MX2007001061A - Tricyclic indeno-pyrrole derivatives as serotonin receptor modulators - Google Patents

Abstract

The present invention generally relates to a series of compounds, to pharmaceutical compositions containing the compounds, and to use of the compounds and compositions as therapeutic agents. More specifically, compounds of the present invention are tricyclic indeno-pyrrole compounds. These compounds are serotonin receptor (5-HT) ligands and are useful for treating diseases, disorders, and conditions wherein modulation of the activity of serotonin receptors (5-HT) is desired (e.g. anxiety, depression and obesity).

Description

TRICYCLIC IN DENO-PIRROL DERIVATIVES AS MODULATORS OF SEROTONIN RECEPTORS FIELD OF THE INVENTION The present invention relates in general to a series of compounds, to pharmaceutical compositions containing the compounds, and to the use of the compounds and compositions as therapeutic agents. More specifically, the compounds of the present invention are tricyclic indene-pyrrole compounds. These compounds are ligands of the serotonin (5-HT) receptors, and are useful for the treatment of diseases, disorders, and conditions where modulation of serotonin (5-HT) receptor activity is desired (e.g. , addiction, anxiety, depression, and obesity).

BACKGROUND OF THE INVENTION Serotonin has been implicated in a number of diseases, disorders, and conditions that originate in the central nervous system, including diseases, disorders, and conditions related to, for example, sleeping, eating, perceiving pain, controlling the body temperature, control blood pressure, depression, anxiety, addiction, and schizophrenia. Serotonin also plays an important role in peripheral systems, such as the gastrointestinal system, where it has been found to mediate a variety of contractile, secretory, and electrophysiological effects. Due to the wide distribution of serotonin within the body, there is a need for drugs that affect the serotonergic systems. In particular, agonists, partial agonists, and antagonists of serotonergic systems are of interest for the treatment of a large number of disorders, including anxiety, depression, hypertension, migraine, obesity, compulsive disorders, schizophrenia, autism, neurodegenerative disorders (for example, Alzheimer's disease, Parkinsonism, and Huntington's chorea), and vomiting induced by chemotherapy. The major classes of serotonin receptors (5-HT1-7) contain from one to seven separate receptors that have been formally classified. See Glennon et al., Neuroscience and Behavioral Reviews, 1990, 14, 35, and D. Hoyer et al., Pharmacol. Rev. 1994, 46, 157-203. For example, the 5-HT2 receptor family contains the 5-HT2a, 5-HT2b, and 5-HT2c subtypes, which have been grouped together based on the primary structure, the secondary messenger system, and the operational profile. The three subtypes of 5-HT2 are coupled with G-protein, activate phospholipase C as a main transduction mechanism, and contain a structure of seven transmembrane domains. There are distinct differences in the distribution of the three subtypes of 5-HT2 in a mammal. The 5-HT2b and 5-HT2a receptors are widely distributed in the peripheral nervous system, with 5-HT2a also found in the brain. The 5-HT2c receptor has been found only in the central nervous system, being highly expressed in many regions of the human brain. See G. Baxter et al., Trends in Pharmacol. Sci. 1995, 16, 105-110. The 5-HT2a subtype has been associated with effects including vasoconstriction, platelet accumulation, and bronchoconstriction, as well as with certain effects on the central nervous system, while the 5-HT2c subtype has been associated with diseases including depression, anxiety, obsessive-compulsive disorder, addiction, panic disorders, phobias, psychiatric syndromes, and obesity. Very little is known about the pharmacological role of the 5-HT2b receptor. See F. Jenck et al., Exp. Opin. Invest. Drugs, 1998, 7, 1587-1599; M. Bos et al., J. Med. Chem., 1997, 40, 2762-2769; J. R. Martin et al., The Journal of Pharmacology and Experimental Therapeutics, 1998, 286, 913-924; S. M. Bromidge et al., 1. Med. Chem., 1998, 41, 1598-1612; G. A. Kennett, Drugs, 1998 1, 4, 456-470; and A. Dekeyne et al., Neuropharmacology, 1999, 38, 415-423. Patents of the United States of North America Numbers 4,622,405; 5,049,564, and 5,244,888, and International Publication Number WO 90/06927, disclose different n-pyrrole derivatives.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to compounds of the formula: wherein: R1 is selected from the group consisting of H, halogen, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, perhaloalkyl, CN, N (R6) 2, SR6, CON (R6) 2, NR6COR7, NR6C02R7, S02N (R6) 2, NR6S02R, aryl, heteroaryl, alkyl of 1 to 10 carbon atoms-aryl, and alkyl of 1 to 10 atoms carbon-heteroaryl; and when m + n = 1, R, it can also be OR6 or OCOR7; R2, R3, and R4 are independently selected from the group consisting of H, halogen, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, per-halo -alkyl, CN, OR6, N (R6) 2, SR6, OCOR7, CON (R6) 2, NR6COR7, NR6C02R7, S02N (R6) 2, NR6S02R7, aryl, heteroaryl, alkyl of 1 to 10 carbon atoms-aryl, and alkyl of 1 to 10 carbon atoms-heteroaryl, or R2 and R3I together with the ring to which they are attached, form a carbocyclic or heterocyclic ring of 5 to 7 members; R5 is selected from the group consisting of H, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, per-haloalkyl, CN, 0R6l N ( R6) 2, SR6l OCOR7, CON (R6) 2, NR6COR7, NR6C02R7, NR6S02R7, aryl, heteroaryl, alkyl of 1 to 10 carbon atoms-aryl, and alkyl of 1 to 10 carbon atoms-heteroaryl, or R4 and R5 , together with the ring with which they are attached, form an aryl or heteroaryl ring of 6 to 8 members; R5a is H; or R5 and R5a, taken together, form a cyclopropane ring; R6 is selected from the group consisting of H, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, perhaloalkyl, alkyl of 1 to 10 carbon atoms-O-alkyl of 1 to 10 carbon atoms, aryl, heteroaryl, alkyl of 1 to 10 carbon atoms-O-aryl, alkyl of 1 to 10 carbon atoms-O-heteroaryl, alkyl of 1 to 10 carbon-aryl atoms, and alkyl of 1 to 10 carbon atoms-heteroaryl; and R7 is selected from the group consisting of alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, perhaloalkyl, alkyl of 1 to 10 atoms carbon-O-alkyl of 1 to 10 carbon atoms, aryl, heteroaryl, alkyl of 1 to 10 carbon atoms-O-aryl, alkyl of 1 to 10 carbon atoms-O-heteroaryl, alkyl of 1 to 10 atoms carbon-aryl, and alkyl of 1 to 10 carbon atoms-heteroaryl; with the understanding that, if R1, R2, R5, and R5a are H, then R3 and / or R4 must be H, and pharmaceutically acceptable salts thereof. The various stereoisomers of the compounds of Formula (I) are included herein. Another embodiment of the present invention provides a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Still another embodiment of the present invention provides a method for the treatment of a disease, disorder, and / or condition in a mammal (e.g., animal or human), wherein a 5-HT2c receptor is involved, and modulation is desired. of a 5-HT2c- function The method comprises administering a therapeutically effective amount of a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, to the mammal. Yet another embodiment of the present invention comprises a method for modulating the function of the 5-HT receptor with an effective amount of a compound of the Formula (I), or a pharmaceutically acceptable salt thereof. A further embodiment of the present invention provides a method for the treatment or prevention of diseases, disorders, and / or conditions of the central nervous system. The method comprises administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the mammal. Diseases, disorders, and / or specific conditions for which the compounds of Formula (I) may have activity include cardiovascular disorders, obesity, depression, schizophrenia, anxiety, obsessive-compulsive disorder, addiction, panic disorders, sleep disorders. , migraine, Type II diabetes, epilepsy, phobias, and psychiatric syndromes. DETAILED DESCRIPTION OF THE INVENTION The following definitions are used, unless otherwise described: As used herein, the term "alkyl" includes the straight and branched chain hydrocarbon groups containing the indicated number of carbon atoms , typically methyl, ethyl, and the straight and branched chain propyl and butyl groups. The term "alkyl" also embraces cycloalkyl, that is, a cyclic hydrocarbon group of 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The reference to a group or individual fraction, such as "propyl", encompasses only the group or straight chain fraction. A branched chain isomer, such as "isopropyl", is specifically referred to. The term "alkenyl", as used herein, alone or in combination, refers to a substituted or unsubstituted straight chain or substituted or unsubstituted branched chain alkenyl radical containing from 2 to 10 carbon atoms. Examples of these radicals include, but are not limited to, ethenyl, E- and Z-pentenyl, decenyl, and the like. The term "alkynyl", as used herein, alone or in combination, refers to a substituted or unsubstituted straight chain alkynyl radical, or substituted or unsubstituted branched chain, containing from 2 to 10 carbon atoms. Examples of these radicals include, but are not limited to, ethynyl, propynyl, propargyl, butynyl, hexynyl, decynyl, and the like. The term "alkoxy", as used herein, alone or in combination, refers to an alkyl ether radical, wherein the term "alkyl" is as defined above. Examples of suitable alkyl ether radicals include, but are not limited to, methoxy, ethoxy, normal propoxy, isopropoxy, normal butoxy, isobutoxy, secondary butoxy, tertiary butoxy, and the like. The term "halo" is defined herein to include fluorine, chlorine, bromine, or iodine. In a similar manner, the term "halogen" is defined herein to include fluorine, chlorine, bromine, or iodine. The term "amino", alone or in combination, includes the group -NH2 or -NRaRb, wherein Ra and Rb are independently hydrogen, alkyl, or aryl. The term "aryl", alone or in combination, is defined herein as a monocyclic or bicyclic aromatic group (e.g., phenyl or naphthyl) which may be unsubstituted or substituted, for example, with one or more, and in particular one to three of the following substituents selected from the group consisting of H, halogen, CN, N02, CF3, N3, alkyl of 1 to 6 carbon atoms, OH, NRaRb, O-alkyl of 1 to 6 carbon atoms , ORa, C (= 0) NRaRb, C (= S) NRaRb, tetrazolyl, triazolyl, amidinyl, guanidinyl, thioguanidinyl, cyano-guanidinyl, and aryl. In general, "aryl" denotes a phenyl group, or an ortho-fused bicyclic carbocyclic group having from nine to ten ring atoms, wherein at least one ring is aromatic (e.g., naphthyl or tetra-hydro-naphthyl). The term "aryl" is also abbreviated in the different chemical structures as "Ar". The term "carbocyclic" includes any closed ring of carbon atoms, including the alicyclic and aromatic structures. The term "heteroaryl" is defined herein as a monocyclic, bicyclic, or tricyclic ring system containing one, two, or three aromatic rings, and containing at least one nitrogen, oxygen, or sulfur atom in an aromatic ring , and which may be unsubstituted or substituted, for example with one or more, and in particular with one to three substituents, such as halogen, alkyl, hydroxyl, hydroxy-alkyl, alkoxy, alkoxy-alkyl, halo-alkyl, nitro, amino , alkyl-amino, acyl-amino, thioalkyl, alkyl-sulfonyl, and alkyl-sulfinyl. Examples of the heteroaryl groups include, but are not limited to, 2H-pyrrolyl, 3H-indolyl, 4H-quinolizinyl, 4H-carbazolyl, acridinyl, benzo [b] thienyl, benzothiazolyl,, 3-carbolinyl, carbazolyl, chromenyl, cyanolinyl. , dibenzo [b, d] furanyl, furazanyl, furyl, imidazolyl, imidizolyl, indazolyl, indolizinyl, indolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, naphtho [2,3-b], oxazolyl, perimidinyl, phenanthridinyl, phenanthrolinyl, fenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxyazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, thiadiazolyl, thiantrenyl, thiazolyl, thienyl, triazolyl, and xanthenyl. In one embodiment, the term "heteroaryl" denotes a monocyclic aromatic ring containing five or six ring atoms containing carbon, and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of oxygen not peroxide, sulfur, and N (Z), wherein Z is absent or is H, O, alkyl of 1 to 4 carbon atoms, phenyl, or benzyl. In another embodiment, heteroaryl denotes an ortho-fused bicyclic heterocycle of about eight to ten ring atoms derived therefrom, in particular a benzo-derivative or one derived by melting a propylene or tetramethylene di-radical therewith. The term "Het" generally represents a heterocyclic group, saturated or partially unsaturated, containing at least one heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur, and optionally substituted with alkyl of 1 to 6 carbon atoms or C (= 0) ORb. Typically, "Het" is a monocyclic, bicyclic, or tricyclic group that contains one or more heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. A "Het" group may also contain an oxo group (= 0) attached to the ring. Non-limiting examples of the Het groups include 1,3-dihydro-benzofuran, 1,3-dioxolane, 1,4-dioxane, 1,4-dithiane, furanyl, imidazolyl, 2H-pyran, 2-pyrazoline, 4H-pyran , chromanyl, imidazolidinyl, imidazolinyl, indolinyl, isochromanyl, isoindolinyl, morpholine, oxazolyl, piperazinyl, piperidine, piperidinyl, pyrazolidin, pyrimidinyl, pyrazolidinyl, pyrazolinyl, pyrrolidine, pyrroline, quinuclidine, and thiomorpholine. Preferably, R1 is alkyl of 1 to 5 carbon atoms, halogen, CF3, aryl, heteroaryl, or H; R2, R3, and R4 are independently alkyl of 1 to 5 carbon atoms, -0-R6, halogen, CF3, aryl, heteroaryl, or H; R5 is alkyl of 1 to 5 carbon atoms, -OR6, or alkene of 2 to 6 carbon atoms; and R6 is alkyl of 1 to 5 carbon atoms or H. Presently, preferred compounds include: 5-methoxy-8-methyl-1, 2,3,3a, 8,8a-hexahydro-indene- [1, 2-c] -pyrrole; -hydroxy-8-methyl-1, 2,3,3a, 8,8a-hexahydro-indene- [1,2-c] -pyrrole; -methoxy-6-chloro-8-methyl-1, 2,3,3a, 8,8a-hexahydro-indene- [1,2-c] -pyrrole; 5- hydroxy-6-chloro-8-methyl-1, 2,3,3a, 8,8a-hexahydro-indene- [1,2-c] -pyrrole; 6- chloro-8-methyl-1, 2,3,3a, 8,8a-hexahydro-indene- [1,2-c] -pyrrole; 5- (4-Fluoro-benzyloxy) -6-chloro-8-methyl-1, 2,3,3a, 8,8a-hexahydro-indene- [1,2-c] -pyrrole; 5-benzyloxy-6-chloro-8-methyl-1, 2,3,3a, 8,8a-hexahydro-indene- [1,2-c] -pyrrole; 5- (2-fluo-o-n-n-oxy) -6-chloro-8-methyl-1, 2,3,3a, 8,8a-hexahydro-indene- [1,2-c] -pyrrole; 5- (3-fluo-o-n-n-oxy) -6-chloro-8-methyl-1, 2,3,3a, 8,8a-hexahydro-indene- [1,2-c] -pyrrole; 1,2,3,3a, 8,8a-hexahydro-indene- [1,2-c] -pyrrole; 6-chloro-1,2,3,3a, 8,8a-hexahydro-indene- [1,2-c] -pyrrole; 6,7-dichloro-8-methyl-1, 2,3,3a, 8,8a-hexahydro-indene- [1,2-c] -pyrrole; 4,5-dimethoxy-6-chloro-8-methyl-1, 2,3,3a, 8,8a-hexahydro-indene- [1,2-c] -pyrrole; 4.6-dichloro-5-methoxy-8-methyl-1, 2,3,3a, 8,8a-hexahydro-indene- [1,2-c] -pyrrole; and 6- (2,6-di-fluo-fe-nyl) -1, 2,3,3a, 8,8a-hexahydro-indene- [1,2-c] -pyrrole. Certain compounds of the invention can exist in different isomeric forms (e.g., enantiomers and diastereoisomers). The invention contemplates all these isomers, both in pure form and in mixture, including racemic mixtures. The enol forms are also included. The compounds of the invention can exist in unsolvated forms, as well as solvates, including hydrated forms, for example the hemi-hydrate. In general, solvated forms, with pharmaceutically acceptable solvents, such as water, ethanol, and the like, are equivalent to unsolvated forms for the purposes of the invention. Certain compounds of the invention also form pharmaceutically acceptable salts, for example acid addition salts. For example, nitrogen atoms can form salts with acids. Examples of acids suitable for the formation of salts are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic, and other mineral carboxylic acids well known to the subject matter experts. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. The free base forms can be regenerated by treating the salt with a suitable dilute aqueous base solution, such as dilute aqueous hydroxide, potassium carbonate, ammonia, and sodium bicarbonate. The free base forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but the acid salts are equivalent to their respective free base forms for the purposes of the invention. (See, for example, S.M. Berge et al., "Pharmaceutical Salts," J. Pharm. Sci., 66: 1-19 (1977), which is incorporated herein by reference).

