TW200819448A - 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

200819448 IX. Description of invention:

L·J^ff Λ U A hydrazine derivative having a combination of a nicotinic acetylcholine receptor promoting action and a dopamine reuptake inhibitory action. 5 [Previous Background of the Invention The present invention relates to azaindole derivatives having the general formula (I):

X 八人 [CH2]n. Μ The symbols therein have the meanings given in the text of this application. The present invention also relates to a pharmaceutical composition containing these compounds, and a method for preparing them for use in the synthesis of these compounds. Novel intermediate 'methods for preparing compositions, and such compounds and combinations

The method of the product, the use of the preparation, the use of the therapeutic effect, the use of the protein, or the regulation of cytokines, cytokines and peptides in the CNS (Brioni, 1997). In addition, the neuroprotective effects of nicotine and various other beneficial pharmacological effects have been proposed (Sjak-shie, 1993; Onaivi, 1994). A variety of compounds targeting nAChRs have been reported for the treatment of a variety of different conditions and disorders (Damaj, 1999; Bannon, 1998; Bencherif, 2002, Levin, 2002; O'Neill, 2002; Breining, 2005). Therapeutic indications discussed in the above cited documents include: CNS disorders such as neuroendocrine, neurological and neuropsychiatric disorders, schizophrenia, memory and learning, drought, attention deficit hyperactivity disorder, anxiety, depression Symptoms, God 10 degenerative disorder, Alzheimer's disease, addictive disorder, nicotine addiction, cocaine addiction 'butazepine addiction, eating disorder e pain (eatingdi〇rders pain), inflammatory process, 痉挛Sexual disorders, visual disorders, glaucoma, macular degeneration, diabetic retinopathy, cardiovascular and gastrointestinal disorders and cancer. The smoke receptor antagonist has good potential as a therapeutic agent because it provides an alternative means of regulating the function of the smoke receptor. A cigarette agonist quickly desensitizes some of the body and substantially inhibits their function. Therefore, inhibition of the receptor function of the test may be a role in conferring clinical utility, suggesting that the smoke receptor antagonist may also be useful in the treatment of diseases for which inflammatory agents are currently being developed. For example, schizophrenia and drug use have been linked to the hyperactivity of the CNS dopaminergic system, and inhibition of the smoke receptor may be beneficial in reducing such hyperactivity. CNS is a disorder that may be drug-induced; may be attributed to genetic susceptibility, infection or trauma; or may be unknown. They include neuropsychiatric disorders, neurological disorders, and psychiatric disorders, 200819448 and include neurodegenerative disorders, behavioral disorders, cognitive disorders, and cognitive dysfunction. Clinical manifestations of a variety of CNS disorders have been attributed to CNS P (pre-existing neurotransmitter release levels, inappropriate neurotransmitter properties, and/or inappropriate neurotransmitters and neurotransmitters) Disorders caused by interaction between receptors 5). Several CNS disorders can be attributed to the lack of acetylcholine, succinylamine, norepinephrine, and/or 5-chromoamine. Relatively common CNS disorders include Alzheimer's disease (early-onset Alzheimer's disease), Alzheimer's disease (Alzheimer's type of dementia), micro-infarct dementia, AIDS-related dementia, vascular dementia, Creutzfeld- Jakob), Pick's disease, Parkinson's disease including Parkinson's disease, Lewy body dementia, progressive supranuclear palsy, Humingt〇n's chorea, retarded dyskinesia, hyperkinesia, epilepsy, mania Attention deficit disorder, anxiety, dyslexia, schizophrenia, depression, obsessive-compulsive disorder, and Tourette syndrome. 15 The role of many neuropharmacological therapeutics involves the regulation of the release, uptake or storage of dopamine, norepinephrine and 5-chromamide in their respective terminals in the CNS. Most neurotransmitters are stored in synaptic vesicles, a prominent feature of the nerve endings. The concentration of vesicles entering is shown to maintain an off-the-shelf supply of neurotransmitters available for extracellular release to the synaptic cleft. Vesicles also have the effect of protecting neurotransmitters from metabolic damage. A transport site on the vesicle membrane is vesicular monoamine transporter-2 (VMAT-2), which acts to transport neurotransmitters from the cytosol into synaptic vesicles. Dihydrotetrabenazine, which is related to the structure of meth〇xytetrabenazine, has been used as a radiolabel to detect the interaction between the drug and ^8^ 八丁二 7 200819448. These two compounds function at the same site on VMAT2. Once the neurotransmitter is released from the terminal into the synaptic space, it interacts with the postsynaptic receptor and is then returned to the terminal by the plasma membrane transporter (i.e., the dopamine transporter and/or the 5-tryptamine transporter). Thus, transporter 5 white alters the concentration of neurotransmitters in the cytosol and vesicle reservoir and thus has the ability to alter subsequent neurotransmission. Dopamine is a monoamine neurotransmitter that plays a key role in the function of the hypothalamic-pituitary-adrenal axis and the integration of information in the sensory, marginal, and motor systems. The main mechanism for terminating dopaminergic neurotransmission is through Na+/Cl_dependent properties 10 membrane transporter reuptake of released dopamine. Depending on the surrounding ionic conditions, the dopamine transporter acts as a mediator for the inwardly directed dopamine transport (i.e., "re-uptake") and the outward-oriented dopamine transport (i.e., "release"). A significant functional property of dopamine transport proteins is their regulation of dopamine neurotransmission, which is achieved by the reuptake of the action of dopamine in the synapse. 15 The dopaminergic reward pathway has been implicated in disorders from addictive behavior. Variants of the dopamine D2 receptor gene have been linked to alcoholism, obesity, pathological gambling, attention deficit hyperactivity disorder, Tcmrette syndrome, cocaine dependence, nicotine dependence, polysubstance abuse and others. Drug dependence. Since reduced dopaminergic function has been found in individuals with a secondary A1 allele of the 20-aminoamine D2 receptor, this has been shown to be a potentiating or rewarding gene for the dopamine D2 receptor. In addition, several studies have shown that the dopamine D2 receptor gene polymorphism is associated with impulsive-addiction-forced behavior, namely "Reward Deficiency Syndrome" (Blum, 1995). 200819448 Dopamine transporters are large presynaptic-localized molecules that play an important role in the pathophysiological processes of the CNS. The dopamine transporter terminates dopaminergic transmission by re-accumulating the released dopamine into presynaptic neurons. In cocaine addiction, the combination of cocaine and dopamine transporter and thus the inhibition of dopamine uptake appears to be related to the reinforcing properties of the drug. Also associated with transport function is the concentration of neurotoxic chemicals in dopaminergic neurons suggested by Parkinson's disease. Transporter macromolecules may be a hallmark of Parkinson's disease, evidenced by the tissue of the putamen in Parkinson's disease. It does not exist. The dopamine transporter also plays a key role in the neurotoxic effects of 10 methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, which induces innate Parkinson's syndrome in humans). Therefore, potent and selective ligands for dopamine transporters have in vivo monitoring of cocaine in the brain, analysis of cocaine binding sites, treatment of cocaine addiction, and monitoring of Parkinson's disease. potential. More than 15 music may lead to physiology and / or d addiction. (4) The most familiar drugs include sputum tablets, such as heroin, hong tablets and morphine; sympathomimetic drugs, including kakain and bupropion; sedative _ hypnotics, including alcohol, benzodiazepine Ratios and barbiturates; and smoke tests, which have similar effects as discoids and sympathomimetic. The drug is characterized by a craving or irresistible use of the drug and its inhalation. In addition, drug dependence involves drug acceptability, reduced drug effects with repeated administration, and withdrawal, physiological and behavioral symptoms when not taking the drug. A sensitization (-ion) occurs if repeated administration of the drug results in an increased response to each dose. Tolerance, sensitization, and withdrawal are evidences of persistent changes in the central nervous system caused by the use of the substance. This change has led to addictive individuals continuing to consume drugs regardless of serious social, legal, physiological and/or professional consequences. Cocaine addiction has been one of the major health problems in the United States. Basic research from many laboratories has shown that cocaine prevents the dopamine receptor from taking up dopamine from the synaptic cleft. Nomi fensine and bupropi〇n are two compounds used as pharmacological standards for dopamine transporter inhibitors. They are both clinically used as antidepressants, and butylbenzamide is one of the few compounds used to treat nicotine addiction. , GBR" compounds are often known for their unusually high selectivity and potency against dopamine transporters. Two of these compounds have affinity in the low nanomolar range (Devries, 1997).

HX- CHU -CH,

Nomifensin Butabufen Varnocillin (GBR 12909)

15 Radiolabeling of these compounds has facilitated the elucidation of neuropharmacological activity. GBR 12909 (varnostrine) dissociated very slowly from DAT by microdialysis, impairing the 20 increase in extracellular dopamine levels induced by leica. This compound is not irritating in human volunteers, but has been shown to block self-administration of cocaine in rhesus monkeys (Dutta, 1993). This 200819448 class study has led to the possibility that a suitable compound can be used as a cocaine antagonist, which is itself non-addictive. One of the effects of nicotine is to release dopamine. Dopamine transporter inhibitors have essentially the same effect, albeit through a completely different mechanism of action 5 . Thus, where an increase in endogenous levels of dopamine is required or desired, a compound having a dual mechanism of action will have a higher effective chance than a compound having only a single mode of action. Compounds having such dual mode of action are known. First identified is a natural product (this happens too often in modern medical history). 10 α - Lobeline (Loberin), a lipophilic non-specific, bioassay component of Indian tobacco, is the major alkaloid found in a family of structurally related compounds found in Lobelia inflata. Lobeline has been reported to have a variety of nicotine-like effects, including tachycardia and hypertension, hyperalgesia, and improvement in learning and memory. Lobeline has a high affinity for nicotinic receptors, but there is no obvious structural similarity between Lo 15 and the smoke test. The relationship between S(-)-smoke and Lobeline's structure and function is not shared. Effect group. In addition, the distinguishing effect between Lobeline and nicotine suggests that these drugs may not be active through a common CNS mechanism, even though Lobeline is considered a mixed nicotine agonist/antagonist.

Lobelin

CH Nicotine 11 20 200819448 Lobeline causes release of dopamine from rat striatal slices. However, the release of dopamine by Loberin is neither dependent on extracellular mom nor sensitive to mecamylamine, a non-competitive nicotinic receptor antagonist. Therefore, lobeline causes 5 dopamine release by a different mechanism from nicotine-induced dopamine release. In this respect, Lobeline also inhibits the uptake of dopamine into the rat striatum synaptic vesicles by interacting with the dihydrotetrabenazine site on VMAT2, thereby increasing the plasma membrane transporter (DAT). Cytoplasmic dopamine is available for reverse transport (Teng, 1997, 1998). Thus, lobeline interacts with the 10 nicotinic receptor to prevent nicotine-induced dopamine release and interacts with dopamine transporters (DAT and VMAT2) to alter the concentration of dopamine in the cytosol and vesicle reservoirs. This changes the subsequent dopaminergic neurotransmission. In US 20030100547 and US 20040266825, ~ 15 series 2,6-disubstituted acridine and pyridazine derivatives are disclosed, which are structural analogs of Lobeline · R4 \

N^, X[Yl, R2 R1 US 20040266824 These compounds were synthesized and tested for their activity in the nicotinic receptor assay and the dopamine transporter and release assay to evaluate the specific amines of these compounds with these specific proteins in the CNS. The presynaptic end of the neurons can be extracted from the interaction of 12 200819448. Some of these compounds have a higher selectivity for interaction with DAT than with nicotinic receptors, while others interact with both nicotinic receptors and DAT, more similar to Lobeline. Some other compounds have a higher selectivity for nicotinic receptors than for DAT. These combinations of pharmacological activities are believed to be beneficial for the treatment of psychostimulant abuse and withdrawal, eating disorders, and central nervous system diseases and pathologies. EP 0 870 768 A1 and EP 1 178 045 A1 disclose azaindole-ethylamine derivatives which are useful as nicotinic acetylcholine receptor binding agents for the treatment of nicotinic receptor depletion in mammals. The condition, especially nicotine into 10 addictions. Some of the disclosed compounds are structurally related to the compounds of the present invention. They are effective displacers for [3H]-nicotine with an IC50 value of less than 2 //M and thus have a pIC5G value of 5.7 or higher. The affinity of a particular individual compound is not disclosed. The above application does not mention the content of dopamine reuptake inhibition. Therefore, rationally, because of the synthesis and testing of the large number of compounds 15 claimed, they showed no activity as inhibitors of dopamine reuptake inhibition. It is an object of the present invention to provide other compounds having a dual mechanism of action: (partially) agonistic effects on the acetaminophen receptor and inhibition of dopamine reuptake. 20 SUMMARY OF THE INVENTION Summary of the Invention Surprisingly, we have found compounds of the general formula (I): 13 200819448 r4 (ο 〜 X is called "R2 wherein -X, Y and Z independently represent N or C, and the ring Containing at least one N-atom and no more than 2, • m and η are independently 〇(zero) or 1, and when 丫 and 2 represent carbon and χ represents nitrogen, m is 0 (zero), 10 15 - R2 and R3 independently represent chlorine, dentate, (Ci sister group, (Cm) block group, NH (Cl. 3 alkyl group, CF3, thiol group, (Ci• oxy group or (tetra) group, t each alkyl group, Tetrahydrot-t-butyl, morphinyl, azepanyl, i-heterobicyclo[2.2.2]octyl or aza-bicyclo[2.2 2]oct-2-enyl, said group + is unsubstituted or substituted by one or more substituents selected from the group consisting of hydrazine, phenyl or phenyl fluorenyl, _R4, :MuR6 independently represents hydrogen, _, D, (Μ Base cf3, nhd alkyl, minus or (Ci 3) alkoxy, and R4 is only present at Y=c, Rs is only present at z = c, and, its tautomers, stereoisomers And N. oxides, and the sigma and its tautomers of the () Stereoisomers and pharmaceutically acceptable salts, hydrates and solubilities of N-oxides are novel and have a partial smog 20. Group transcripts for inhibition of receptor agonism and inhibition of dopamine reuptake The invention particularly relates to the following compounds of the formula (1) in which (10) 蜀14 200819448 domain represents hydrogen or ketone kissinyl, tetrahydrogen, morphinyl, aza-heptanyl, 1-aza-bicyclo[ 2·2·2] octyl or oxa-bicyclo[2·2·2] octyl-dilutyl, the group is unsubstituted, or is selected from one or more selected from the group consisting of leucine Substituted by a substituent of a strepyl or benzyl group, h, ~ and heart independently represent hydrogen, 4, (Ci, or I, oxy, and 4 is present only in Y Ck, r5 is only at z = c When present, X, γ, z, paw and n have the meanings given above.

