hydroxyl or alkyloxy , with the proviso that R4 exists only when Y = C, and R5 only when Z = C, useful in the synthesis of some compounds of the general formula (I). 1. Use of a compound according to any of claims 1-6, for the preparation of a pharmaceutical composition for the treatment of CNS disorders selected from: neuroendocrine, neurological and neuropsychiatric disorders, schizophrenia, memory impairments and the study, hyperactivity disorder with attention deficit, anxiety disorders, depressive disorders, neurodegenerative disorders, Alzheimer's disease, addiction disorders, nicotine addiction, ***e addiction, addiction to amphetamine, pain due to eating disorders, inflammatory processes, disorders seizures, eye disorders, glaucoma, macular degeneration, diabetic retinopathy, cardiovascular and gastrointestinal disorders and cancer. 12. Use of a compound according to any of claims 1-6 for the preparation of a pharmaceutical composition for the treatment of an addiction disorder selected from nicotine addiction, ***e addiction and addiction to amphetamine.