As used herein, the term "composition" is intended to encompass a product comprising specified ingredients in the specified amounts, as well as any product that results, directly or indirectly, from a combination of the specified ingredients in the specified amounts. The compounds of the present invention can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids. The phrase "pharmaceutically acceptable salt" means salts which, within the scope of a reliable medical judgment, are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and they are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. Describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences., 1977, 66: 1 et seq. The salts can be prepared in situ during the isolation and final purification of the compounds of the invention, or separately by the reaction of a free base function with a suitable organic acid. Representative acid addition salts include, but are not limited to, acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorrate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride. , hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate (isothionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate, and undecanoate. Also, groups containing basic nitrogen can be quaternized with agents such as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides.; dialkyl sulfates such as dimethyl, diethyl, dibutyl, and diamyl sulfates; long chain halides, such as chlorides, bromides, and decyl, lauryl, myristyl, and stearyl iodides; aryl-alkyl halides such as benzyl and phenethyl bromides, and others. In this way, soluble or dispersible products are obtained in water or oil. Examples of acids that can be employed to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and organic acids such as oxalic acid, maleic acid, acid succinic, and citric acid. The base addition salts can be prepared in situ during the isolation and final purification of the compounds of this invention, by reacting a carboxylic acid containing fraction with a suitable base, such as the hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, or with ammonia, or with a primary, secondary, or tertiary organic amine. Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali metals or alkaline earth metals, such as lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and the like, and nontoxic cations of quaternary ammonia and amine, including ammonium, tetramethyl-ammonium, tetraethyl-ammonium, methyl-ammonium, dimethyl-ammonium, trimethyl-ammonium, triethyl-ammonium, diethyl-ammonium, and ethyl-ammonium, among others. Other representative organic amines useful for the formation of base addition salts include ethylene diamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like. Dosage forms for topical administration of a compound of this invention include powders, aerosols, ointments, and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any necessary preservatives, pH regulators, or propellants that may be required. Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated within the scope of this invention. The actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention can be varied to obtain an amount of the active compounds that is effective to achieve the desired therapeutic response for a particular patient, the compositions, and the mode of administration. The selected dosage level will depend on the activity of the particular compound, the route of administration, the severity of the condition being treated, and the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start with doses of the compound at levels lower than those required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved. When used in the above or other treatments, a therapeutically effective amount of one of the compounds of the present invention may be employed in pure form, or, where such forms exist, in the form of a pharmaceutically acceptable salt, ester, or pro -drug. Alternatively, the compound can be administered as a pharmaceutical composition containing the compound of interest in combination with one or more pharmaceutically acceptable excipients. The phrase "therapeutically effective amount" of the compound of the invention means a sufficient amount of the compound to treat the disorders, with a reasonable benefit / risk ratio applicable to any medical treatment. However, it will be understood that the total daily use of the compounds and compositions of the present invention will be decided by the physician attending, within the scope of a reliable medical judgment. The specific level of therapeutically effective dose for any particular patient will depend on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; age, body weight, general health, sex, and the patient's diet; the time of administration, the route of administration, and the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincident with the specific compound used; and similar factors well known in the medical field. For example, it is well within the ability of the art to start with doses of the compound at levels lower than those required to achieve the desired therapeutic effect, and to gradually increase the dosage until the desired effect is achieved. The total daily dose of the compounds of this invention administered to a human or a lower animal may be in the range of about 0.0001 to about 1000 milligrams / kilogram / day. For purposes of oral administration, the most preferable doses may be in the range of about 0.001 to about 5 milligrams / kilogram / day. If desired, the effective daily dose can be divided into multiple doses for the purposes of administration; consequently, the single dose compositions may contain the amounts or submultiples thereof to form the daily dose. The present invention also provides pharmaceutical compositions comprising the compounds of the present invention, formulated together with one or more non-toxic pharmaceutically acceptable carriers. The pharmaceutical compositions can be formulated especially for oral administration in solid or liquid form, for parenteral injection or for rectal administration. The pharmaceutical compositions of this invention can be administered to humans and other mammals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), buccally, or as an oral or nasal spray. The term "parenterally", as used herein, refers to modes of administration that include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, and intra-articular injection and infusion. In another aspect, the present invention provides a pharmaceutical composition comprising a component of the present invention, and a physiologically tolerable diluent. The present invention includes one or more compounds as described above, formulated in compositions together with one or more physiologically tolerable or acceptable diluents, carriers, adjuvants or non-toxic vehicles, which are collectively referred to herein as diluents, for parenteral injection, for intranasal delivery, for oral administration in solid or liquid form, for rectal or topical administration, among others. The compositions can also be delivered through a catheter for local delivery to a target site, by means of an intracoronary stent (a tubular device composed of a fine wire mesh), or by means of a biodegradable polymer. The compounds can also complex with ligands, such as antibodies, for targeted delivery. Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable carriers, diluents, solvents or aqueous and non-aqueous vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), vegetable oils (such as olive oil), injectable organic esters, such as oleate. of ethyl, and suitable mixtures thereof. These compositions may also contain adjuvants, such as preservative agents, humectants, emulsifiers, and dispersants. The prevention of the action of the microorganisms can be ensured by different anti-bacterial and anti-fungal agents, for example parabens, chloro-butanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be caused by the use of agents that delay absorption, for example, aluminum monostearate and gelatin. The suspensions, in addition to the active compounds, may contain suspending agents, such as, for example, ethoxylated isostearyl alcohols, sorbitol and polyoxyethylene sorbitan esters, microcrystalline cellulose, aluminum meta-hydroxide, bentonite, agar-agar, and tragacanth. , or mixtures of these substances, and the like. In some cases, in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of a crystalline or amorphous material with poor solubility in water. The rate of absorption of the drug then depends on its rate of dissolution, which in turn may depend on the size of the crystal and the crystalline form. Alternatively, the delayed absorption of a parenterally administered drug form is carried out by dissolving or suspending the drug in an oily vehicle. Injectable depot forms are made by forming microencapsulated matrices of the drug in biodegradable polymers, such as polylactide-polyglycolide. Depending on the ratio of the drug to the polymer, and the nature of the particular polymer employed, the rate of release of the drug can be controlled. Examples of other biodegradable polymers include poly- (o / "fo-esters) and poly- (anhydrides) Injectable depot formulations are also prepared by trapping the drug in liposomes or microemulsions that are compatible with body tissues. they can be sterilized, for example, by filtration through a bacteria retention filter, or by the incorporation of sterilizing agents in the form of sterile solid compositions, which can be dissolved or dispersed in sterile water or in other sterile injectable medium. just before use Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules In these solid dosage forms, the active compound can be mixed with at least one pharmaceutically acceptable excipient or carrier, such such as sodium citrate or calcium diphosphate, and / or) fillers or extenders, such such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, such as carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; c) humectants, such as glycerol; d) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarding agents, such as paraffin; f) absorption accelerators, such as quaternary ammonium compounds; g) wetting agents, such as cetyl alcohol and glycerol monostearate; h) sorbents, such as kaolin and bentonite clay, and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form can also comprise pH regulating agents. Solid compositions of a similar type can also be employed as fillings in soft and hard gelatin capsules, using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols, and the like. The solid dosage forms of the tablets, dragees, capsules, pills, and granules, can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulating art. Optionally they may contain opacifying agents, and may also be of a composition such that they release the active ingredients only, or preferably, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of the embedment compositions that can be used include polymeric substances and waxes. The active compounds may also be in a micro-encapsulated form, if appropriate, with one or more of the aforementioned excipients. Solid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents, and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate. , ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, peanut, corn, germ, olive, castor bean, and sesame oils), glycerol , tetrahydrofurfuryl alcohol, polyethylene glycols, and sorbitan fatty acid esters, and mixtures thereof. In addition to the inert diluents, the oral compositions may also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweeteners, flavors, and perfuming agents. Compositions for rectal and vaginal administration are preferably suppositories, which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or vehicles, such as cocoa butter, polyethylene glycol, or a suppository wax, which are solid at room temperature, but liquid at body temperature, and therefore melt in the rectum or vaginal cavity, and release the active compound. The compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals, which are dispersed in an aqueous medium. Any non-toxic physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions, in the form of liposomes, may contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like. Preferred lipids are natural and synthetic phospholipids and phosphatidyl-cholines (lecithins), which are used separately or together. Methods for forming liposomes are known in the art. See, for example, Prescott, Editor, Methods in Cell Biology, Volume XIV, Academic Press, New York, N. Y. (1976), pages 33 et seq. The term "pharmaceutically-acceptable prodrugs", as used herein, represents prodrugs of the compounds of the present invention, which, within the scope of a reliable medical judgment, are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, in a manner commensurate with a reasonable benefit / risk ratio, and that are effective for their intended use, as well as zwitterionic forms, where possible, of the compounds of the invention. The prodrugs of the present invention can be rapidly transformed in vivo to the parent compound of the above formula, for example, by hydrolysis in the blood. A full discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Volume 14 of the ACS Symposium Series, and in Edward B. Roche, Editor, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987), incorporated herein by reference. The compounds of the present invention can be prepared by the procedures stipulated in Schemes 1, 2, and 3. In all the examples, the general analytical conditions stipulated after the Schemes were employed.

Scheme 1. Synthesis of 8-substituted indeno-pyrroles by a 3 + 2 cycloaddition on substituted indenones. Scheme 2. Synthesis of indeno-pyrroles by reconfiguration of Beckmann on substituted indenos.

Scheme 3. Synthesis of 8-substituted indeno-pyrroles by cycloaddition 3 + 2 on ethyl esters of phenyl-acrylic acid c / s-substituted.

General Analytical Cond icions: Analysis and purification by H PLC were carried out using a Waters 2525 binary gradient pump, a Waters 2767 sample handler, a Waters 2487 ultraviolet detector (220 and 254 nanometers), and a spectra detector. Waters Micromass ZQ electrospray mass The Micromass ZQ was established for both positive and negative ionization (cone voltage = 25 and 50, respectively). The analysis of analytical PLC H was carried out as follows: Waters XTerra MS Column C 8, 50 x 4.6 thousand, 3.5 microns.

Mobile phase: 10 mM ammonium acetate regulator at a pH of 5.75, and acetonitrile. Acetonitrile: 10 to 75 percent in 3.5 minutes, 75 to 99 percent in 3.9 minutes, support in 99 percent to 4.2 minutes, 99 to 10 percent in 4.5 minutes, rebalancing. The HPLC preparation was carried out as follows: Waters XTerra Prep MS C18 Column, 50 x 19 millimeters, 5 microns. Mobile phase: 10 mM ammonium acetate regulator at a pH of 5.75, and acetonitrile. Acetonitrile: 10 to 99 percent in 8 minutes, support in 99 percent to 9 minutes, 99 to 10 percent in 9.5 minutes, rebalancing. Nuclear magnetic resonance (NMR) analysis was carried out using a Bruker BioSpin U ItraS hield NMR (300 MHz). EXAMPLES Example 1 5-methoxy-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole Step A. 3-Bromo-5-methoxy-1-indanone. (Scheme 1). N-bromo-succinimide (12.1 grams, 67.9 millimoles) and 2,2'-azo-bissobutyronitrile (0.1 grams, 0.6 millimoles) were added to a solution of 5-methoxy-1-indanone (10.0 grams, 61.7 millimoles) in carbon tetrachloride (104 milliliters). The reaction mixture was stirred for 3 hours at 85 ° C, and then allowed to cool to room temperature. The reaction mixture was filtered through Celite, which was then washed with CH2Cl2 (100 milliliters). The filtrate was washed with brine (50 milliliters), dried over MgSO4, and concentrated to give the subtitle compound, which was used without further purification. MS calculated for C10HgBrO2 + H: 241; observed: 241. Step B. 5-methoxy-inden-1 -one. DBU (9.2 milliliters, 61.7 millimoles) was added dropwise to a solution of 5-methoxy-3-bromo-1-indanone (14.8 grams, 61.7 millimoles) in tetrahydrofuran (100 milliliters) at -10 ° C for 10 minutes. The resulting solution was stirred at -10 ° C for 20 minutes, quenched by the addition of saturated aqueous NH Cl (100 milliliters), and extracted with EtOAc (100 milliliters, 3 times). The combined organic extracts were washed with brine (100 milliliters), dried over MgSO4, and concentrated. The crude product was purified by column chromatography (SiO2) using a gradient of 0 to 35 percent ethyl acetate-hexanes, to provide 5.4 grams (55 percent-two steps) of the subtitle compound. H NMR (CDCl3300 MHz) d 7.42 (d, 1H), 7.38 (d, 1H), 6.62 (s, 1H), 6.60 (d, 1H), 5.89 (d, 1H), 3.85 (s, 3H), ppm . MS calculated for Ci0H8O2 + H: 161; observed: 161. Step C. 2-Benzyl-5-methoxy-2,3,3a, 8a-tetrahydro-1α-2-aza-cyclopenta [a] inden-8-one. N- (methoxy-methyl) -N- (trimethyl-silyl-methyl) -benzyl-amine (17.3 milliliters, 67.6 millimoles) and trifluoroacetic acid (3.4 milliliters) were added to a solution of 5-methoxy-inden-1 -one (5.4 grams, 33.8 millimoles) in CH2CI2 (165 milliliters) at 0 ° C. The reaction was stirred for 3 hours at room temperature, and quenched with saturated aqueous NaHCO3 (165 milliliters). The organic layer was separated, washed with brine (100 milliliters), dried over MgSO, and concentrated to provide the subtitle compound, which was used without further purification. MS calculated for C19H19N02 + H: 294; observed: 294. Step D. 2-Benzyl-5-methoxy-8-methylene-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole. Methyltriphenylphosphonium bromide (18.1 grams, 50.7 millimoles) and potassium terbutoxide (5.7 grams, 50.7 millimoles) were added to a solution of 2-benzyl-5-methoxy-2,3,3a, 8a, tetrahydro-1 ? -2-aza-cyclopenta [a] inden-8-one (9.9 grams, 33.8 mmol) in anhydrous ether (68 milliliters). The reaction mixture was stirred for 1 hour at room temperature, and then filtered through Celite. The Celite was washed with ether (200 milliliters), and the filtrate was concentrated. The crude product was purified by column chromatography (Si02) using a gradient of 0 to 35 percent ethyl acetate-hexanes, to provide 8.1 grams (82 percent-two steps) of the subtitle compound. MS calculated for C20H2iNO + H: 292; observed: 292.

Step E. 5-Methoxy-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole. Ammonium (8.1 grams) and palladium (10 percent by weight on activated carbon, 4.0 grams) format were added to a solution of 2-benzyl-5-methoxy-8-methylene-1, 2,3,3a, 8 , 8a-hexahydro-indene- [1, 2-c] -pyrrole (8.1 grams, 27.8 mmol) in MeOH (140 milliliters). The reaction mixture was stirred for 4 hours at 60 ° C, and then filtered through Celite. The Celite was washed with MeOH (200 milliliters), and the filtrate was concentrated to provide 5.6 grams (quantitative yield) of the title compound. An aliquot of the crude product was purified by reverse phase liquid chromatography to provide the title compound. MS calculated for C 13 H 17 NO + H: 204; observed: 204. Example 2 5-hydroxy-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole Step A. Ethyl N-carbamate-5-methoxy-8-methyl-1, 2,3, 3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole. (Scheme 1). Sodium carbonate (11.7 grams, 139 millimoles) and ethyl chloro-formate (3.2 milliliters, 33.4 millimoles) were added to a solution of 5-methoxy-8-methyl-1, 2,3,3a, 8,8a- hexahydro-indene- [, 2-c] -pyrrole (from Example 1, Step E) (5.6 grams, 27.8 mmol) in tetrahydrofuran / H20 (140 milliliters, 1/1, volume / volume), and stirred for the night at room temperature. The reaction mixture was quenched by the addition of an aqueous solution of HCl (200 milliliters, 1.0 M), and the product was extracted with EtOAc (100 milliliters, 3 times). The combined organic extracts were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (Si02) using a gradient of 0 to 35 percent ethyl acetate-hexanes, to provide 2.7 grams (35 percent) of the subtitle compound. 1 H NMR (CDCl 3 300 MHz) d 7.07 (d, 1 H), 6.78 (m, 2 H), 4.09 (m, 2 H), 3.79 (m, 5 H), 3.63 (m, 1 H), 3.52 (m, 1 H), 3.32 (m, 1H), 3.07 (m, 1H), 2.95 (m, 1H), 1.26 (m, 6H) ppm. MS calculated for C 16 H 2iN 0 3 + H: 276; observed: 276. Step B. 5-hydroxy-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole. The N-carbamate of ethylo-5-methoxy-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole (12 milligrams, 0.045 mmol) was dissolved in concentrated HCl (2 milliliters), and stirred for 20 hours at 120 ° C. The reaction solution was cooled to room temperature, diluted with H20 (2 milliliters), and washed with EtOAc (5 milliliters). The aqueous solution was concentrated in a speed vac, to provide the title compound as the hydrochloride salt. MS calculated for Ci2H15NO + H: 190; observed: 190. Example 3 5-methoxy-6-chloro-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole Step A. Ethyl N-carbamate-5-methoxy-6-chloro-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole. (Scheme 1). N-chlorosuccinimide (0.22 grams, 1.6 mmol) and acetic acid (8 milliliters) were added to a solution of ethyl N-carbamate-5-methoxy-8-methyl-1, 2,3,3a, 8,8a hexane-hydro-indene- [1, 2-c] -pyrrole (from Example 2, Step A) (0.45 grams, 1.6 mmol) in DCE (8 milliliters) and stirred for 3 hours at 60 ° C. The reaction mixture was cooled to room temperature, diluted with CH2Cl2 (50 milliliters), and washed with H2O (50 milliliters). The organic extract was dried over MgSO, and concentrated. The crude product was purified by column chromatography (Si02) using a gradient of 0 to 35 percent ethyl acetate-hexanes, to provide 250 milligrams (51 percent) of the subtitle compound. MS calculated for C16H2oCIN03 + H: 310; observed: 310. Step B. 5-methoxy-6-chloro-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole. Barium hydroxide octahydrate (0.63 grams, 2.0 mmol) was added to a solution of ethyl N-carbamate-5-methoxy-6-chloro-8-methyl-1, 2,3,3a, 8,8a- hexa-hydro-indene- [1,2-c] -pyrrole (61 milligrams, 0.2 mmol) in MeOH (4 milliliters), and stirred for 24 hours at reflux. The reaction mixture was cooled to room temperature, and neutralized to a pH = 7 with aqueous HCl (50 milliliters, 1 M). The product was extracted with CH2Cl2, dried over MgSO4, and concentrated. The crude product was purified by reverse phase liquid chromatography to provide the title compound. MS calculated for C 13 H 16 CINO + H: 238; observed: 238. Example 4 5-hydroxy-6-chloro-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole A solution of ethyl N-carbamate-5-methoxy-6-chloro-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole (from Example 3, Step A) (61 milligrams, 0.2 mmol) in concentrated HCl, was stirred overnight at 120 ° C. The reaction solution was cooled to room temperature, and concentrated in a speed vac. The crude product was purified by reverse phase liquid chromatography to provide the title compound. 1 H NMR (d 6 -DMSO 300 MHz) d 7.04 (s, 1 H), 6.73 (s, 1 H), 3.52 (m, 1 H), 3.22 (m, 2 H), 2.83 (m, 3 H), 2.41 (m, 1 H) ), 1.18 (d, 3H) ppm. MS calculated for C12H14CINO + H: 224; Observed: 224. Example 5 6-Chloro-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole Step A. Ethyl N-carbamate-5-hydroxy-6-chloro-8-methyl-1,2,3,3a, 8,8a-hexahydro-indene- [1,2-c] -pyrrole. (Scheme 1). BBr3 (3.7 milliliters, 1.0 M in CH2Cl2) was added to a solution of ethyl N-carbamate-5-methoxy-6-chloro-8-methyl-1, 2,3,3a, 8,8a-hexahydroxy. indeno- [, 2-c] -pyrrole (from Example 3, Step A) (0.49 grams, 1.6 mmol) in CH2Cl2 (32 milliliters), and stirred overnight at room temperature. The excess BBr3 was quenched by the dropwise addition of H20 (10 milliliters), and washed with saturated aqueous NaHCO3 (50 milliliters) and brine (50 milliliters). The organic extract was dried over MgSO4 and concentrated to provide the subtitle compound, which was used without further purification. S calculated for C15H18CIN03 + H: 296; observed: 296. Step B. Ethyl N-carbamate-5-hydroxy-6-chloro-8-methyl-1,2,3,3a, 8,8a-hexahydro-indene- [1,2-c] -pyrrole, O-trifluoromethanesulfonate. Pyridine (0.23 milliliters, 2.85 millimoles) and trifluoromethanesulfonic anhydride (0.32 milliliters, 1.90 millimoles) were added to a solution of ethyl N-carbamate-5-hydroxy-6-chloro-8-methyl. -1.2, 3, 3a, 8, 8a-hexa-hldro-indene- [1, 2-c] -pyrrole (0.28 grams, 0.95 mmol) in CH2Cl2 (10 milliliters), and stirred for 1.5 hours at room temperature ambient. The reaction was diluted with CH2Cl2 (10 milliliters), washed with H20 (10 milliliters), aqueous HCl (1.0M, 10 milliliters), saturated aqueous NaHCO3 (10 milliliters), and brine (10 milliliters). The organic extract was dried over MgSO4, and concentrated, to provide the subtitle compound, which was used without further purification. MS calculated for C16H17F3CIN05S + H: 428; observed: 428. Step C. Ethyl N-carbamate-6-chloro-8-methyl-1, 2,3,38,8,8a-hexahydro-indene- [1,2-c] -pyrrole. To a mixture of ethyl N-carbamate-5-hydroxy-6-chloro-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole, o-trifluoromethane sulfonate (60 milligrams, 0.14 millimoles), palladium acetate (11) (6 milligrams, 0.028 millimoles), and 1,3-bis- (diphenyl-phosphino) -propane (12 milligrams, 0.035 millimoles) in MeOH (0.5 milliliters), and dimethyl sulfoxide (0.5 milliliters), Et3N (0.2 milliliters, 1.4 millimoles) was added. The resulting mixture was stirred for 2 hours at 80 ° C, and then cooled to room temperature. The reaction mixture was diluted with EtOAc (5 milliliters), and then washed with H20 (2 milliliters). The organic extract was dried over MgSO4 and concentrated to provide 15 milligrams (35 percent yield) of the subtitle compound, which was used without further purification. MS calculated for C15H18CIN02 + H: 280; observed: 280. Step D. 6-Chloro-8-methyl-1, 2,3,3a, 8,8a-hexahydro-indene- [1,2-c] -pyrrole. The title compound was prepared by the method of Example 4, using ethyl N-carbamate-6-chloro-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1, 2-c] -pyrrole. The crude product was purified by reverse phase liquid chromatography to provide the title compound. MS calculated for Ci2H14CIN + H: 208; observed: 208. EXAMPLE 6 5- (4-Fluoro-benzyloxy) -6-chloro-8-methyl-1, 2,3,3a, 8,8a-hexahydro-indene- [1,2- c] -pirro I Step A. Ethyl N-carbamate-5- (4-fluoro-benzyloxy) -6-chloro-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1, 2- c] -pyrrole. (Scheme 1). 4-Fluoro-benzyl bromide (23 microliters) was added, 0.19 millimoles) and potassium carbonate (100 milligrams, 0.78 millimoles) to a solution of ethyl N-carbamate-5-hydroxy-6-chloro-8-methyl-1, 2,3,3a, 8,8a-hexa -hydro-indene- [1, 2-c] -pyrrole (from Example 5, Step A) (46 milligrams, 0.16 millimoles) in acetonitrile (3 milliliters), and stirred overnight at 80 ° C. The reaction was cooled to room temperature, concentrated by rotary evaporation, and absorbed in H20 (5 milliliters). The product was extracted with EtOAc (10 milliliters, 3 times). The combined organic extracts were dried over MgSO4, and concentrated to provide the subtitle compound, which was used without further purification. MS calculated for C22H23CIFNO3 + H: 404; observed: 404. Step B. 5- (4-Fluoro-benzyloxy) -6-chloro-8-methyl-1, 2, 3, 3a, 8, 8a-hexa-hydro-indene- [1, 2-c] -pyrrol. The title compound was prepared by the method of Example 3, Step B, using ethyl N-carbamate-5- (4-fluoro-benzyloxy) -6-chloro-8-methyl-1, 2,3,3a, 8 , 8a-hexahydro-indene- [1, 2-c] -pyrrole. The crude product was purified by reverse phase liquid chromatography to provide the title compound. 1 H NMR (d 6 -DMSO 300 MHz) d 7.51 (m, 2 H), 7.23 (m, 3 H), 7.09 (s, 1 H), 5.18 (m, 2 H), 3.63 (m, 1 H), 3.27 (m, 2 H) ), 2.7-3.0 (m, 3H), 2.45 (m, 1H), 1.18 (d, 3H) ppm. S calculated for C19H19CIFNO + H: 332; observed: 332. EXAMPLE 7 5-Benzyloxy-6-chloro-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole Step A. Ethyl N-carbamate-5-benzyloxy-6-chloro-8-methyl-1,2,3,3a, 8,8a-hexahydro-indene- [1,2-c] -pyrrole. (Scheme 1). The title compound was prepared by the method of Example 6, Step A, using the ethyl N-carbamate-5-hydroxy-6-chloro-8-methyl-1, 2, 3, 3, 8, 8a. hexahydro-indene- [1, 2-c] -pyrrole (from Example 5, Step A) and benzyl bromide. The crude product was obtained without further purification. MS calculated for C22H24CINO3 + H: 386; observed: 386. Step B. 5-Benzyloxy-6-chloro-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole. The title compound was prepared by the method of Example 3, Step B, using the ethyl N-carbamate-5-benzyloxy-6-chloro-8-methyl-1, 2,3,3a, 8,8a- hexahydro-indene- [1, 2-c] -pyrrole. The crude product was purified by reverse phase liquid chromatography to provide the title compound. 1 H NMR (d6-D SO 300 MHz) d 7.28 - 3.60 (m, 5H), 7.19 (s, 1H), 7.10 (s, 1H), 5.18 (m, 2H), 3.63 (m, 1H), 3.27 ( m, 2H), 2.7-3.0 (m, 3H), 2.45 (m, 1H), 1.18 (d, 3H) ppm. MS calculated for Ci9H20CINO + H: 314; observed: 314. EXAMPLE 8 5- (2-Fluoro-benzyloxy) -6-chloro-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] - pyrrole Step A. Ethyl N-carbamate-5- (2-fluoro-benzyloxy) -6-chloro-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1, 2 -c] -pyrrole. (Scheme 1). The subtitle compound was prepared by the method of Example 6, Step A, using the ethyl N-carbamate-5-hydroxy-6-chloro-8-methyl-1, 2,3,3a, 8,8a-hexa- hydro-indene- [1,2-c] -pyrrole (del Example 5, Step A) and 2-fluoro-benzyl bromide. The crude product was obtained without further purification. MS calculated for C22H23CIFNO3 + H: 404; observed: 404. Step B. 5- (2-Fluoro-benzyloxy) -6-chloro-8-methyl-1, 2, 3, 3a, 8, 8a-hexa-hydro-indene- [1,2-c] -pyrrol. The title compound was prepared by the method of Example 3, Step B, using the ethyl N-carbamate-5- (2-fluoro-benzyloxy) -6-chloro-8-methyl-1, 2,3,3a, 8,8a-hexahydro-indene- [1, 2-c] -pyrrole. The crude product was purified by reverse phase liquid chromatography to provide the title compound. 1 H NMR (de-DMSO 300 MHz) d 7.58 (m, 1 H), 7.44 (m, 1 H), 7.25 (m, 2 H), 7.19 (s, 1 H), 7.09 (s, 1 H), 5.20 (m, 2 H) ), 3.63 (m, 1H), 3.27 (m, 2H), 2.7-3.0 (m, 3H), 2.45 (m, 1H), 1.22 (d, 3H) ppm. MS calculated for C19H19CIFNO + H: 332; observed: 332. Example 9 5- (3-f luoro-benzyloxy) -6-chloro-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pirro I Step A. Ethyl N-carbamate-5- (3-fluoro-benzyloxy) -6-chloro-8 methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1, 2-c ] -pyrrole. (Scheme 1).