10 15

The compound of the formula (1) of the present invention and a pharmaceutically acceptable salt thereof have (partial) agonistic activity against the test, and inhibit dopamine reuptake. = They have been used to treat the above-mentioned four (4) disorders, or can be manipulated by manipulation of these styles. For example, neuroendocrine, neurological and neuropsychiatric lines, schizophrenia, memory and learning shifts, attention deficit & amnesia 'anxiety disorder, depression, neurodegenerative information, A curry' Addiction, addiction, cocaine addiction, bupropion = addiction 'dietary disorder pain, inflammatory process, spasm, visual disorder, p-eye macular degeneration, diabetic retinopathy, heart Blood vessels as well as gastrointestinal disorders and cancer. The invention further comprises: a pharmaceutical composition for treating, for example, a disorder or money treatable by activating and/or blocking the receptor, the composition comprising a compound of formula (1) or a pharmaceutically acceptable salt thereof, and A pharmaceutically acceptable carrier; a method of treating a disorder or condition that can be treated by activating and/or preventing the above receptors. The method comprises administering to a mammal in need of such treatment a compound of formula (I) or Pharmaceutically acceptable salt; 15 200819448 Pharmaceutical composition for treatment, for example selected from the group consisting of neuroendocrine, neurological and neuropsychiatric disorders, schizophrenia, memory and learning disorders, attention deficit hyperactivity disorder, anxiety disorders, depression , neurodegenerative disorder, Alzheimer's disease, addictive disorder, cigarette addiction, cocaine addiction, Ding 5 ampicillin addiction, eating disorder pain, inflammatory process, spastic disorder, visual disturbance, glaucoma, A disorder or condition of the group consisting of macular degeneration, diabetic retinopathy, cardiovascular and gastrointestinal disorders and cancer; treatment of a disorder or condition selected from the group consisting of the disorders listed herein; The method comprises administering to a mammal in need of such treatment a compound of formula (1), or a pharmaceutically acceptable salt thereof; a pharmaceutical composition for treating a disorder or condition selected from the group consisting of the disorders listed herein, The composition comprises a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; a method of treating a disorder or condition selected from the group consisting of the disorders listed herein, the method comprising The therapeutically-treated patient is administered a compound of formula (I) or a pharmaceutically acceptable salt thereof. A method of activating a nicotinic receptor and/or inhibiting dopamine uptake, the method comprising administering to a subject in need thereof an effective amount of a compound of formula (1). The invention also provides the use of a compound or salt according to formula (1) for the manufacture of a medicament 20. The invention further relates to a combination therapy wherein a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or formulation comprising a compound of the invention, simultaneously or sequentially or as a combined preparation with additional one or more therapeutic agents Administration, for treating one or more of the listed conditions. Such other therapeutic agents can be administered prior to, concurrently with, or after administration of a compound of the invention 16 200819448. The present invention also provides a method for treating a compound selected from the group consisting of a disorder or a condition, and a composition of a drug. The package is called a medicinal gg. The compound of formula (I) or its agonistic === is discussed in the smear of the smear of the receptor (partial) such as (four) / multi (10). The materials are shown in the demonstrations, returned by the literature or known in the art. 10 15 20 ^_ provides intermediates for the preparation of the present invention and for use in such methods. The compounds of the present invention may contain one or more (four) centers, whereby the two spittings are oxime, racemic mixtures, mono-enantiomers, non-amps, and individual diastereomers. presence. Depending on the nature of the various substituents, there may be additional asymmetric centers. Each such ==% center will independently produce two optical isomers. All possible light = conformational and non-isomers, in the (tetra) complex, or as a pure 3 file-purified compound, are within the scope of the invention. The present invention encompasses all such isomeric forms of these compounds. Formula (1) shows the structure of such compounds: a structure having a preferred stereochemistry. The separation of these diastereomers or the chromatographic separation of them is obtained by appropriate modification of the methods disclosed in the art, which is known from the prior art. The absolute stereochemistry of the crystalline product or the crystalline intermediate can be determined by χ-ray crystal climbing, and if necessary, the crystalline product or crystalline intermediate is biochemically synthesized with an asymmetric center containing the known absolute «. The racemic mixture of the compounds can be separated into the various enantiomers 17 200819448 by methods well known in the art, for example, by coupling a racemic mixture of the compound with an enantiomerically pure compound to form a diastereomeric The heterostructure is then separated, and the various diastereomers are separated by standard methods, such as fractional crystallization or coloring. Coupling usually consists of the formation of a salt, which is carried out with an enantiomerically pure acid or domain, such as with (-)-di-p-tolyl-yl-D-tartaric acid and/or (1)-di-pair Toluene-based _L-tartaric acid is used. The diastereomeric derivative can then be converted to the pure enantiomer by cleaving the added chiral residue. It is also possible to use a chiral stationary phase to directly separate a racemic mixture of compounds by chromatography. This is a method well known in the art. Alternatively, any enantiomer of the compound can be obtained by stereoselective synthesis by methods well known in the art, using optically pure starting materials or reagents of known configuration. Tautomers of the compounds of formula (I) or pharmaceutically acceptable salts thereof are also within the scope of the invention. Some crystalline forms of the compound may exist as polymorphs: this also belongs to the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or form solvates with common organic solvents. Such solvates are also within the scope of the invention. Isotope-labeled compounds of formula (I) or pharmaceutically acceptable salts thereof, including isotopically-labeled compound 20 of formula (1) which can be detected by PET or SPECT, are also within the scope of the invention. The same applies to the formulas labeled with [i3c]-, [14c]- '[3η]-, [18F]-, [i25]- or with other isotopically enriched atoms suitable for receptor binding or metabolic studies. Compound of (I). Definitions of Chemical and Other Terms The term "alkyl" refers to a straight or branched saturated hydrocarbon group. For example, the alkyl group 18 200819448 (Q·3)" represents methyl, ethyl, n-propyl or isopropyl, alkyl, (Cm), which means methyl, ethyl, n-propyl, iso Propyl, n-butyl, 2-butyl, isobutyl or 2-mercapto-n-propyl. The term, alkenyl, refers to a straight or branched chain having one or more carbon-broken double bonds. a hydrocarbon group such as a vinyl group, an allyl group, a butene 5 group or the like which preferably represents a (C2-4) alkenyl group. In the alkynyl group, a linear or branched hydrocarbon group Has one or more carbon-carbon triple bonds, such as ethynyl, propynyl, 1-butynyl, 2-butynyl, etc., which preferably represents a (CM) alkynyl group. The term "mercapto" refers to an alkyl group ( Ch) carbonyl, arylcarbonyl or aryl-alkyl (C^) Rotamyl. 10 Teeth or narcotics means chlorine, fluorine, bromine or argon; in,,,,,,,,,,,,,,,,, "Miscellaneous" means having one or more N, 〇*s atoms. ",heteroalkyl" includes an alkyl group having a hetero atom at any position, thereby including an N-bonded, 〇-bonded or S-bonded alkyl group. The term is used herein as part of another group" Oxygen (0Xy),,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, A linker such as a hydroxyl group, an oxyalkyl group, a sulfanyl group, a carboxyalkyl group or the like. The term "amino" as used herein alone or as part of another group refers to a nitrogen atom which may be at the end or a link between two other groups, wherein the group may be primary or secondary. Or an amine of 20 (three hydrogen atoms bonded to a nitrogen atom, one hydrogen atom bonded to a nitrogen atom, and no hydrogen atom bonded to a nitrogen atom). The term sulfinyl, and, sulfonyl, as used herein as part of another group, denotes a -SO- or -S02. group, respectively, unless otherwise indicated. The term, leaving group, as used herein, shall mean a charged or uncharged atom or group that is removed during the substitution or displacement reaction of 19 200819448. Suitable examples include, but are not limited to, Br, Cl, I. , mesylate, tosylate, etc. The N-oxides of the above-mentioned compounds belong to the invention. The tertiary amines may or may not produce N-oxide metabolites. - The degree of oxidation may vary from trace to near quantitative conversion. N-oxides may be more active or less active than their corresponding tertiary amines, although N-oxides can be readily chemically converted. Reducing to their corresponding tertiary amines, but in humans 'this proceeds to varying degrees. Some N-oxides undergo nearly quantitative reduction conversions, reduction to the corresponding tertiary amines, and in other cases, transformations Just a trace reaction, or even a complete Does not exist (Bickel, 1969). When referring to a substituent, the term, independently, means that when there may be more than one such substituent, they may be the same or different from each other. To provide a more precise description, this article gives Some of the quantitative expressions are not defined by the term, and are defined by a large number. It should be understood that regardless of whether the term is explicitly used or not, each quantity given herein represents the actual value given, and It is also an absolute approximation of such a given value that can reasonably be inferred by one of ordinary skill in the art, including approximations due to experimental and/or measurement conditions for such a given value. In the specification and claims of the text of the present application, the term "includes", and variations of the word, for example, includes "comprising" and, "comprises" does not mean the exclusion of other additives or components. , integer or step. Any compound that is metabolized in vivo to provide a biologically active agent (ie, a compound of formula (I)) is a prodrug, which is within the scope and spirit of the present application 20 200819448. Uranium is A therapeutic agent that is not active by itself, but which can be converted into one or more active metabolites. Thus, in the methods of treatment of the present invention, the term, administration, will include the use of a clearly disclosed compound, or it may not be explicitly disclosed but administered. A patient is converted to a compound of the indicated compound in vivo to treat a variety of 5. The prodrug is a bioreversible derivative of a drug molecule that overcomes some of the barriers to the use of the parent drug molecule, including but not limited to solubility, Permeability, stability, presystemic metabolism and dry direction limitation (Bundgaard, 1985; King, 1994; Stella, 2004; Ettmayer, 2004; Hrvinen, 2005). Prodrugs, ie compounds which are metabolized to a compound of formula (I) when administered to any human by any known route, are within the invention. Particular such prodrugs are described as having a primary or secondary amino group Or a compound of a hydroxy group. Such a compound can be reacted with an organic acid to produce a compound of formula (1) in which additional groups are readily removed after administration, such as, but not limited to, hydrazine, enamine, Mannich domain, hydroxy- A mercapto derivative, a 〇-(醯15 oxymethylene carbamate) derivative, an amino phthalate, an ester, a guanamine or an ketamine. The terminology used herein, composition And a product comprising a specified ingredient in a predetermined amount or ratio, and any product directly or indirectly from a specified ingredient in a specified amount. For a pharmaceutical composition, the term 20 includes one or more active ingredients and An optional product comprising a carrier of an inert ingredient, and directly or indirectly from a combination, combination or aggregation of two or more of any of the ingredients, or from one or more of the ingredients Dissociation, or any product from other types of reactions or interactions that are intermediate species or species. Typically, pharmaceutical compositions are prepared by uniformly and intimately loading the active ingredient 21 200819448 with a liquid carrier or finely divided solids. The body is combined, and then, if necessary, the product is molded into a desired formulation. The pharmaceutical composition contains sufficient active target compound to produce a desired effect when the disease progresses. Therefore, the pharmaceutical composition of the present invention Included is any material prepared by premixing a compound of the invention with a pharmaceutically acceptable carrier. "Pharmaceutically acceptable" means that the carrier, diluent or excipient should be compatible with, and acceptable for, the other ingredients of the formulation. It is harmless. dose. The affinity of the compounds of the invention to the smoke receptor and dopamine uptake was determined as described below. From the binding affinities measured for a given compound of formula (1), the theoretically lowest effective dose can be estimated. Nearly 100% of the receptor will be occupied by the compound when it is equal to the measured compound concentration of twice the Ki value. Assuming the ideal bioavailability, the theoretically lowest effective dose is obtained by converting this concentration to mg of compound per kg of patient. Pharmacokinetics, pharmacodynamics, and other considerations may change the 15 doses actually administered to higher or lower values. The dosage of the compound to be administered will depend on the relevant indication, the age, weight and sex of the patient, which may be determined by the physician. The dose will preferably be in the range of 1 mg/kg to 10 mg/kg. The typical dose per active ingredient is in a wide range and will depend on a variety of factors, such as the relevant indication, the route of administration, the age, weight and sex of the patient, 20 which may be determined by the physician. Generally, oral and parenteral doses will range from 0.1 to 1000 mg of total active ingredient per day. The term "therapeutically effective amount" as used herein refers to an amount of a therapeutic agent used to treat a condition treatable by administering a composition of the invention. This amount is sufficient to demonstrate detectable therapeutic or improvement in the tissue system, animal or human 22 200819448 The amount of response. Effects can include, for example, treating the conditions listed herein. The precise effective amount for the subject will depend on the subject's size and health, the nature and extent of the condition being treated, the recommendation of the treating physician (researcher, veterinarian, doctor or other clinician) and the selection for administration. Therapy or a combination of 5 therapies. Therefore, it is not necessary to specify the exact effective amount in advance. The term "pharmaceutically acceptable salt" refers to a salt which, within the scope of reliable pharmaceutical evaluation, is suitable for use in contact with tissues of humans and lower animals, and which is free from undue toxicity, irritation, allergic reactions, etc. A reasonable benefit/risk ratio match. Pharmaceutically acceptable salts are well known in the art. They may be prepared "in situ" upon final isolation and 10 purification of the compounds of the invention, or may be prepared separately by reacting them with a pharmaceutically acceptable non-toxic domain or acid, including inorganic or organic domains and inorganic or organic acids. The term "treating" as used herein refers to any treatment of a condition or disease of a mammal, preferably a human, which includes (1) inhibiting the disease or condition 9 15 preventing its development, and (2) reducing the disease or condition. , that is, the condition is retrogressive, or (3) the symptoms of the disease are terminated. The term "medical therapy" as used herein is intended to include prophylactic, diagnostic, and therapeutic regimens for in vivo or ex vivo administration to humans or other mammals. The term "subject" as used herein refers to an animal, preferably a mammal, and most preferably a human, which is the target of treatment, observation or experimentation. 23 200819448 Fine-grained APT-binding proton test 9-BBN 9-boronbicyclo[3.3.1]decane BOC tert-butoxycarbonyl 5 n-BuLi n-butyllithium CNS central nervous system CUR air curtain gas DA dopamine DAT dopamine transporter 10 DCM Dichloromethane DF Deflection Voltage DHBE Dihydro--Dihydro-Wan-erythroidne DMAP 4-Dimethylamino Acridine DMC Chlorinated 2-Gas-1,3-Dimethylimidazoline 15 DME 1,2·Dimethoxyethane DMF N,N'-dimethylformamide DMG Direct metallization group DMSO Dimethylhydrazine DOM Direct ortho-methylation 20 EP inlet potential EtOAc acetic acid Ethyl ester EtOH Ethanol FAB Fast atom bombardment FP Focus potential 24 200819448 g g h hour HMDS hexamethyldiazepine HPLC High performance liquid chromatography - 5 IS ion spray voltage • LDA diisopropyl gas based mCIPBA m-chloroperbenzene Formic acid Mel iododecane " MeOH methanol 10 mg mg min min ml ml mp melting point cq melting MS mass spectrometry 15 NaOEt sodium ethoxide NaOMe sodium methoxide 1 NBS N-brominated amber quinone imine NEB atomizing gas PE petroleum ether (40 -6 0) 20 PET positron emission tomography QTOF quadrupole flight time Rf retention factor (thin layer chromatography) Rt retention time (LC/MS) SEMCI 2-(trimethylformamidinyl) ethoxymethyl chloride 25 200819448 SPECT TBAF TEA TEM THF TIPS TIPSCI TMEDA TMSA VMAT2 Single photon emission computed tomography fluorinated tetrabutylammonium triethylamine temperature 5 10 15 tetrahydrofuran triisopropylformamyltriisopropyltrichlorochlorodecanetetradecylethylenediamine ethynyl-three Methyl decane vesicle monoamine transporter-2 [Finance] Detailed description of the preferred embodiment f Analytical method "nuclear magnetic resonance" spectrum CHNMR and 13C NMR, APT), unless otherwise specified, using Bruker ARX 400 (4: 400) MHz, 13C: 100 MHz) at 300 K, measured in the indicated solvent. The 19F NMR and 13C NMR experiments were performed using a 5 mm SW probe on a Varian Inova 500 spectrometer operating at 11.74 1 (^: 499.9 MHz; 13C: 125.7 MHz; 50.7 Mhz, 19F): 470.4 MHz. The spectra were determined in a gas-to-gas or methylene chloride obtained from Cambridge Isotope Laboratories Ltd. The chemical shift (δ) is expressed in ppm and is the downfield from trimethylnonane (1H, 13C) or CC13F (19F). The coupling constant J is expressed in Hz. The peak shape in the NMR spectrum uses the symbols 'q' (quadruple peak), 'dq' (two sets of quadruple peaks), 't' (triplet), 'dt' (two sets of triplet), d' ( Double peaks), 'dd' (two sets of double peaks), 's' (single peaks), 'bs' (width 26 200819448 peaks) and 'm' (multiple peaks). The NH and OH signals were identified after mixing the sample with the droplets of d2〇. "Flash chromatography" refers to the purification using a specified eluent and any of Shiki (Acros · 0·030_0·075 mm or Merck 60 60·· 5 0.040-0.063 mm). "Column chromatography" was carried out using Shi Xisheng 60 (0.063-0.200 mm, Merck). "Melting point" is recorded on a Btichi B-545 melting point apparatus. Mass Spectrometry was recorded on a Micromass QT0F_2 instrument with MassLynx application software for obtaining and reconstructing data. Accurate mass measurements were made with excimer 10 [M+H]+. Use the je〇L JMS-SX/SX 102 A tandem mass spectrometer to perform accurate mass measurements using fast atom bombardment. For high-resolution FAB mass spectrometry, the resolution of 1 〇, 〇〇〇 (1〇〇/0 valley definition) was used. All reactions involving moisture sensitive compounds or conditions are carried out under anhydrous nitrogen. The reaction was monitored using a thin layer chromatography (TLC) on a cerium oxide coated plastic sheet (Merck precoated silicone 60 F254) with the indicated eluent. Spots were observed by UV light (254 nm) or 12. The "extinction coefficient" was measured using an HP 8453 UV-Vis spectrophotometer. 20 Analytical HPLC was carried out on a C18 column (Inertsil ODS-3, particle size 3 mm; 4.6 mm 50 mm) using the following elution gradient: 5 ° / 〇 to 95 % aqueous CH3CN (containing 0.04 % HC02H), 5 Minutes, then 95% CH3CN in water (containing 0.04% HC02H) was carried out for 2 minutes at 2.0 ml min-1. The product was detected at λ = 254 nm. 27 200819448 Liquid Chromatography-Mass Spectrometry ([(^]^) The LC-MS system consists of 2 Perkin elmer 200 series micropumps. The pumps are connected to each other via a 50//1 T-type mixer and connected to a Gilson 215 autosampler. The method is as follows: Step Total time flow rate (// 1/min) A (%) Β (°λ 0 0 2000 95 5 1 1.8 2000 0 100 2 2.5 2000 0 100 10 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

15 B= 100% ACN with 〇·〇 25% HCOOH The autosampler has a 2 /zl injection ring. The autosampler was connected to a Waters Atlantis C18 30*4.6 mm column with 3 #m particles. The column was thermostated at 40 °C in a perkin Elmer 200 series column incubator. The column is connected to a Perkin Elmer 200 Series UV meter with a 20 2.7 // 1 flowed flow. The wavelength is set to 254 nm. The UV meter is connected to the Sciex API 150EX mass spectrometer. The mass spectrometer has the following parameters: Scan range: 150-900 amu·; Polarity: Positive; Scan mode: profile; Resolution Q1: UNIT; Step size: 0.10 amu·; Each sweep 28 200819448 Trace time · 0.500 seconds , NEB · l〇; CUR : l〇; IS : 5200 ; ΤΈΜ : 325 ; DF : 30 ; FP : 225 and ΕΡ : 1〇. The light scattering detector is coupled to the Sciex API 150. The light scattering detector is Sedere Sedex 55, which operates at 50 C and 3 bar N2. The entire system is controlled by G3 powermac. 5 Example 2 General Aspects of Synthesis The compounds of formula (I) are prepared from readily available starting materials. Substituted lH-n than ardeno-[2,3-b]acridine is available from commercial sources or is known in the chemical literature (Synthesis, 1992; Heterocycles, 1999; US 2002/0061892; Current Organic Chemistry, 2001) 〇10 In an example of a general program (flow 1), in the presence of a domain, '1Η-σΛ洛和-[2,3-leaf bite (7-azaindole (1)) and 1_ The reaction of benzyl-3-guanazone-3-ketone (2) produces the lone-3-ol compound 3 instead of the benzyl analog of compound 5 (Bioorganic & Medicinal Chemistry Letters, 2002). The benzyl group can be removed by a known method. The specific conditions are ammonium formate 15 and palladium hydroxide, which are reacted in furfuryl alcohol to give compound 5 which is dehydrated (5) and reduced to give the desired 3-oxaridin-3-yl-1H-pyrrolo-[2 , 3-b]pyridine (6), using the procedure set forth in Scheme 1, some specific compounds of structure 7 can be obtained from (4, 5 or 6) substituted 1H-pyrrolo-[2,3-b]pyridine. In the specific example 2〇 'R represents lower alkyl, alkoxy and fluorine. 29 200819448 Flowing (Scheme) 1

Scheme 2 illustrates an alternative method of preparing the compound of Structural Formula 7. The body 6 was synthesized to synthesize 6-gas _3_yl-1 Η-σ bilol. Thus, compound 6 was reacted with di-tert-butyl dicarbonate to form compound 9 in a two-step process. Greene (1999) provides more information on the addition and subsequent removal of protecting groups in organic synthesis. L〇, a similar selective gasification of 7-azaindole at the 6-position is obtained by a known method (Synthesis, 1992) by a reaction of Reissert_Henze (via N_oxide 1〇A). Thus, the Νι_methoxycarbonylation obtained from the reaction was converted to the compound 12 under the conditions of the test. Compound 13 was obtained by removing the N-t-Boc group. 30 15 200819448

NH NH ' N40

NH

OB

(In another example of a general procedure (Scheme 3), 7-azaindole (1) 5 is reacted with 1_azabicyclo[2,2,2]-oct-3-one (14) to give Dehydrated product 15, which is reduced to give the desired 3-(1Η-pyrrolo-[2,3-b]pyridin-3-yl)-1-aza-bicyclo[2,2,2]-octyl Alkane (16) 31 10 200819448 Process 3

The generation of ortho 5-membered anions for aromatic systems used in the synthetic schemes described in this application is encompassed by those skilled in the art as general synthetic strategies known as direct ortho-metallization (DOM). In this field, a large number of functional groups known as direct metallization groups (DMG, s) have been studied for this purpose. The 1-benzophenone yellow-branched group at the 1-position of the azaindole analog makes it possible to capture the 2-position and thus the functionalization (Synthesis, 10 20052; Tetrahedron, 1997) ° Alpha-metallization of a 2-lithium derivative of 17 (1.1 equivalents of LDA, THF, -10 ° C to 0 ° C) prepared on a few grams of scale yields compound 18 which is deprotected to yield the desired alcohol 19 and Enamine 20. Reduction of 20 yielded 3-(1Η-indolo-[2,3-b]pyridin-2-yl)-1-aza-bicyclo[2,2,2]-octane (21). 32 200819448 Process 4

CI

Referring to Scheme 3, starting material 17 is converted to compound 22 (Scheme 4). After domain hydrolysis of 5 Nr benzenesulfonyl (23), the preferred order is dehydration (9) after removal of benzyl (24) 33 200819448. The restoration produced the desired Qin scale and _[2, 3 handsome _. References! 2, reduction with = UAH is the preferred side of the production of (iv) H3 compound (28). In addition, the starting material 27 is converted to a separable mixture of 3 and 31 by the procedure described in Scheme 2 (Scheme 4 ). Those skilled in the art will be able to understand the non-selectivity of this Reissert-Henze type reaction (by N_oxide 29A). Domain hydrolysis, followed by removal of the N+Boc protecting group, yielding the corresponding b (or 4)·Ga-2-acridin-3-yl-1H-pyrrolo-[2,3-b]pyridine (32 and 33 ). 10 Process 5

HO

17 S02Ph

So2ci2 ΐίΐ〇·£ /DCM 0

Cl Η / /DCM HO

) Continued ~〇 0 36 f 35

〇 35 LDA/THF

HC!/EtOH/THF 37 S02PH

Suspected ^o2ph H

H2NNH, xH20 KOH

υ 〇 U

"N N ^ N H 39A H

OH 17 + 36

NO

38B S02PN

N,, N, Η H 398

3BA/B

NaBH(OAc)3 CHXO

4DA/B SO, Ph

H2NMH2xH20 _ KQH

NI 41A/B (A=R-ch3 b - s« v^jvjr j 34 200819448 In another aspect, 5-(R)-[3,3,〇]-l-aza-2-thia-3 -oxabicyclooctane-2,2-dioxide (compound 35, Scheme 5) or 5-(3)-analog (compound 36, Tetra bedron Asymmetry, 1990) is used as the invention set forth for Formula I The starting material of the compound. The lithium derivative of 5 17 reacts with (R)-thiosulphonate 35 to produce a lithium-sulfonate 37' which is subsequently hydrolyzed to yield 38A. Nl-phenylsulfonyl Removal can be accomplished using known methods, for example, by reacting compound 38A with potassium hydroxide in diethylene glycol in the presence of hydrazine to form (R)_2_pyrrole-2-ylmethyl-1. -H-pyrrolo-[2,3_b]pyridine (39A). De(S)-derivative 39B was obtained from (S)-thioproline 10 ester 36. The 39A was reduced to the compound 41A ( Scheme 5) can be accomplished using different methods, with the conversion of 26 to 28 (Scheme 4), the reductive methylation of 38A and the subsequent removal of Ni-phenylsulfonyl in compound 40A, which yields the desired (R)-2-(P-methyl-pyrrolidin-2-ylmethyl)-1-indolyl-pyrrolo-[2,3-b]pyridine (4 1A) 15 20 35 200819448

clBrF II II = R6R6R6

45A/B 46A/B 47A/B

50 : R5 = Br 52A/B : R5 = Br 51 : R5 = CH3 53A/B : R5 = CH3 Scheme 6 illustrates the formula for which R5 and R6 represent halogen, (C!_3) alkyl or pyroxy 5 oxy 1 Preparation of a compound. The above procedure (using chiral thiourethane 35 and 36) was used to convert 42 and 43 (Synthesis, 1992), 44 (Scheme 7), 50 (Heterocycles? 1999) and 5l (Current Organic Chemistry, 2001) into The corresponding compounds 45A/B, 46A/B, 47A/B, 52A/B and 53A/B. Production of (R)-6-methoxy-2-pyrrolidine-2ylmethyl-1-H by the copper (I) catalyzed conversion of 48 (and subsequent removal of 10 t-Boc protecting groups) - Pyrrolo-[2,3-b]pyridine (49), to illustrate examples of functionalization of the 7-azaindole system at the 6 position. It should be emphasized that the synthesis of 6-fluoro-7-azaindole (44) has not been reported. The invention thus provides a method of producing compound 44, but this is based on a synthetic strategy known to those skilled in the art and is set forth in Scheme 7. 36 200819448 Process 7

54 NH4OH 125 °C 9,2bar

55

CH3CN 56 H

Commercially available 2,6-difluoro. The pyridine (54) is converted to 2-amino-6-fluoro-acridine 5 (55, Tetrahedron, 2002). Different DMG groups (e.g., 2,2-dimethyl-propionamide) were examined (Heterocycles, 1999; WO 2003/053970). However, we have found that the amino phthalate ester of DMG (Chem Pharm· Bull·, 1987) produces compound 57 (6-fluoro-3-iodo-pyridin-2-yl)-carbamic acid B for the selective iodinated compound 56. Ester is necessary. 10 Subsequent Sonogashira chemistry followed by ring closure in the presence of copper (I) telluride (Synthesis, 20051) gave compound 59. Cleavage of the %-carbamate yields 6-fluoro-1H-pyrrolo-[2,3-b]pyridine (44). The synthesis of compound 47A/B is illustrated in Scheme 6 following the procedure set forth in Scheme 5. 37 200819448 Another illustration of a compound of formula I of the present invention is shown in Scheme 8. Process 8