The subtitle compound was prepared by the method of Example 6, Step A, using the ethyl N-carbamate-5-hydroxy-6-chloro-8-methyl-1, 2,3,3a, 8,8a-hexa -hydro-indene- [1, 2-c] -pyrrole (from Example 5, Step A) and 3-fluoro-benzyl bromide. The crude product was obtained without further purification. MS calculated for C22H23CIFNO3 + H: 404; observed: 404. Step B. 5- (3-Fluoro-benzyloxy) -6-chloro-8-methyl-1, 2, 3, 3a, 8, 8a-hexa-hydro-indene- [1, 2 c] -pirroI. The title compound was prepared by the method of Example 3, Step B, using the ethyl N-carbamate-5- (3-fluoro-ben cy I oxy) -6-cl or ro-8-methyl-1, 2 , 3,3a, 8,8a-hexahydro-indene- [1,2-c] -pyrrole. The crude product was purified by reverse phase liquid chromatography to provide the title compgence. 1 H NMR (de-DMSO 300 MHz) d 7.38 (m, 1 H), 7.23 (m, 2 H), 7.14 (m, 2 H), 7.02 (s, 1 H), 5.16 (m, 2 H), 3.58 (m, 1 H) ), 3.24 (m, 2H), 2.7-3.0 (m, 3H), 2.45 (m, 1H), 1.14 (d, 3H) ppm. MS calculated for Ci9H19CIFNO + H: 332; observed: 332. Example 10 1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole Step A. 2,2a, 7,7a-tetrahydro-cyclobute [a] inden-1 -one. (Scheme 2) · To a suspension of indene (1.2 milliliters, 10.0 millimoles) and activated zinc (1.6 grams, 25.0 millimoles) in ether (100 milliliters), was added a solution of trichloro-acetyl chloride (3.4 milliliters, 30.0 millimoles) in ether (40 milliliters). The resulting mixture was stirred for 4 hours at reflux. The reaction was cooled to room temperature, filtered through Celite, and Celite was washed with ether (100 milliliters, 2 times). The organic filtrate was washed with H20 (100 milliliters), dried over MgSO4, and concentrated. The organic residue was dissolved in MeOH (100 milliliters). To this solution was slowly added zinc (5.0 grams) and NH4CI (4.0 grams). The reaction mixture was stirred overnight at reflux. The reaction mixture was cooled to room temperature, filtered through Celite, the Celite was washed with MeOH (200 milliliters), and concentrated. The crude product was purified by column chromatography (SiO2) using a gradient of 0 to 35 percent ethyl acetate-hexanes, to provide 1.4 grams (89 percent-two steps) of the subtitle compound. 1 H NMR (CDCl3300 MHz) S 7.24 (m, 4 H), 4.06 (m, 2 H), 3.63 (m, 1 H), 3.29 (d, 1 H), 3.10 (m, 1 H), 2.88 (d, 1 H) ppm. Step B. 2,2a, 7,7a-tetrahydro-cyclobute [a] inden-1 -one oxime. Sodium acetate (1.45 grams, 17.7 millimoles) and hydroxylamine hydrochloride (0.68 grams, 9.75 millimoles) were added to a solution of 2.2a, 7.7a-tetrahydro-cyclobute [a] inden-1 -one (1.4 grams, 8.86 mmol) in MeOH (18 milliliters), and stirred overnight at room temperature. The reaction solution was concentrated by rotary evaporation. The residue was dissolved in CH2Cl2 (100 milliliters), washed with H20 (50 milliliters), dried over MgSO4, and concentrated to give the subtitle compound, which was used without further purification. MS calculated for CuH ,, NO + H: 174; observed: 174. Step C. 3,3a, 8,8a-tetrahydro-2H-2-aza-cyclopenta [a] inden-1 -one.

Thionyl chloride (1.9 milliliters, 26.4 millimoles) was added to a solution of 2,2a, 7,7a-tetrahydro-cyclobuta [a] indenone-oxime (1.5 grams, 8.8 millimoles) in 1,4-dioxane ( 44 milliliters), and stirred overnight at room temperature. The reaction was quenched with saturated aqueous NaHCO3 (100 milliliters), and extracted with EtOAc (50 milliliters, 3 times). The organic extracts were washed with brine, dried over MgSO4, and concentrated to give the subtitle compound and its regioisomer, which were used without further purification. MS calculated for C ,, HnNO + H: 174; observed: 174. Step D. 1, 2,3,3a, 8,8a-hexahydro-indene- [1,2-c] -pyrrole. A solution of 3,3a, 8,8a-tetrahydro-2H-2-aza-cyclopenta [a] -inden-1-one (1.5 grams, 8.8 millimoles) in tetrahydrofuran (44 milliliters) was cannulated into a solution of LAH in tetrahydrofuran (26.4 milliliters, 1.0 M solution in tetrahydrofuran). The resulting solution was stirred for 4 hours at 70 ° C, and then overnight at room temperature. The reaction was quenched by stepwise addition of H20 (1 milliliter), aqueous NaOH (1 milliliter, 2.0M solution), and H20 (3 milliliters). The resulting mixture was filtered through Celite, the Celite was washed with hot MeOH (200 milliliters), and the filtrate was concentrated to give the subtitle compound and its regioisomer, which were used without further purification. MS calculated for C H 3 N + H: 160; observed: 160. Step F. Terbutyl-N-carbamate-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole. Diterbutyl dicarbonate (2.0 grams, 9.4 millimoles) and sodium acid carbonate (4.0 grams, 47 millimoles) were added to a solution of 1, 2.3.3a, 8.8a-hexa-hydro-indene- [1, 2-c] -pyrrole (1.5 grams, 9.4 millimoles) in H20 / tetrahydrofuran (46 milliliters, 1/1, volume / volume), and stirred overnight at room temperature. The reaction mixture was diluted with H20 (50 milliliters), and extracted with EtOAc (100 milliliters, 3 times). The combined organic extracts were dried over MgSO4, and concentrated. The crude products (mixture of regioisomers) were purified and separated by column chromatography (Si02), using a gradient of 0 to 35 percent ethyl acetate-hexanes, to provide 110 milligrams (5 percent yield - 5 steps ) of the subtitle compound. MS calculated for C16H2iN02 + H: 260; observed: 260. Step F. 1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole. The N-carbamate of terbutyl-1,2,3, 3a, 8, 8a-hexa-hydro-indene- [1,2-c] -pyrrole (110 milligrams, 0.42 millimoles) was dissolved in a solution of HCl ( milliliters, 4.0 M solution in 1,4-dioxane), and stirred for 2 hours at room temperature. The reaction was concentrated by rotary evaporation. The crude product was purified by reverse phase liquid chromatography to provide the title compound. 1 H NMR (d 6 -DMSO 300 Hz) d 7.16 (m, 4 H), 3.71 (m, 1 H), 3.25 (m, 1 H), 3.0 - 3.18 (m, 2 H), 2.79 -3.00 (m, 2 H), 2.72 (m, 1H), 2.45 (m, 1H) ppm. MS calculated for C H13N + H: 160; observed: 160. EXAMPLE 11 6-chloro-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole Step A. 6-chloro-1 H-indene. (Scheme 2). Sodium borohydride (2.3 grams, 60.2 mmol) was added to a solution of 5-chloro-1-indanone (10.0 grams, 60.2 mmol) in MeOH (300 milliliters), and stirred for 3 hours at room temperature. The reaction was quenched with H20 (100 milliliters), and extracted with CH2Cl2 (100 milliliters, 3 times). The combined extracts were dried over MgSO, and concentrated. The organic residue was dissolved in toluene (300 milliliters), and treated with p-toluenesulfonic acid monohydrate (1.2 grams, 6.02 mmol), which was stirred for 1 hour at 90 ° C. The reaction was cooled to room temperature, washed with brine (150 milliliters), dried over MgSO4, and concentrated, to give 6.9 grams (76 percent-two steps) of the subtitle compound, which was used without further purification .

Step B. 5-chloro-2, 2a, 7,7a-tetrahydro-cyclobute [a] inden-1 -one. The subtitle compound was prepared by the method of Example 10, Step A, using 6-chloro-1 H-indene (3.4 grams, 22.6 millimoles). The crude product was obtained without further purification. Step C. 5-Chloro-2,2a, 7,7a-tetrahydro-cyclobute [a] inden-1 -one-oxime. The subtitle compound was prepared by the method of Example 10, Step B, using 5-chloro-2,2a, 7,7a-tetrahydro-cyclobuta [a] inden-1 -one (2.0 grams, 10.4 millimoles). The crude product was obtained without further purification. MS calculated for CHHTOCINO + H: 208; observed: 208. Step D. 6-Chloro-3,3a, 8,8a-tetrahydro-2H-2-aza-cyclopenta [a] -inden-1 -one. The subtitle compound was prepared by the method of Example 10, Step C, using 5-chloro-2,2a, 7,7a-tetrahydro-cyclobuta [a] inden-1 -one (2.0 grams, 10.4 millimoles). The crude product was obtained without further purification. MS calculated for CnH ^ CINO + H: 208; observed: 208. Step E. 6-chloro-1, 2,3,3a, 8,8a-hexahydro-indene- [1,2-c] -pyrrole. The subtitle compound was prepared by the method of Example 10, Step D, using 6-chloro-3,3a, 8,8a-tetrahydro-2H-2-aza-cyclopenta [a] inden-1-one (2.0 grams, 10.4 millimoles). The crude product was obtained without further purification. MS calculated for CnH ^ CIN + H: 194; observed: 194. Step F. Terbutyl-N-carbamate-6-chloro-1, 2,3,3a, 8,8a-hexahydro-indene- [1,2-c] -pyrrole. The subtitle compound was prepared by the method of Example 10, Step E, using 6-chloro-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole ( 2.0 grams, 10.4 millimoles). The crude product was obtained without further purification. MS calculated for Ci6H2oCIN02 + H: 294; observed: 294. Step G. 6-Chloro-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole. The title compound was prepared by the method of Example 10, Step F, using the tert-butyl N-carbamate-6-chloro-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1, 2 -c] -pyrrole. The crude product was purified by reverse phase liquid chromatography to provide the title compound. 1 H NMR (d 6 -DMSO 300 MHz) d 7.25 (m, 3 H), 3.71 (m, 1 H), 3.19 (m, 2 H), 3.05 (m, 2 H), 2.88 (m, 1 H), 2.77 (m, 1 H) ), 2.45 (m, 1H) ppm. MS calculated for CnH13CIN + H: 194; observed: 194. Example 12 6- (2,6-difluoro-phenyl) -1,2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole Step A. Terbutyl N-carbamate-6- (2,6-difluoro-phenyl) -1,2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole. (Scheme 2). Triphenyl-phosphine (2 milligrams), palladium (ll) acetate (1 milligram), 2,6-difluoro-phenyl-boronic acid (20 milligrams, 0.12 millimole), and aqueous sodium carbonate (0.15 milliliters, 0.3 millimole) were added. to a solution of (tert-butyl N-carbamate-6-chloro-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole (from Example 11, Step F) (30 milligrams, 0.1 mmol) in acetonitrile (1 milliliter), and stirred for 24 hours at 80 ° C. The reaction mixture was concentrated, diluted with EtOAc (5 milliliters), and washed with H20 (5 milliliters). The organic extract was dried over MgSO4, and concentrated to give the subtitle compound, which was used without further purification, MS calculated for C22H23F2N02 + H: 372, observed: 372. Step B. 6- (2,6- difluoro-phenyl) -1, 2,3,3a, 8,8a-hexahydro-indene- [1, 2-c] -pyrrole The title compound was prepared by the method of Example 10, Step F. crude product was purified by reverse phase liquid chromatography, to provide the title compound. MS calculated for Ci7H15F2N + H: 272; observed: 272. EXAMPLE 13 5-Methyl-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole A. Ethyl-ester of 3-m-tolyl-acrylic acid. (Scheme 3). KHMDS (4.0 grams, 20.0 mmol) was added to a solution of [bis- (2,2,2-trifluoro-ethoxy) -phosphinyl] -acetic acid ethyl ester (4.7 milliliters, 20.0 mmol) and 18-crown-6 (10.6 mmol). grams, 40.0 mmol) in tetrahydrofuran (200 milliliters) at -78 ° C, and stirred for 30 minutes. M-tolualdehyde (2.1 milliliters, 18 mmol) was added, and the reaction mixture was stirred for 3 hours from -78 ° C to room temperature. The reaction was quenched with aqueous hydrochloric acid (1M solution, 100 milliliters), and the product was extracted with EtOAc (100 milliliters, 3 times). The organic extracts were washed with brine (100 milliliters), dried over MgSO4, and concentrated, to provide the subtitle compound, which was used without further purification. MS calculated for C12H1402 + H: 191; observed: 191. Step B. 1-Benzyl-4-m-tolyl-pyrrolidin-3-carboxylic acid ethyl ester. The subtitle compound was prepared by the method of Example 1, Step C, using 3-m-tolyl-acrylic acid ethyl ester (18.0 mmol). The crude product was purified by column chromatography (Si02), using a gradient of 10 to 50 percent ethyl acetate-hexanes, to provide 4.7 grams (81 percent-two steps) of the subtitle compound. MS calculated for C21H25 O2 + H: 324; observed: 324. Step C. 1-Benzyl-4-m-tolyl-pyrrolidine-3-carboxylic acid. The ethyl ester of 1-benzyl-4-m-tolyl-pyrrolidine-3-carboxylic acid (4.6 grams, 14.5 mmol) was suspended in aqueous HCl (73 milliliters, 18.0 M), and stirred overnight at 80 ° C. C. The reaction mixture was concentrated by rotary evaporation, and placed in the vacuum line. MS calculated for C19H2iN02 + H: 296; observed: 296. Step D. 2-Benzyl-5-methyl-2,3,3a, 8a-tetrahydro-1α-2-aza-cyclo-penta [a] inden-8-one. Dimethyl formamide (16 drops) and oxalyl chloride (4.1 milliliters, 43.5 mmol) were added to a solution of 1-benzyl-4-m-tolyl-pyrrolidine-3-carboxylic acid (4.3 grams, 14.5 mmol) in CH2Cl2 ( 29 milliliters) at 0 ° C The reaction mixture was stirred overnight at room temperature, and then concentrated by rotary evaporation, and placed in the vacuum line without further purification. A solution of the acid chloride intermediate in CH 2 Cl 2 (29 milliliters) was added slowly to a solution of AICI 3 (4.9 grams, 43.5 mmol) in CH 2 Cl 2 (29 milliliters) at 0 ° C. The reaction mixture was stirred for 3 hours from 0 ° C to room temperature, and then quenched by the slow addition of a saturated solution of sodium bicarbonate (290 milliliters). The product was extracted with CH2Cl2 (100 milliliters, 3 times). The organic extracts were washed with brine, dried over MgSO4, and concentrated. The crude product was purified by column chromatography (Si02) using a gradient of 10 to 50 percent ethyl acetate-hexanes, to give 0.91 grams (23 percent - two steps) of the subtitle compound, and 0.12 grams (3 percent - two steps) of the regioisomeric 2-benzyl-7-methyl-2,3,3a, 8a-tetrahydro-1 H-2-aza-cyclopenta [a] inden-8-one. MS calculated for Ci9H19NO + H: 278; observed: 278. Step E. 2-Benzyl-5-methyl-8-methylene-1, 2,3,3a, 8,8a-hexa-hydro-2-aza-cyclopenta [a] indene. The subtitle compound was prepared by the method of Example 1, Step D, using 2-benzyl-5-methyl-2,3,3a, 8a-tetra-hydro-1 H-2-aza-cyclopenta [a] inden -8-one (3.2 millimoles). The crude product was purified by a plug of silica, eluting with ethyl acetate-hexanes (3/1, volume / volume), to give 0.88 grams (98 percent) of the subtitle compound. MS calculated for C20H2iN + H: 276; observed: 276. Step F. 5-Methyl-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole. The title compound was prepared by the method of Example 1, Step E, using 2-benzyl-5-methyl-8-methylene-1,2,3,3a, 8,8a-hexa-hydro-2-aza- Cyclopenta [a] ndene (3.2 mmol). An aliquot of the crude product was purified by reverse phase liquid chromatography to provide the title compound. 1 H NMR (d 6 -DMSO 300 MHz) d 6.98 (m, 3 H), 3.55 (m, 1 H), 3.25 (m, 2 H), 2.85 (m, 3 H), 2.45 (m, 1 H), 2.24 (s, 3 H) ), 1.22 (d, 3H) ppm. MS calculated for C 13 H 17 N + H: 188; observed: 188. EXAMPLE 14 4-Methyl-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole Step A. Ethyl-3-acid ester -or-to-acrylic. (Scheme 3). The subtitle compound was prepared by the method of Example 13, Step A, using o-tolualdehyde (9.0 mmol). The crude product was obtained without further purification. MS calculated for C12H1402 + H: 191; observed: 191. Step B. 1-Benzyl-4-o-tolyl-pyrrolidine-3-carboxylic acid ethyl ester. The subtitle compound was prepared by the method of Example 1, Step C, using the 3-o-tolyl-acrylic acid ethyl ester (9.0 mmol). The crude product was purified by column chromatography (SiO2) using a gradient of 10 to 50 percent ethyl acetate-hexanes, to provide 2.3 grams (79 percent-two steps) of the subtitle compound. MS calculated for C2iH25N02 + H: 324; Observed: 324. Step C. 1-Benzyl-4-o-tolyl-pyrrolidine-3-carboxylic acid. The subtitle compound was prepared by the method of Example 13, Step C, using the ethyl ester of -benzyl-4-α-tolyl-pyrrolidine-3-carboxylic acid (7.1 mmol). The crude product was obtained without further purification. MS calculated for Ci9H21N02 + H: 296; observed: 296. Step D. 2-Benzyl-4-methyl-2,3,3a, 8a-tetrahydro-1α-2-aza-cyclo-penta [a] inden-8-one. The subtitle compound was prepared by the method of Example 13, Step D, using 1-benzyl-4-o-tolyl-pyrrolidin-3-carboxylic acid (7.1 mmol). The crude product was purified by column chromatography (SiO2), using a gradient of 15 to 60 percent EtOAc-hexanes, to provide 0.73 grams (37 percent - two steps) of the subtitle compound. MS calculated for Ci9H19NO + H: 278; observed: 278. Step E. 2-Benzyl-4-methyl-8-methylene-1, 2,3,3a, 8,8a-hexa-hydro-2-aza-cyclopenta [a] indene. The subtitle compound was prepared by the method of Example 1, Step D, using 2-benzyl-4-methyl-2,3,3a, 8a-tetrahydro-H-2-aza-cyclopenta [a] inden-8-one (2.6 millimoles). The crude product was purified by a plug of silica eluting with EtOAc-hexanes (3/1, volume / volume), to give the subtitle compound. MS calculated for C2oH2iN + H: 276; observed: 276. Step F. 4-Methyl-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole. The title compound was prepared by the method of Example 1, Step E, using 2-benzyl-4-methyl-8-methylene-1, 2,3,3a, 8,8a-hexa-hydro-2-aza- cyclopenta [a] indene (2.6 millimoles). An aliquot of the crude product was purified by reverse phase liquid chromatography to provide the title compound. 1 H NMR (d 6 -DMSO 300 MHz) d 7.10 (m, 1 H), 6.98 (m, 2 H), 3.72 (m, 1 H), 3.48 (m, 1 H), 3.22 (m, 1 H), 2.97 (m, 2 H) ), 2.72 (m, 1H), 2.45 (m, 1H), 2.21 (s, 3H), 1.22 (d, 3H) ppm. MS calculated for C 13 H 17 N + H: 188; Observed: 188 Example 15 6-methyl-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole Step A. Ethyl-ester of 3-p-tolyl-acrylic acid. (Scheme 3). The subtitle compound was prepared by the method of Example 13, Step A, using p-tolualdehyde (4.5 mmol). The crude product was obtained without further purification. MS calculated for C12H1402 + H: 191; observed: 191. Step B. 1-Benzyl-4-p-tolyl-pyrrolidine-3-carboxylic acid ethyl ester. The subtitle compound was prepared by the method of Example 1, Step C, using the 3-p-tolyl-acrylic acid ethyl ester (4.5 mmol). The crude product was purified by column chromatography (S02) using a gradient of 10 to 60 percent EtOAc-hexanes, to provide 1.15 grams (79 percent-two steps) of the subtitle compound. MS calculated for C2iH25N02 + H: 324; observed: 324. Step C. 1-Benzyl-4-p-tolyl-pyrrolidine-3-carboxylic acid. The subtitle compound was prepared by the method of Example 13, Step C, using the 1-benzyl-4-β-tolyl-pyrrolidine-3-carboxylic acid ethyl ester (3.6 mmol). The crude product was obtained without further purification. MS calculated for C19H21N02 + H: 296; observed: 296. Step D. 2-Benzyl-6-methyl-2,3,3a, 8a-tetrahydro-1? -2-aza-cyclo-penta [a] inden-8-one. The subtitle compound was prepared by the method of Example 13, Step D, using 1-benzyl-4-p-tolyl-pyrrolidine-3-carboxylic acid (3.6 mmol). The crude product was purified by column chromatography (Si02), using a gradient of 15 to 60 percent EtOAc-hexanes, to provide 0.50 grams (50 percent - two steps) of the subtitle compound. MS calculated for C19H19NO + H: 278; observed: 278. Step E. 2-Benzyl-6-methyl-8-methylene-1, 2,3,3a, 8,8a-hexa-hydro-2-aza-cyclopenta [a] indene. The subtitle compound was prepared by the method of Example 1, Step D, using 2-benzyl-6-methyl-2,3,3a, 8a-tetra-hydro-1 H-2-aza-cyclopenta [a] inden -8-one (1.8 millimoles). The crude product was purified by a plug of silica, eluting with EtOAc-hexanes (3/1, volume / volume), to give the subtitle compound. MS calculated for C2oH2iN + H: 276; observed: 276. Step F. 6-Methyl-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole. The title compound was prepared by the method of Example 1, Step E, using 2-benzyl-6-methyl-8-methylene-, 2,3,3a, 8,8a-hexa-hydro-2-aza-cyclopenta. [a] indene (1.8 millimoles). An aliquot of the crude product was purified by reverse phase liquid chromatography to provide the title compound. 1 H NMR (de-DMSO 300 MHz) d 7.00 (m, 3 H), 3.61 (m, 1 H), 3.30 (m, 2 H), 2.9 (m, 3 H), 2.42 (m, 1 H), 2.27 (s, 3 H) ), 1.22 (d, 3H) ppm. MS calculated for C 13 H 17 N + H: 188; observed: 188. Example 16 7-methyl-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole Step A. 2-Benzyl-7-methyl-8-methylene-1, 2,3,3a, 8,8a-hexa-hydro-2-aza-cyclopenta [a] indene. (Scheme 3). The subtitle compound was prepared by the method of Example 1, Step D, using 2-benzyl-7-methyl-2,3,3a, 8a-tetra-hydro-1 H-2-aza-cyclopenta [a] inden -8-one (from Example 13, Step D, regioisomer) (0.43 mmol). The crude product was purified by a plug of silica, eluting with EtOAc-hexanes (3/1, volume / volume), to give the subtitle compound. MS calculated for C2oH2iN + H: 276; observed: 276. Step B. 7-methyl-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole. The title compound was prepared by the method of Example 1, Step E, using 2-benzyl-7-methyl-8-methylene-1, 2,3,3a, 8,8a-hexa-hydro-2-aza- cyclopenta [a] ndene (0.43 mmol). An aliquot of the crude product was purified by reverse phase liquid chromatography to provide the title compound. 1 H NMR (de-DMSO 300 MHz) d 7.05 (m, 3 H), 3.62 (m, 1 H), 3.39 (m, 2 H), 2.99 (m, 3 H), 2.77 (m, 1 H), 2.28 (s, 3 H) ), 1.27 (d, 3H) ppm. MS calculated for C 13 H 17 N + H: 188; observed: 188. EXAMPLE 17 4-Fluoro-8-metii-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole Step A. Ethyl-ester of 3-o-fluoro-acrylic acid. (Scheme 3). The subtitle compound was prepared by the method of Example 13, Step A, using 2-fluoro-benzaldehyde (9.0 mmol).