LOA THF »30°Ctot «20°C

MeO

63 Η MO / OMe (GH3)3AI / !' V- V;

17

Nickname MeOH PdCOHyC

H2_H2.H50 KOH (HOC^CHs^O SO^h 63

The mildness and selectivity of 9-9-BBN demonstrates the ability of the commercially available terpene amine 61 (Tetrahedron Letters, 1999) to reduce the indoleamine moiety to cyclic amine 62. The cyclic amine 62 is converted to Weinreb®. Amine 63 (Tetrahedron

Letters, 1997). Referring to Scheme 5, the 2_lithium derivative of π is reacted with Weinreb decylamine 63 to produce compound 64. In the general method of reacting with 2_lithium derivative 17 and a suitable 10 electrophile (see the foregoing scheme), the optimum conditions are a temperature of about -5 ° C to -UTC, preferably -3 (TC). It is carried out for about 2 hours at a temperature of -20 ° C. The compound 64 is subjected to yellow dragon reduction, followed by cleavage of Nr benzene sulfonyl group, 38 200819448 to produce a hydration agent 65. Subsequent reduction cleavage of benzyl group can be preceded by This is done under the conditions described in Scheme 4), yielding 2_. 烧3 ylmethyl-1H-pyrrolo-[2,3-b] pyridine (66). The transformation described using the method described in 耘4 At 67, then reduced to yield 5 compounds 68. f

69 70 S02Ph 72: Y = C, X: N 73: Y - N, X * C Η, ΝΝΗ, Ή^Ο r KOH

N one

Separation of isomers

78 :Υ-αχ-Ν 79:Y=N,X = C

Ha

Pd(0H}2

MeOH / \ In another example of the general procedure (Scheme 9), 17 (or 70) of the 2-10 lithium derivative is reacted with cerium (III) chloride (J. Med Chem, 2002), followed by The 3-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (71) is captured to yield the corresponding tertiary alcohol (72, 73). Referring to Scheme 5, the Νι-cleavage of the phenyl hydrazino group yields compounds 74, 75. Removal of the Nt-Boc protecting group catalyzed by an acidic medium (preferably, 6 M HCl), and subsequent dehydration, yields compounds 76, 77, 39 200819448 which are subsequently reduced to the desired 2·11 ratio.洛?-3-yl·1Η-ϋΛρ-[2,3-b]pyridine (78) and 2-pyrrolidin-3-yl-1H-pyrrolo-[3,2-b]pyridine (79) . About Preparation 83 (Process 10, European Journal of Medicinal Chemistry, 2004) ° 5 Process 10

81Α/Β

N丨H 80Α/Β S0^Ph

The 2-lithium derivative of 70 and/or 83 (preferably completed with t-BuLi/TMEDA in THF) is reacted with 35 and/or 36 to give the corresponding compound 10, 80A/B and 84. 80A/B. The transition from 84 to 81A/B and 85 can be performed using the method described in Flow 5. The bromination at the 3' position of the azaindoles of different isomeric forms can be accomplished by known methods (Heterocycles, 1999, 2000; Tetrahedron Letters, 1969; W02004/078757). Surprisingly 40 200819448 Now, the preferred condition is NBS/DMF, which allows bromination (69 to 86) to occur in near quantitative yields. Appropriate selection of protecting groups (especially triisopropylmethanyl (TIPS)) enables the exchange of 3-bromine to a 3_lithium derivative of 87, which is subsequently followed by (R)-thioproline _ (Compound 35) capture. Acid removal of Tips by 5 followed by hydrolysis of the sulfonate group (refer to Scheme 5) yielded the desired (R)-3-pyrrolidin-2-ylmethyl-1H-pyrrolo-[3,2-b]pyridine ( 88). Another illustration of the compounds of formula I which are described herein is shown in Scheme 11. The commercially available 4-chloro-7H-pyrrolo-[2,3-d]pyrimidine (89) was reductively converted to 7H-pyrrolo-[2,3-d]pyrimidine (90). The 2-position of the oxime derivative as the 〇14〇 2_(tris10-methylmethyl decyl) ethoxy-methyl group enables the lithiation of the 2-position (Helvetica Chimica Acta, 1993) 〇 flow 11

lEM Is 93

NIS Η

'N

NH

NIS

NH

NIH uses this known method to capture a 2-hour derivative of 91 with, for example, Compound 35. To avoid the problems associated with the use of an alkyl or a dialkylamino clock, the correct choice is the tetramethyl lone bite (92). Thus, a 2-bell derivative of 91 is reacted with (R)_41 200819448 thiourethane (35) to yield compound 93, followed by removal of the SEM protecting group (94). Hydrolysis of the sulfonate group under standard conditions (as described above) as described above yields the desired (R)-6-pyrrolidin-2-ylmethyl-7-H-pyridin 5 Butyr-[2,3-d]pyrimidine (95). The pharmaceutically acceptable salts can be obtained by standard procedures well known in the art, for example by mixing a compound of the invention with a suitable acid such as a mineral or organic acid. EXAMPLE 3 Synthesis of a Hydrazine Compound 10 The specific compounds synthesized as described below are intended to be used in further detail to illustrate the invention 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 <RTIgt; The detailed description and examples are to be considered as illustrative only. 15 g mercapto-3-indole-pyrrolo-r2.3-blpyridine-3-)-pyrimidine-3 conjugate 3) 60% dispersion of NaH (9.5 g, 179 mmol) in mineral oil Slowly added to 150 ml of EtOH (〇.〇. Add this solution to 7-azaindole (5·3 g, 44.9 mmol) and 11.25 g (44.9 mmol) of 1-benzyl-anthran-3-one The 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 sat. NaHC03 solution, dried (NajO4), filtered and concentrated. The residue obtained was purified (diethyl ether / ethyl acetate gradient 1:1 to purified ethyl acetate) to afford compound 3 as oil (1 〇·3 g, 74.7%). h-NMRGOO MHz, 42 200819448 CDC13 ) : (5 10.0(bs,1H), 8.27 (dd, J = 5 Hz, 2 Hz, 1H), 8.14 (dd, J = 8 Hz, 2 Hz, 1H), 7.35-7.24 (m, 6H), 7.03 (dd, J = 5 Hz, 8 Hz, 1H), 3.96-3.88 (bs, 1H), 3.60 (dd, J gem = 13 Hz, 2H), 3.07-3.01 (m, 1H), 2.95-2.89 ( m,1H), 2.39 (d, J = 10 Hz, 5 1H), 2.16.16.96 (m, 2H), 1.92-1.78 (m, 2H), 1.72-1.65 (m, 1H). (TLC EtOAc R f 0_09) 3_(1H-pyrrolo-f2.3-blpyridin-3-yl)-acridin-3-ol (Compound 4) Compound 3 (2.4 g, 7.8 mmol), 1.5 g ammonium citrate (23.8 mmol) And 20% Pd(OH)2/C (240 mg) in MeOH (50 ml), warmed to EtOAc EtOAc EtOAc. The title compound (1.5 g, 6.9 mmol, 88%) eluted eluted eluted eluted eluted -8. (m, 1H), 2.06-1.8 (m, 3H), 1.5-1.42 (m, lH). (TLC MeOH / triethylamine 97/3 Rf 0.16). Lr(l,2,5,6-tetrahydro-pyridin-3-yl V1H-pyrrole and 2.3-bl pyrimidine (compound 5) 10 ml of acetamidine chloride was slowly added to 200 ml of EtOH (-1 〇 ° After 15 minutes, the solution was added to compound 4 (5 g, 16·3 mmol) and heated to reflux for 1 hour. The mixture was cooled, concentrated and redissolved in MeOH. The title compound (1.43 g, 7.18 mmol, 44·1 α/0) 〇ιΗ- 43 200819448 NMR (400 MHz, CDC13): 5 11.4-10.8 (bs, 1H), 8.32 (dd, J = 5 Hz, 2 Hz, 1H), 8.2 (dd, J = 8 Hz, 2 Hz, 1H), 7.15 (dd, J = 8 Hz, J = 5 Hz, 1H), 6.32-6.27 (m, 1H), 3.76-3.72 (m, 2H), 3.10-3.04 (m, 2H), 2.36-2.29 (m, 2H). (TLC MeOH/triethylamine 5 (97/) 3 Rf 0.25). 3- 孤定定-3_基-1H-口比洛和"2,3-bl 口比口定定f彳h合6) 10 ml of acetamidine slowly added to 200 ml EtOH Medium (-10 ° C). After 15 minutes, the solution was added to compound 5 (1.43 g, 7.18 mmol) and 20% Pd(OH) 2 / C (130 mg). The mixture was hydrogenated at 50 psi for one hour. Filtered by 10 and concentrated Subsequent filtration of 8 (:: 乂-2, followed by flash chromatography (MeOH/triethylamine (97/3)) provided compound 6 (〇·81 g, 4 〇 2 mmol, 55 %), which reacts with the equivalent of fumaric acid in Et0H and is concentrated. Recrystallization from EtOH/ethyl acetate provides solid (free domain/fumaric acid (2 · 1)), mp &gt; 225 C (decomposition). NMR (400 15 MHz, D20): 5 8.04 (bd? J = 5 Hz5 1H)? 7.93 (bd? J = 8 Hz5 1H)5 7.13(bs, 1H)? 7.01(dd , J = 8 Hz? 5 Hz? 1H)? 6.36(s? 1H)? 3.46'40(m,1H), 3.37-3.31(m,1H),3 14_3〇4(m,m), 2.92-2.82 (m, 2H), 2.0-1.87 (m, 2H), 1.8, i.54 (m, 2H). And "2" bit each group of acid t-butyl hydrazine % 20 (compound 9) compound 6 ( 0.3 g, 1.5 mmol), 2 g of di-tert-butyl dicarbonate (4.58 mm 〇l) and 0.5 ml of triethylamine were combined in dichloromethane (2 mL) and warmed to reflux for 15 min. The mixture was cooled and concentrated under vacuum. The resulting residue was dissolved in ethyl acetate (washed with brine, dried (Na.sub.2.sub.4.sub.4). (no need for further purification) jh_nmr (4〇〇mhz, CDCI3): 5 8.5 (dd, J = 5 Hz, 2 Hz, 1H), 7.98-7.91 (bd, J = 8 HZ, 1H), 7 39 ( S,1H),71_,]=8 Hz, 5 Hz,1H), 5 4.48-4.〇4(m, 2H), 2.97-2.75(m, 3H), 2.2.2.14(m, 1H), 1.84 -163 (% 3H), 9H), 149 (s, 9h). (tlc dietherification 0.39). This material (8) was dissolved in i〇 ml 3 ^ 2 n N capsule. The reaction mixture was taken up for 0.5 hour at room temperature. Ethyl acetate was added to the mixture, and the organic layer was washed three times with 2N Na?H, dried (Na?s?), filtered and concentrated. The residue obtained by flash chromatography (diethyl (6) was purified to provide compound 9 as oil (0.25 g, 〇83 · 〇1, 55% (in general)). R (4 〇〇 MHz, CDC13) ) : δ 9 8(bs, lH), 8 3 (call)

=5 Hz, 1H), 8.04-7.98 (bd, J = 8 Hz, lH)j 7.13(bs, 1H), 7.07(dd, J = 8 Hz, 5 Hz, 1H), 4.45-4.02(m, 2H ), 3.04-2.76 (m, 15 3H), 2.2-2.14 (m, 1H), 1.83-1.60 (m, 3H), 1.49 (s, 9H) ° (TLC diethyl ether Rf 0.13). Η2Α:1ϋι_°比罗农基)·Acridine small t-butyl ester (compound 10Α) Compound 9 (0.23 g, 0.76 mmol) and 〇·23 g m-benzoic acid 20 (!.4eq·, l. 7 mmol) was combined in dimethoxy ethane (1 mL) and stirred at room temperature for 10 min. The mixture was concentrated on EtOAc (EtOAc) elute EtOAc (EtOAc) 8, 〇.72 111111〇1, 95%). 111· NMR (400 MHz, CDC13) ·· 6 8.2 (bd, J = 5 Hz, 1H), 45 200819448 7.8-7.5 (bs, 1H), 7.22 ( s, 1H), 7.04 (dd, J = 8 Hz, 5 Hz, 1H), 4.44_4. 〇 2 (m, 2H), 2.99-2.78 (m, 3H), 2.2-2.12 (m5 1H), 1.81- 1.60 (m, 3H), 1.48 (s, 9H) 3-oxaridin-3-yl-1H-pyrrolo-Obipyridine 7-vapor (Compound 5 10B) 0.4 ml of acetamidine was slowly added to 10 ml of EtOH ( After 10 minutes, the HCl/EtOH solution was added to the compound 10 Α (0·27 g, 0.85 mmol), and then warmed to reflux for 1 hour. The mixture was cooled and partially concentrated. The obtained precipitate was collected by filtration and washed with diisopropyl ether. Compound (10B, HCl) was obtained as a solid (220 mg, 100%) mp &gt; 145 ° C (decomposition). NMR (400 MHz, D20) : (5 NrH is invisible, 8.21-8.18 (m, 1H), 8.15-8.12 (m, 1H), 7.40 (bs, 1H), 7.25-7.0 (m, lH), 3.56 -3.49 (m, 1H), 3.41-3.34 (m, 1H), 3.31-3.22 (m, 1H), 3.04-2.90 (m, 2H), 2.14-2.06 (m, 1H), 2.05-1.94 (m, 1H), 15 1.86-1.66(m, 2H). 6 - chaotic-3-gull-defining -3 -yl-1H-port bilu and "2,3-bl mouth ratio determination (4 chelate 13) Compound 10A (0.22 g, 0.69 mmol) and 0.15 ml of 1,1,1,3,3,3-hexamethyldioxane (0.72 mmol) were co-dissolved in 10 ml of THF. 0.14 was added to the solution. The mixture was stirred at room temperature for 30 min. Washed with brine, dried (Na2~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Α-ΝΜΕ^ΟΟΜΗζ,ΟϋαΟ 5 7.95-7.84(bd? J = 8 46 200819448

Hz, 1H), 7.53 (s, 1H), 7.24 (d, J = 8, 1H), 4.42-4.20 (m, 1H), 4.10-4.01 (m, 1H), 4.09 (s, 3H), 3.14 2.84 (m, 2H), 2.84-2.68 (m, 1H), 2.19-2.11 (m, 1H), 1.82-1.60 (m, 3H), 1.49 (s, 9H). (TLC diethyl ether / PE (l / l) Rf 0.19). 5 Dissolve compound 11 (0.16 g) in 25 ml containing 3 ml 2N NaOH

It was stirred at room temperature for 18 hours in MeOH. The reactants were concentrated under vacuum. The residue obtained was dissolved in dichloromethane, washed with EtOAc EtOAc EtOAc EtOAc EtOAc ^- NMR (400 MHz, CDC13) 5 10 7.99-7.91 (bd, J = 8 Hz, 1H), 7.12-7.07 (m, 2H), 4.42-4.20 (m, 1H), 4.16-4.02 (m, 1H) ), 3.02-2.75 (m, 3H), 2.20-2.12 (m, 1H), 1.82-1.60 (m, 3H), 1.49 (s, 9H). (TLC diethyl ether / PE (1/1) Rf 0.17). 0.2 ml of acetamidine chloride was slowly added to 10 ml of EtOH (-10QC). After 15 minutes 15 , the solution was added to compound 12 (0.13 g, 0.39 mmol) and warm to reflux for 1.5 h. The mixture was cooled, partially concentrated, ethyl acetate was added, and the obtained precipitate was collected by filtration and washed with diisopropyl ether. The title compound, 6-chloro-3-acridin-3-yl-1H-pyrrolo[2,3-b] 20 pyridine 13 (HC1 salt) was obtained as a solid (80 mg, 76%). Mp &gt; 279 ° C (decomposition). NMR (400 MHz? D20): 5 7.60 (d? J = 8 Hz? 1H)? 7.14 (s5 1H), 6.99 (d, J = 8 Hz, 1H), 3.52-3.44 (m, 1H), 3.40- 3.32 (m, 1H), 3.19-3.09 (m, 1H), 2.97-2.87 (m, 2H), 2.08-1.91 (m, 2H), 1.84-1.60 (m, 2H). 47 200819448 3-(111_1? than 17 each and 2, 3-1) 10 to bite-3-yl)-1-gas-----------------, 221 Xin X compound 16) Will be in mineral oil A 60% dispersion of NaH (4 g, 75 mmol) was slowly added to 75 ml of EtOHWC. This solution was added to 7-azapine (2 g 5 16·9 mmol) and 3.4 g (21 mmol) l- Aza-bicyclo[2·2·2] osin·3_嗣(14) (HC1 salt). The obtained mixture was subjected to a 24 hour drop at 60 ° C. The solution was returned to room temperature. 0.5 ml of H2 hydrazine and 25 g of Si〇2, followed by concentration under vacuum, purified by flash chromatography (di-hexane/MeOH/7N NH3/MeOH (960/35/5 to 910/100/10)) 10 residue, giving compound 15 as a solid (2.5 g, 69%). mp 180 〇 C. 1H-NMR (400 MHz, D6 DMSO): δ 11.8 (bs? 1H)? 8.24 (dd? J = 5 Hz , 2 Hz, 1H), 8.12 (dd, J = 8 Hz, 2 Hz, 1H), 7.61 (s, lH), 7.08 (dd, J = 5 Hz, 8 Hz, 1H), 6.87 (d, J = 2 Hz, 1H), 3.14-3.09 (m, 1H), 3.01-2.91 (m, 2H), 2.64-2.54 (m, 2H), 15 1.78_1.69 (m, 2H), 1.59-1.49 (m, 2H). Compound 15 (1.9 g, 7.11.95 mmol) and 20% Pd(OH) 2/C (190 mg) Dissolved in MeOH (100 ml). The mixture was hydrogenated at 50 psi for 72 hours. The mixture was filtered and concentrated on 25 g EtOAc EtOAc EtOAc EtOAc EtOAc 5~2〇910/100/10)) The residue obtained was purified to give the title compound 16 (1.55 g? 57%) mp 185 °C 〇1H-NMR (400 MHz? D6 DMSO): 5 11.35 (bs, 1H), 8.17 (dd, J = 5 Hz, 2 Hz, 1H), 7.85 (dd, J = 8 Hz, 2 Hz, 1H), 7.31 (d, J = 2 Hz, 1H), 6.98 ( Dd, J = 5 Hz, 8 Hz, 1H), 3.32-3.24 (m, 1H), 3.22-2.95 (m, 1H), 3.0-2.83 (m, 48 200819448 4H), 2.78-2.68 (m, 1H) , 1.95-1.91 (m, iH), 1.84-1.54 (m, 3H), 1.35-1.24 (m? 1H) anthracene ring d21 octyl compound 18) 5 at -10 ° C, N2, LDA (THF / In heptane, 2.0 M) (5.5 ml, 11 mmol) was added to 100 ml of anhydrous THF and a solution of compound 17 (Tetrahedr〇n, 1997) (2.58 g, 1 〇mm0l) in THF was added dropwise (1 〇)

Ml). After the addition, the obtained solution was stirred at -i〇〇c_〇〇c for 3 minutes. The temperature is then lowered to _70 cC. At this temperature, a solution of 14 (125 g, 1 〇 10 mmol) in 10 ml of THF was added dropwise. The free domain of the commercially available HC1 salt of aza-bicyclo[2 2 2]oct-3-one (14) is passed through SCX-2 (Me〇H, followed by j N

Filtration on NHg/MeOH) followed by evaporation. After the addition of 14, the temperature was raised to -30 ° C to 25 ° C, and the resulting solution was stirred for 6 minutes. Let the solution return to room temperature. 5 ml of H2 hydrazine and 5 〇g of 15 Si〇2 were added to the reaction mixture, followed by concentration in vacuo. The residue obtained was purified by flash chromatography (dichloromethane / EtOAc / EtOAc (EtOAc) i-NMRQOO MHz, CDC13): 5 8.30 (dd, J = 5 Hz, 2 Hz, 1H), 8.15-8.05 (m, 2H), 7.75 (dd, J = 8 Hz, 2 Hz, 1H), 7.60- 7.38 (m, 3H), 7.12 (dd, Bu 5 Hz 8 20 Hz, 1H), 6.71 (s, 1H), 5.10-4.85 (bs, 1H), 3.20_2.74 (m, 6H), 2.45-2.25 (m, 1H), 2_08-1.92 (m, 2H), 1.74-1.44 (m, 2H) (TLC methylene chloride / MeOH / 7N NH3 / MeOH (960/35/5)) Rf 0 33).

(Compound 21) 49 200819448 Compound 18 (2.4 g, 6.26 mmol) and 31 ml of 2N NaOH were dissolved in EtOH (310 ml) and warmed to reflux for 2 h. Cool the mixture and concentrate. To the residue were added 50 g of SiO 2 and 100 ml of MeOH. The mixture was concentrated under vacuum then purified by flash chromatography (diluent m/EtOAc/EtOAc/EtOAc/EtOAc/EtOAc 38.3%). i-NMRGOO MHz, CDC13): 5 11.3 (bs, 1H), 8.33 (dd, J = 5 Hz, 2 Hz, 1H), 7.87 (dd, J = 8 Hz, 2 Hz, 1H), 7.14-7.02 ( m, 2H), 6.52 (bs, 1H), 3.25-2.65 (m, 5H), 1.95-1.40 (m, 4H) (TLC dichloromethane / MeOH / 7N NH3 / MeOH (960/35/5)) 10 Rf 0.20) The second compound (19) obtained during this chromatography was obtained as a solid (0.71 g, 46.6%). Mp 272 ° C. h-NMRGOO MHz, D6DMSO): 5 11.38 (s, 1H), 8.17 dd, J = 5 Hz, 2 Hz, 1H), 7.87 ((dd, J = 8 Hz, 2 Hz, 1H), 7.02 (dd, J = 8 Hz, 5 Hz, 1H), 6.43 (d, J = 2 Hz, 15 1H), 5, 32-5.28 (bs, 1H), 3.5-3.43 (m, 1H), 2.97-2.88 (m, 2H), 2.84-2.64 (m, 3H), 2.24-2.12 (m5 2H), 1.48-1.37 (m? 2H), l-33-1.24 (m, 1H). (TLC di-methane/MeOH/7N NH3 /MeOH (960/35/5)) Rf 0.09) 〇2〇 Compound 20 (0.54 g, 2.4 mmol), 0.76 g of ammonium formate (12 mmol)

It was combined with 20% Pd(〇H) 2/C (54 mg) in MeOH (50 ml) and warmed to reflux for 2 h. The mixture was cooled, filtered, concentrated and redissolved in MeOH then filtered over EtOAc. Purification by flash chromatography (dichloromethane / MeOH / 7 N NH3 / MeOH 50 </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Mp 190 ° C. NMR (400 MHz, CDC13): 5 11 65 (bs 1H), 8.21 (dd, J = 5 Hz, 2 Hz, 1H), 7.88 (dd, J = 8 Hz, 2 Hz 1H), 7.06 (dd, J = 8 Hz, 5 Hz, 1H), 6.34 (s, 1H), 3.46-3.37 (m 5 1H), 3.29-3.20 (m, 2H), 3.03-2.93 (m, 3H), 2.91-2.80 (m, 1H) 2.27-2.21 (m5 1H), 1.90-1.78 (m, 2H), 1.7 (M.60 (m, 1R) 1.43-1.33 (m, 1H). 1-styl-methyl-specifically, r2, 3_b~KL bit -2-) 23) LDA (THF/heptane, 2. 〇Μ) (28ηι1^ό mmol) was added to 200 ml of anhydrous THF at -10 °C, N2. A solution of the hepatitis D containing the compound 17Q4.Mg 111111〇1) (2〇1111) was added dropwise. After joining, at -1 〇. 〇: -0 ° 〇 The obtained solution was stirred for 30 minutes. The temperature was then lowered to -70 °C. At this temperature, a solution of 2 (11.5 g, 60.8 mmol) in 25 ml of THF (1 min) was added dropwise. The free domain of the HCl salt of 1-benzyl-acridine-3-one (2) obtained in the market of 15 was obtained by filtration on SCX-2 (MeOH, followed by 1 N NHVMeOH) and subsequent evaporation. After the addition of 2, the temperature was raised to -35 ° C to 30 ° C, and the resulting solution was stirred for 2 hours. Allow the solution to warm to ambient temperature and pour into nh4C1 solution (10 g / 50 ml H20). Ethyl acetate was added and the organic layer was washed with EtOAc EtOAc EtOAc EtOAc The residue was purified by flash chromatography eluting elut elut elut elut elut elut elut iH-NMRGOO MHz, CDC13): 5 8.31 (dd, J = 5 Hz, 2 Hz, lH), 8.10-8.05 (m, 2H), 7.55 (dd, J = 8 Hz, 2 Hz, 1H), 7.51-7.45 ( m,1H), 7.41-7.24 (m, 51 200819448 7H), 7.09 (dd, J = 5 Hz, 8 Hz, 1H), 6.80 (s, 1H), 4.97-4.86 (bs, 1H), 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, 1H), 1.96-1.83 (m, 1H), 1.68- 1.44 (m, 2H). (TLC 二乙 _ Rf0.2). 5 Compound 22 (1.49 g, 3.3 mmol) and 3.1 ml of 2N NaOH were dissolved in MeOH (3 ml) and warmed to reflux for 2 h. Cool the mixture and concentrate. Ethyl acetate was added and the organic layer was washed with EtOAc EtOAcjjjjj The residue was purified by EtOAc (EtOAc) Recrystallization from ethyl acetate / diisopropyl ether. Yield: 〇·68 g, 66.5%. Mp 122-126°C° !Η-ΝΜΚ(400 MHz, CDC13) : δ l〇.9(bs,1H), 8.26(dd,J = 5 Hz, 2 Hz, 1H), 7.84 (dd, J = 8 Hz, 2 Hz, 1H), 7.34-7.22 (m, 5H) 7.02 (dd, J = 5 Hz, 8 Hz, 1H), 6.28 (d, J = 2 Hz, 1H), 3.98-3.86 (bs, lH), 3.59 (dd, J gem = 13 Hz, 15 2H), 2.93 - 2.83 (m, 2H), 2.45 - 2.39 (m, lH), 2.25 - 1.95 (m, lH), 2.04-1.80 (m, 3H), 1.75-1.66 (m, 1H) (TLC diethyl ether Rf 0.2). 3-indole-pyrrolo-f2,3-blpyridin-2-y)-acridin-3-ol (Compound 24) Compound 23 (3.07 g, 10 mmol), 3.5 g of ammonium formate (58.3 mmol) and 20%? (1(011)2/(:(34〇11^)) was dissolved in ^^011 (10〇1111) and heated to reflux for 1 hour. The mixture was cooled, filtered, concentrated and redissolved in MeOH The title compound 24 (without SB, 1.73 g) was purified by flash chromatography eluting with EtOAc EtOAc EtOAc , 80% piH_ NMR (400 MHz, D6 DMSO) ·· 5 11.4 (bs, 1H), 8.15 (dd, J = 5 52 200819448

Hz, 2 Hz, 1H), 7.84 (dd, J = 8 Hz, 2 Hz, 1H), 7.01 (dd, J = 8 Hz, J = 5 Hz, 1H), 6.32 (bs, 1H), 5.24-5.0 (bs, 1H), 2.99_2.85 (m, 3H), 2.63-2.56 (m, 1H), 2.12-2.02 (m, 1H), 1.97-1.75 (m, 2H), 1.51-1.42 (m, 1H) ). (TLC MeOH/triethylamine (97/3 Rf 0.26). 5 2-Azulidine-3-yl-1H-pyrrolof2,3-blpyridine Hh厶# Compound 24 dissolved in 75 ml of 6N HCl ( 1.73 g, 7.97 mmol) was heated to reflux for 18 h. The mixture was cooled and concentrated, crystallised from ethyl acetate/EtOAc to afford compound 25 (1.99 g, 92% (as hexanes)) mp 10 1H), 8.33 , J = 5 Hz, 2 Hz, 1H), 8.24 (dd, J = 8 Hz, 2 Hz, 1H), 7.30 (dd, J = 8 Hz, J = 5 Hz, 1H), 6.89-6.85 (m, 1H), 6.42 (bs, 1H), 4.1 (M.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 15 mg) were co-dissolved in 100 ml of MeOH and hydrogenated at 50 psi for 1 hour. Filtration and subsequent filtration on 30 g of SCX-2 (MeOH followed 1 N NH3 /MeOH) afforded compound 26 (1.06 g, 84%) with 1 equivalent of fumaric acid in EtOH Reaction and concentration. Recrystallization from EtOH / ethyl acetate afforded a solid (free / / / / / / / / / / / / / / / / / / ·· (5 12.75(bs, 1H), 8.33 (dd, J = 5 Hz, 2 Hz, 1H), 8.24 (dd, J = 8 Hz, 2 Hz, 1H), 7.30 (dd, J = 8 Hz, J = 5 Hz, 1H), 6.89-6.85 (m, 1H), 6.42 (bs, 1H), 4· 10-4.04 (m, 2H), 3.34 - 3.27 (m, 2H), 2.65-2.58 (m, 2H) (TLC MeOH / triethylamine (97 / 3) Rf 0.14) 53 200819448 Using a chiral column (Chimlpak AD 20 # m, mo χ 4.6, MeOH/EtOH 1/1, 2 ml/min) Separation of enantiomerically pure isomers, 5 = 22 〇 11111 艮: 5.6 1^11 (26 VIII), ([〇:]1) 25+4 ((:1, toluene) and Rt: 8.3 min (26B), ([ a ] D25 -4 (c 1, toluene). 5 2-(lH_u than drink: _ 丨 2,3-bl η than carboxylic acid tert-butyl!!_(Compound 27) By the method described for compound 9, compound 26 (8·3 弘, 41.29 Methyl) was converted to the title compound (27). The yield was 1 〇 9 gr (36 21 mmol, 87.7%). mp 144-145 ° C. (TLC diethyl ether Rf 〇 2 〇). 10 _ (1 H· fox Pyridin-3-yl)-1Η-吼 rabbit complex pyridine (compound 28)

Compound 27 (0.54 g, 1.8 mmol) was dissolved in 5 mi anhydrous thF. The resulting solution was slowly added to a stirred solution of LiAlH4 (0.2 g, 5.2 mmol) in 25 mL of dry THF (60 C, &amp; After stirring for 15 hours, 15 the mixture was cooled. To the obtained mixture, 〇 2 such as h 2 〇, 〇 4 ml 2 N NaOH and 0.2 ml of H20 were added under N 2 and warmed at 60 ° C. The mixture was cooled, filtered, washed with MeOH then filtered with &lt;RTI ID=0.0&gt;&gt; Purification by flash chromatography (Me0H / triethylamine (97/3)) afforded the title compound 28 (0.32 g, 83%) as a solid, The diacid reacts and is concentrated. Recrystallization from Et 〇 H / ethyl acetate afforded a solid ( s. 47 g, free domain / fumaric acid (1: ;)), mp > 218 ° C (decomposition). NMR (400 MHz, D6 DMSO): 5 11.58 (bs, 1H), 8.13 (dd, J = 5 Hz, 2 Hz, 1H), 7.83 (dd, J = 8 Hz, 2 Hz, 54 200819448 1H), 7.00 ( Dd, 卜 8 Hz, 5 Hz, 1H), 6.56 (s, 2H), 6.20 (bs, 1H), 3.36-3.30 (m, 1H), 3.18-3. 〇 4 (m, 2H), 2 56_2 5 〇(m,1H), 2 47 (s9 3H)? 2.41-2.32(m? 1H)9 2.11-2.03(m? 1H)? 1.86.1.67(m5 2H), 1.58-1.45 (m, 1H). ' 5 k guanidin-3-yl·1·Ιίι1 ratio pyridine compound 29B) Compound 27 (5.95 g, 19.7 mmol) and 5 g of m-chloro-p-benzoic acid (23 2 mmol) were dissolved in dimethoxyacetamidine. (6〇ml), stir up the clock at room temperature. The reaction was concentrated under vacuum. The residue obtained was dissolved in ethyl ethyl acetate, washed with 2N NaHH, dried (NaJO4), filtered and evaporated. The mixture was fractionated on Si〇2 and purified by flash chromatography (ethyl acetate / MeOH / triethylamine (90/10/1)) to afford compound 29A

Shape, 5.48 g, 87.5%). LCMS ; Rt: 1.50 min, ([M+H]+ = 318), (TLC

MeOH/ethyl acetate / triethylamine (10/90/1 Rf 〇. 46). Compound 29A (0.44 g, 1.38 mmol) was converted to the title compound (29B). The title compound (29B, HCl salt) was obtained as a solid (0.33 s, 95%). 11^&gt;245°(:(decomposition).1^1^; Rt · 0.63 min5 ([M+H]+ = 218), 'H-NMR (400 MHz5 D20) : δ NrH not visible, 8.20-8.16 (m, 1H), 8.10-8.05 (m, 1H), 20 7.25_7.20 (m, lH), 6.53 (bs, 1H), 3.64_3.57 (m, 1H), 3.40-3.33 (m, 1H) ), 3.31_3.22 (m, 1H), 3.10 (bt, J = 10 Hz, 1H), 2.99-2.90 (m, 1H), 2.19-2.12 (m, 1H), 2.0M.94 (m, 1H) ), 1.85-1.66 (m, 2H). Gas-2-biting-3-yl-ΙΗ-πί^ each "2,3-bHb pyridine compound 32" and 55 200819448 yl-1H-pyrrole "2 , 3-bl pyrimidine, compound 29 Α (4·87 g, 15.36 mmol) and 3.4 ml 1,1,1,3,3,3-hexamethyldioxane (16.30 mmol) co-dissolved in 100 In ml THF, 3.2 ml (41.4 mmol) of methyl decanoate was added to the bath, and the mixture of the reaction 5 was stirred under reflux for 1.5 hours. The reaction was cooled and concentrated under vacuum. Washed with 5% aq. NaHCO3, then brine, dried (Na.sub.2.sub.4), filtered and concentrated in vacuo. Purification provided Compound 30A (amorphous, 2.08 g, 34.4% &gt; (TLC diethyl ether / PE (1/1) 10 Rf 〇·Π). The second compound (31A) obtained during the chromatography was obtained as an oil (2.7) g, 44.6%) (TLC diethyl ether / PE (1/1) Rf 〇·〇8) The domain cleavage of Ν1_carbamate was carried out according to the method described for compound 12. For this purpose, compound 30 Α ( 2·08 g, 5.29 mmol) was dissolved in 75 ml of MeOH containing 20 ml of 2N NaOH, and the mixture was applied at room temperature. The mixture was concentrated under vacuum. The residue obtained was dissolved in dichloromethane. Washing with 5% NaHC〇3 solution, followed by brine (NaJCU), filtered and concentrated in vacuo. Purification by flash chromatography (diethyl ether/PE: 1/1) affords compound 3 〇B Set 98%) (TLC diethyl ether / PE (1/1) Rf 〇 · 21) LCMS 匕 ' · 2·33 20 min, ([M+H]+ = 336). Compound 31 Α (0·35 g, 〇·89 mmol) was dissolved in containing 2

NaOH in 8 ml of MeOH was stirred at room temperature for 18 hours. The reaction is condensed under true *. The residue obtained was dissolved in dichloromethane, washed with 5% &lt;RTI ID=0.0&gt;&gt;&gt;&gt;&gt; Compound 31B (amorphous, 0.1 g, 33%) was obtained by re-purification by flash chromatography (diethyl ether/PE: 1/1). (TLC diethyl ether Rf 0.3). LCMS; Rt: 2.27 min, ([M+H]+ = 336). 2 ml of acetamidine chloride was slowly added to 40 ml of EtOH (10 QC). After 15 minutes 5, the solution was added to compound 30B (1.67 g, 5 mmol) The mixture was cooled, partially concentrated, ethyl acetate was added, and the obtained precipitate was collected by filtration and washed with diisopropyl ether. The title compound 6-gas-2-private bite 3-yl-1 Η-ϋbilozepine [2,3-b]吼. 1032 (HC1 salt) was obtained as a solid (1.29 g, 100%). Mp &gt; 290 ° C (decomposition). !H-NMR (400 MHz5 D6DMSO): δ 12.0 (bs, 1H), 7.93 (d, J = 8 Hz, 1H), 7.08 (d, J = 8 Hz, 1H), 6.31 (d, J = 2 Hz) , 1H), 3.58-3.49 (m, 1H), 3.34-3.24 (m, 2H), 3.15-3.02 (m, 1H), 2.92-2.79 (m, 1H), 2.18-2.10 (m, 1H), 1.94 -1.80 (m, 2H), 15 1.78-1.64 (m, 1H). Separation of the corresponding isomeric pure isomers was achieved using a chiral column (Chiralpak AD-H 5um, 250 x 4.6, 100% EtOH + O.l% diethylamine, 0.5 ml/min). 5 = 220 nm, Rt: 18.4 min (32 A), ([a] D25-10 (c 1, toluene) and 艮: 25.2 11^11 (326), ([〇:]〇25+10((:1) , toluene. 20 Both isomers were reacted with 1 equivalent of fumaric acid in EtOH and concentrated. Recrystallization from EtOH / ethyl acetate provided solid (free domain / anti-butene) Acid (1:1)), mp &gt; 206QC (decomposition) 0.22 ml of acetamidine chloride was slowly added to 5 ml of EtOH (-10 ° C). After 15 minutes, the solution was added to compound 31B (0.1 g, 0.3). Methyl), heated to back to 57, at the end of the period of </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Guarin-3_yl-1H-pyrrolo[2,3-7]pyridine (HC1 salt), (52 mg, 64%).mp &gt; 5 250 ° C (decomposition) · nMR (400 MHz, D2〇 ··· 5 ΝγΗ is not visible, 8.30 (bd, J = 8 Hz, 1H), 7.39 (bd, j = 8 Ηζ, 1Η), 6.63 (bs, 1H), 3.66-3.58 (m, 1H), 3.42 3.23(m,2H),,3.16-3.06(m,1H), 3.0-2.90(m? 1H)? 2.23-2.14(m? 1H)? 2.04-1.92(m5 1H)? 1.86-1.67(m,2H ) 10 Methyl-1H-pyrrolo[~2·3_]ί1 is hn called h compound 39A) and burns 2_yl group 皋_出-也嘻 and "2.3-hl pyridine to servate compound 39B" - 1〇°[, Wherever, add 12 ml (24 with 〇1) to the anhydrous THF' solution (75 mi) containing compound 17 (62匕24 〇1) [〇八( in τ ̄ heptane 15 '2·0 M). After the addition, in the 〇 〇 〇 对 对 对 对 对 对 对 对 对 对 对 对 授 授 授 授 授 授 授 授 授 授 授 授 授 授 授 授 授 授 授 授 授 授 授 授 授 授 授 授 授 授Solution (1 〇 min). After adding 35, the temperature was raised to -20 C, and the resulting solution was subjected to 2 hours of disruption. The mixture was allowed to warm to ambient temperature and stirred for another 2 hours. 20 Condensation reaction mixture , dissolve the residue in 40 ml IN HC1, 40 ml

EtOH and 40 ml in THF. In (iv) the mixture was put down for 8 hours. The reaction mixture was concentrated under vacuum. The residue obtained was dissolved in ethyl acetate, washed with 2N EtOAc EtOAc (EtOAc) Purification by flash chromatography (MeOH/Ketamine 97/3) provided the compound emblem (no. 58 200819448 stereotype, 3.63 g, 44%). W-NMK^OO MHz, CDC13): δ 8.35 (bd, J = 5 Hz, 1H), 8.09 (bd, J = 8 Hz, 2H), 7.67 (bd, J = 8 Hz, 1H), 7·57 · 7.41 (ηι, 3H), 7.12 (dd, J = 8 Hz, 5 Hz, 1H), 6.46 (s, 1H), 3.70-3.58 (m, 1H), 3.39-3.31 (m, 1H)? 3.23-3.15(m? 1H), • 5 3.13-3.〇3(m,1H), 2.98-2.86(m,1H),2.10-1.70(m,3H), - L5:M.44(m, 1H). (TLC MeOH / triethylamine 97/3 Rf 0.18). LCMS: Rt: 1.27 min, ([M+H]+ = 342).