The crude product was obtained without further purification. MS calculated for C H FOz + H: 195; observed: 195. Step B. Ethyl ester of 1-benzyl-4-o-fluoro-pyrrolidine-3-carboxylic acid. The subtitle compound was prepared by the method of Example 1, Step C, using the 3-o-fluoro-acrylic acid ethyl ester (9.0 mmol). The crude product was purified by column chromatography (Si02), using a gradient of 10 to 50 percent EtOAc-hexanes, to provide the subtitle compound in a quantitative yield. MS calculated for C20H22FNO2 + H: 328; observed: 328. Step C. 1-Benzyl-4-o-fluoro-pyrrolidine-3-carboxylic acid. The subtitle compound was prepared by the method of Example 13, Step C, using the 1-benzyl-4-β-fluoro-pyrrolidine-3-carboxylic acid ether ester (9.0 mmol). The crude product was obtained without further purification. MS calculated for Ci8H18FN02 + H: 300; observed: 300. Step D. 2-Benzyl-4-fluoro-2,3,3a, 8a-tetrahydro-1α-2-aza-cyclo-penta [a] inden-8-one. The subtitle compound was prepared by the method of Example 13, Step D, using 1-benzyl-4-o-fluoro-pyrrolidine-3-carboxylic acid (9.0 mmol). The crude product was purified by column chromatography (Si02), using a gradient of 0 to 50 percent EtOAc-hexanes, to provide 0.59 grams (23 percent-four steps) of the subtitle compound. MS calculated for C18H16FNO + H: 282; observed: 282. Step E. 2-Benzyl-4-fluoro-8-methylene-1, 2,3,3a, 8,8a-hexa-hydro-2-aza-cyclopenta [a] indene. The subtitle compound was prepared by the method of Example 1, Step D, using 2-benzyl-4-fluoro-2,3,3a, 8a-tetra-hydro-1 H-2-aza-cyclopenta [a] inden -8-one (2.1 millimoles). The crude product is purified by a plug of silica, eluting with EtOAc-hexanes (3/1, volume / volume), to give the subtitle compound. MS calculated for C29H18FN + H: 280; observed: 280. Step F. 4-Fluoro-8-methyl-1, 2,3,3a, 8,8a-hexahydro-indene- [1,2-c] -pyrrole. The title compound was prepared by the method of Example 1, Step E, using 2-benzyl-4-fluoro-8-methylene-1,2,3,3a, 8,8a-hexa-hydro-2-aza- Cyclopenta [a] indene (2.1 millimoles). An aliquot of the crude product was purified by reverse phase liquid chromatography to provide the title compound. 1 H NMR (d 6 -DMSO 300 MHz) d 7.26 (m, 1 H), 6.99 (m, 2 H), 3.83 (m, 1 H), 3.39 (m, 2 H), 2.99 (m, 3 H), 2.51 (m, 1 H) ), 1.26 (d, 3H) ppm. MS calculated for C 2 H FN + H: 192; observed: 192. EXAMPLE 18 5-fluoro-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole Step A. Ethyl-ester of 3-m-fluoro-acrylic acid. (Scheme 3). The subtitle compound was prepared by the method of Example 13, Step A, using m-fluoro-benzaldehyde (18.0 mmol). The crude product was obtained without further purification. MS calculated for C H FOj + H: 195; observed: 195. Step B. Ethyl ester of 1-benzyl-4-m-fluoro-pyrrolidine-3-carboxylic acid. The subtitle compound was prepared by the method of Example 1, Step C, using 3-m-fluoro-acrylic acid ethyl ester (18.0 mmol). The crude product was purified by column chromatography (SiO2) using a gradient of 10 to 50 percent EtOAc-hexanes, to provide the subtitle compound in a quantitative yield. MS calculated for C2oH22FN02 + H: 328; observed: 328. Step C. 1-Benzyl-4-m-fluoro-pyrrolidine-3-carboxylic acid. The title compound was prepared by the method of Example 13, Step C, using the 1-benzyl-4-m-fluoro-pyrrolidine-3-carboxylic acid ethyl ester (18.0 mmol). The crude product was obtained without further purification. MS calculated for C18H18FN02 + H: 300; observed: 300. Step D. 2-Benzyl-5-fluoro-2,3,3a, 8a-tetrahydro-1α-2-aza-cyclo-penta [a] inden-8-one. The subtitle compound was prepared by the method of Example 13, Step D, using 1-benzyl-4-m-fluoro-pyrrolidine-3-carboxylic acid (18.0 mmol). The crude product was purified by column chromatography (Si02) using a gradient of 0 to 50 percent EtOAc-hexanes, to provide 2.7 grams (53 percent-four steps) of the subtitle compound. MS calculated for C18H16FNO + H: 282; observed: 282. Step E. 2-Benzyl-5-fluoro-8-methylene-1, 2,3,3a, 8,8a-hexa-hydro-2-aza-cyclopenta [a] indene. The subtitle compound was prepared by the method of Example 1, Step D, using benzyl-5-fluoro-2,3,3a, 8a-tetrahydro-1 H-2-aza-cyclopenta [a] inden-8-one (9.6 millimoles). The crude product was purified by a plug of silica, eluting with EtOAc-hexanes (3/1, volume / volume), to give the subtitle compound. MS calculated for C29H18FN + H: 280; observed: 280. Step F. 5-fluoro-8-metN-1,2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole. The title compound was prepared by the method of Example 1, Step E, using 2-benzyl-5-fluoro-8-methylene-1, 2,3,3a, 8,8a-hexa-hydro-2-aza- cyclopenta [a] indene (9.6 millimoles). An aliquot of the crude product was purified by reverse phase liquid chromatography to provide the title compound. 1 H NMR (d 6 -DMSO 300 MHz) d 7.18 (m, 1 H), 7.02 (m, 2 H), 3.68 (m, 1 H), 3.33 (m, 2 H), 2.98 (m, 3 H), 2.45 (m, 1 H) ), 1.21 (d, 3H) ppm. MS calculated for Ci2H14FN + H: 192; observed: 192. Example 19 6-fluoro-8-methyl-1,2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole Step A. Ethyl-ester of 3-p-fluoro-acrylic acid. (Scheme 3). The subtitle compound was prepared by the method of Example 13, Step A, using p-fluoro-benzaldehyde (9.0 mmol). The crude product was obtained without further purification. MS calculated for C H F ^ + H: 195; observed: 195. Step B. Ethyl ester of 1-benzyl-4-p-f luoro-pyrrolidine-3-carboxylic acid. The subtitle compound was prepared by the method of Example 1, Step C, using the 3-p-fluoro-acrylic acid ethyl ester (9.0 mmol). The crude product was purified by column chromatography (S02) using a gradient of 10 to 50 percent EtOAc-hexanes, to provide the subtitle compound in a quantitative yield. MS calculated for C20H22F O2 + H: 328; Observed: 328. Step C. 1-Benzyl-4-p-fluoro-pyrrolidine-3-carboxylic acid. The subtitle compound was prepared by the method of Example 13, Step C, using the 1-benzyl-4-β-fluoro-pyrrolidine-3-carboxylic acid ethyl ester (9.0 mmol). The crude product was obtained without further purification. MS calculated for Ci8H18FN02 + H: 300; observed: 300. Step D. 2-Benzyl-6-fluoro-2,3,3a, 8a-tetrahydro-1α-2-aza-cyclopenta [a] inden-8-one. The subtitle compound was prepared by the method of Example 13, Step D, using 1-benzyl-4-p-fluoro-pyrrolidin-3-carboxylic acid (9.0 mmol). The crude product was purified by column chromatography (SiO2) using a gradient of 0 to 50 percent EtOAc-hexanes, to provide 1.12 grams (44 percent-four steps) of the subtitle compound. MS calculated for C18H16FNO + H: 282; observed: 282. Step E. 2-Benzyl-6-fluoro-8-methylene-1, 2,3,3a, 8,8a-hexa-hydro-2-aza-cyclopenta [a] ndene. The subtitle compound was prepared by the method of Example 1, Step D, using 2-benzyl-6-fluoro-2,3,3a, 8a-tetra-hydro-1 H-2-aza-cyclopenta [a] inden -8-one (4.0 millimoles). The crude product was purified by a plug of silica, eluting with EtOAc-hexanes (3/1, volume / volume), to give the subtitle compound. MS calculated for C29H18FN + H: 280; observed: 280. Step F. 6-Fluoro-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole. The title compound was prepared by the method of Example 1, Step E. using 2-benzyl-5-fluoro-8-methylene-1, 2,3,3a, 8,8a-hexa-hydro-2-aza-cyclopenta [a] indene (4.0 mil i moles ). An aliquot of the crude product was purified by reverse phase liquid chromatography to provide the title compound. 1 H NMR (d 6 -DMSO 300 MHz) d 7.18 (m, 1 H), 6.99 (m, 2 H), 3.62 (m, 1 H), 3.29 (m, 2 H), 2.87 (m, 3 H), 2.45 (m, 1 H) ), 1.22 (d, 3H) ppm. MS calculated for Ci2H14FN + H: 192; observed: 192. EXAMPLE 20 5-Chloro-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -inol Step A. Ethyl-ester of 3-m-chloro-acrylic acid. (Scheme 3). The subtitle compound was prepared by the method of Example 13, Step A, using 3-chloro-benzaldehyde (9.0 mmol). The crude product was obtained without further purification. MS calculated for CnH CIC ^ + H: 211; observed: 211. Step B. 1-Benzyl-4-m-chloro-pyrrolidin-3-carboxylic acid ethyl ester.

The subtitle compound was prepared by the method of Example 1, Step C, using 3-m-chloro-acrylic acid ethyl ester (9.0 mmol). The crude product was purified by column chromatography (SiO2) using a gradient of 10 to 50 percent EtOAc-hexanes, to provide the subtitle compound in a quantitative yield. MS calculated for C20H22CI O2 + H: 344; observed: 344. Step C. 1-Benzyl-4-m-chloro-pyrrolidine-3-carboxylic acid. The subtitle compound was prepared by the method of Example 13, Step C, using the 1-benzyl-4-m-chloro-pyrrolidine-3-carboxylic acid ethyl ester (9.0 mmol). The crude product was obtained without further purification. MS calculated for Ci8H18CIN02 + H: 316; observed: 316. Step D. 2-Benzyl-5-chloro-2,3,3a, 8a-tetrahydro-1α-2-aza-cyclopenta [a] inden-8-one. The subtitle compound was prepared by the method of Example 13, Step D, using 1-benzyl-4-m-chloro-pyrrolidine-3-carboxylic acid (9.0 mmol). The crude product was purified by column chromatography (Si02) using a gradient of 0 to 50 percent EtOAc-hexanes, to provide 0.59 grams (22 percent - four steps) of 2-benzyl-7-chloro-2, 3,3a, 8a-tetrahydro-1 H-2-aza-cyclopenta [a] inden-8-one. MS calculated for Ci8H16CINO + H: 298; observed: 298. Step E. 2-Benzyl-5-chloro-8-methylene-1, 2,3,3a, 8,8a-hexa-hydro-2-aza-cyclopenta [a] indene.