Compound 38 Α (3·63 g, 10.6 mmol), 11 g KOH and 22 ml hydrazine [monohydrate dissolved in 2-(2-hydroxy-ethoxy)-ethanol (100 ml) at 10 10 〇 Stir at °C for 1 hour. Add ethyl acetate to the cooled reaction with 2N

The resulting organic layer was washed with EtOAc EtOAc (EtOAc)EtOAc. The mixture was dissolved in MeOH and filtered on 40 g EtOAc EtOAc. Subsequent purification by flash chromatography (Me EtOAc / EtOAc (EtOAc) (EtOAc) (Amorphous, M2 g, 66%) ([α ]d25 _5〇(c ^ ; f benzene)' which reacts with one equivalent of fumaric acid in Et〇H and is concentrated. 11/ethyl acetate recrystallization provided solid (free domain / fumaric acid (1 · 1)), mp &gt; 163 ° C (decomposition). NMR (4 〇〇 MHz, D6DMs 〇): 11.7 ( Bs, 1H), 8.13 (dd, J = 5 Hz, 2 Hz, 1H), 7.84 (dd, J = 8 20 Hz, 2 Hz, 1H), 7.0 (dd, J = 8 Hz, 5 Hz, 1H) , 6 51 (s, 2H), 6 32 (s9 1H) 9 3.85-3.77 (m? 1H)? 3.26-3.04 (m? 4H)? 2.09-1.80^ 3H), 1.71-1.61 (m, 1H). ' (8)-2-t each of the hospitals using the method described for compound 39A to obtain (2) 3 ratios.定(合合59 200819448物39B). ([a]D25 +50(c 1,toluene). (Min) Di-2-(1-methylpyrrolidine-2_ylcarboxamide) (Compound 41A) and (g)-2 - (1 - Methyl-pyrrole % ^ and "2,3-blpyridine (Compound 41B) 5 Compound 38A (0·39 g, 1-14 mmol), 〇·5 g NaBH (〇Ac^ and 0.2 ml formaldehyde (37%) Dissolved in dichloroethane (15-claw) and stirred at room temperature for 1 h. The reaction was concentrated in vacuo. The mixture was concentrated under vacuum to give 40A (amorphous, 0.40 g, 98%). 10 MHz, CDC 13): δ 8.35 (dd, J = 5 Hz, 2 Hz, 1H), 8.12-8.07 (m, 2H) ), 7.69 (dd, J = 8 Hz, 2 Hz, 1H), 7.56-7.41 (m, 3H), 7.12 (dd J = 8 Hz, 5 Hz, 1H), 6.40 (s, 1H), 3.73 - 3.67 (m, 1H), 3.16-3.10 (m, 1H), 2.87-2.73 (m, 2H), 2.47 (s, 3H), 2.33 - 2.25 (m, 1H), 1.95-1.50 (m, 4H). Compound 40 Α (〇·4 g, 11.2 mmol), ll g KOH and 2.2 ml hydrazine monohydrate were co-dissolved in 2-(2-hydroxy-ethoxy)-ethanol (1 〇ml) at 100 槚Mix for 1 hour. Add acetic acid to the cooled reaction. The resulting organic layer was washed with 2N NaOH, dried (EtOAc EtOAc), filtered and concentrated in vacuo. The mixture was dissolved in Me0H* at 4 〇g scx_2 (Me〇H, 20 after 1 NNI^/ The title compound 41A (solid, 〇 19 g, 76%) was obtained eluted with EtOAc (EtOAc) 1, toluene). ηη·Ν]·(4〇〇MHz, CDC13): 6 l〇.4(bs,1H), 8.18 (dd, J = 5 Hz, 2 Hz, 1H), 7.79 (dd, J = 8 Hz, 2 HZ, 1H), 6.99 (dd, J = 8 Hz, 5 Hz, 1H), 6.18 (bs, 1H), 60 200819448 3.18-3.07 (m, 2H), 2.90-2.83 (m, 1H) ), 2.61-2.53 (m, 1H), 2.45 (S, 3H), 2.25 々.17 (m, 1H), 1.89-1.79 (m, 1H), 1.69-1.43 (m, 3H). Using the method described for compound 41, (8)_2_(1_methyl-5pyrrolidin-2-ylmethyl)_1H-pyrrolo[2,3_b]pyridine (compound 4ib) was obtained. ([a]D -42(c I toluene).mp 130-131〇C. Each calcination_2_1曱基·1ΙΚ 佑||2,3-blpyridine (compound 45A) and alk-2-yl group丄仏pyrrolo and 2,3_bl gold (compound 45 Β;) 10 In a hydrazine, 6-chloro-7-azaindole (9.3 g, 61.1 mmol) prepared as described in (Synthesis, 1992) was dissolved in 1 〇〇 ml of anhydrous THF. Add 〇c to a 60 〇 / 〇 dispersion of NaH 3.5 g (65.9 mmol) in mineral oil. After shaking for 1 hour at room temperature, the mixture is cooled (〇 ° C) 8.7 ml (67.2 mmol) of benzene was dissolved in 2 ml of anhydrous THF. The mixture of the reaction 15 was stirred at room temperature for 1 hour. Ethyl acetate was added to the mixture, and the mixture was stirred with saturated NaHC? The layers were washed three times, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (diethyl ether/PE gradient 1:1 to pure diethyl ether) to give 1-phenylsulfonyl- 6 Chloro-1H-pyrrolo[2,3-b]pyridine (amorphous, μ 4 g, 8 〇 7% x TL diethyl ether / pe (1/1) Rf 20 0.37). LCMS; Rt: 1.98 min, ( [M+H]+ = 293) -78 ° C, in N2, containing the compound I-benzene To a solution of p-[2,3-b]pyridine (2.52 g, 8.6 mmol) in dry THF (100 ml), EtOAc (EtOAc (EtOAc) The resulting solution was stirred at -78 ° C for 6 minutes. At this temperature, a solution of 61 200819448 35 (1.4 g, 8.6 mmol) in 10 ml of THF was added dropwise (5 minutes). After adding %, the temperature was raised. Up to 1 C, the obtained solution was allowed to stand for 2 hours. The mixture was allowed to warm to ambient temperature and stirred for another 2 hours. The reaction was quenched and the residue was dissolved in 5 volumes, 40 ml Et0H and 4 The mixture was subjected to i8 hours of sandalwood mixing. The reaction mixture was concentrated under vacuum. The obtained residue was added to acetic acid, washed with 2NNa〇H, dried (Na2S〇4), and transferred. Concentration under vacuum. Drying by flash chromatography (Me〇H/triethylamine 98/2) afforded (R)-l-phenylsulfonyl-6-chloro-2-pyrrolidine-2-yl Methyl_ιη· 10 pyrrolo[2,3-b]pyridinium (amorphous, 10! g, 31%) (TLC Me〇HG ethylamine 98/2 Rf 0.32). (R)-l- Phenylsulfonyl-6-aero-2-pyrrolidin-2-ylmethyl·ιη_pyrrolo[2, 3_b]pyridine (1.01 g, 2.69 mmol), 20 ml of 2 NaOH and 30 ml of isopropyl alcohol were combined and stirred at 100 ° C for 3 hours. Add B 15 ethyl acetoacetate to the cooled reaction, wash the organic layer with 2N NaOH, and dry (Na2s 〇 4).

Filter and concentrate under vacuum. The mixture was dissolved in Me 〇 H and allowed to pass on i </ RTI> </ RTI> <RTIgt; </RTI> <RTIgt; The title compound 45A (solid, 366 mg, 58%). ([ a ]D25 -48(c 1,toluene).b-NMRGOO 20 MHz,CDC13) : 5 11.0-10.0(bs,1H),7.52(d,J = 8 Hz,1H), 7.01(d,J = 8 Hz, 1H), 6.16 (s, 1H), 3.50-3.42 (m, 1H), 3.02-2.90 (m, 3H), 2.81-2.73 (m, 1H), 1.95-1.85 (m, 1H), 1.82_1.64 (m, 2H), 1.43_1.33 (m, 1H). Using compound 45 a with

One equivalent of fumaric acid in EtOH is reacted and concentrated. Recrystallization from ethyl acetate afforded a solid (free domain / fumaric acid (2: 1)), mp &gt; 222 ° C (decomposition) from Et. (S)-6-Chloro-2-pyrrolidin-2-ylmethyl-1H-pyrrolo[2,3-b]pyridine (Compound 45B) was obtained using the method described for compound 45A. ([a] D25 5 +44 (c 1, toluene). Compound 45B was reacted with 1 equivalent of fumaric acid in EtOH and concentrated. Recrystallization from EtOH / ethyl acetate afforded a solid ( Free domain / fumaric acid (1:1)), mp 189-190 ° C. &gt; odor 2-port biro-2-yl fluorenyl-1 Loa f2,3-bl ^ ratio p (4 chelate 46A) and bromo-2-.pyrrolidine-2-ylmethyl-1H-pyrrolo and 2,3-bl 10 pyridine (compound 46B) using the above method, according to (Synthesis, 1992) The prepared 6-bromo-7-azaindole (4.65 g, 23.6 mmol) was converted to 1-phenylsulfonyl-6-bromo-1H-pyrrolo[2,3-b]pyridine (solid, mp 121- 124 ° C) (7.57 g, 95%) 1H-NMR (400 MHz, CDC13): δ 8.28-8.22 (m, 2H), 15 7.70-7.50 (m, 5H), 7.32 (d, J = 8 Hz , 1H), 6.56 (d, J = 4 Hz, 1H). (TLC diethyl ether Rf 0.55). Using the method described above '1 - Benzene aryl-6- &gt; odor-1 Η-ϋ Biro[2,3-b]acridine (2·07 g, 6.1 mmol) is converted to (R)-l-phenylsulfonyl-6-bromo-2-indolebi-2-ylmethyl -1Η-ϋ比洛和[2,3-1)]πι^σ定(amorphous, 1.24 g, 20 48%). h-NMRGOO MHz, CDC13) : 5 8.21-7 .97 (m, 2H), 7.61-7.47 (m, 5H), 7.25 (d, J = 8 Hz, 1H), 6.46 (s, 1H), 3.65-3.57 (m, 1H), 3.37-3.31 (m , 1H), 3.09-3.03 (m, 1H), 2.96-2.89 (m, 1H), 2.06-1.73 (m, 3H), 1.54-1.45 (m, 1H). (TLC MeOH / triethylamine 97/3 R 0.22). 63 200819448 (R)-l-Benzenesulfonyl-6-bromo-2-pyrrolidin-2-ylmethyl-1H-pyrrolo[2,3-b]pyridine (1.24 g, 2.95 The mixture was stirred at 30 ° C for 30 min. Concentrate in vacuo. The mixture was taken up in MeOH and filtered on EtOAc EtOAc. The title compound 46A (amorphous, 630 mg, &lt;RTI ID=0.0&gt; ([a]D25 -50 (c 1, toluene), which is converted to its salt (free domain / fumaric acid (1:1)), iH-NMRGOO MHz, 10 D6 DMSO): 5 NrH is not visible, 7.82 (d, J = 8 Hz, 1H), 7.18 (d, J = 8 Hz, 1H), 6.49 (s, 2H), 6.38 (s, 1H), 3.82-3.72 (m, 1H), 3.27-3.05 (m, 4H), 2.09-1.80 (m, 3H), 1.7 (M. 60 (m, 1H). (s)_6-bromo-2-° was obtained (from 36) using the method described for compound 46A. Biloxy-2-ylmethyl-1 Η-declozolo[2,3-1)] oxime (Compound 46B). 15 ([a]D25 +50(c 1,toluene). (BQ-6·Fluorine is more than 2-methyl-lH-η than the absorption of [·2,3-Ϊ3ΐρι^. 47Α) and (g&gt;6-fluoro-2-pyrrolidine-2-J-based-丨η_pyrrolo-~2,3-bl pyridine (Compound 47B, Compound 55 (18 g, 161 mmol), 70 g of k2CO3 (506 mmol) 20 and 15·4 ml (161 mmol) of ethyl chloroformate were dissolved in CH3CN (400 ml) and stirred at 40 ° C for 4 days. TLC showed moderate conversion. Add 1541111 gas Ethyl formate, stirring was continued for another 2 days. The mixture was cooled, ethyl acetate was added to the mixture, and the organic layer was washed with saturated NaHC EtOAc solution, dried (Na.sub.2). (1:3)) 64 200819448 The residue obtained was purified to give (6-fluoropyridin-2-yl)-carbamate (56) (amorphous, 19.68 g, 66.5%). W-NMRGOO MHz, CDC13 ··· 5 7.83 (dd, J = 8 Hz, 2 Hz, 1H), 7.80-7.73 (m, 1H), 7.50-7.40 (bs, 1H), 6.61-6.57 (m, 1H), 4.25 (q, J = 8 Hz, 2H), 5 1.32 (t, J = 8 Hz, 3H) ° (TLC diethyl ether / PE l / lRf 0.5). Add 28.6 ml (0.18 mol) of TMEDA to dissolve in 300 ml without A solution of compound 56 (13.41 g, 72.9 mmol) in water THF. The mixture was cooled to -78 ° C (in N2). To the stirred reaction mixture was added 76 ml (2.5 M n-BuLi). The mixture was stirred at -78 ° C for 2 hours. After adding 10 I 2 (48 g, 0.17 mol), the mixture was stirred at -78 ° C for 1 hour. Then the reaction mixture was quenched with saturated Na 2 S 203 solution to warm it to The organic layer was washed with a saturated solution of NaHCO.sub.3, dried (Na2SO4), filtered and concentrated. The residue gave (6-fluoro-3-iodo-pyridine 15- 2yl)-carbamate (57) (amorphous, 15.86 g, 70%). MHz, CDC13): 5 8.07 (bt, J = 8 Hz, 1H), 7.24 - 7.14 (bs, 1H), 6.49 (dd, J = 8 Hz, 3 Hz, 1H), 4.29 (q, J = 8 Hz, 2H), i.35 (t, j = 8 Hz, 3H). (TLC diethyl ether / PE 1 / 1 Rf 0.27) 〇 stirred compound 57 (4 g, 12.9 mmol), 3.3 ml (23.4 20 mmol) TMSA (ethynyl tridecyl-decane), 246 mg (1.29 mm 〇1) a mixture of molybdenum (I), 454 mg (0.65 mmol) PdCl2 (PPh3) 2 (454 mg, 〇·64 mm〇i) and triethylamine (6.3 ml), degassed (NO. obtained at 100QC) The reaction mixture was stirred for 10 minutes (closed), cooled, and poured into a br. br. br. br. br. br. br. br. br. / ΡΕ (1/3)) Purify the residue to give (6-fluoro-3-trimethyldecyiethynylpyridin-2-yl)-carbamic acid ethyl ester (58) (oil, 1.5 g, 42%) WNMR (200 MHz, CDC13): δ 7.76 (bt, J = 8 Ηζ, 1 Η), 7.68-7.60 (bs, 1H), 6.56 (dd, J = 8 Hz, 3 Hz, 1H), 4.29 (q, J = 8 5 Hz, 2H), 1.34 (t, J = 8 Hz, 3H), 0.3 (s, 9H). (TLC diethyl ether/PE 1/1 Rf 0.39). Compound 58 (6 g, 21.4 mmol) And a mixture of 8.2 g (43 mmol) of copper (I) is dissolved in 100 ml of DMF and degassed for 0.5 hours. The reaction mixture is mixed at 150 ° C (preheated oil bath) Stirring was carried out for 30 minutes. The mixture was combined with EtOAc EtOAc (EtOAc m. Purification of compound 59 (amorphous, 2.58 g, 12.4 mmol, 57, 9%), 1H-NMR (200 MHz? CDC13): δ 7.95 (bt, J = 8 Hz? 1H)? 7.69 (d? J = 4 Hz, 1H), 6.87 (dd, J = 8 Hz, 2 Hz, 1H), 6.57 (d, J = 4 Hz, 15 1H), 4.55 (q, J = 8 Hz, 2H), 1.49 ( t, J = 8 Hz, 3H. (TLC diethyl ether/PE l/l Rf 〇·42). Compound 59 (2.58 g, 12.4 mmol) was dissolved in 50 ml MeOH and 20 ml 2 N NaOH. The reaction mixture was stirred for 30 minutes. Ethyl acetate was added to the mixture and the organic layer was washed with 5% aqueous NaHCO3, dried (Na2SO4), filtered and concentrated to give 6-fluoro-1H-pyrrole as a semi-solid. [2,3-b]pyridine (6-fluoro-7-azaindole, compound 44) (1.68 g, 12.3 mmol, 99%). NMR (400 MHz, CDC13): 5 9.6 (bs, 1H), 7.95 (bt, J = 8 Hz, 1H), 7.31-7.27 (m, 1H), 6.75 (dd, J = 8 Hz, 2 Hz, 1H ), 6.55-6.50 (m, 1H). (TLC hexane 66 200819448 ether / PE (1/1) Rf 0.34). LCMS; Rt: 1.39 min, ([M+H]+ = 137). 6-Fluoro-7-azaindole (Compound 44, 1.72 g, 12.6 mmol) was reacted with benzenesulfonyl chloride according to the procedure described for the synthesis of 45A/B to give 1-phenylsulfon-5-mercapto-6 -Fluoro-1H-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). ; Rt : 1.79 min, ([M+H]+ = 277). Conversion of 1-phenylsulfonyl-6-fluoro-1H-indolo[2,3-b]acridine (0.8 g, 2.9 mmol) to (R)-l using the method described for 45A/B -Benzenesulfonyl 10 -6-gas-2-indolebiprofen-2-ylmethyl-1H- °pirox [2,3-b]. Specific bite (amorphous, 0.31 g, 30%). (TLC MeOH / triethylamine (97 / 3) Rf 0.28). (R)-l-Benzenesulfonyl-6-fluoro-2-pyrrolidin-2-ylmethyl-1H-pyrrolo[2,3-b] was used under the conditions described for 45A/B. Bipyridine (0.26 g, 0.72 mmol) was converted to (R)-6-fluoro-2-pyrrolidin-2-ylmethyl·1Η-indolo[2,3-b]acridine 15 (Compound 47A, 90 mg, 57%). The title compound 47A (amorphous), ([a]D25-38 (c 1, toluene) is converted to its (amorphous) salt (free domain / fumaric acid (1:1)), iH-NMRGOO MHz ? D6 DMSO) : δ 12.2-11.7 (bs, 1Η), 8.0 (bt, J = 8 Ηζ, 1Η), 6.76 (bd, J = 8 Hz, 1H), 6.51 (s, 2H), 6.37 (s, 1H) ), 3.83 - 3.74 (m, 20 1H), 3.26 - 3.03 (m, 4H), 2.10 - 1.79 (m, 3H), 1.71-1.61 (m? 1H). (TLC MeOH / triethylamine (97 / 3) Rf 0.22). (S)-6-Fluoro-2-pyrrolidin-2-ylmethyl-1H-pyrrolo[2,3-b]pyridine (Compound 47B) was obtained (from 36) using the method described for compound 47A. ([a] D25 +38 (cl, toluene). 67 200819448 yl-2-pyrrolidine-2-ylmethyl-1H-pyrrolo-[2.37- inflammatory (compound 49) using the compound Method, converting (R)-6-bromo-2-pyrrolidin-2-ylindenyl-1H-pyrrolo[2,3-b]pyridine (46A, 0.67 g, 2.39 mmol) to 5 as anthracene. (Boc protected) analog 48 (amorphous, 0.72 g, overall 79%) 〇 NMR (400 MHz? CDC13): ά 9.4 (bs5 1H)? 7.66 (bd, J = 8 Hz, 1H), 7.18 (bd, J = 8 Hz, 1H), 6.19 (bs, lH), 4.10-4.03 (m, 1H), 3.42-3.25 (m, 2H), 3.16-3.07 (m, lH), 10 3.04-2.88 (m, 1H), 2.0-1.89 (m, 1H), 1.8-1.63 (m, 3H). Compound 48 (0.34 g, 0.89 mmol) was dissolved in 4 ml DMF and 2·5 ml MeOH (in N2) To the mixture were added 1.6 g (29·6 mmol) of NaOMe and 0.25 g (1.74 mmol) of copper (I), and the mixture was stirred at room temperature for 1 hour. The organic layer was dried (Na2SO4), filtered and evaporated in vacuo. The purified residue was purified by flash chromatography (diethyl ether) to afford Precursor (〇.32g, 56%). (TLC diethyl ether Rf 0.8) NMR (400 MHz, CDC13): 5 8.7 (bs, 1H), 7.68 (bd, J = 8 Hz, 1H), 6.52 ( Bd, J = 8 Hz, 1H), 6.1 (bs, 1H), 4.11-4.01 (m, 20 1H), 3.94 (s, 3H), 3.46-3.23 (m, 2H), 3.18-2.96 (m, 1H) ), 2.93-2.78 (m, 1H), 1.97-1.84 (m, 1H), 1.83-1.71 (m, 3H), 1.51 (s, 9H), which is deprotected (as described above, HCl/EtOH) The title compound (49) (amorphous, hygroscopic) was obtained as the HCl salt. The yield was 〇·180 mg (80%) ^ ([a ]D25 -12 (c 1? MeOH). LCMS ; Rt : 1.17 68 200819448 min, ([M+H]+ = 232). Compound 49 (free domain obtained after filtration of HC1 salt on SCX-2) was converted to its salt (using the method described above) (free domain / Fumaric acid (1:1), amorphous), iH-NMRGOO MHz, D6DMSO): δ 11.61 (bs, 1 Η), 7.75 (d, J = 8 Ηζ, 1 Η), 6.49 (s, 5 2H) , 6.47 (d, J = 8 Hz, 1H), 6.21 (s, 1H), 3.84 (s, 3H), - 3.78-3.71 (m5 1H), 3.23-3.18 (m, 1H), 3.14 - 3.08 (m , 1H), 3.01-2.95 (m, 1H), 2.05-1.80 (m, 3H), 1.67-1.59 (m, 1H). (R)-5-bromo-2-pyrrolidin-2-ylmethyl-1H-pyrrolo[2,3-blpyridine (Chemical Compound 52A) and (S)-5-bromo-2-pyrrolidine- 2-yl-methyl-1H-pyrrolo-&quot;2.3-bl 10 pyridine (Compound 52B) Commercially available 5-bromo-7-azaindole (5.19 g, using the method described for 45A/B) 26.3 mmol) was converted to 1-phenylsulfonyl-5-bromo-1H-pyrrolo[2,3-b]pyridine. Solid, mp 141-142 ° C. (6.9 g, 78%) i-NMR (400 MHz, CDC13): 3 8.45 (d, J = 2 Hz, 1H), 8.19-8.15 (m, 15 2H), 7.98 (d, J = 2 Hz, 1H) ), 7.74 (d, J = 4 Hz, 1H), 7.62-7.47 (m, 3H), 6.55 (d, J = 4 Hz, lH) 〇 LCMS; Rt: 1.92 min, ([M+H]+ , =337). Using the method described for 45A/B, 1-phenylsulfonyl-bromo-bromo-bi-[2,3-b]. The specific bite (5.52 g, 16.3 mmol) was converted to (R) berbite xanthine 20-yl-5-bromo-2-pyrrolidine-2-ylmethyl-1H-pyrrolo[2,3-b]pyridine ( A mixture of amorphous '3_02 g' compounds containing approximately 7% of the expected c2_regioisomer regi〇isorner). (TLC MeOH/triethylamine (97/3) Rf 0.3) </ RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; Using the method described for 45A/B (repeated flash chromatography), will contain 69 200819448 (R) small benzenesulfonyl-5-bromo-2-pyrrolidin-2-ylmethyl-1H-pyrrole The above mixture of [2,3-b]pyridine (3.02 g, ca. 7 ι mmol) was converted to the title compound 52A (amorphous, 〇.5 g, approximately 25°/.) which was converted to its salt / fumaric acid (1:1), iH-NMRGOO MHz, D6DMSO): 6 NrH 5 not visible, 8.16 (d, J = 2 Hz, 1H), 8.06 (d, J = 2 Hz, 1H) , 6.46 (s, 2H), 6.3 〇 (s, 1H), 3.80-3.72 (m, 1H), 3.23 - 3.03 (m, 4H), 2.06-1.77 (m, 3H), 1674.57 (1^1H). (S)-5-Bromo-2-pyrrolidinylmethyl-1H-pyrrolo[2,3-b]pyridine (Compound 52B) was obtained (from 36) using the procedure described for compound 52A. 10 LCMS; Rt: 1.27 min, ([M+H]+ = 280). ([a] D25+38 (c 1, toluene). Methyl-2-pyrrolidine-2- 曱-1H-pyrrole and 2.3-bl pyridine (compound 53A) using the method described for 45A/B Convert 5-methyl-7-azaindole 15 (4.15 g, 31.4 mmol) to 1-phenylsulfonyl-5-methyl-1H-pyrrolo[2,3-b]pyridine (amorphous) , 7.07 g, 82%). b-NMRGOO MHz, CDC13): 6 8.25 (bd, J = 2 Hz, 1H), 8.19-8.15 (m, 2H), 7.66 (d, j == 4 Hz, 1H) , 7.62 (bd, J = 2 Hz, 1H), 7·58, 7·43 (ιη, 3H), 6.5l (d, J = 2 Hz, 1H), 2.38 (s, 3H). (TLC diethyl ether Rf 2 〇 〇e 52) ° LCMS; Rt: 1.75 min, ([M+H]+ = 273). Conversion of 1-phenylsulfonyl-5-methyl-1H-pyrrolo[2,3,b]indole (3.15 g, 11.5 mmol) to (R)-l using the method described for 45A/b - Phenylxanthyl-5-nonylpyrrolidene-2-ylmethyl-1Η_σ ratio Ρ Ρ, 3 七] ° 唆 (amorphous, 7·04 §, 610 / 〇). LCMS; Rt: 1.41 min, ([M+H]+ = 356). 70 200819448

I \ (R)-l_benzenesulfonyl-5-methyl-2-n-pyrrolidin-2-ylmethyl-1H-pyrrole and [2,3-b]° ratio bite (1 · 5 g, 4.22 mmol), 3.5 g KOH and 1 ml hydrazine monohydrate co-dissolved in 2-(2-hydroxy-ethoxy)-ethanol (25 ml) at l〇〇°C hour. MeOH was added to the cooled reaction and the reaction mixture was filtered with &lt;RTI ID=0.0&gt;&gt; The title compound 53A (amorphous, 〇·46 g, 50%) was obtained by purification by flash chromatography (Me0H / triethylamine (9 /2). ([a] D25 -10 (c 1, dioxane) which is reacted with 1 equivalent of fumaric acid in MeOH and concentrated to afford the title compound 53A (amorphous) Fumaric acid 10 (1:1)) 〇^. NMR (400 MHz 5D6 DMSO): 5 11.6 (bs? 1H)5 7.97 (bs, 1H), 7.63 (bs, 1H), 6.51 (s, 2H), 6.22 (s, 1H), 3.84-3.77 (m, 1H), 3.26-3.03 (m, 4H), 2.33 (s, 3H), 2.07-1.81 (m, 3H), 1.69-1.61 (m, 1H). k piroxicam-3-yl-ethyl raspberry oxime 2,3 pyridine (Compound 66) Stir 8 8.83 g (91 mm 〇i) methoxymethylamine (HC1 salt) in 200 ml anhydrous water (0〇C, under N2). Add 46·2...trimethylaluminum/toluene (2.5M), stir the mixture for 2·5 hours at 〇〇C. Add compound 62 (6) dissolved in benzene. 73 g, 30·7 curry 1), the obtained reaction mixture was subjected to (iv) at room temperature for 1 hour, and then saturated 20 NaHC0, C) and ethyl acetate were added to the mixture. The organic layer was washed with a 5% leg (10) solution - dried (Na2SO4), filtered and concentrated. The residue obtained by flash chromatography (10) ethyl acetate (1/9)) gave the benzylidene succinic acid-methyl-bristamine (compound 63, 6·76 g, 88.7%). Heart tenderness (400 MHz, CDC13): δ 7.38-7.22 (m, 5Η), 3.69-3.62 (m, 5Η), 71 200819448 3.45-3.35 (m, 1H), χ s, sister), 3 catch 2&quot; m •1〇C 'under ~, add 13 6 such as lda (tpengeng, 2 〇5) to an anhydrous THF solution (75 ml) containing compound 17 (7.2 g, 27·ι mm〇1) Μ) After the addition, the obtained solution was given for 3 minutes at _10 C_〇c. Then the temperature was lowered to - at this temperature, U mmol) solution in 25 mi of THF was added dropwise (1 min. ). After the addition of μ, the temperature was raised to -30 ° C (0.5 hour), and the obtained solution was stirred (3) in the _3 generation. Then use a saturated battle (: 1 solution in _3 〇〇 c to stop the mixture, let it warm to 10 ° C. Add acetic acid, wash the organic layer with 5% NaHc 〇 3, dry (NaJO4), filter and Concentration in vacuo. Purification by flash chromatography (diethyl ether followed by ethyl acetate) afforded compound 64 ( amorphous 5.38 g, 44.6%) LCMS; Rt: 1 · 27 min, ([M+H]+ = 342). Compound 64 (1.05 g, 2.35 mmol), 2 g KOH and 3.56 肼15 monohydrate were dissolved in 2_(2·hydroxy-ethoxy)-ethanol (20 ml) and stirred at 100 ° C. 30 minutes (under A), followed by stirring for 45 minutes at 2 ° C. Add ethyl acetate to the cooled reaction and wash the resulting organic layer with 2N NaOH 'dry (NajO4), filtered and under vacuum Concentration. The mixture was dissolved in MeOH and filtered on EtOAc (EtOAc over EtOAc EtOAc EtOAc. 65 (amorphous, 0.6 g, 83%). ιΗ_ NMR (400 MHz, CDC13): 5 10.65 (bs, 1H), 8.20 (dd, J = 5 Hz, 2 Hz, 1H), 7.80 (dd, J = 8 Hz, 2 H z, 1H), 7.37-7.20 (m, 5H), 7.02 (dd, J = 8 Hz, 5 Hz, 1H), 6.17 (s, 2H), 3.63 (dd, J gem = 72 200819448 13 Hz, 2H) , 2.95-2.90 (m, 2H), 2.77-2.54 (m, 4H), 2.43 - 2.38

(m, 1H), 2.12-2.02 (m, 1H), 1.65-1.55 (m, 1H). LCMS; Rt: 1.46 min, ([M+H]+ = 292). Compound 65 (0.52 g, 1.8 mmol), 0. 3 g ammonium citrate (4.7 mmol) and 20% Pd(OH) 2 / C (50 mg) were dissolved in 5 MeOH (10 ml) and warmed to Reflux for 1 hour. The mixture was cooled, filtered, concentrated and dissolved in MeOH. Subsequent filtration on 25 g of SCX 2 (MeOH, followed by 1 N NHVMeOH) gave the title compound: 2-[rhohhhhhhhhhhhhhhhhhhhhhhhh 66, 0.34 g, 94%), which was reacted with 1 equivalent of fumaric acid in MeOH and concentrated to give the title compound 66 (amorphous) (free domain / fumaric acid ( 1 : 1)). 'H-NMR (400 MHz5 D6 DMSO): δ 11.6 (bs? 1Η)? 8.11 (dd? J = 5 Hz, 2 Hz, 1H), 7.81 (dd, J = 8 Hz, 2 Hz, 1H), 6.99 ( Dd, J = 8 Hz, 5 Hz, 1H), 6.5 (s, 2H), 6.21 (bs, 1H), 3.29-3.22 (m, 2H), 3.17_3.09 (m, lH), 29〇_2 76(m,3H),2 72-261(m,m), 15 2·06-1·97(ιη' 1H), i.69_l 59(m,1H)(TLC Me〇H/triethylamine ( 97/3) Rf 〇.〇8) 0 A V1H-pyrrole Obipyridine (Compound 68) 20 Compound 66 (0.3 g, 1.49) was owed to compound 67 using the procedure described for compound 9. Yield: 0.362 g (80.7%). (TLC diethyl ether f 〇 11) &amp;&lt;RTIID=0.0&gt;&gt;&gt;&gt;&gt; NMR (400 MHz, CDC13) · δ Ki-H ώ 1 η not visible, 8.16 (dd, J = 5 Ηζ, 2 Hz, 1 Η), 7.77 (dd? J - Ήζ, 2 Hz, 1H), 6.98 (dd , J = 8 Hz, 5 Hz, 1H), 73 200819448 6.16(bs? ih)? 2.92-2.84(m5 2H)? 2.76-2.64(m? 2H)? 2.62-2.50(m? 2H)? 2.34(s 3H)? 2.40-2.31 (m? 1H)? 2.11-2.01 (m, 1H), 163-1.53 (1^ih) ° (TLC MeOH / triethylamine (97 / 3) Rf 〇 2). 5 base-1_proportionate pyridine (compound 78) 10 C 'N2 lower' To a solution of compound 17 (6.0 g, 23.2 mmol) in dry THF (75 ml), 12.5 ml (24 mmol) LDA (in THF) /Heptane in '2·〇M). After the addition, the reaction solution was stirred for 30 minutes, and then cooled to -70 °C. 10 Anhydrous CeCl3 (6 g, 24.3 mmol) was added to 50 ml of anhydrous 1TM, and the obtained mixture was stirred for 5 hours (N2t) at 3 °C. This mixture was added to the 2-lithium derivative of 17 while maintaining the temperature at _7 〇〇c. The temperature was raised to -10 ° C and stirred for 10 minutes. Subsequently, the temperature is lowered to _5〇qc:. Compound 71 (5 g, 28 5 mm 〇1) dissolved in 50 ml of THF was added to the reaction mixture, and the obtained mixture was stirred at -30 ° C for 2 hours. Allow the mixture to warm to ambient temperature and mix for 2 hours. The mixture was concentrated in vacuo, EtOAc (EtOAc)EtOAc. The residue obtained is purified by flash chromatography (diethyl ether / PE gradient 1:1 to pure diethyl ether) to give compound 72: 3-(1-phenylsulfonyl-1H-indolo) · 3 · tert-butyl perrhenoridine-1-carboxylate (amorphous, 6 〇g, 58 〇 / 〇). ^-NMR (400 MHz, CDC13): δ 8.38-8.32 (m? 1Η)? 8.17-8.12 (m, 2Η), 7.80-7.50 (m, 1Η), 7.60-7.43 (m, 3Η), 7.17-7.12 (m, 1H), 6.55 (s, 1H), 4.90 and 4.85 (2 x bs, 1H), 4.24 - 4.13 (m, 74 200819448 1H), 3.92-3.79 (m, 1H), 3.75-3.48 (m, 2H), 2.68-2.47 (m, 2H), 1.49 (s, 9H). LCMS; Rt · 1.83 min, ([M+H]+ = 444). Compound 72 (8.6 g, 19.4 mmol), 12 g KOH and 20 ml hydrazine monohydrate were dissolved in 2-(2-hydroxy-ethoxy)-ethanol (150 ml) and stirred at 5 l〇〇QC. 30 minutes (under N2). The resulting organic layer was washed several times with 2N NaOH, dried (Na.sub.2), filtered and concentrated in vacuo. Subsequent purification by flash chromatography (diethyl ether followed by ethyl acetate) afforded compound 74 (oil, 4.97 s, 84%). </ RTI> <RTIgt; (dd, J = 8 Hz, 5 Hz, 1H), 6.38 (d, J = 2 Hz, 1H), 5.67 (bs, 1H), 3.61-3.41 (m, 4H), 2.37-2.28 (m, 1H) , 2.16-2.07 (m, 1H), 1.43 and 1.41 (2 xs, 9H). LCMS; Rt: 1.48 min, ([M+H]+ = 304). Compound 74 (4.92 g, 16.23 mmol), 100 ml H20 and 100 15 ml 38% EtOAc was combined and evaporated to reflux. The mixture was cooled, concentrated and taken up in MeOH. Filtration on 50 g of EtOAc (MeOH, EtOAc (EtOAc): NMR (400 MHz, D6 DMSO): δ 12.1 (bs, 1H), 8.22 (dd, J = 5 Hz, 2 Hz, 20 1H), 7.92 (dd, J = 8 Hz, 2 Hz, 1H), 7.05 (dd , J = 8 Hz, 5 Hz, 1H), 6.55-650 (m, 1H), 6.49 (s, 1H), 4.23-4.17 (m, 2H), 4.07-4.02 (m, 2H). LCMS; Rt: 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 2 psi 75, 2008 19448 at 50 psi. The mixture was filtered, concentrated, EtOAc EtOAc mjjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH : 2-Pyridin π -3-yl-1 Η-σ &amp; σ each [2,3_1&gt;] mouth bite (Compound 78). (Amorphous, 1 〇 9 g 5 59%). LCMS; Rt: 0.75 min, ([M+H]+ = 188). Separation of the corresponding isomeric pure isomers was achieved on a chiral column (Chiralpak AD 20um, 250 X 4.6, 20% MeOH, 20% EtOH, 60% heptane, 2 ml/min). δ = 220 nm, Rt: 6.0 min (78A), ([a]D25 -l〇(c 1, MeOH) and Rt: 7.9min (78B), ([a]D25+12(cl, MeOH). Both isomers are reacted with one equivalent of fumaric acid in MeOH and concentrated to provide the title compound as a salt. mp 130-133 ° C. (free domain / fumaric acid (1) : 1.5)) NMR (400 MHz, D6 DMSO): δ 11.7 (bs, 1H), 8.08 (dd, J = 5 Hz, 2 Hz, 1H), 7.78 (dd, J = 8 Hz, 2 Hz, 1H) , 6.95 (dd, J = 8 Hz, 5 Hz, 1H), 6.4 (s, 3H), 15 6_27 (bs, 1H), 3.63-3_53 (m, 2H), 3.33 - 3.15 (m, 3H), 2.36 -2.25 (m, 1H), 2.08-1.97 (m, 1H). 2-pyrrolidin-3-yl-1H-pyrrolo "3,2- pyridine (compound 79) as described for 45A/B, Or, as described in Eur. J. of Med. Chem (2004), reacted with benzenesulfonium chloride with compound 69 (commercially available) in a yield of 80-90%. Compound 70 is obtained as an oil, which is placed after being placed. Crystallization 1H-NMR (400 MHz, CDC13): 5 8.54 (dd? J = 5 Hz? 2 Hz, 1H)5 8.27 (bd, J = 8 Hz, 1H), 8.0-7.85 (m, 2H), 7.81 (d, J = 4 Hz, 1H), 7.60-7.54 (m, 1H), 7·49·7·43 (ιη, 2H), 7.24 (dd, J = 8 Hz , 5 Hz, 1H), 6.88 (bd, J = 4 Hz, 1H) 76 200819448 Compound 70 was reacted with compound 71 using compound 70 (2.58 g, 10 mmol) to give compound 73. 73: 3-(1-benzene-flavor-based -1H- ° ratio slightly p,2-b]吼σ定-2_ base)-3-perylene-σ ratio burned-1 -teric acid tert-butyl vinegar ), (amorphous 1 23 g, 5 28%). W-NMRGOO MHz, CDC13): 5 8·52_8 48 (m, a), 8.28-8.21 (m, 2H), 7.82-7.78 (m, 2H) , 7.58-7.51 (m, 1H), 7.45-7.39 (m, 2H), 7.23_7.17 (m, 1H), 6.93 (bs, 1H), 4.58 and 4.53 (2 x bs, 1H), 4.14-4.08 (m, 1H), 3.81-3.50 (m, 3H), 2.64-2.45 (m, 2H), 1.49 (s, 9H). The compound is t-butyl t-butyl group based on kibylolo[3,2-1)]° hydroxy-2-pyrrolidine-1-carboxylate, which is used for the aforementioned compound 74. The procedure described for the synthesis was obtained from compound 73 (1.2 g, 2.7 mmol). Compound 75, (amorphous, 〇·42 g, 51%). iH-NMRGOO MHz, CDCI3) exhibits a rotational isomer (r〇tati〇nal isomer) (described in the important 15 some) H〇2 and 9.0 (2 X s, 1H), 8.40-8.32 (m, 1H) , 7.66-7.59 (m, 1H), 7.08-7.02 (bdd, J = 8 Hz, 5 Hz, 1H), 6.41 and 6.33 (2 x bs, 1H) 0 Compound 77: 2·(2,5-dihydrogen -1H-pyrrol-3-yl)_1H-pyrrolo[3,2]acridine was obtained from the compound 20 75 (0.42 g, 1.38 mmol) using the method for the synthesis of the aforementioned compound 76. Compound 77 ' (amorphous, 〇·2 g, 78%). t NMR (400 MHz, D6 DMSO): 5 11.4 (bs, 1H), 8.19 (bd, J = 5 Hz, 1H), 7.61 (bd, J = 8 Hz, lH), 7.0 (dd, J = 8 Hz, 5 Hz, 1H), 6.43-6.38 (m, 2H), 3.93-3.88 (m, 2H), 3.77-3.72 (m, 2H). 77 200819448 The title compound: 2-σpyrazine-3-yl-1Η-αΛluo[3,2-b]11 is determined by sigma (compound 79) from compound 77 (0.19) using the method for the synthesis of the aforementioned compound 78. g, 1.02 mmol) obtained. Compound 79 (amorphous, 〇·16 g, 83%) was reacted with 1 5 eq. of fumaric acid in MeOH and concentrated to give the title compound as a salt ( amorphous, free domain / Fumaric acid (1: 1.5)). NMR (4 〇〇 MHz, D6 DMSO) ·· 5 11.6 (bs, 1H), 8.26 (bd, J = 5 Hz, 1H), 7.69 (bd, J = 8 Hz, 1H), 7.05 (bdd, J = 8 Hz, 5 Hz, 1H), 6.54 (s 3H), 6.48 (bs, 1H), 3.74-3.62 (m, 2H), 3.40-3.25 (m, 2H), 10 2.44-2.37 (m, 1H), 2.09 -1.97 (m, 1H).叹 校 -2--2-ylmethyl-imbp each and 81A) and £^2_pyrrolidin-2-ylmethyl-1H_pyrrolo and "3-2-bl pyriazine 81B" A step of the compound 39A is carried out by lithiation (LDA) of 15 compound 70 (1·42 g, 5.05 mmol) and subsequent reaction with 35. Compound 80A: (R)-l-phenylsulfonyl- 2-Pyrrolidin-2-ylmethyl-1H-port ratio [3,2-b]pyridine. (1.32 g, 70%). Towel-NMR (400 MHz, CDCl3): (5 8.48 (dd) , J = 5 Hz, 2 Hz, 1H), 8.40 (bd, J = 8 Hz, 1H), 7.73-7.7 〇 (m, 2H), 7.57-7.53 (m, 1H), 7.44-7.40 (m, 2H) ), 20 7.18 (dd? J - 8 Hz? 5 Hz? 1H)? 3.62-3.55(m? 1H)? 3.23-3.13(m5 2H), 3·〇8_3·〇2(ιη,1H), 2.95- 2.88 (m, 1H), 2.0-1.95 (m, 1H), L9 (M.75 (m, 1H), 1.51-1.42 (m, 1H). ' Preparation 4 〇ml MeOH 247 mg KOt-Bu(ll The solution of eq) was stirred in N2 for 30 minutes. Compound 80A (683 mg, 2 78 2008 19448 mmol) was added and the mixture was stirred for 20 hours at 50 ° C. The mixture was cooled, filtered, concentrated and redissolved in MeOH With 25 g SCX-2 (MeOH, followed by 1 NNH3/MeOH) Filtration followed by flash chromatography (MeOH/triethylamine (97/3)) afforded the title compound: r) </RTI> </RTI> </RTI> pyrrolidin-2-ylmethyl-1H-5 pyrrolo[3,2-b]pyridine (Compound 81A). ([a]D25-74 (c 1, toluene)· 'H-NMR (400 MHz? D6 DMSO): 5 ll. 〇 (bs, 1H), 8.20 (bd, J = 5 Hz, 1H ), 7.62 (bd, J = 8 Hz, 1H), 6.98 (dd, J = 8 Hz, 5 Hz, 1H), 6.30 (bs, 1H), 3.37-3.28 (m, 1H), 2.90-2.70 (m , 4H), 1.82-1.55 (m, 3H), 1.37-1.28 (m, 1H). 10 Using thiosulphate 36, (S)-2-pyrrolidine was obtained by the method described for compound 81A. 2-ylmethyl-1pyrrolo[3,2-b]pyridine (Compound 81B) ° ([a] D25 +74 (c 1, toluene). (R)-5·methoxy-2-pyrrolidine-2-some formazan_ih_pyrrolo l~3,2-blpyrrole (compound 85)