The subtitle compound was prepared by the method of Example 1, Step D, using 2-benzyl-5-chloro-2,3,3a, 8a-tetra-hydro-1 H-2-aza-cyclopenta [a] inden -8-ona (2.0 millimoles). The crude product was purified by a plug of silica, eluting with EtOAc-hexanes (3/1, volume / volume), to give the subtitle compound. MS calculated for C19H18CIN + H: 296; observed: 296. Step F. 5-Chloro-8-methylene-1, 2,3,3a, 8,8a-hexahydro-2-aza-cyclopenta [a] indene. ACE-CI (1.08 milliliters, 9.9 millimoles) and K2C03 (1-4 grams, 9.9 millimoles) were added to a solution of 2-benzyl-5-chloro-8-methylene-1, 2,3,3a, 8,8a -hexa-hydro-2-aza-cyclopenta [a] indene (2.0 mmoles) in dichloro-ethane (10 milliliters) at 0 ° C. The reaction mixture was filtered through Celite, the Celite was washed with CH2Cl2, and the filtrate was concentrated. The carbamate intermediate was dissolved in MeOH (10 milliliters), and stirred for 1 hour at 40 ° C. The solution was cooled to room temperature, and concentrated by rotary evaporation. MS calculated for C12H12CIN + H: 206; observed: 206. Step G. Terbutyl-N-carbamate-5-chloro-8-methylene-1, 2,3,3a, 8,8a-hexa-hydro-2-aza-cyclopenta [a] indene. Diterbutyl dicarbonate (0.43 grams, 2.00 millimoles) and DIEA (1.0 milliliters, 6.0 millimoles) were added to a solution of 5-chloro-8-methylene-1, 2,3,3a, 8,8a-hexa-hydro-2 -aza-cyclopenta [a] indene (2.0 millimoles) in CH2CI2 (10 milliliters) at 0 ° C. The reaction mixture was stirred for 2 hours from 0 ° C to room temperature, and then quenched with aqueous HCl (10 milliliters, 0.1 M). The organic extracts were washed with brine, dried over MgSO4, and concentrated to provide the subtitle compound in a quantitative yield. MS calculated for Ci7H2oCIN02 + H: 306; observed: 306. Step H. Terbutyl N-carbamate-5-chloro-8-methyl-1, 2, 3, 3a, 8, 8a-hexa-hydro-2-aza-cyclopenta [a] indene. The N-carbamate of tert-butyl-5-chloro-8-methylene-1, 2, 3, 3a, 8,8a-hexa-hydro-2-aza-cyclopenta [a] indene (0.6 grams, 2.0 mmol) was dissolved in EtOAc (10 milliliters), and purged with N2. Palladium on charcoal (0.2 grams, 10 weight percent) was added, and the flask was purged with N2, and then charged with a balloon of H2. The reaction mixture was stirred for 2 hours at room temperature, and then filtered through Celite. The Celite was washed with EtOAc, and the filtrate was concentrated to provide the subtitle compound in a quantitative yield. MS calculated for Ci7H22CIN02 + H: 308; observed: 308. Step I. 5-Chloro-8-methyl-, 2,3,3a, 8,8a-hexahydro-indene- [1,2-c] -pyrrole. The N-carbamate of tert-butyl-5-chloro-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-2-aza-cyclopenta [a] indene (10 milligrams, 0.03 mmol) was dissolved in a solution of HCl (3 milliliters, 4 M in dioxane). The reaction was stirred for 2 hours at room temperature, and then concentrated to provide the title compound. An aliquot of the crude product was purified by reverse phase liquid chromatography to provide the title compound. H NMR (d6-DMSO 300 MHz) d 7.21 (m, 3 H), 3.68 (m, 1 H), 3.31 (m, 2 H), 2.92 (m, 3 H), 2.45 (m, 1 H), 1.22 (d, 3 H) ) ppm. MS calculated for C12H14CIN + H: 208; observed: 208. EXAMPLE 21 5-methyl-6-chloro-8-methyl-1, 2, 3,3a, 8,8a-hexa-h id ro-indeno- [1,2-chloroprol Step A. Ethyl N-carbamate-5-methyl-8-methyl-1, 2, 3, 3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole. (Scheme 3). Ethyl chloroformate (0.29 milliliters, 3.0 millimoles) and DIEA (1.6 milliliters, 9.0 millimoles) were added to a solution of 5-methyl-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro -indeno- [1, 2-c] -pyrrole (from Example 13, Step F) (0.56 grams, 3.0 mmol) in CH2Cl2 (15 milliliters) at 0 ° C. The reaction was stirred for 2 hours from 0 ° C to room temperature. The reaction was quenched with aqueous HCl (15 milliliters, 1M). The desired product was extracted with CH2Cl2 (15 milliliters, 3 times). The organic extracts were washed with brine, dried over MgSO4, and concentrated. The crude product was purified by column chromatography (Si02) using a gradient of 10 to 60 percent EtOAc-hexanes, to provide 0.36 grams (46 percent) of the subtitle compound. MS calculated for C16H2iN02 + H: 260; observed: 260. Step B. Ethyl-N-carbamate-5-methyl-6-chloro-8-methyl-1, 2,3,3a, 8,8a-hexahydro-indene- [1,2- c] -pyrrole. NCS (27 milligrams, 0.2 mmol) and acetic acid (1 milliliter) were added to a solution of ethyl N-carbamate-5-methyl-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro -indeno- [1, 2-c] -pyrrole (50 milligrams, 0.2 mmol) in dichloro-ethane (1 milliliter). The reaction solution was stirred for 3 hours at 60 ° C. The reaction was diluted with CH2Cl2 (3 milliliters) and H20 (3 milliliters), and filtered through an Extrelut column. The column was washed with CH2Cl2, and the filtrate was concentrated. The crude product was purified by column chromatography (S02) using a gradient of 0 to 60 percent ethyl acetate-hexanes, to give the subtitle compound. MS calculated for C16H20CINO2 + H: 294; observed: 294. Step C. 5-Methyl-6-chloro-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole. The title compound was prepared by the method of Example 3, Step B, using the ethyl N-carbamate-5-methyl-6-chloro-8-methyl-1, 2,3,3a, 8,8a-hexa- hydro-indene- [1, 2-c] -pyrrole. The crude product was purified by reverse phase liquid chromatography to provide the title compound. MS calculated for C13H16CIN + H: 222; observed: 222. EXAMPLE 22 5-Methyl-6-bromo-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole Step A. Ethyl N-carbamate-5-methyl-6-bromo-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole. (Scheme 3). NBS (34 milligrams, 0.2 mmol) was added to a solution of ethyl N-carbamate-5-methyl-8-methyl-, 2,3,3a, 8,8a-hexa-hydro-indene- [1, 2- c] -pyrrole (from Example 21, Step A) (50 milligrams, 0.2 mmol) in acetonitrile (1 milliliter), and stirred overnight at room temperature. The reaction was diluted with CH2Cl2 (3 milliliters) and H20 (3 milliliters), and filtered through an Extrelut column. The column was washed with CH2Cl2, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2) using a gradient of 0 to 50 percent EtOAc-hexanes, to give the subtitle compound. MS calculated for C6H20BrNO2 + H: 338; observed: 338. Step C. 5-Methyl-6-bromo-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole. The title compound was prepared by the method of Example 3, Step B, using the N-carbamate ethyl-5-methyl-6-bromo-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1, 2-c ] -pyrrole. The crude product was purified by reverse phase liquid chromatography to provide the title compound. H NMR (d6-DMSO 300 MHz) d 7.29 (s, 1H), 7.12 (s, 1H), 3.70 (m, 3H), 2.92 (m, 3H), 2.45 (m, 1H), 2.29 (s, 3H) ), 1.22 (d, 3H) ppm. MS calculated for C13Hi6BrN + H: 266; observed: 266. EXAMPLE 23 5-Chloro-6-methyl-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole Step A. Ethyl N-carbamate-6-methyl-8-methyl-1, 2, 3, 3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole. (Scheme 3). The subtitle compound was prepared by the method of Example 21, Step A, using 6-methyl-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c ] -pyrrole (from Example 15, Step F) (1.8 mmol). The crude product was purified by column chromatography (S02) using a gradient of 10 to 60 percent EtOAc-hexanes, to provide 0.25 grams (54 percent) of the subtitle compound. MS calculated for C16H2iN02 + H: 260; observed: 260. Step B. Ethyl N-carbamate-5-chloro-6-methyl-8-methyl-1, 2, 3, 3a, 8, 8a-hexa-hydro-indene- [1,2-c] -prol. The subtitle compound was prepared by the method of Example 21, Step B, using the ethyl N-carbamate-6-methyl-8-methyl-1, 2,3,3a, 8,8a-hexahydro-indene- [1, 2-c] -pyrrole (0.2 mmol). The crude product was purified by column chromatography (S02) using a gradient of 0 to 60 percent EtOAc-hexanes, to provide the subtitle compound. MS calculated for Ci6H2oCIN02 + H: 294; observed: 294. Step C. 5-Chloro-6-methyl-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole. The title compound was prepared by the method of Example 3, Step B, using the ethyl N-carbamate-5-chloro-6-methyl-8-methyl-1, 2,3,3a, 8,8a-hexa- hydro-indene- [1, 2-c] -pyrrole. The crude product was purified by reverse phase liquid chromatography to provide the title compound. 1 H NMR (d 6 -DMSO 300 MHz) d 7.21 (s, 1 H), 7.10 (s, 1 H), 3.61 (m, 1 H), 3.29 (m, 2 H), 2.88 (m, 3 H), 2.45 (m, 1 H) ), 2.29 (s, 3H), 1.22 (d, 3H) ppm. MS calculated for C13H16CIN + H: 222; observed: 222. EXAMPLE 24 5-Bromo-6-methyl-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole Step A. Ethyl N-carbamate-5-bromo-6-methyl-8-methyl-1, 2,3,3a, 8,8a-hexahydro-indene- [1, 2-c ] -pyrrole. (Scheme 3). The subtitle compound was prepared by the method of Example 22, Step A, using the ethyl N-carbamate-6-methyl-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene - [1, 2-c] -pyrrole (from Example 23, Step A) (0.2 mmol). The crude product was purified by column chromatography (SiO2) using a gradient of 0 to 50 percent EtOAc-hexanes, to give the subtitle compound. MS calculated for Ci6H2oBrN02 + H: 338; observed: 338. Step B. 5-Bromo-6-methyl-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole. The title compound was prepared by the method of Example 3, Step B, using the ethyl N-carbamate-5-bromo-6-methyl-8-methyl-1, 2,3,3a, 8,8a-hexa- hydro-indene- [1, 2-c] -pyrrole. The crude product was purified by reverse phase liquid chromatography to provide the title compound. MS calculated for C 13 H 16 Brn + H: 266; observed: 266. EXAMPLE 25 4-Chloro-5-methoxy-8-methyl-1, 2,3,3a, 8,8a-hexahydro-indene- [1,2-c] -pyrrole Step A. Ethyl N-carbamate-4-chloro-5-methoxy-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole. (Scheme 1). N-chlorosuccinimide (0.39 grams, 2.9 mmol) and acetic acid (3 milliliters) were added to a solution of ethyl N-carbamate-5-methoxy-8-methyl-1, 2,3,3a, 8,8a hexane-hydro-indene- [1,2-c] -pyrrole (from Example 2, Step A) (0.80 grams, 2.9 mmol) in dichloro-ethane (3 milliliters). The resulting solution was stirred for 3 hours at 60 ° C. The reaction mixture was cooled to room temperature, diluted with CH2Cl2 (50 milliliters), and washed with H2O (50 milliliters). The organic extract was dried over MgSO4 and concentrated. The crude product was purified by column chromatography (Si02) using a gradient of 0 to 35 percent EtOAc-hexanes, to provide 50 milligrams (6 percent) of the subtitle compound (the major product is ethyl N-carbamate) -5-methoxy-6-chloro-8-methyl-1, 2,3,3a, 8,8a-hexahydro-indene- [1,2-c] -pyrrole, 78 percent). MS calculated for C 16 H 20 CINO 3 + H: 310; observed: 310. Step B. 4-Chloro-5-methoxy-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole. The title compound was prepared by the method of Example 3, Step B, using the ethyl N-carbamate-4-chloro-5-methoxy-8-methyl-1, 2,3,3a, 8,8a-hexa- hydro-indene- [1, 2-c] -pyrrole (0.16 mmol). The crude product was purified by reverse phase liquid chromatography to provide the title compound. 1 H NMR (d 6 -DMSO 300 MHz) d 7.08 (d, 1 H), 6.98 (d, 1 H), 3.81 (s, 3 H), 3.64 (m, 1 H), 3.47 (m, 1 H), 3.29 (m, 1 H) ), 2.91 (m, 3H), 2.45 (m, 1H), 1.21 (d, 3H) ppm. MS calculated for C 13 H 16 CINO + H: 238; observed: 238. Example 26 5,6-dichloro-8-methyl-1, 2,3,3a, 8, 8a-hexa-h id ro-indeno- [1, 2-c] -pyrrole Step A. Ethyl 3- (3,4-dichloro-phenyl) -acrylic acid ester.

(Scheme 3). The subtitle compound was prepared by the method of Example 13, Step A, using 3,4-dichloro-benzaldehyde (9.0 mmol). The crude product was obtained without further purification. MS calculated for C ^ HÍOC C ^ + H: 245; observed: 245. Step B. 1-Benzyl-4- (3,4-dichloro-phenyl) -pyrrolidin-3-carboxylic acid ethyl ester. The subtitle compound was prepared by the method of Example 1, Step C, using the ethyl ester of 3- (3,4-dichloro-phenyl) -acrylic acid (9.0 mmol). The crude product was purified by column chromatography (SiO2) using a gradient of 10 to 50 percent EtOAc-hexanes, to provide the subtitle compound in a quantitative yield. MS calculated for C20H22Cl2 O2 + H: 378; observed: 378. Step C. 1-Benzyl-4- (3,4-dichloro-phenyl) -pyrrolidine-3-carboxylic acid. The subtitle compound was prepared by the method of Example 13, Step C, using the 1-benzyl-4- (3,4-dichloro-phenyl) -pyrrolidine-3-carboxylic acid ethyl ester (9.0 mmol). The crude product was obtained without further purification. MS calculated for Ci8H18CI2N02 + H: 350; observed: 350. Step D. 2-Benzyl-5,6-dichloro-2,3,3a, 8a-tetrahydro-1α-2-aza-cyclopenta [a] inden-8-one. The subtitle compound was prepared by the method of Example 13, Step D, using 1-benzyl-4- (3,4-dichloro-phenyl) -pyrrolidine-3-carboxylic acid (9.0 mmol). The crude product was purified by column chromatography (S¡Q2) using a gradient of 0 to 50 percent EtOAc-hexanes, to give 0.59 grams (20 percent-four steps) of the subtitle compound, and 0.30 grams (10). percent - four steps) of the regio-isomeric 2-benzyl-6,7-dichloro-2,3,3a, 8a-tetrahydro-1 H-2-aza-cyclopenta [a] inden-8-one. MS calculated for Ci8H16Cl2NO + H: 332; observed: 332. Step E. 2-Benzyl-5,6-dichloro-8-methylene-1, 2,3,3a, 8,8a-hexa-hydro-2-aza-cyclopenta [a] indene. The subtitle compound was prepared by the method of Example 1, Step D, using 2-benzyl-5,6-dichloro-2,3,3a, 8a-tetrahydro-1 H-2-aza-cyclopenta [a ] inden-8-one (0.9 millimoles). The crude product was purified by a plug of silica, eluting with EtOAc-hexanes (3/1, volume / volume), to give the subtitle compound. MS calculated for C19H18Cl2N + H: 330; observed: 330. Step F. 5,6-dichloro-8-methylene-1, 2,3,3a, 8,8a-hexa-hydro-2-aza-cyclopenta [a] indene. The subtitle compound was prepared by the method of Example 20, Step F, using 2-benzyl-5,6-dichloro-8-methylene-1, 2,3,3a, 8,8a-hexa-hydro-2- aza-cyclopenta [a] indene (0.9 mmol). The crude product was obtained without further purification. MS calculated for Ci2H12Cl2N + H: 240; observed: 240. Step G. Terbutyl N-carbamate-5,6-dichloro-8-methylene-1, 2,3,3a, 8,8a-hexa-hydro-2-aza-cyclopenta [a] indene.

The subtitle compound was prepared by the method of Example 20, Step G, using 5,6-dichloro-8-methylene-1, 2, 3, 3a, 8,8a-hexa-hydro-2-aza- cyclopenta [a] indene (0.9 mmol). The crude product was obtained without further purification. MS calculated for C17H2oCI2 02 + H: 340; observed: 340. Step H. Terbutyl N-carbamate-5,6-dichloro-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-2-aza-cyclopenta [a] indene. The subtitle compound was prepared by the method of Example 20, Step H, using the terbutyl N-carbamate-5,6-dichloro-8-methylene-1, 2,3,3a, 8,8a-hexa- hydro-2-aza-cyclopenta [a] indene (0.9 mmol). The crude product was obtained without further purification. MS calculated for C 17 H 22 Cl 2 NO 2 + H: 342; observed: 342. Step I. 5,6-dichloro-8-metM-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole. The subtitle compound was prepared by the method of Example 20, Step I, using the N-carbamate of tert-butyl-5,6-dichloro-8-methyl-, 2,3,3a, 8,8a-hexa-hydro-2-aza-cyclopenta [a] indene. An aliquot of the crude product was purified by reverse phase liquid chromatography to provide the title compound. MS calculated for C 12 H 14 Cl 2 N + H: 242; observed: 242. EXAMPLE 27 6,7-Dichloro-8-methyl-1,2,3,3a, 8,8a-hexahydro-indene- [1,2-c] -pyrrole Step A. 2-benzyl- 6,7-dichloro-8-methylene-1, 2,3,3a, 8,8a-hexa-hydro-2-aza-cyclopenta [a] indene. (Scheme 3). The subtitle compound was prepared by the method of Example 1, Step D, using 2-benzyl-6,7-dichloro-2,3,3a, 8a-tetrahydro-1 H-2-aza-cyclopenta [a ] inden-8-one (from Example 26, Step D, regioisomer) (1.8 mmol). The crude product was purified by a plug of silica, eluting with EtOAc-hexanes (3/1, volume / volume), to give the subtitle compound. MS calculated for Ci9H18Cl2N + H: 330; observed: 330. Step B. 6,7-Dichloro-8-methylene-1, 2,3,3a, 8,8a-hexa-hydro-2-aza-cyclopenta [a] indene. The subtitle compound was prepared by the method of Example 20, Step F, using 2-benzyl-6,7-dichloro-8-methylene-1, 2,3,3a, 8,8a-hexa-hydro-2- aza-cyclopenta [a] indene (1.8 mmol). The crude product was obtained without further purification. MS calculated for C12H12Cl2N + H: 240; observed: 240. Step C. Terbutyl N-carbamate-6,7-dichloro-8-methylene-1, 2,3,3a, 8,8a-hexa-hydro-2-aza-cyclopenta [a] indene. The subtitle compound was prepared by the method of Example 20, Step G, using 6,7-dichloro-8-methylene-1, 2, 3, 3a, 8,8a-hexa-hydro-2-aza-cyclopenta [ a] indene (0.9 millimoles). The crude product was obtained without further purification. MS calculated for Ci 7 H 20 Cl 2 NO 2 + H: 340; observed: 340. Step D. N-carbamate of terbutyl-6,7-dichloro-8-methyl-1, 2, 3, 3a, 8, 8a-hexa-hydro-2-aza-cyclopenta [a] indene .

The subtitle compound was prepared by the method of Example 20, Step H, using the terbutyl N-carbamate-6,7-dichloro-8-methylene-1, 2,3,3a, 8,8a-hexahydroxycarbamate. 2-aza-cyclopenta [a] indene (1.8 mmol). The crude product was obtained without further purification. MS calculated for C 17 H 22 Cl 2 NO 2 + H: 342; observed: 342. Step E. 6,7-Dichloro-8-methyl-1, 2,3,3a, 8,8a-hexahydro-indene- [1,2-c] -pyrrole. The title compound was prepared by the method of Example 20, Step I, using the terbutyl N-carbamate-6,7-dichloro-8-methyl-1, 2,3,3a, 8,8a-hexahydroxycarbamate. 2-aza-cyclopenta [a] indene.

An aliquot of the crude product was purified by reverse phase liquid chromatography to provide the title compound. H NMR (d6-DMSO 300 MHz) d 7.46 (d, 1H), 7.20 (d, 1H), 3.68 (m, 1H), 3.51 (m, 1H), 3.23 (m, 1H), 3.08 (m, 1H) ), 3.88 (m, 3H), 1.37 (d, 3H) ppm. MS calculated for C 12 H 14 Cl 2 N + H: 242; observed: 242. EXAMPLE 28 4,6-Dichloro-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole Step A. Ethyl-ester-dichloro-phenyl) -acrylic.

(Scheme 3). The subtitle compound was prepared by the method of Example 13, Step A, using 3,4-dichloro-benzaldehyde (18.0 mmol). The crude product was obtained without further purification. MS calculated for CiiH10CI2O2 + H: 245; observed: 245. Step B. 1-Benzyl-4- (2,4-dichloro-phenyl) -pyrrolidine-3-carboxylic acid ethyl ester. The subtitle compound was prepared by the method of Example 1, Step C, using the ethyl ester of 3- (2,4-dichloro-phenyl) -acrylic acid (18.0 mmol). The crude product was purified by column chromatography (Si02) using a gradient of 10 to 50 percent EtQAc-hexanes, to provide the subtitle compound in a quantitative yield. MS calculated for C20H22Cl2 O2 + H: 378; observed: 378. Step C. 1-Benzyl-4- (2,4-dichloro-phenyl) -pyrrolidine-3-carboxylic acid. The subtitle compound was prepared by the method of Example 13, Step C, using 1-benzyl-4- (2,4-dichloro-phenyl) -pyrrolidine-3-carboxylic acid ethyl ester (18.0 mmol). The crude product was obtained without further purification. MS calculated for Ci8H18CI2N02 + H: 350; observed: 350. Step D. 2-Benzyl-4,6-dichloro-2,3,3a, 8a-tetrahydro-1α-2-aza-cyclopenta [a] inden-8-one. The subtitle compound was prepared by the method of Example 13, Step D, using 1-benzyl-4- (2,4-dichloro-phenyl) -pyrrolidine-3-carboxylic acid (18.0 mmol). The crude product was purified by column chromatography (Si02) using a gradient of 0 to 50 percent EtOAc-hexanes, to provide 1.5 grams (25 percent-four steps) of the subtitle compound.

MS calculated for C18H16Cl2NO + H: 332; observed: 332. Step E. 2-Benzyl-4,6-dichloro-8-methylene-1, 2,3,3a, 8,8a-hexahydro-2-aza-cyclopenta [a] indene. The subtitle compound was prepared by the method of Example 1, Step D, using 2-benzyl-4,6-dichloro-2,3,3a, 8a-tetrahydro-1 H-2-aza-cyclopenta [a ] inden-8-one (4.5 millimoles). The crude product was purified by a plug of silica, eluting with EtOAc-hexanes (3/1, volume / volume), to give the subtitle compound. MS calculated for Ci9H18Cl2N + H: 330; observed: 330. Step F. 4,6-dichloro-8-methylene-1,2,3,3a, 8,8a-hexa-hydro-2-aza-cyclopenta [a] indene. The subtitle compound was prepared by the method of Example 20, Step F, using 2-benzyl-4,6-dichloro-8-methylene-1, 2,3,3a, 8,8a-hexa-hydro-2- aza-cyclopenta [a] indene (4.5 mmol). The crude product was obtained without further purification. MS calculated for C12H12Cl2N + H: 240; observed: 240. Step G. N-carbutyl tert-butyl-4,6-dichloro-8-methylene-1, 2,3,3a, 8,8a-hexa-hydro-2-aza-cyclopenta [a] indene. The subtitle compound was prepared by the method of Example 20, Step G, using 4,6-dichloro-8-methylene-1, 2, 3, 3a, 8,8a-hexa-hydro-2-aza-cyclopenta [ a] indene (4.5 millimoles). The crude product was obtained without further purification. MS calculated for C 17 H 20 Cl 2 NO 2 + H: 340; observed: 340. Step H.T-Butyl N-carbamate-4,6-dichloro-8-methyl-1, 2, 3, 3a, 8, 8a-hexa-hydro-2-aza-cyclopenta [a] indene.

The subtitle compound was prepared by the method of Example 20, Step H, using the tert-butyl N-carbamate-4,6-dichloro-8-methylene-1, 2,3,3a, 8,8a-hexahydroxycarbamate. 2-aza-cyclopenta [a] indene (0.9 mmol), to provide 0.33 grams (22 percent - 4 steps) of the subtitle compound. MS calculated for C 17 H 22 Cl 2 NO 2 + H: 342; observed: 342. Step I. 4,6-dichloro-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole. The title compound was prepared by the method of Example 20, Step I, using the tert-butyl N-carbamate-4,6-dichloro-8-methyl-1, 2,3,3a, 8,8a-hexahydroxycarbamate. 2-aza-cyclopenta [a] indene. An aliquot of the crude product was purified by reverse phase liquid chromatography to provide the title compound. MS calculated for Ci2H14Cl2N + H: 242; observed: 242. EXAMPLE 29 5-Ethoxy-6-chloro-8-methyl-1, 2,3,3a, 8,8a-hexahydro-indene- [1,2-c] -pyrrole Step A. Ethyl N-carbamate-5-hydroxy-6-chloro-8-methyl-1, 2,3,3a, 8,8a-hexahydro-indene- [1,2-c] -pyrrol. BBr3 (0.3 milliliters, 0.30 millimoles, 1 M in CH2Cl2) was added to a solution of ethyl N-carbamate-5-methoxy-6-chloro-8-methyl-1, 2,3,3a, 8,8a-hexa -hydro-indene- [1, 2-c] -pyrrole (from Example 3, Step A) (46 milligrams, 0.15 mmol) at 0 ° C, and stirred overnight at room temperature. The reaction solution was quenched with H20, and filtered through an Extrelut column. The column was washed with CH2Cl2, and the filtrate was concentrated. The crude product was obtained without further purification. MS calculated for C15H18CIN03 + H: 296; observed: 296. Step B. Ethyl-N-carbamate-5-ethoxy-6-chloro-8-methyl-1, 2,3,3a, 8, 8a-hexa-hydro-indene- [1, 2-c] -pyrrol. Bromo-ethane (17 milliliters, 0.23 millimoles) and K2C03 (105 milligrams, 0.75 millimoles) were added to a solution of Nica rba mato of ethyl-5-hydroxy-6-chloro-8-methyl-1, 2,3,3a , 8,8a-hexahydro-indene- [1,2-c] -pyrrole (44 milligrams, 0.15 millimoles) in CH 3 CN (1.5 milliliters). The reaction was stirred overnight at 70 ° C, diluted with H20 and CH2Cl2, and filtered through an Extrelut column. The column was washed with CH2Cl2, and the filtrate was concentrated. The crude product was obtained without further purification. MS calculated for C17H22CIN03 + H: 324; observed: 324. Step C. 5-Ethoxy-6-chloro-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole. The title compound was prepared by the method of Example 3, Step B, using the N-carbamate ethyl-5-ethoxy-6-chloro-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1, 2-c ] -pyrrole (0.15 millimoles). The crude product was purified by reverse phase liquid chromatography to provide the title compound. 1 H NMR (d6-DIVIDE 300 MHz) d 7.18 (s, 1 H), 7.00 (s, 1 H), 4.09 (m, 2 H), 3.68 (m, 1 H), 3.31 (m, 2 H), 2.99 (m, 3 H) ), 2.45 (m, 1H), 1.33 (t, 3H), 1.21 (d, 3H) ppm. MS calculated for C 14 H 18 CINO + H: 252; observed: 252. EXAMPLE 30 5-methoxy-6-bromo-8-methyl-1,2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole Step A. Ethyl N-carbamate-5-methoxy-6-bromo-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrolidone . (Scheme 1). NBS (70 milligrams, 0.4 mmol) was added to a solution of methyl N-carbamate-5-methoxy-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1, 2 -c] -pyrrole (from Example 2, step A) (0.1 grams, 0.36 mmol) in CH3CN (3.6 milliliters), and stirred overnight at room temperature. The reaction was diluted with H20 and EtOAc, and filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated to provide 120 milligrams (94 percent) of the subtitle compound. MS calculated for C16H2oBrN03 + H: 342; observed: 342. Step B. 5-methoxy-6-bromo-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole. The title compound was prepared by the method of Example 3, Step B, using the ethyl N-carbamate-5-methoxy-6-bromo-8-methyl-1, 2,3,3a, 8,8a- hexahydro-indene- [1, 2-c] -pyrrole (0.17 mmol). The crude product was purified by reverse phase liquid chromatography to provide the title compound. 1 HOUR NMR (d6-DMSO 300 MHz) d 7.29 (s, 1H), 6.93 (s, 1H), 3.81 (s, 3H), 3. 61 (m, 1H), 3.28 (m, 2H), 2.98 (m, 1H), 2.83 (m, 2H), 2.45 (m, 1H), 1. 33 (t, 3H), 1.21 (d, 3H) ppm. MS calculated for C13H16BrNO + H: 282; observed: 282. EXAMPLE 31 5-Hydroxy-6-bromo-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [2-c] -pyrrole Step A. Ethyl N-carbamate-5-hydroxy-6-bromo-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole. (Scheme 1). The title compound was prepared by the method of Example 29, Step A, using the N-carbamate of ethyl-5-methoxy-6-bromo-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1, 2- c] -pyrrole (del Example 30, Step A) (0.09 mmol). The crude product was obtained without further purification. MS calculated for C15H18BrN03 + H: 340; observed: 340. Step B. 5-Hydroxy-6-bromo-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-ndeno- [1,2-c] -pyrrole. The title compound was prepared by the method of Example 3, Step B, using the ethyl N-carbamate-5-hydroxy-6-bromo-8-methyl-1, 2,3,3a, 8,8a-hexahydro-indene- [1, 2 -c] -pyrrol (0.09 mmol). The crude product was purified by reverse phase liquid chromatography to provide the title compound. MS calculated for C 12 H 14 BrNO + H: 268; observed: 268. EXAMPLE 32 5-methoxy-6- (2-thienyl) -8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole Step A. Ethyl N-carbamate-5-methoxy-6- (2-thienyl) -8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrol. (Scheme 1). Thiophen-2-boronic acid (44 milligrams, 0.34 millimoles), Pd (PPh3) 4 (19 milligrams, 0.02 millimoles), K2C03 (71 milligrams, 0.51 millimoles), and H20 (0.17 milliliters), were added to a solution of N ethyl carbamate-5-methoxy-6-bromo-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole (from Example 30, Step A) (60 milligrams, 0.17 millimoles) in dioxane (3 milliliters), and stirred overnight at 100 ° C. The reaction mixture was diluted with EtOAc and H20, and filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude product was purified by a plug of silica, eluting with Hexanes / EtOAc (2/1, volume / volume). MS calculated for C20H25NO3S + H: 358; observed: 358 Step B. 5-Methoxy-6- (2-thienyl) -8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole. The title compound was prepared by the method of Example 3, Step B, using the ethyl N-carbamate-5-methoxy-6- (2-thienyl) -8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1, 2-c] -pyrrole (0.17 mmol). The crude product was purified by reverse phase liquid chromatography to provide the title compound. 1 H NMR (d 6 -DMSO 300 MHz) d 7.52 (d, 1 H), 7.49 (d, 1 H), 7.41 (s, 1 H), 7.10 (t, 1 H), 6.97 (s, 1 H), 3.88 (s, 3 H) ), 3.66 (m, 1H), 3.31 (m, 2H), 3.00 (m, 1H), 2.88 (m, 2H), 2.45 (m, 1H), 1.29 (d, 3H) ppm. MS calculated for Ci7H19NOS + H: 286; observed: 286. EXAMPLE 33 5-methoxy-6-cyano-8-methyl-1, 2,3,3a, 8,8a-hexahydro-indene- [1,2-c] -pyrrole Step A. Ethyl N-carbamate-5-methoxy-6-cyano-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole. (Scheme 1). CuCN (68 milligrams, 0.85 millimoles) was added to a solution of ethyl N-carbamate-5-methoxy-6-bromo-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1, 2-c] -pyrrole (from Example 30, Step A) (60 milligrams, 0.17 mmol) in dimethylformamide (1.7 milliliters), and stirred overnight at 100 ° C. The reaction mixture was diluted with EtOAc and H20, and filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude product was purified by a plug of silica, eluting with Hexanes-EtOAc (2/1, volume / volume). S calculated for C 7 H 2 O N 203 + H: 301; observed: 301. Step B. 5-methoxy-6-cyano-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [, 2-c] -pyrol I. The compound of title was prepared by the method of Example 3, Step B, using the ethyl N-carbamate-5-methoxy-6-cyano-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene - [1, 2-c] -pyrrole (0.17 mmol). The crude product was purified by reverse phase liquid chromatography to provide the title compound. 1 H NMR (d 6 -DMSO 300 Hz) d 7.44 (s, 1 H), 7.04 (s, 1 H), 3.88 (s, 3 H), 3.65 (m, 1 H), 3.23 (m, 2 H), 2.88 (m, 1 H) ), 2.78 (m, 2H), 2.40 (m, 1H), 1.21 (d, 3H) ppm. MS calculated for C 14 H 16 N 20 + H: 229; observed: 229. EXAMPLE 34 4,5-Dimethoxy-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole Step A. 3-Bromo-4,5-dimethoxy-1-indanone. (Scheme 3). The subtitle compound was prepared by the method of Example 1, Step A, using 4,5-dimethoxy-1-indanone (26.0 mmol). The crude product was obtained without further purification. MS calculated for C H BrOs + H: 271; observed: 271. Step B. 4,5-dimethoxy-inden-1 -one. The subtitle compound was prepared by the method of Example 1, Step B, using 3-bromo-4,5-dimethoxy-1-indanone (26.0 mmol). The crude product was obtained without further purification.

MS calculated for CnH10O3 + H: 191; observed: 191. Step C. 2-Benzyl-4,5-dimethoxy-2,3,3a, 8a-tetrahydro-1α-2-aza-cyclopenta [a] inden-8-one. The subtitle compound was prepared by the method of Example 1, Step C, using 4,5-dimethoxy-inden-1 -one (26.0 mmol). The crude product was purified by a plug of silica, eluting with hexanes / EtOAc (3/1, volume / volume), to provide 4.2 grams (50 percent - 3 weight) of the subtitle compound. MS calculated for C20H21NO3 + H: 324; observed: 324. Step D. 2-Benzyl-4,5-dimethoxy-8-methylene-1, 2,3,3a, 8,8a-hexahydro-indene- [1,2-c] -pyrrole. The subtitle compound was prepared by the method of Example 1, Step D, using 2-benzyl-4,5-dimethoxy-2,3,3a, 8a-tetrahydro-H-2-aza-cyclopenta [a] inden-8-one (13.0 mmol). The crude product was purified by a plug of silica, eluting with hexanes / EtOAc (3/1, volume / volume), to provide the subtitle compound in a quantitative yield. MS calculated for C 21 H 23 NO 2 + H: 322; observed: 322. Step E. 4,5-Dimethoxy-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole.

The subtitle compound was prepared by the method of Example 1, Step E, using 2-benzyl-4,5-dimethoxy-8-methylene-1, 2,3,3a, 8,8a-hexahydro-indene- [1, 2-c] -pyrrole (13.0 mmol). The crude product was obtained without further purification. MS calculated for C14H19N02 + H: 234; observed: 234. Step F. Ethyl-N-carbamate-4,5-dimethoxy-8-methyl-1, 2, 3, 3a, 8, 8a-hexahydro-indene- [1,2-c] -pyrrole . The subtitle compound was prepared by the method of Example 2, Step A, using 4,5-dimethoxy-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1, 2 -c] -pyrrole (13.0 mmol). The crude product was purified by column chromatography (SiO2) using a gradient of 0 to 50 percent EtOAc-hexanes, to give the subtitle compound. MS calculated for C 17 H 23 NO 4 + H: 306; observed: 306. Step G. 4,5-dimethoxy-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1, 2-c] -pyrrole. The title compound was prepared by the method of Example 3, Step B, using the ethyl N-carbamate-4,5-dimethoxy-8-methyl-1, 2,3,3a, 8,8a-hexahydroxycarbamate. indeno- [1, 2-c] -pyrrole (0.03 mmol). The crude product was purified by reverse phase liquid chromatography to provide the title compound. 1 H NMR (d 6 -DMSO 300 MHz) d 6.88 (d, 1 H), 6.79 (d, 1 H), 3.72 (m, 7 H), 3.32 (m, 1 H), 3.21 (m, 1 H), 2.84 (m, 3 H) ), 2.40 (m, 1H), 1.19 (d, 3H) ppm. MS calculated for Ci4H19N02 + H: 234; observed: 234.

Example 35 4,5-dimethoxy-6-chloro-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole Step A. Ethyl N-carbamate-4,5-dimethoxy-6-chloro-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole . (Scheme 3). The subtitle compound was prepared by the method of Example 3, Step A, using the N-carbamate ethyl-4,5-dimethoxy-8-methyl-1,2, 3,3a, 8, 8a-hexa-hydro-indene- [1,2-cj-pyrrole (from Example 34, Step F) (0.58 millimoles). The crude product was obtained without further purification. MS calculated for C17H22CI O4 + H: 340; observed: 340. Step B. 5-methoxy-6-chloro-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole. The title compound was prepared by the method of Example 3, Step B, using the ethyl N-carbamate-4,5-dimethoxy-6-chloro-8-methyl-1, 2,3,3a, 8,8a- hexahydro-indene- [1, 2-c] -pyrrole (0.12 mmol). The crude product was purified by reverse phase liquid chromatography to provide the title compound. 1 H NMR (d 6 -DMSO 300 MHz) d 6.88 (d, 1 H), 6.79 (d, 1 H), 3.72 (m, 7 H), 3.32 (m, 1 H), 3.21 (m, 1 H), 2.84 (m, 3 H) ), 2.40 (m, 1H), 1.19 (d, 3H) ppm. MS calculated for Ci4H18CIN02 + H: 268; observed: 268.

Example 36 4,5-dimethoxy-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole Step A. 3-Bromo-5,6-dimethoxy-1-indanone. (Scheme 3). The subtitle compound was prepared by the method of Example 1, Step A, using 5,6-dimethoxy-1-indanone (52.0 mmol). The crude product was obtained without further purification. MS calculated for CnH Br03 + H: 271; observed: 271. Step B. 5,6-Dimethoxy-inden-1 -one. The subtitle compound was prepared by the method of Example 1, Step B, using 3-bromo-5,6-dimethoxy-1-indanone (52.0 millimoles). The crude product was obtained without further purification. MS calculated for CiiH10O3 + H: 191; observed: 191. Step C. 2-Benzyl-5,6-dimethoxy-2,3,3a, 8a-tetrahydro-1α-2-aza-cyclopenta [a] inden-8-one. The subtitle compound was prepared by the method of Example 1, Step C, using 5,6-dimethoxy-inden-1 -one (52.0 mmol). The crude product was purified by a plug of silica, eluting with hexanes / EtOAc (3/1, volume / volume), to give the subtitle compound. MS calculated for C20H21NO3 + H: 324; observed: 324. Step D. 2-Benzyl-5,6-d-methoxy-8-methylene-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole .

The subtitle compound was prepared by the method of Example 1, Step D, using 2-benzM-5,6-dimethoxy-2,3,3a, 8a-tetrahydro-1 H-2-aza-cyclopenta [a] inden-8-one (3.1 millimoles). The crude product was purified by a plug of silica, eluting with hexanes / EtOAc (3/1, volume / volume), to provide the subtitle compound in a quantitative yield. MS calculated for C21H23N02 + H: 322; observed: 322. Step E. 5,6-Dimethoxy-8-methyl-1, 2,3,3a, 8,8a-hexahydro-indene- [1,2-c] -pyrrole. The subtitle compound was prepared by the method of Example 1, Step E, using 2-benzyl-5,6-dimethoxy-8-methylene-1, 2,3,3a, 8,8a-hexa-hydro-indene- [, 2-c] -pyrrole (3.1 millimoles). The crude product was obtained without further purification. MS calculated for C14H19N02 + H: 234; observed: 234. Step F. N-carbutyl-tert-butyl-4,5-dimethoxy-8-methyl-1, 2,3,3a, 8,8a-hexahydro-indene- [1,2-c] -pyrrole . The subtitle compound was prepared by the method of Example 20, Step G, using 5,6-dimethoxy-8-methyl-, 2, 3, 3a, 8,8a-hexa-hydro-indene- [2-c ) -pyrrole (3.1 millimoles). The crude product was purified by column chromatography (SiO2) using a gradient of 0 to 50 percent EtOAc-hexanes, to give the subtitle compound. MS calculated for C19H27 04 + H: 334; observed: 334. Step G. 4,5-Dimethoxy-8-methyl-1, 2,3,3a, 8,8a-hexahydro-indene- [1,2-c] -pyrrole.

The title compound was prepared by the method of Example 20, Step H, using the tert-butyl N-carbamate-5,6-dimethoxy-8-methyl-1 ^ .S.Sa.S.Sa-hexa-hydro-indene -p ^ -cl-pyrrole (0.15 millimoles). The crude product was purified by reverse phase liquid chromatography to provide the title compound. 1 H NMR (d 6 -DMSO 300 MHz) d 6.92 (s, 1 H), 6.80 (s, 1 H), 3.72 (m, 7 H), 3.55 (m, 1 H), 3.21 (m, 4 H), 2.65 (m, 1 H) ), 1.26 (d, 3H) ppm. MS calculated for C14H19N02 + H: 234; observed: 234. Example 37 5-methoxy-6-chloro-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole Step A. 2-Benzyl-5-methoxy-1, 2,3,3a, 8,8a-hexa-hydro-2-aza-cyclopenta [a] inden-8-ol. (Scheme 1). NaBH 4 (0.27 grams, 6.8 mmol) was added to a solution of 2-benzyl-5-methoxy-2,3,3a, 8a-tetrahydro-1 H-2-aza-cyclopenta [a] -inden-8-one ( of Example 1, Step C) (1.0 grams, 3.4 mmol) in MeOH (17 milliliters), and stirred for 2 hours at room temperature. The reaction solution was concentrated by rotary evaporation, and the residue was dissolved in EtOAc. The organic solution was washed with a saturated aqueous solution of NaHCO 3 and brine, dried over MgSO 4, and concentrated. The crude product was obtained without further purification. MS calculated for Ci9H2iN02 + H: 296; Observed: 296 Step B. 2-Benzyl-5-methoxy-1, 2,3,3a, 8,8a-hexahydro-indene- [1,2-c] -pyrrole. LnCI3 (0.38 grams, 1.7 mmol) and chlorodiphenylsilane (1.3 milliliters, 6.8 mmol) were added to a solution of 2-benzyl-5-methoxy-1, 2,3,3a, 8,8a-hexa-hydro -2-aza-cyclopenta [a] inden-8-ol (3.4 mmol) in dichloro-ethane (17 milliliters), and stirred overnight at 60 ° C. The reaction mixture was washed with H20, a saturated aqueous solution of NaHCO3, and brine. The organic extracts were dried over MgSO4, and concentrated. The crude product was obtained without further purification. MS calculated for C19H21 NO + H: 280; observed: 280. Step C. 5-methoxy-, 2,3,3a, 8,8a-hexahydro-indene- [1,2-c] -pyrrole.