To a solution of 9.5 ml (59 mmol) of TMEDA in anhydrous THF (60 ml) was added dropwise 10.5 ml of t-butyllithium (15 M) in pentane. After the addition, the obtained solution was stirred at -70QC for 15 minutes. At this temperature, a solution of 83 (3.7 g, 14.3 mmol) in 25 ml of THF (10 min) was added dropwise. The mixture was stirred at -70 ° C for 60 minutes. At this temperature, a solution of 35 (2·33 g, 20 14.3 mm 〇1) in 3 ml of anhydrous THF was added, and the mixture was incubated at -70 ° C for 30 minutes to be followed by liter. Allow the mixture to warm to ambient temperature and then stir for 20 hours. The reaction mixture was concentrated, and the residue was dissolved in MeOH (1%). The mixture was subjected to 2 〇 夺 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 The residue was dissolved in EtOAc (EtOAc) (EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 2.83 g, 53%).mp 101-103 ° C. t NMR (400 MHz, 5 CDC13): 5 8.30 (d5 J = 9 Hz? 1H)? 7.71.7.65 (m? 2H)?? 7.57-7.50 ( m,1H), 7.45-7.35 (m, 2H), 6.65 (d, J = 9 Hz, 1H) 6.54 (s, 1H), 3.94 (s, 3H), 3_56-3.47 (m, 1H), 3· 15_2·98(ιη, 4H), 2.05-1.65 (m, 3H), 1.48-1.37 (m, 1H). Compound 84 was converted to the title compound (85) using the method of synthesizing 39A. :(R)-5-decyloxy-2-pyrrolidene-2_ylmethyl_1H_ is obtained as a slurry (1.18 g, 68%) in the mouth of each [3,2-b] acridine. , [α ]d25 _42 (c 1,CHCI3), which is reacted with one equivalent of fumaric acid in MeOH and concentrated to give the title compound 95 (undetermined (free domain / anti-butyric acid (1:1)). mp 180-182oC. 15 皮皮·2·ylmethyl-1H-pyridinium oxime 88) 4.6g (25.8 mmol) NBS was added to 3.05 g (25.8 mmol) of 4-azaindole in 4 mL of DMF (〇°〇. in 〇. (: The mixture was stirred for 3 minutes. MeOH was added and the mixture was filtered on SCX-2. Following rapid layer 20 (ethyl acetate, then *Me 〇H) afforded 3-bromo-1H-[3,2-b]pyridine (86) mp 241 〇 C (4.52 g, 89% as solid) NMR (400 MHz, D6 DMSO): 5 117 (bs, 1H), 8.39 (dd, J = 5 Hz, 2 Hz, 1H), 7.85 (s, 1H), 7.82 (dd, J - 8 Hz, 2 Hz, 1H), 7.19 (dd J = 8 Hz 5 Hz, 1H). 80 200819448 _78QC Under N2, add 4.6 to an anhydrous THF solution (75 ml) containing compound 86 (2 28 匕n 6 mm 〇 1). Ml n-Buli (2.5 Μ in hexane). After the addition, the obtained solution was stirred at _78QC for 45 minutes. At this temperature, a solution of TIPS-Cl (2.73 ml) in 1 ml of THFt was added dropwise. After the addition, the obtained solution was stirred at -78 ° C for 1 hour. The mixture is then allowed to warm to ambient temperature. The reaction mixture was concentrated, EtOAc EtOAc m. Purification by flash chromatography (diethyl ether/PE (1/1)) afforded 3-bromo-1-tri-tert-butyl-l-yl-lH-pyrrolo[3,2-b]pyridine 10 (87) as a solid. Mp 79-80 C (3.52 g, 86%). iH-NMRGOO MHz, CDC13) · 5 8.55 (dd, J = 5 Hz, 2 Hz, 1H), 7.76 (dd, J = 8 Hz, 2 Hz, 1H), 7.49 (s, 1H), 7.13 (dd, J = 8 Hz, 5 Hz, 1H) 1·73·1·60 (πι, 3H), 1.15 and 1.13 (2 xs, 18H). To a solution of compound 87 (3 42 g, 9 69 mm 〇1) in 15 THF without water (100 ml) at -78 ° C was added dropwise 3·9 ml n-Buli (2.5 M, hexane ). After the addition, the resulting solution was stirred at -78 ° C for 6 minutes. At this temperature, a solution of 35 (1.58 g, 9.69 mmol) in 10 ml of THF was added dropwise (5 min). After adding 35, the temperature was raised to -20. Thereafter, the obtained solution was stirred for 2 hours. The mixture was allowed to warm to ambient temperature and stirred for additional 2 hours. 2〇 The reaction mixture was concentrated, and the residue was dissolved in 40 ml of THF, 40 ml EtOH and 40 ml of THF. At 80. The mixture was stirred for 18 hours. The reaction mixture was concentrated under vacuum. MeOH (25 ml) was added and the mixture was concentrated on 25 g si. Subsequent flash chromatography (MeOH/triethylamine (98/2)) gave the title compound: (R) </ </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Pyridine (Compound 88), (amorphous, 〇32 g, 0.72 mmol, 9.3%). 1H-NMR (400 MHz, CDC13): 5 9.1 (bs5 1H)? 8.42 (dd? J = 5 Hz, 2 Hz, 1H), 7.58 (dd, J = 8 Hz, 2 Hz, 1H), 7.20 (s) , 1H), 7.06 (dd, J = 8 Hz, 5 Hz, 1H), 3.59-3.51 (m, 1H), 3.14-3.02 (m, 5 2H), 2.97-2.85 (m, 2H), 2.0- 1.90 (m,1H),1.86-1.71(m,2H), 1.54-1.43(m,1H). LCMS : Rt ; 0.64 min, ([M+H]+ = 202)· [a]D25-10(cl , Dioxane Institute). (R)-6-Pyrrolidin-2-ylmethyl-7H-pyrido-[2,3-dl-pyrimidine (Compound 95) 10 Commercially available 6-gas-7-deazapurine (1.58 g, 10.3 111111〇1), 3.25 8 ammonium formate (51.6 111111〇1) and 20%?(1(011)2/(:(14〇11^) are co-dissolved in MeOH (50 ml), warm Heat to reflux for 2 h. The mixture was cooled, filtered, concentrated and evaporated with EtOAc EtOAc EtOAc EtOAc EtOAc Ship 6〇11(9/1)) provides compound 90 (1.2 §, 4.02 mmol, 97%) which is an amorphous material. 1H-NMR (400 MHz, CDC13): 5 ll.l (bs, 1H) , 9.1 (bs, 1H), 9.0 (bs, 1H), 7.45-7.40 (m, 1H), 6.68-6.62 (m, 1H). Under N2, 7Η-σι^ each [2,3-( 1]^σ定(1.16 g,9.74 mmol) 20 Dissolved in 100 ml of anhydrous THF. At 0 ° C, add 0.51 g of NaH in a 60% dispersion in mineral oil. Stir the mixture at ambient temperature and add to dissolve. 2.93 ml (9.8 mmol) (2-methoxymethoxyethyl)-trimethyl-nonane in 15 ml of dry THF. The reaction mixture was stirred at room temperature for 2 h then concentrated under vacuum Ethyl acetate was added to the mixture, and the organic layer was washed with EtOAc EtOAc EtOAc (EtOAc m. 2_trimethylsulfonyl-ethoxymethyl-7H form, 〇·84 g, 35%). Pyrrolo[2,3-d]pyrimidine (compound 91), (undefined

〇.l(s,9H) 0 0. 62 ml (3.7 mmol) of 2,2,6,6-tetramethylacridine was added to 20 ml of anhydrous THF (-78 C). Add n_BuH 1 3 ml (2.5 M, 3.33 ίο mm〇i)' to the reaction mixture: mix for 3 minutes. Compound 91 (0.83 g, 2.16 mmol) dissolved in mi thf was added and the mixture was stirred for 3 min. Compound 35 (557 mg, 216 mmol) dissolved in 5 ml of THF was added. After the addition of 35, the temperature was raised to _3 〇 ° C, and the resulting solution was stirred for 2 hours. The mixture was allowed to warm to ambient temperature and stirred for additional 2 hours. To the reaction mixture was added a saturated ΝΗβΙ solution (5 ml), followed by 25 g of Si〇2, and then the mixture was dried under vacuum. The residue was purified by flash chromatography (EtOAc /EtOAc /EtOAc /EtOAc ([M+H]+ = 413). Compound 93 (0.63 §, 1.53 111111〇1), 11.4 1111 tetrabutylammonium fluoride 20 (1M in THF) and 25 ml of THF were combined and the mixture was warmed to reflux (36 h). The mixture was cooled, 25 g of Si〇2 was added, and then concentrated under vacuum. The residue obtained was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc NMR (400 83 200819448 MHz, CDC13): 5 11.3 (bs, 1H), 8.8 〇 (bs, 1H), 8.65 (bs, 1H), 6.2 (bs, 1H), 3·95-3·88 (πι, 1H), 3·65, 3 58 (m, 1H), 3 24_3 17 (m, 2H), 2.89-2.82 (m, 1H), 2·05·ι·96 (ιη, 2H),! n 6 (m, 2H). 5 Compound 94 (0.35 g, i·24 mm〇l), l〇 ml IN HC1 and 10 mi

The EtOH was combined and heated to reflux for 18 h. The reaction mixture was cooled and concentrated under vacuum. The residue obtained was taken up in ethyl acetate, washed with 2N EtOAc. Purification by flash chromatography (MeOH/triethylamine (π/3)) gave the title compound: (r) _6_ 10 pyrrolidine 2 ylmethyl-7H-pyrrolo[2}d]pyrimidine (95 ), (amorphous, 7〇mg, 27.9%). LCMS ; Rt : 〇 · 68 min, ([M+H]+ = 203), which is

Reaction of one equivalent of fumaric acid in MeOH afforded the title compound 95 (amorphous) (free domain / succinic acid (1:2)). NMR (400 MHz, D6 DMSO): δ 12.8-11.8 (bs, 1 Η), 8.86 (s, 1 Η), 8.68 (S, m), 15 6.54 (s, 4H), 6.45 (s, 1H), 3.85-3.79 (m,1H), 3.25-3_19(m,2H), 3.17-3.〇9(m,2H), 2.10-2.03(m,1H),2.0(M.92(m,1H)), 1.9〇 -1.82 (m, 1H), 1.69-1.62 (m, 1H). The results of the above synthesized compounds of the present invention are shown in the following tables. R4 _ /[CH2]m—R3 ]| J~1 [CH2]n — r2

H 20 (I) 84 200819448 Compound XY znm R2 R3 R4 R5 Re 79 CN c 0 0 \ HHHHH 78 NC c 0 0 HHHH 78A NC c 0 0 \ (S) HHHHH 78B N cc 0 0 \ (R) HHHHH 26 N Cc 0 0 \ HHHHH 29B N 丄0 cc 0 0 HHHHH 26A N cc 0 0 (S) 丨HHHHH 26B N cc 0 0 V (R) 丨HHHHH 6 N cc 0 0 H n NH HHH 10B N 丄0 cc 0 0 H nk/NH HHH 33 N cc 0 0 HH Cl HH 32 N cc 0 0 HHH Cl 85 200819448

32A NC c 0 0 (S) HHHH Cl 32B NC c 0 0 V (R) HHHH Cl 13 N cc 0 0 H / 〇HHH Cl 28 N cc 0 0 1 HHHH 25 N cc 0 0 HHHHH 24 N cc 0 0 HHHHH 19 N cc 0 0 OH HHHHH 21 N cc 0 0 HHHHH 10A N cc 0 0 H HO, 〇nh HHH 16 N cc 0 0 H / ^NH HHH 20 N cc 0 0 H / ^NH HHH 86 200819448

,,,, 39 NC c 1 0 MHHHH (R)/(S) 1:9 39A N cc 1 0 HHHH 95 N c N 1 0 HHHH 52A N cc 1 0 HH Br H 53A N cc 1 0 HH ch3 H 85 CN c 1 0 (R) HHH och3 H 81A CN c 1 0 HHHH 88 c N c 0 1 H (R) HHHH 81B c N c 1 0 (S)HHHHH 47A NC c 1 0 (R)h HHHF 45A N cc 1 0 (R)h HHH Cl 46A N cc 1 0 (R)h HHH Br 49 N cc 1 0 (R) HHHH och3 〆' 39B N cc 1 0 (S)HHHHH , , , · 52B N cc 1 0 ( S)HHH Br H 41B N cc 1 0 HHHH 47B N cc 1 0 HHHF 87 200819448 45B NCC 1 0 Η Η Η C1 46B NCC 1 0 ,,,,,Ν, (S)丨Η Η Η Br 41A NCC 1 0 〆(1 Η Η Η Η 66 NCC 1 0 / 1 ΝΗ Η Η Η Η 68 NCC 1 0 1 Η Η Η Η 65 NCC 1 0 0 Η Η Η Η The following table lists the names of the compounds. Acridine-3-yl-1Η-pyrrolo[2,3-b]吼Acridine 10Α 3-(1Η-pyrrolo[2,3-b]pyridin-3-yl)-acridin-3-ol 10Β 3 - fox bite-3 -yl-1Η -debbiline [2,3 - b ] 0 σ 定 7 - oxide 13 6 · gas - 3 - fox bite - 3 - yl - 1 Η - 吼 并 [2,3 - b ] ^ than bite 16 3- (1 Η - 吼 并 [2 ,3-b]Acridine-3-yl)-1-aza-bicyclo[2.2.2]octane 19 3-(1Η-吼[1,3-b]acridin-2-yl)- 1-Aza-bicyclo[2.2.2]oct-3-ol 20 3-(111-indolo[2,3-1)]acridin-3-yl)-1-aza-bicyclo[2.2. 2] oct-2-ene 21 3-(1 沁吼 并[2,3-1)]acridin-2-yl)-1-aza-bicyclo[2.2.2]octane 24 3 - (1Η - 0 is more than [2,3 -b ] 0 is determined by -2 - base) - bite bite - 3 - leaven 25 2- (1, 2, 5, 6 - four mice - ° ratio -3 _基)-111_111 比哈和[2,3-13]'3 比〇定26 2-Acridine-3-yl-1H-pyrrolo[2,3-b]acridine 26Α (S)-2- Acridine-3-yl-1H-pyrrolo[2,3-b]acridine 26Β (R)-2-fox bit-3 -yl-1 Η -debbiline[2,3 -b] 0 ratio 〇28 2-(1-Methyl-acridin-3-yl-1H-indolo[2,3-b]acridine 29Β 2-acridin-3-yl-1H-pyrrolo[2,3 -b]pyridine 7-oxide 32 6 - gas-2-fox 0- 3 -yl-1 H-port piroxi[2,3 -b] 0 ratio bite 32 Α (S)-6-gas-2-呱-3-yl-1H-pyrrolo[2,3-b]pyridine 32Β(R)-6-Ga-2-acridin-3-yl-1H-indolo[2,3-b]pyridine 33 4 -Ga-2-Aridin-3-yl-1H-indolo[2,3-b]acridine 39 2-pyrrolidin-2-ylmethyl-1H-pyrrolo[2,3-b]pyridine 39Α(R)-2-Pyrrolidin-2-ylmethyl-1H-pyrrolo[2,3-b]pyridine 39Β(S)-2-pyrrolidin-2-ylmethyl-1H-pyrrolo[2 ,3-b]pyridine 88 200819448

41A

41B

45A (S)-2-(l-methyl·ρ ratio ρ 烧-2-ylmethyl(R)-2-(l-methyl-pyrrolidin-2-ylmethyl(R)-6- Gas-2-pyrrolidin-2-ylmethyl

45B

46A 虱-2-pyridin-2-violet methyl-1H-pyrrol (S)-6-aero-2-pyrrolidin-2-ylmethyl

46B (R) -6-Imp-2-pyrrolidin-2-ylindenyl (S) -6-inferior-2-° piroxicam-2-ylmethyl-1Η-σΗ^ϋΓΓΓ!Τ'^ΐ !^σ定

47A

47B (S)-6-Bromo-2-pyrrolidin-2-ylmethyl(R)-6-fluoro-2-pyrrolidine-indenyl 49 (S)-6-fluoro-2-pyrrolidine -2-ylmethyl-(R)-6-methoxy-2-pyrrolidin-2-ylmethyl

52A

52B (R)-6-Methoxy-2-pyrrolidin-2-ylmethyl(R)-5-bromo-2-pyrrolidin-2-ylmethyl(S)-5-bromo-2-pyrrolidine -2-A certain -1H-port ^

53A (S)-5-bromo-2-pyrrolidin-2-ylmethyl-(R)-5-methyl-2-pyrrolidin-2-ylformidine 65 66 f \ 68 0-5- Methyl-2-pyrrolidin-2-ylmethyl-lH-ring^^^^: 2-(1-benzyl-pyrrolidin-3-ylmethyl-2-pyrrolidin-3-ylmethyl- 1H-pyrrolo 2-indole-pyridyl-pyrrolidin-3-one formazan V1H-咐78 (1-methyl-pyrrolidin-3-ylmethyl-2-pyrrolidin-3-yl-1H-pyrrole [2,3_b] settings

78A

78B (S)-2-Pyrrolidin-3-yl-1H-pyrrolo[2,3-ilj^ 79 (R)-2-pyrrolidin-3-yl-1 Η-pyrrolo[2,33Tg^ 2 -0 is more than p-burning _3-based-1 H-Pbb-and-[3,2-b] °

81A

81B (11)-2-0 Biluoyuan-2-ylmethyl-11^bilo[^7^^^ 85 (S)-2·pyrrolidin-2-ylmethyl-1Η-pyrrole Preparation: Μ: _〇oi Tiangan-'ΓΤΤ-'^疋(R)-5-methoxy-2-pyrrolidine-2-ylmethyl port 4 mouth Yisong and Tiantian _ι u_〇i4· μ and r, bis(R)-3-p piroxicam-2-yl fluorenyl-1H-P birodo(R)-6-pyrrolidin-2-ylmethyl-7H-pyrrole

ί (R)-3-Pyrrolidin-2-ylmethyl-1H-pyrrolo and (SV3-pyrrolidin-2-ylindenyl-1H·pyrrolo-"2.3-bH^ ing compound 97)) 2.2 equivalents of n-Buli metallize 3-bromo-7-azaindole (

Heterocyclic Chem., 1984) gives a dilithium derivative which is captured by thioproline (35QC, N2). Using the method described for 39A, the title compound 96 · (R) - 3 ° pyrrol-2-ylmethyl-1H-debbiol and [2,3_b] oxime ratio (46%) was obtained. . LCMS; Rt; 0.91 min, ([M+H]+ = 202). [a]D25 -8 (c 1, MeOH), 10 which was converted to its salt (free domain / anti-succinic acid (1: 1)), (amorphous). iH-NMRGOO MHz, D6DMS0) ·· 5 11.5(bs,1H), 8.21 (dd, J = 5 Hz 89 200819448 2 Hz, 1H), 8.02 (dd, J = 8 Hz, 2 Hz, 1H), 7.42 ( s, 1H), 7.05 (dd, J = 8 Hz, 2 Hz, 1H), 3.79-3.71 (m, 1H), 3.27-3.21 (m, 1H), 3.19-3.09 (m, 2H), 3.05-2.99 (m, 1H), 2.03-1.79 (m, 3H), 1.69-1.61 (m, 1H). (S)-3-pyrrole 5 -alkyl-2-ylmethyl-1H-pyrrolo[2,3-b]pyridine (compound 91) ([a] was obtained using the method described for compound 96 (from 36) D25 +8(c 1, MeOH) (ΙΟ-3-Π-fluorenyl-pyrrolidino-2-ylindenyl)-1Η-pyrrolof2,3-blpyrholine (compound 98) and 03-Π -Methyl-pyrrolidin-2-ylmethyl)-1 Η-pyrrolo 2,3-blpyridine (Compound 99) 10 Conversion of Compounds 96 and 97 to Compound 98 and &quot; as described in EP 1 178 045 . Compound 98: LCMS; Rt; 0.94 min, ([^1+11]+ = 216)·[a]D25+68 (c 1, dioxane). Compound 99: [a] D25-68 (c 1, dioxane). The structures of the above four compounds are listed in the following table. 15