The subtitle compound was prepared by the method of Example 1, Step E, using 2-benzyl-5-methoxy-1, 2, 3, 3a, 8,8a-hexa-hydro-indene- [1, 2-c ] -pyrrole (3.4 mmol). The crude product was obtained without further purification. MS calculated for C12H15NO + H: 190; observed: 190. Step D. Ethyl N-carbamate-5-methoxy-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole. The subtitle compound was prepared by the method of Example 2, Step A, using 5-methoxy-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole (3.4 mmol). The crude product was purified by column chromatography (SiO2) using a gradient of 0 to 50 percent EtOAc-hexanes, to give the subtitle compound. MS calculated for C 5 H 19 N 0 3 + H: 262; observed: 262. Step E. Ethyl N-carbamate-5-methoxy-6-chloro-1,2,3, 3a, 8,8a-hexahydro-indene- [1,2-c] -pyrrole. The subtitle compound was prepared by the method of Example 3, Step A, using the ethyl N-carbamate-5-methoxy-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1, 2 -c] -pyrrole (0.19 mmol). The crude product was obtained without further purification. MS calculated for 015? 18 ??? 03+ ?: 296; observed: 296. Step F. 5-methoxy-6-chloro-1, 2,3, 3a, 8, 8a-hexahydro-indene- [1,2-cl-pyrrole. The title compound was prepared by the method of Example 3, Step B, using the ethyl N-carbamate-5-methoxy-6-chloro-1, 2,3,3a, 8,8a-hexahydro-indene- [1, 2-c] -pyrrole (0.19 mmol). The crude product was purified by reverse phase liquid chromatography to provide the title compound. 1 H NMR (d 6 -DMSO 300 MHz) d 7.17 (s, 1 H), 6.97 (s, 1 H), 3.81 (s, 3 H), 3.62 (m, 1 H), 3.00 (m, 5 H), 2.60 (m, 2 H) ) ppm. MS calculated for C12H14CINO + H: 224; observed: 224. EXAMPLE 38 4,6-Dichloro-5-methoxy-8-methyl-1, 2,3,3a, 8,8a-hexahydro-indene- [1,2-c] - pyrrole Step A. Ethyl N-carbamate-4,6-dichloro-5-methoxy-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] - pyrrole. (Scheme 1). NCS (63 milligrams, 0.47 millimoles) and acetic acid (1 milliliter) were added to a solution of ethyl N-carbamate-5-methoxy-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro -indeno- [1, 2-c] -pyrrole (from Example 2, Step A) (43 milligrams, 0.16 millimoles) in dichloro-ethane (1 milliliter), and the reaction solution was stirred for 3 hours at 70 °. C. The reaction was quenched with H20, and the solution was filtered through an Extrelut column. The column was washed with CH2Cl2, and the filtrate was concentrated. The subtitle compound was obtained without further purification. MS calculated for C16Hi9Cl2N03 + H: 344; observed: 344. Step B. 4,6-Dichloro-5-methoxy-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole. The title compound was prepared by the method of Example 3, Step B, using the ethyl N-carbamate-4,6-dichloro-5-methoxy-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1, 2 -c] -pyrrole (0.16 millimoles). The crude product was purified by reverse phase liquid chromatography to provide the title compound. 1 H NMR (d 6 -DMSO 300 MHz) d 7.28 (s, 1 H), 3.78 (s, 3 H), 3.71 (m, 1 H), 3.29 (m, 2 H), 2.84 (m, 3 H), 2.60 (m, 1 H) ), 1.21 (d, 3H) ppm. MS calculated for C 13 H 15 Cl 2 NO + H: 272; observed: 272. EXAMPLE 39 5-Cyclopropyl-methoxy-6-chloro-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole Step A. Ethyl N-carbamate-5-hydroxy-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole. (Scheme 1). BBr3 (1.1 milliliters, 1.0 M in dichloromethane) was added to a solution of ethyl N-carbamate-5-methoxy-8-methyl-1, 2, 3, 3a, 8,8a-hexa-hydro-indene - [, 2-c] -pyrrole (from Example 2, Step A) (0.31 grams, 1.1 mmol) in CH2Cl2 (10 milliliters) at 0 ° C, and stirred overnight. The excess BBr3 was quenched by the dropwise addition of water (2 milliliters), and washed with saturated aqueous NaHCO3 (10 milliliters) and brine (10 milliliters). The organic extract was dried over MgSO4, and concentrated. The subtitle compound was obtained without further purification. S calculated for Ci5H19N03 + H: 262; observed: 262. Step B. Ethyl-N-carbamate-5-cyclopropyl-methoxy-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole . (Bromo-methyl) -cyclopropane (13 milligrams, 0.09 millimoles) and K2C03 (24 milligrams, 0.17 millimoles) were added to a solution of ethyl N-carbamate-5-hydroxy-8-methyl-, 2,3,3a , 8,8a-hexahydro-indene- [1, 2-c] -pyrrole (23 milligrams, 0.09 mmol) in CH 3 CN, and stirred overnight at 80 ° C. The reaction mixture was diluted with H20 and CH2Cl2, and filtered through an Extrelut column. The column was washed with CH2Cl2, and the filtrate was concentrated. The subtitle compound was obtained without further purification. MS calculated for C19H25NO3 + H: 316; observed: 316. Step C. Ethyl-N-carbamate-5-cyclopropyl-methoxy-6-chloro-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1, 2- c] -pyrrole. NCS (38 milligrams, 0.28 millimoles) and acetic acid (1 milliliter) were added to a solution of ethyl N-carbamate-5-cyclo-propyl-methoxy-8-methyl 1-1, 2.3.3a, 8 , 8a-hexahydro-indene- [1,2-c] -pyrrole (89 milligrams, 0.28 mmol) in dichloro-ethane (2 milliliters), and the reaction solution was stirred for 3 hours at 70 ° C. The reaction was quenched with H20, and the solution was filtered through an Extrelut column. The column was washed with CH2Cl2, and the filtrate was concentrated. The subtitle compound was obtained without further purification. MS calculated for C 9H24CIN03 + H: 350; observed: 350. Step D. 5-Cyclopropyl-methoxy-6-chloro-8-methyl-1, 2,3,3a, 8,8a-hexahydro-indene- [1,2-c] -pyrrol. The title compound was prepared by the method of Example 3, Step B, using the ethyl N-carbamate-5-cyclopropyl-methoxy-6-chloro-8-methyl-1, 2,3,3a, 8,8a- hexahydro-indene- [1, 2-c] -pyrrole (0.32 mmol). The crude product was purified by reverse phase liquid chromatography to provide the title compound. 1 H NMR (d 6 -DMSO 300 MHz) d 7.14 (s, 1 H), 6.9 (s, 1 H), 3.88 (d, 2 H), 3.24 (m, 3 H), 2.84 (m, 3 H), 2.45 (m, 1 H) ), 1.21 (m, 4H), 0.58 (d, 2H), 0.32 (d, 2H) ppm. MS calculated for Ci6H20CINO + H: 278; observed: 278 Example 40 5-Trifluoro-methoxy-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole Step A. Ethyl ester of 3- (3-trifluoro-methoxy-phenyl) -acrylic acid.

(Scheme 3). The subtitle compound was prepared by the method of Example 13, Step A, using 3- (trifluoromethyl) -benzaldehyde (12.5 mmol). The crude product was obtained without further purification. MS calculated for C12HHF3O3 + H: 261; observed: 261. Step B. 1-Benzyl-4- (3-trifluoro-methoxy-phenyl) -pyrrolidine-3-carboxylic acid ethyl ester. The subtitle compound was prepared by the method of Example 1, Step C, using the 3- (3-trifluoromethoxy-phenyl) -acrylic acid ethyl ester (12.5 mmol). The crude product was purified by column chromatography (Si02) using a gradient of 10 to 50 percent EtOAc-hexanes, to give 3.5 grams (72 percent - two steps) of the subtitle compound. MS calculated for C21 H22F3NO3 + H: 394; observed: 394. Step C. 1-Benzyl-4- (3-trifluoro-methoxy-phenyl) -pyrrolidine-3-carboxylic acid. The subtitle compound was prepared by the method of Example 13, Step C, using 1-benzyl-4- (3-trifluoro-methoxy-phenyl) -pyrrolidine-3-carboxylic acid ethyl ester (8.9 mmol) . The crude product was obtained without further purification. MS calculated for C19H18F3N03 + H: 366; observed: 366. Step D. 2-Benzyl-5-trifluoro-methoxy-2,3,3a, 8a-tetrahydro-1 H-2-aza-cyclopenta [a] inden-8-one. The subtitle compound was prepared by the method of Example 13, Step D, using 1-benzyl-4- (3-trifluoromethoxy-phenyl) -pyrrolidine-3-carboxylic acid (8.9 mmol). The crude product was purified by column chromatography (Si02) using a gradient of 15 to 60 percent EtOAc-hexanes, to give 0.50 grams (16 percent - two steps) of the subtitle compound. MS calculated for Ci9Hi6F3N02 + H: 348; observed: 348. Step E. 2-Benzyl-5-trifluoro-methoxy-8-methylene-1, 2,3, 3a, 8, 8a-hexa-hydro-2-aza-cyclopenta [a] indene. The subtitle compound was prepared by the method of Example 1, Step D, using 2-benzyl-5-trifluoro-methoxy-2,3,3a, 8a-tetrahydro-H-2-aza-cyclopenta [a] inden- 8-one (0.5 millimoles). The crude product was purified by a plug of silica, eluting with EtOAc-hexanes (3/1, volume / volume), to give the subtitle compound. MS calculated for C2oHi8F3NO + H: 346; observed: 346. Step F. 5-Trifluoro-methoxy-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole.

The title compound was prepared by the method of Example 1, Step E, using 2-benzyl-5-trifluoro-methoxy-8-methylene-1, 2,3,3a, 8,8a-hexa-hydro-2- aza-cyclopenta [a] indene (0.5 m limeles). An aliquot of the crude product was purified by reverse phase liquid chromatography to provide the title compound. H NMR (d6-DMSO 300 MHz) d 7.19 (m, 3H), 3.65 (m, 1H), 3.28 (m, 2H), 2.83 (m, 3H), 2.45 (m, 1H), 1.25 (d, 3H) ) ppm. MS calculated for Ci3H14F3NO + H: 258; observed: 258. Example 41 4,5-dichloro-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole Step A. Ethyl ester of 3- (2,3-dichloro-phenyl) -acrylic acid. The subtitle compound was prepared by the method of Example 13, Step A, using 3,4-dichloro-benzaldehyde (29.0 mmol). The crude product was obtained without further purification. MS calculated for Cu H10Cl2O2 + H: 245; observed: 245. Step B. Ethyl ester of 1-benzyl-4- (2,3-dichloro-phenyl) -pyrrolidine-3-carboxylic acid. The subtitle compound was prepared by the method of Example 1, Step C, using the 3- (2,3-dichloro-phenyl) -acrylic acid ethyl ester (29.0 mmol). The crude product was purified by column chromatography (Si02) using a gradient of 0 to 70 percent EtOAc-hexanes, to provide 5.3 grams (49 percent-two steps) of the subtitle compound. MS calculated for C20H22Cl2NO2 + H: 378; observed: 378. Step C. 1-Benzyl-4- (2,3-dichloro-phenyl) -pyrrolidine-3-carboxylic acid. The subtitle compound was prepared by the method of Example 13, Step C, using the 1-benzyl-4- (2,3-dichloro-phenyl) -pyrrolidine-3-carboxylic acid ethyl ester (14.0 mmol). The crude product was obtained without further purification. MS calculated for C18H18Cl2N02 + H: 350; observed: 350. Step D. 2-Benzyl-4,5-dichloro-2,3,3a, 8a-tetrahydro-1α-2-aza-cyclopenta [a] inden-8-one. The subtitle compound was prepared by the method of Example 13, Step D, using 1-benzyl-4- (2,3-dichloro-phenyl) -pyrrolidine-3-carboxylic acid (14.0 mmol). The crude product was purified by column chromatography (SiO2) using a gradient of 0 to 50 percent EtOAc-hexanes, to give the subtitle compound. MS calculated for C18H16Cl2NO + H: 332; observed: 332. Step E. 2-Benzyl-4,5-dichloro-8-methylene-1, 2,3,3a, 8,8a-hexa-hydro-2-aza-cyclopenta [a] indene. The subtitle compound was prepared by the method of Example 1, Step D, using 2-benzyl-4,5-dichloro-2,3,3a, 8a-tetrahydro-1 H-2-aza-cyclopenta [a ] inden-8-one (14.0 mmol). The crude product was purified by a plug of silica, eluting with EtOAc-hexanes (3/1, volume / volume), to give 1.7 grams (35 percent-three steps) of the subtitle compound. MS calculated for C19H18Cl2N + H: 330; observed: 330. Step F. 4,5-Dichloro-8-methylene-1, 2,3,3a, 8,8a-hexa-hydro-2-aza-cyclopenta [a] indene. The subtitle compound was prepared by the method of Example 20, Step F, using 2-benzyl-4,5-dichloro-8-methylene-1, 2,3,3a, 8,8a-hexahydrate. 2-aza-cyclopenta [a] ndene (4.9 mmol). The crude product was obtained without further purification. MS calculated for Ci2H12Cl2N + H: 240; observed: 240. Step G. Ethyl N-carbamate-4,5-dichloro-8-methylene-1, 2, 3, 3a, 8, 8a-hexa-hydro-2-aza-cyclopenta [a] indene. The subtitle compound was prepared by the method of Example 2, Step A, using 4,5-dichloro-8-methylene-1, 2, 3, 3a, 8,8a-hexa-hydro-2-aza-cyclopenta [ a] indene (4.9 millimoles). The crude product was purified by column chromatography (Si02) using a gradient of 0 to 60 percent EtOAc-hexanes, to provide 0.32 grams (21 percent - two steps) of the subtitle compound. MS calculated for C15H15Cl2N02 + H: 312; observed: 312. Step H. Ethyl N-carbamate-4,5-dichloro-8-methyl-1, 2, 3, 3a, 8, 8a-hexa-hydro-2-aza-cyclopenta [a] indene. The subtitle compound was prepared by the method of Example 20, Step H, using the ethyl N-carbamate-4,5-dichloro-8-methylene-1, 2,3,3a, 8,8a-hexa-hydro- 2-aza-cyclopenta [a] indene (1.0 mmol). The crude product was purified by column chromatography (Si02) using a gradient of 0 to 60 percent EtOAc-hexanes, to provide 0.10 grams (32 percent) of the subtitle compound. MS calculated for C15Hi7Cl2N02 + H: 314; observed: 314. Step I. 4,5-Dichloro-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole. The title compound was prepared by the method of Example 3, Step B, using the ethyl N-carbamate-4,5-dichloro-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro- 2-aza-cyclopenta [a] indene (0.06 mmol). An aliquot of the crude product was purified by reverse phase liquid chromatography to provide the title compound. H NMR (d6-DMSO 300 MHz) d 7.46 (d, 1H), 7.16 (d, 1H), 3.76 (m, 1H), 3.36 (m, 2H), 2.85 (m, 3H), 2.45 (m, 1H) ), 1.23 (d, 3H) ppm. MS calculated for C 12 H 13 Cl 2 N + H: 242; Observed: 242. Example 42 6-chloro-7-fluoro-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole Step A. 3- (3-Fluoro-4-chloro-phenyl) -acrylic acid methyl ester.

(Scheme 3).

The subtitle compound was prepared by the method of Example 13, Step A, using 3,4-dichloro-benzaldehyde (34.0 mmol). The crude product was obtained without further purification. MS calculated for Ci0H8CIFO2 + H: 215; observed: 215. Step B. 1-Benzyl-4- (3-fluoro-4-chloro-phenyl) -pyrrolidine-3-carboxylic acid methyl ester. The subtitle compound was prepared by the method of Example 1, Step C, using the methyl ester of 3- (3-fluoro-4-chloro-phenyl) -acrylic acid (34.0 mmol). The crude product was purified by column chromatography (S02) using a gradient of 0 to 45 percent EtOAc-hexanes, to provide 6.3 grams (53 percent - two steps) of the subtitle compound. MS calculated for C19H19CIFN02 + H: 348; observed: 348. Step C. 1-Benzyl-4- (3-fluoro-4-chloro-phenyl) -pyrrolidine-3-carboxylic acid. The subtitle compound was prepared by the method of Example 13, Step C, using the 1-benzyl-4- (2,3-dichloro-phenyl) -pyrrolidine-3-carboxylic acid ethyl ester (18.1 mmol). The crude product was obtained without further purification. MS calculated for C18H17CIFN02 + H: 334; observed: 334. Step D. 2-Benzyl-6-chloro-7-fluoro-2,3,3a, 8a-tetrahydro-1α-2-aza-cyclopenta [a] inden-8-one. The subtitle compound was prepared by the method of Example 13, Step D, using 1-benzyl-4- (3-fluoro-4-chloro-phenyl) -pyrrolidine-3-carboxylic acid (18.1 mmol). The crude product was purified by column chromatography (SiO2) using a gradient of 0 to 50 percent EtOAc-hexanes, to give the subtitle compound. MS calculated for Ci8H15CIFNO + H: 316; observed: 316. Step E. 6-Chloro-7-fluoro-2,3,3a, 8a-tetrahydro-1? -2-aza-cyclopenta [a] inden-8-one. The subtitle compound was prepared by the method of Example 20, Step F, using 2-benzyl-6-chloro-7-fluoro-2,3,3a, 8a-tetrahydro-1 H-2-aza-cyclopenta [a ] inden-8-one (2.1 millimoles). The crude product was obtained without further purification. MS calculated for C HgCIFNO + H: 226; observed: 226. Step F. Ethyl N-carbamate-6-chloro-7-fluoro-2,3,3a, 8a-tetrahydro-1 H-2-aza-cyclopenta [a] inden-8-one. The subtitle compound was prepared by the method of Example 2, Step A, using 6-chloro-7-fluoro-2,3,3a, 8a-tetra-hydro-1 H-2-aza-cyclopenta [a] inden -8-one (2.2 millimoles). The crude product was purified by column chromatography (Si02) using a gradient of 0 to 55 percent EtOAc-hexanes, to provide the subtitle compound in a quantitative yield. MS calculated for Ci H13CIFN03 + H: 298; observed: 298. Step G. Ethyl N-carbamate-6-chloro-7-fluoro-8-methylene-1, 2,3,3a, 8,8a-hexahydro-2-aza-cyclopenta [a indeno. The subtitle compound was prepared by the method of Example 2, Step A, using 4,5-dichloro-8-methylene-1, 2, 3, 3a, 8, 8a-hexahydro-2-aza-c clopenta [a] ndene (1.5 millimoles). The crude product was purified by column chromatography (Si02) using a gradient of 10 to 55 percent EtOAc-hexanes, to provide 0.43 grams (66 percent - two steps) of the subtitle compound in a quantitative yield. MS calculated for C15H15CIFN02 + H: 296; observed: 296. Step H. Ethyl N-carbamate-6-chloro-7-methyl-1, 2,3,3a, 8,8a-hexa-hydro-2-aza-cyclopenta [a] indene. The subtitle compound was prepared by the method of Example 20, Step H, using the ethyl N-carbamate-6-chloro-7-fluoro-8-methylene-1, 2,3,3a, 8,8a-hexa- hydro-2-aza-cyclopenta [a] indene (0.2 mmol). The crude product was purified by column chromatography (S02) using a gradient of 0 to 60 percent EtOAc-hexanes, to provide the subtitle compound in a quantitative yield. MS calculated for Ci5Hi7CIFN02 + H: 298; Observed: 298. Step I. 6-Chloro-7-fluoro-8-methyl-1, 2,3,3a, 8,8a-hexahydro-indene- [1, 2-c] -pyrin I. The title compound was prepared by the method of Example 3, Step B, using the N-carbamate of ethyl-6-chloro-7-fluoro-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-2-aza-cyclopenta [a] indene (0.06 mmol). An aliquot of the crude product was purified by reverse phase liquid chromatography to provide the title compound. 1 H NMR (d 6 -DMSO 300 MHz) d 7.30 (d, 1 H), 7.19 (d, 1 H), 3.92 (m, 1 H), 3.65 (m, 1 H), 3.44 (m, 2 H), 3.30 (m, 2 H) ), 2.88 (m, 1H), 1.33 (d, 3H) ppm. MS calculated for C12H13CIFN + H: 226; observed: 226. EXAMPLE 43 5-Benzyloxy-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole Step A. Ethyl-5-hydroxy-8-methyl-1, 2, 3, 3a, 8,8a-hexahydro-indene- [1, 2-c] -pyrrole N-carbamate. (Scheme 1). BBr3 in CH2Cl2 (1.1 milliliter, 1.1 mmol, 1 M) was added to a solution of ethyl N-carbamate-5-methoxy-8-methyl-1, 2, 3, 3a, 8,8a-hexa-hydro-indene - [1, 2-c] -pyrrole (from Example 2, Step A) (100 milligrams, 0.36 millimoles) at 0 ° C. The reaction mixture was stirred overnight from 0 ° C to room temperature, and quenched with H20. The solution was filtered through an Extrelut column, the column was washed with CH2Cl2, and the filtrate was concentrated. The crude product was obtained without further purification. MS calculated for Ci5H19N03 + H: 262; observed: 262. Step B. Ethyl N-carbamate-5-benzyloxy-8-methyl-1, 2, 3, 3a, 8, 8a-hexa-hydro-indene- [1,2-c] -pyrrole. Benzyl bromide (15 microliters, 0.12 mmol) and K2C03 (70 milligrams, 0.5 mmol) were added to a solution of ethyl N-carbamate-5-hydroxy-8-methyl-1, 2,3,3a, 8,8a -hexa-hydro-indene- [1, 2-c] -pyrrole (26 milligrams, 0.1 mmol) in CH3CN (2 milliliters). The resulting mixture was stirred overnight at 80 ° C. The reaction was cooled to room temperature, concentrated by rotary evaporation, and absorbed in H20 (2.5 milliliters). The product was extracted with ethyl acetate (5 milliliters, 3 times). The combined organic extracts were dried over MgSO4, and concentrated to provide the subtitle compound, which was used without further purification. MS calculated for C22H25 O3 + H: 352; observed: 352. Step C. 5-Benzyloxy-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole. The title compound was prepared by the method of Example 3, Step B, using the ethyl N-carbamate-5-benzyloxy-8-methyl-1, 2,3,3a, 8,8a-hexahydro-indene- [1, 2-c] -pyrrole (0.1 mmol). The crude product was purified by reverse phase liquid chromatography to provide the title compound. MS calculated for C19H21NO + H: 280; observed: 280. EXAMPLE 44 5- (2-fluo-o-n-n-oxy) -8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole Step A. Ethyl N-carbamate-5- (2-f luoro-benzyloxy) -8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] - pyrrole. (Scheme 1).