90 200819448

Ex. ll (rac) refers to Example 11 of EP 1 178 045, which is disclosed as a racemate. Example 5 Pharmacological Methods In vitro affinity for rat nicotinic cholinergic receptors. 5 The compound affinity for nicotinic receptors in rat brain receptors was determined by CEREP (Celle l6vescault, France) using a known test method (Pabreza, 1991). In vitro affinity for human immunoassay receptors. Compound affinity for human nicotinic receptors cloned into SK-N-F1 neuroblastoma cells was determined by Novascreen (Hanover, MD, U.S.A.) using the known test 10 method (Perry, 1995). Compound affinity for the receptor in the rat brain receptor. In vitro [3H]-dopamine release The striatal brain slices were used to measure dopamine release as described (Stoof, 1980). Male rats (Wistar Hsd/Cpb: WU; 175-200 g) were sacrificed and the striatum was quickly removed from the brain. Sections (〇·3 X 0·3 X 2·00 mm) were prepared by using a Mcllwain slicer (chopper). Stromal cuts of 6 rats were collected and incubated for 15 minutes in 5 ml of Krebs_Ringer bicarbonate medium (containing 0.37 MBq [3H]-DA). After labeling, transfer the sections into each of the 24 chambers in the super perfusion 2〇 (1) chamber

Weaving, volume of 0·20 ml), followed by super-perfusion (0.20 ml/min) with medium. All super-perfusion experiments were performed in Kreb's bicarbonate buffer with the following composition: 118 mM NaQ, 2.4 mM KC1, 2.4 mM CaCl2.2H20, 1.2 mM MgS04.7H20, 1.2 mM KH2P〇4, 25 mM 91 200819448

NaHC〇3 and l〇 mM glucose, which were buffered to ρΗ 7.4, were saturated with 95% 仏/5〇/C〇2. After 45 minutes of pre-super-perfusion period, one ° Wenshu wood 20 copies of 10 minutes (t = o start). During super-perfusion, calcium-dependent neurotransmitter release was induced at t = 1〇(s = = ~) U(S2) and t = 90 minutes (S3), which was exposed to the following medium In this medium, the concentration of κ+= has been increased to 10 mM, and the NaCl concentration is thus reduced to maintain osmolarity. ^ At t = 50 (10·8 M) and t = 90 minutes (ΙΟ · 6 M), the test compound or echinoderma was added to the medium together with the K+ pulse. In the presence of a non-specific nicotinic receptor antagonist mecamylamine (m) or specific α^2η•乙乙胆^ In the case of the body antagonist DHBE (l〇·6 Μ), the test compound was assayed in parallel. At the end of the experiment, the remaining radioactivity was extracted from the tissue with 〇.1M HCl. 'Superperfusion system and tissue were determined by liquid scintillation counting Radioactivity in extract 15. The output flux of radioactivity during each collection is expressed as a percentage of the amount of radioactivity in the slice at the beginning of each collection period. To calculate the induced [3h]-dopamine release, from stimulation and grafting Subtracting spontaneous radioactivity loss from total radioactivity during the 15 minute period The amount of S2/S1 and S3/S1 is used as the stimulus for the stimuli of the stimuli of the stimuli. Parameters of release. The effect of the test compound was calculated as a percentage of the control group. The mecaramin or DHBE sensitive release was expressed as a percentage inhibition of [3H]-dopamine release in response to the test compound. In each test, Each test compound was repeated using 2-3 chambers, and the weight value of 92 200819448 was averaged. In vitro [3H]-dopamine uptake of male rats (Wistar Hsd/Cpb ·· WU; 175-200 g) and rapid removal Striatum, preparation of the crude synaptosome fraction (P2) by homogenization and centrifugation. 5 Pre-incubation of synaptosomes at 37 ° C for 15 minutes in the absence or presence of test compound, which is contained Monoamine oxidase inhibitor pargyline (7xl (T6M) in medium (Coyle, 1969). Subsequently, [3H]-dopamine (2x10-7M final concentration) was added and incubation continued for 1 min. [3H]-dopamine uptake, use The acid buffered saline 10 was washed four times with the synaptosome. The amount of [3H]-dopamine in the synaptosome was determined by Betaplate liquid scintillation counting. The concentration range was tested at 1〇·9 to 1〇_5 M. Compound. The inhibition of [3H&gt; dopamine uptake was expressed using the pic% value (the negative logarithm of the concentration at which the drug caused 50% uptake inhibition). The inhibition of DA uptake was repeated twice. 15 Paste Example I Pharmacological Waves Zhuwa f _ The pharmacological test results obtained according to the protocol given above are shown below.

93 200819448 Nomifensin 6.6 Butanone 124 5.4 GBR 12909 7.0 Compound 96 5.6 124 &lt; 97 5.2 122 &lt; 98 &lt; 132 &lt; 99 5.9 112 &lt; Compound 6 5.5 &lt; 139 5.4 13 5.5 &lt; 174 5.8 16 5.4 6.8 21 5.3 6.8 26A &lt;&lt; 139 5.6 26B 5.3 6.0 121 6.2 32 &lt; 173 32B 5.3 &lt; 170 6.4 39A 6.9 6.1 151 5.1 39B 5.5 &lt; 133 41A 5.4 &lt; 100 45A 6.9 6.0 115 45B 5.4 6.0 153 5.6 46A 6.1 5.9 92 46B &lt; 5.9 123 47A 6.3 137 47B 6.0 128 5.4 49 &lt;&lt; 160 5.2 52A 5.0 &lt; 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 6.3 119 5.2 81A 5.8 &lt; 153 5.0 81B 5.2 &lt; 120 5.2 85 131 5.1 88 &lt; 110 5.1 &lt;* means: &lt;5·0 (inactive at 1〇-5Μ) The information given in the above table can be It is apparent that the compound of the present invention (i.e., the compound of the formula (I)) binds to the acetylcholine receptor with high affinity, and the pro-94 200819448 is comparable to the nicotine or gorse domain, and the present invention Compound with Dopamine reuptake inhibitor activity, the activity of the standard inhibitor of dopamine re-uptake rather bupropion and nomifensine. This is in contrast to those structurally similar compounds disclosed in EP 1 178 045. Those compounds did not act as inhibitors of the multi-baramine reuptake inhibitor. When comparing enantiomeric pairs (the above table contains a table containing structural data), it is apparent that the (R)-enantiomer is more effective than the (S)-enantiomer. EXAMPLE 7 Pharmaceutical Formulations for Clinical Use, Formulation of Compounds of Formula (I) as Pharmaceutical Compositions, Pharmaceutical Compositions are important and novel embodiments of the invention as they contain the compounds, and more particularly, disclosed herein Specific compound. Types of pharmaceutical compositions that may be used include, but are not limited to, tablets, chewable tablets, capsules (including microcapsules), solutions, parenteral solutions, ointments (creams or gels), suppositories, and the compositions disclosed herein. Other types or other types apparent to those skilled in the art from this 15 application file and the general knowledge in the art. The compositions are for oral, intravenous, subcutaneous, transtracheal, transbronchial, intranasal, transpulmonary, transdermal, buccal, rectal, parenteral or otherwise. The pharmaceutical preparations contain at least one compound of formula (I) which is premixed with a pharmaceutically acceptable adjuvant, diluent and/or carrier. The total amount of active ingredient which is suitably present is in the range of from about 0.1% (w/w) to about 95%, suitably from 0.5% to 50% (w/w), preferably from 1% to 25%, in the formulation. (w/w). The compounds of the present invention can be incorporated into a form suitable for administration by conventional procedures, using auxiliary substances such as liquid or solid, powdered ingredients, for example, pharmaceutical liquid or solid fillers and 95 200819448 Extenders, solvents, emulsifiers, lubricants, perfumes, colorants and/or buffers. Commonly used auxiliary substances include magnesium carbonate, titanium dioxide, lactose, Yan sugar, sorbitol, mannitol and other sugars or sugar alcohols, talc, such as protein, gelatin, starch, amylopectin, cellulose and their derivatives. , animal and vegetable oils (for example, cod liver oil, sunflower oil, peanut oil or sesame oil), polyethylene glycol and solvents, for example, sterile water, and mono- or polyhydric alcohols, such as glycerin, and disintegrants and lubricants, such as stearic acid Barium, calcium stearate, sodium stearyl fumarate and polyethylene glycol wax. The mixture can then be processed into granules or compressed into tablets. 10 The active ingredient may be pre-mixed separately with the other inactive ingredients prior to mixing to form the formulation. The active ingredient may also be mixed with each other before being mixed with the inactive ingredients to form a preparation. Soft gelatin capsules may be prepared using capsules containing the active ingredient mixtures of the invention, vegetable oils, fats or other suitable carriers suitable for use in soft gelatine capsules. Hard gelatin capsules may contain granules of the active ingredient. Hard gelatine capsules may also contain active ingredients together with solid powder ingredients such as lactose, sucrose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatin. . The dosage unit for rectal administration can be prepared as (1) a suppository form containing an active substance mixed with a natural fat 20 base; (ii) a gelatin rectal capsule containing a mixture with a vegetable oil, a paraffin oil or a gelatin rectal capsule suitable for use in gelatin. The other carrier is mixed with the active substance; (iii) is in the form of a microenema; or (iv) is in the form of a dry microenema formulation which is reconstituted in a suitable solvent just prior to administration. 96 200819448 A granulating agent is prepared as a slurry, _, _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 5 == a mixture of propylene glycol and polyethylene glycol. If desired, the night body preparation may contain a coloring agent, a flavoring agent, a preservative, saccharin = methyl cellulose or other thickening agent. The liquid preparation may also be It is prepared in the form of a powder: it is reconstituted with a suitable solvent before use. The solution for parenteral administration can be made into a sputum-solution of the present invention in a pharmaceutically acceptable solvent. These solutions may also contain a bismuth ingredient, a preservative and/or a buffer. The solution for parenteral administration may also be prepared as a dry preparation which is reconstituted with a suitable solvent prior to use. ▲ According to the present invention, there is also provided a kit comprising one or more of the following containers and parts, which are filled with one of the ingredients of the U pharmaceutical composition of the present invention or a variety of for medical treatment. With this type of (Japanese) container The association may be in the form of a variety of written materials, such as instructions for use, or in the form of a government agency for the production, use or sale of a pharmaceutical product, which reflects the institution’s production and use for human or veterinary use. Or the end of sale. The invention also encompasses the use of a formulation of the invention in the manufacture of a medicament for the treatment of a dopamine receptor activation and/or inhibition of dopamine uptake in a condition for the treatment of a dopamine receptor Is a need or desire, and the invention also includes a method of medical treatment of a patient suffering from or suspected of suffering from the following conditions or a method comprising administering to the patient a therapeutically effective total amount of at least one compound of formula (1), In the case of the disease, activation of dopamine receptors and/or inhibition of dopamine uptake is a reference or reference for people who need 97 200819448

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Claims (1)

200819448 X. Patent application scope: ^ A compound of the formula (1): R4 R3 (l) [CH2]n-r2 wherein 5-in, Y and Z independently represent N or C, and the ring contains at least one N- Atom, and no more than 2, -ηι and n are independently 〇(zero) or 卜 and when γ and z represent carbon and X represents nitrogen, m is 〇(zero), -R2 and R3 independently represent hydrogen, Alizarin, (Ci3) alkyl, (Ci3) block, nh (c"3) alkyl, Cf3, thiol, (Ci 3) methoxy or guar oxime, pyrrolidinyl, tetrahydropyridyl a group of morpholinyl, azepanyl, aza-bicyclo[2·2·2]octyl or 1-aza-bicyclo[2.2.2]oct-2-enyl is not Substituted, or substituted by one or more substituents selected from halogen, (C!-3-3)alkyl, phenyl or benzyl, _ 1, R 5 and R 6 independently represent hydrogen, halogen, (Cm)alkyl , ^2 3) alkynyl, CF3, NHD alkyl, perylene or (Ci 3) alkoxy, and R4 exists only at y = c, r5 exists only at z = c, and its recognition Construct, stereoisomer pure oxide, and the compound of the formula (I) and their mutual variation The pharmaceutically acceptable salts, hydrates and solvates of the constituents, stereoisomers and N-20 oxides. 2. The compound of the formula (1) m 102 200819448 and r3 independently represent hydrogen as described in claim i. Or ^1 melon base, indolopyrene, tetrahydrogen ratio, morpholino, azepanyl, 1_aza-bicyclo[2.2.2]octyl or 1-aza- Bicyclo[2.2.2]oct-2-enyl, the group being unsubstituted or substituted by one or more selected from halogen, (C^)alkyl, phenyl or benzoinyl Substituent, R4, R5 and R6 independently represent hydrogen, halogen, (Cb3)alkyl or (Ci_3) alkoxy" and 'R4 is present only at Y=C' R5 only exists at Z = C, X, Y, Z, m and η have the meanings given in claim 1. 3. The compound according to claim 1, which is 2-pyrrolidin-3-yl-1Η-pyrrolo[3,2- b]pyridine 10 2-pyrrolidin-3-yl-1H-pyrrolo[2,3-b]acridine(S)-2-pyrrolidin-3-yl-1H-pyrrolo[2,3-b] Pyridine(R)-2_pyrrolidin-3-yl-1H-pyrrolo[2,3-b]pyridine 2-1[^11定_3-yl-111-11 to 1^[2,3- 13]11 than the oral 2 - acridine-3-yl-111_pyrrole [2,3-b]pyridine 7-oxide 15 (8)-2-1^11--3-yl-111-11piro[2,3_1)]11 ratio bite (R) _2-acridine -3-yl-1H-pyrrolo[2,3-b]pyridine 3-acridine_3_yl_1H-pyrrolo[2,3-b]pyridine 3-acridine_3_yl-1H-pyrrole And [2,3-b]pyridine 7-oxide 4 - gas ^ 3 -yl - 1 Η · ϋΛ 鸣 ► and [2,3 - b] ° ratio ° 6 6 - gas-2-fox ϋ -3 -yl 1 H-ntt 嘻[2,3 -b] ° ratio (S) _6-chloro-2-acridin-3-yl-1H-pyrrolo[2,3-b]pyridine (R)_6_Chloro-2_acridin-3-yl-1H-pyrrolo[2,3-b]pyridine 6-chloro-3-. Melon bites 3-yl-111-indole [2,3-13]. The ratio of 2-( 1 -methyl-isospin _3-yl-1 Η-σ is more than [2,3-b]° 唆103 200819448 2- (1,2,5,6·4 Hydropyridin-3-yl)·1Η·pyrrolo[2,3-b]pyridine 3-(1Η-pyrrolo[2,3-b]pyridin-2-yl)-acridin-3·ol 3-( 1Η-吼 并[2,3-b]acridin-2-yl)-1-aza-bicyclo[2.2.2]oct-3-ol 5 3-(1Η-吼 吼[2,3_b] Pyridine-2-yl)-1azabicyclo[2.2.2]octane 3-(1Η-pyrrolo[2,3-b]pyridin-3-yl)-acridin-3-ol 3-(1Η-吼[2,3_b]Acridine-3-yl)-1-aza-bicyclo[2.2.2] Octane 10 3_(1H-indolo[2,3-b]acridin-3-yl --1-Aza-bicyclo[2.2.2]oct-2-ene 2-pyrrolidin-2-ylmethyl-1H-pyrrolo[2,3-b]pyridine (&amp;)-2-0 ratio鸣^烧*-2-ylmethyl-111-11 to 1^ and [2,3-13]11 to 17 (R)-6-pyrrolidin-2-ylmethyl-7H_pyrrolo[2 ,3-d]pyrimidine 15 (R)-6-gas_2·ϋpyrrolidene-2·ylmethyl_ 1 Η-ϋbiro[2,3-b] ntb σ(R)-6 - gas 嘻 _2 _2 基 Η Η · ϋ ϋ ϋ [ 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 And [2,3-b]pyridine (R)-6-methoxy-2-portyrrolidin-2-ylmethyl-1H-pyrrolo[2,3-b] ° ratio 20 (R)-5_ &gt;Smell-2-11 piroxicam-2-ylmethyl-1 Η_ϋ比洛和[2,3 _b]ϋ定定(R)-5 -Methyl-2·ϋ Biloxy-2-ylmethyl-1 Η ϋ ϋ 洛 并 并 [2,3-b] ϋ 口 定 (R)-5-methoxy-2-pyrrolidine-2-ylmethyl-1 Η-pyrrole And [3,2-b] mouth ratio 104 200819448 (R)-2-pyrrolidine-2·ylmethyl-1H-pyrrolo[3,2-b]pyridine(R)-3-pyrrolidine_ 2-ylmethyl-1H-pyrrolo[3,2_b]pyridine(S)-2-pyrrolidin-2-ylindenyl·1Η-pyrrolo[3,2-b]pyridine(S)-2-pyrrole Alkano-2_ylmethyl-1H-pyrrolo[2,3-b]pyridine 5 (S)-6-disorder-2-indolebioxazepine_2_ylindolyl-1 Η_ϋ比洛和[2, 3 _b] ϋ ratio 17 (8) -6-gas-2-11 piroxime _2-yl fluorenyl-111-1|3 bilox [2, 3-1)] 0 to 17 (S - 6-bromo-2·pyrrolidin-2-ylmethyl-1Η-pyrrolo[2,3_b]pyridine(S)-5-bromo-2-pyrrolidine-2-ylmethyl-1H-pyrrole [2,3-b]pyridine (S)-2-(l-methyl-pyrrolidin-2-ylmethyl)-1Η-pyrrolo R,3-b] 10 ° 唆(R)-2- (l-methyl-pyrrolidin-2-ylmethyl)-1Η-pyrrolo[2,3-b] ° than 唆2-pyrrolidin-3-ylindolyl-1H-pyrrolo[2,3- b]pyridine 2-(1-methyl-pyrrolidin-3-ylmethyl)-1Η-pyrrolo[2,3-b] Pyridine 15 2-(1-Benzyl-pyrrolidin-3-ylmethyl)_1H-pyrrolo[2,3-b]pyrridine 4. Formula (I) as described in claim 1 (R)-enantiomer of the compound, wherein the rule 2 and R3 independently represent an orphan 11 group, a σ pyrrolidone group, a tetrahydropyridyl group, a morpholinyl group, an azepanyl group, 1 - aza-bicyclo[2.2.2] 20 octyl or 1-aza-bicyclo[2.2.2]oct-2-enyl, said group being unsubstituted or selected from one or more selected from Substituted by a halogen, (Cm)alkyl, phenyl or benzyl substituent, and the ring is attached directly to the azaindole core (when ni and η are 0) or via a methylene bridge (m or η is an asymmetric carbon atom of 1), and wherein all other symbols have the meaning given in the claim 105 200819448. 5. 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 according to any one of claims 1 to 4, or a salt thereof As an active ingredient. A method of preparing a pharmaceutical composition according to claim 5, wherein the compound according to any one of claims 1 to 4 is formulated into a form suitable for administration. 7. A compound as claimed in any one of claims 1 to 4, for use as a medicament. 10 8. A compound of the formula (I*) r4 1 /[CH2]m- -r3 R6 X 1 , [CH2]n- (1*) -r2 Q wherein Q represents a protecting group: ^^Si-CH3 CH3 ίΗ3 -X, Y and Z independently represent N or C, and the ring contains at least one N-atom and no more than 2, -m and η are independently 0 (zero) or 1 And when Y and Z represent carbon and X represents nitrogen, m is 0 (zero), 106 15 200819448 R2 and R3 independently represent a fox bite group, a pyrrolidinyl group, a tetragas hydrazine group, a morphine group, an aza Cycloheptyl, 1-azabicyclo[2·2.2]octyl or 1-l-heterobicyclo[2·2·2]octylalkenyl, said group being unsubstituted or by- or Substituting a plurality of substituents selected from halogen, (Ci3)alkyl, phenyl or benzyl, wherein when the ring contains a nitrogen atom, the nitrogen atom is replaced by a hydrogen atom, a benzyl group, a t-BOC group or Substituted with a SOHDH group, -R4, R^R6 independently represent hydrogen, halogen, (Ci3)alkyl, alkynyl, CF3, fluorenyl ((3) alkyl, hydroxy or alkoxy, and &amp; Present at YC, r5 is only present at z = c, which can be used to synthesize some compounds of formula (I). 9. A 6-fluoro-1H-pyrrolo[2,3-b]pyridine having a structural formula : Η It can be used to synthesize some of the compounds of formula (I). 10. The use of a compound 15 as claimed in any one of claims 1 to 4 for the preparation of a pharmaceutical composition for treating a CNS disorder, such as neuroendocrine, neurological Sexual and neuropsychiatric disorders, schizophrenia, memory and learning disabilities, attention deficit hyperactivity disorder, anxiety disorders, depression, neurodegenerative disorders, Alzheimer's disease, addictive disorders, nicotine addiction, cocaine Addiction, bupropion 20, addiction, eating disorder, inflammatory process, spasticity disorder, visual disturbance, glaucoma, macular degeneration, diabetic retinopathy, cardiovascular and gastrointestinal disorders and cancer. 107. The use of a compound as claimed in any one of claims 1 to 4 for the preparation of a pharmaceutical composition selected from the group consisting of nicotine addiction and cocaine. An adultergic disorder of the group consisting of addiction and bupropion. 108 200819448 VII. Designation of representative representatives: (1) The representative representative of the case is: ( ). (None) (2) A brief description of the symbol of the representative figure: 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: r4 /[CH2]m— - R3 1 , [CH2]n- ( I) R wide XN Η a r2 4