The subtitle compound was prepared by the method of Example 43, Step B, using the ethyl N-carbamate-5-hydroxy-8-methyl-1, 2,3,3a, 8,8a-hexahydro-indene- [1, 2-c] -pyrrole (from Example 43, Step A) (0.1 mmol) and 2-fluoro-benzyl bromide. The crude product was obtained without further purification. MS calculated for C22H24FNO3 + H: 370; observed: 370. Step B. 5- (2-Fluoro-benzyloxy) -8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole. The title compound was prepared by the method of Example 3, Step B, using the ethyl N-carbamate-5- (2-fluoro-benzyloxy) -8-methyl-1, 2,3,3a, 8,8a- hexahydro-indene- [1,2-c] -pyrrole (0.1 mmol). The crude product was purified by reverse phase liquid chromatography to provide the title compound. MS calculated for C19H20FNO + H: 298; Observed: 298. EXAMPLE 45 5- (3-Fluoro-benzyloxy) -8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole Step A. N-carbamate of ethyl-5- (3-f luoro-benzyloxy) -8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1, 2-c ] -pyrrole. (Scheme 1). The subtitle compound was prepared by the method of Example 43, Step B, using N-ethyl carbonate-5-hydroxy-8-methyl-1,2, 3,3a, 8, 8a-hexa-hydro-indene - [1, 2-c] -pyrrol (of Example 43, Step A) (0.1 mmol) and 3-fluoro-benzyl bromide. The crude product was obtained without further purification. MS calculated for C22H24FNO3 + H: 370; observed: 370. Step B. 5- (3-Fluoro-benzyloxy) -8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole. The title compound was prepared by the method of Example 3, Step B, using the ethyl N-carbamate-5- (3-fluoro-benzyloxy) -8-methyl-1, 2,3,3a, 8,8a- hexahydro-indene- [1, 2-c] -pyrrole (0.1 mmol). The crude product was purified by reverse phase liquid chromatography to provide the title compound. MS calculated for Ci9H20FNO + H: 298; Observed: 298. EXAMPLE 46 5- (4-f lu oro-be nciloxi) -8-meti 1-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] - pyrrole Step A. Ethyl N-carbamate-5- (4-fluoro-benzyloxy) -8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole . (Scheme 1). The subtitle compound was prepared by the method of Example 43, Step B, using the N-carbamate of ethyl-5-hydroxy-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1, 2-c] -pyrrole (from Example 43, Step A) (0.1 mmol) and 4-fluoro-benzyl bromide. The crude product was obtained without further purification. MS calculated for C22H24F O3 + H: 370; observed: 370. Step B. 5- (4-Fluoro-benzyloxy) -8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole. The title compound was prepared by the method of Example 3, Step B, using the ethyl N-carbamate-5- (4-fluoro-benzyloxy) -8-methyl-1, 2,3,3a, 8,8a- hexahydro-indene- [1, 2-c] -pyrrole (0.1 mmol). The crude product was purified by reverse phase liquid chromatography to provide the title compound. MS calculated for C 9 H 20 FNO + H: 298; observed: 298. EXAMPLE 47 5- (2,6-difluoro-phenyl) -8-methyl-1,2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole Step A. Ethyl N-carbamate-5-triflate-8-methyl-1, 2, 3, 3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole. (Scheme 1). Pyridine (0.9 milliliters, 1.08 millimoles) and trifluoro-methanesulfonic anhydride (0.12 milliliters, 0.72 millimoles) were added to a solution of ethyl N-carbamate-5-hydroxy-8-methyl-1, 2, 3, 3a , 8,8a-hexahydro-indene- [1,2-c] -pyrrole (from Example 43, Step A) (94 milligrams, 0.36 millimoles) in CH 2 Cl 2 (4 milliliters) at 0 ° C. The reaction solution was stirred for 2 hours from 0 ° C to room temperature, and then diluted with CH 2 Cl 2. The crude product was washed with aqueous HCl (1M), saturated aqueous NaHCO3, and brine. The organic extracts were dried over MgSO4 and concentrated to provide 52 milligrams (58 percent) of the subtitle compound. MS calculated for C 16 H 18 F 3 N 0 5 S + H: 394; observed: 394. Step B. Ethyl-N-carbamate-5- (2,6-difluoro-phenyl) -8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1, 2-c] -pyrrole. 2,6-difluoro-phenyl boronic acid (41 milligrams, 0.26 millimoles), Pd (dppf) (5 milligrams), and Et3N (0.2 milliliters), were added to a solution of ethyl N-carbamate-5-triflate- 8-methyl-1, 2, 3, 3a, 8,8a-exa-hydro-indene- [1,2-c] -pyrrole (52 milligrams, 0.13 millimoles) in DME (2.6 milliliters), and stirred during the night at 90 ° C. The solution was cooled to room temperature, partitioned between CH2Cl2 and H20, and filtered through an Extrelut column. The column was washed with CH2Cl2, and the filtrate was concentrated. The crude product was obtained without further purification. MS calculated for C2i H21 F2N02 + H: 358; observed: 358. Step C. 5- (2,6-difluoro-phenyl) -8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole . The title compound was prepared by the method of Example 2, Step B, using the ethyl N-carbamate-5- (2,6-difluoro-phenyl) -8-methyl-1, 2,3,3a, 8, 8a-hexahydro-indene- [1, 2-c] -pyrrole (0.1 mmol). The crude product was purified by reverse phase liquid chromatography to provide the title compound.

MS calculated for C18H17F2N + H: 286; observed: 286. EXAMPLE 48 5-methoxy-8-ethyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole Step A. 2-Benzyl-5-methoxy-8-ethylene-1, 2,3,3a, 8,8a-hexahydro-indene- [1,2-c] -pyrrole. (Scheme 1). Ethyl-triphenyl-phosphonium bromide (0.6 grams, 1.6 mmol) and potassium terbutoxide (0.18 grams, 1.6 mmol) were added to a solution of 2-benzyl-5-methoxy-2,3,3a, 8a-tetrah dro-1? -2-aza-cyclopenta [a] inden-8-one (from Example 1, Step C) (0.32 grams, 1.1 mmol) in anhydrous ether (2.2 milliliters). The reaction mixture was stirred for 1 hour at room temperature, and then filtered through Celite. The Celite was washed with ether (10 milliliters), and the filtrate was concentrated. The crude product was purified by column chromatography (Si02) using a gradient of 0 to 35 percent EtOAc-hexanes, to provide the subtitle compound in a quantitative yield. MS calculated for C21H23NO + H: 306; observed: 306. Step B. 5-methoxy-8-ethyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole. Ammonium (0.3 grams) and palladium (10 percent by weight on activated carbon, 0.3 grams) were added to a solution of 2-benzyl-5-methoxy-8-ethylene-1, 2.3.3a, 8,8a-hexahydro-indene- [1,2-cJ-pyrrole (0.34 grams, 1.1 mmol) in eOH (5 milliliters). The reaction mixture was stirred for 4 hours at 60 ° C, and then filtered through Celite. The Celite was washed with MeOH (20 milliliters), and the filtrate was concentrated. The crude product was purified by reverse phase liquid chromatography to provide the title compound. 1 H NMR (d 6 -DMSO 300 MHz) d 7.05 (d, 1 H), 6.75 (m, 2 H), 3.69 (s, 3 H), 3.58 (m, 1 H), 3.28 (m, 1 H), 3.05 (m, 1 H) ), 2.90 (m, 3H), 2.31 (m, 1H), 2.05 (m, 1H), 1.28 (m, 1H), 1.05 (t, 3H) ppm. MS calculated for C 14 H 19 NO + H: 218; observed: 218. Example 49 5-hydroxy-8-ethyl-1, 2, 3, 3a, 8, 8a-hexa-hic.ro -i n den o- [1, 2-c] -pyrrole Step A. Ethyl N-carbamate-5-methoxy-8-ethyl-1, 2, 3, 3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole. (Scheme 1). Ethyl chloroformate (0.16 milliliters, 1.65 millimoles) was added to a solution of 5-methoxy-8-ethyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] - pyrrole (from Example 48, Step B) (0.24 grams, 1.1 mmol) in CH2Cl2 (6 milliliters) at 0 ° C. The resulting solution was stirred overnight at room temperature. The reaction mixture was quenched with an aqueous solution of HCl (20 milliliters, 1.0 M), and the product was extracted with EtOAc (10 milliliters, 3 times). The combined organic extracts were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (SiO2) using a gradient of 0 to 35 percent EtOAc-hexanes, to provide 40 milligrams (13 percent) of the subtitle compound. MS calculated for C 17 H 23 NO 3 + H: 290; observed: 290. Step B. 5-Hydroxy-8-ethyl-1, 2,3,3a, 8,8a-hexahydro-indene- [1,2-c] -pyrrole. The title compound was prepared by the method of Example 2, Step B, using the ethyl N-carbamate-5-hydroxy-8-ethyl-1, 2,3,3a, 8,8a-hexahydro-indene- [, 2-c] -pyrrole (0.07 mmol). The crude product was purified by reverse phase liquid chromatography to provide the title compound. 1 H NMR (d 6 -DMSO 300 MHz) d 6.98 (d, 1 H), 6.59 (m, 2 H), 3.68 (m, 1 H), 3.44 (m, 1 H), 3.05 (m, 4 H), 2.45 (m, 1 H) ), 1.98 (m, 1H), 1.25 (m, 1H), 1.05 (t, 3H) ppm. MS calculated for C 13 H 17 NO + H: 204; observed: 204. Example 50 5,6- (2- (3-methyl) -furan) -8-methyl-1, 2,3,3a, 8,8a-hexahydro-indene- [1,2-c ] -pyrrol Step A. Ethyl N-carbamate-5-methoxy-6-iodo-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c] -pyrrole. (Scheme 1). Icl (0.12 grams, 0.72 millimoles) and CaCO3 (72 milligrams, 0.72 millimoles) were added to a solution of ethyl N-carbamate-5-methoxy-8-methyl-1 ^ .S.Sa.e.e. hexahydro-indene-II ^ -cl-pyrrole (from Example 2, Step A) (0.1 grams, 0.36 mmol) in MeOH (3.6 milliliters), and stirred overnight at room temperature. The reaction mixture was filtered through Celite, the Celite was washed with MeOH, and the filtrate was concentrated. The crude material was dissolved in EtOAc, and washed with aqueous sodium bisulfite (5 percent solution) and brine. The organic extracts were dried over MgSO4 and brine. The crude product was purified by a plug of silica, eluting with hexanes / EtOAc (3/1, volume / volume), to give 0.14 grams (97 percent) of the subtitle compound. MS calculated for Ci6H2olN03 + H: 402; observed: 402. Step B. Ethyl-N-carbamate-5-hydroxy-6-iodo-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1,2-c ] -pyrrole. BBr3 (0.7 milliliters, 0.7 mmol, 1 M in CH2Cl2) was added to a solution of ethyl N-carbamate-5-methoxy-6-iodo-8-methyl-1, 2,3,3a, 8,8a-hexa -hydro-indene- [1, 2-c] -pyrrole (120 milligrams, 0.3 mmol) at 0 ° C. The reaction mixture was stirred overnight from 0 ° C to room temperature, and quenched with H20. The solution was filtered through an Extrelut column, the column was washed with CH2Cl2, and the filtrate was concentrated. The crude product was obtained without further purification. MS calculated for Ci5H18IN03 + H: 388; observed: 388. Step C. Ethyl-5-allyloxy-6-iodo-8-methyl-1, 2,3,3a, 8,8a-hexahydro-indene- [1, 2-N-carbamate] c] -pyrrole. Allyl bromide (52 microliters, 0.6 mmol) and DBU (65 microliters, 0.6 mmol) were added to a solution of ethyl N-carbamate-5-hydroxy-6-iodo-8-ethyl-1, 2.3.3a , 8,8a-hexahydro-indene- [1,2-c] -pyrrole (116 milligrams, 0.3 mmol) in CH 2 Cl 2 (3 milliliters), and stirred for 2 hours at room temperature. The reaction solution was diluted with H20 and filtered through an Extrelut column. The column was washed with CH2Cl2, and the filtrate was concentrated. The crude product was purified by a plug of silica, eluting with hexanes / EtOAc (3/1, volume / volume), to provide 50 milligrams (39 percent - two steps) of the subtitle compound. MS calculated for C18H22IN03 + H: 428; observed: 428. Step D. N-ethyl carbamate-5,6- (2- (3-methyl) -furan) -8-methyl-1, 2,3,3a, 8,8a-hexa-h id ro -indeno- [1, 2-c] -pirro I. KOAc (40 milligrams, 0.36 millimoles), nBu4NBr (50 milligrams, 0.12 millimoles), PPh3 (3 milligrams, 0.1 millimoles), and Pd (OAc) 2 were added ( 2 milligrams, 6 micromoles) to a solution of Nica rba mato of ethyl-5-allyloxy-6-iodo-8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1, 2 -c] -pyrrole (50 milligrams, 0.12 mmol) in dimethyl formamide (1 milliliter), and stirred overnight at 100 ° C. The reaction solution was diluted with H20 and CH2Cl2, and filtered through an Extrelut column. The column was washed with CH2Cl2, and the filtrate was concentrated. The crude product was obtained without further purification. MS calculated for Ci8H2iN03 + H: 300; observed: 300. Step E. 5,6- (2- (3-methyl) -furan) -8-methyl-1, 2,3,3a, 8,8a-hexa-hydro-indene- [1, 2- c] -pyrrole. The title compound was prepared by the method of Example 3, Step B, using the ethyl N-carbamate-5,6- (2- (3-methyl) -furan) -8-methyl-1,2,3, 3a, 8,8a-hexahydro-indene- [1, 2-c] -pyrrole (0.1 mmol). The crude product was purified by reverse phase liquid chromatography to provide the title compound. MS calculated for C15H170NO + H: 228; observed: 228. Example 51 5-methoxy-2,3,3a, 8a-tetrahydro-1 H-2-aza-cyclopenta [a] inden-8-one The title compound was prepared by the method of Example 1, Step E, using 2-benzyl-5-methoxy-2,3,3a, 8a-tetrahydro-1 H-2-aza-cyclopenta [a] inden-8 -one (from Example 1, Step C) (2.1 mmol). The crude product was purified by reverse phase liquid chromatography to provide the title compound. 1 H NMR (ds-DMSO 300 MHz) d 7.48 (d, 1 H), 7.12 (d, 1 H), 6.95 (dd, 1 H), 3.87 (s, 3 H), 3.72 (m, 1 H), 2.98 (m, 4 H) ), 2.81 (m, 1H) ppm. MS calculated for C12H13N02 + H: 204, observed: 204. EXAMPLE 52 4-Chloro-5-methoxy-2,3,3a, 8a-tetrahydro-1 H-2-aza-cyclopenta [a] -inden-8-one Step A. Ethyl N-carbamate-5-methoxy-2,3,3a, 8a-tetrahydro-1 H-2-aza-cyclopenta [a] inden-8-one. (Scheme 1). Ethyl chloroformate (0.18 milliliters, 1.9 millimoles) and DIEA (1.0 milliliters, 5.7 millimoles) were added to a solution of 5-methoxy-2,3,3a, 8a-tetrahydro-1 H-2-aza-cyclopenta [a ] inden-8-one (from Example 51) (0.38 grams, 1.9 mmol) in CH2Cl2 (10 milliliters) at 0 ° C, and stirred overnight at room temperature. The reaction was quenched with aqueous HCl (1M), and washed with brine. The organic extracts were dried over MgSO4, and concentrated. The crude product was obtained without further purification. MS calculated for Ci5H17N04 + H: 276, observed: 276. Step B. N-carbamate ethyl-4-chloro-5-methoxy-2,3,3a, 8a-tetra h id ro-1? -2-aza- Penta [a] inden -8-one cycle. NCS (0.25 grams, 1.9 mmol) and acetic acid (10 milliliters) were added to a solution of ethyl carbamate-5-methoxy-2,3,3a, 8a-tetrahydro-1 H-2-aza-cyclopenta [a] inden-8-one (0.52 grams, 1.9 mmol) in dichloro-ethane (10 milliliters), and stirred overnight at 60 ° C. The reaction was quenched with aqueous HCl (1M), and washed with brine. The organic extracts were dried over MgSO4, and concentrated. The crude product was purified by column chromatography (Si02) using a gradient of 0 to 60 percent EtOAc-hexanes, to give the subtitle compound as a mixture of regioisomers. MS calculated for C15hi6clno4 + H 310, observed: 310. Step C. 4-Chloro-5-methoxy-2,3,3a, 8a-tetrahydro-1α-2-aza-cyclopenta [a] inden-8-one. The subtitle compound was prepared by the method of Example 2, Step B, using the ethyl N-carbamate-4-chloro-5-methoxy-2,3,3a, 8a-tetrahydro-1 H-2-aza-cyclopenta [a] inden-8-one (0.32 mmol). The crude product was obtained without further purification as a mixture of regioisomers. MS calculated for C12H 2CIN02 + H: 238, found: 238. Step D. N-Terbutyl-carbamate-4-chloro-5-methoxy-2,3,3a, 8a-tetrahydro-1 H-2-aza-cyclopenta [ a] inden-8-one. The subtitle compound was prepared by the method of Example 20, Step G, using 4-chloro-5-methoxy-2,3,3a, 8a-tetrahydro-1 H-2-aza-cyclopenta [a] inden-8-one (1.02 mmol). The crude product was purified and separated by column chromatography (SiO2) using a gradient of 0 to 60 percent EtOAc-hexanes, to give the subtitle compound and its regioisomer, N-carbutyl-5-methoxy-methoxy -chloro-2,3,3a, 8a-tetrahydro-H-2-aza-cyclopenta [a] inden-8-one. MS calculated for C17H2oCIN04 + H: 338, observed: 338. Step E. 4-Chloro-5-methoxy-2,3,3a, 8a-tetrahydro-1α-2-aza-cyclopenta [a] inden-8-one . The title compound was prepared by the method of Example 20, Step I, using the tert-butyl N-carbamate-4-chloro-5-methoxy-2,3,3a, 8a-tetrahydro-1 H-2-aza-cyclopenta [a] inden-8-one (0.10 millimoles). The crude product was purified by reverse phase liquid chromatography to provide the title compound. 1 H NMR (de-DMSO 300 MHz) d 7.70 (d, 1 H), 7.47 (d, 1 H), 4.18 (m, 1 H), 4.00 (s, 3 H), 3.65 (m, 2 H), 3.58 (m, 2 H) ), 3.45 (m, 1H) ppm. S calculated for Ci2H12CIN02 + H: 238, observed: 238. Example 53 5-methoxy-6-chloro-2,3,3a, 8a-tetrahydro-1? -2-aza-cyclopenta [a] inden-8- ona The title compound was prepared by the method of Example 20, Step I, using the tert-butyl N-carbamate-5-methoxy-6-chloro-2,3,3a, 8a-tetrahydro-1 H-2-aza-cyclopenta [a] inden-8-one (from Example 52, Step D) (0.10 mmol). The crude product was purified by reverse phase liquid chromatography to provide the title compound. MS calculated for Ci2H12CIN02 + H: 238, observed: 238. Example 54 4-Chloro-5-methoxy-2,3,3a, 8a-tetrahydro-1α-2-aza-cyclopenta [a] inden-8-ol Step A. Terbutyl N-carbamate-4-chloro-5-methoxy-2,3,3a, 8a tetrahydro-1 H-2-aza-cyclopenta [a] inden-8-ol. (Scheme 1).

NaBH4 (4 milligrams, 0.1 mmol) was added to a solution of tert-butyl N-carbamate-4-chloro-5-methoxy-2,3,3a, 8a-tetrahydro-1 H-2-aza-cyclopenta [a] inden -8-one (from Example 52, Step D) (20 milligrams, 0.06 mmol) in MeOH (2 milliliters), and stirred for 1 hour at room temperature. The reaction was partitioned between H20 and CH2Cl2, and filtered through an Extrelut column. The column was washed with CH2Cl2, and the filtrate was concentrated. The crude product was obtained without further purification as a mixture of diastereomers. MS calculated for C17H22CIN04 + H: 340, observed: 340. Step B. 4-Chloro-5-methoxy-2,3,3a, 8a-tetrahydro-1? -2-aza-cyclopenta [a] inden-8-ol . The title compound was prepared by the method of Example 20, Step I, using the tert-butyl N-carbamate-4-chloro-5-methoxy-2,3,3a, 8a-tetrahydro-1 H-2-aza-cyclopenta [a] inden-8-ol (0.10 mmol). The crude product was purified by reverse phase liquid chromatography to provide the title compound. MS calculated for C12H12CIN02 + H: 240, observed: 240. Example 55 5-methoxy-6-chloro-2,3,3a, 8a-tetrahydro-1? -2-aza-cyclopenta [a] inden-8- ol Step A. Terbutyl N-carbamate-5-methoxy-6-chloro-2,3,3a, 8a-tetrahydro-1 H-2-aza-cyclopenta [a] inden-8-ol. NaBH4 (4 milligrams, 0.1 mmol) was added to a solution of tert-butyl N-carbamate-5-methoxy-6-chloro-2,3,3a, 8a-tetrahydro-1 H-2-aza-cyclopenta [a] inden -8-one (from Example 52, Step D, regioisomer) (20 milligrams, 0.06 mmol) in eOH (2 milliliters), and stirred for 1 hour at room temperature. The reaction was partitioned between H20 and CH2Cl2, and filtered through an Extrelut column. The column was washed with CH2Cl2, and the filtrate was concentrated. The crude product was obtained without further purification as a mixture of diastereomers. MS calculated for C17H22CIN04 + H: 340, observed: 340. Step B. 5-methoxy-6-chloro-2,3,3a, 8a-tetrahydro-1? -2-aza-cyclopenta [a] inden-8-ol . The title compound was prepared by the method of Example 20, Step I, using the tert-butyl N-carbamate-4-chloro-5-methoxy-2,3,3a, 8a-tetrahydro-1 H-2-aza-cyclopenta [a] inden-8-ol (0.10 mmol). The crude product was purified by reverse phase liquid chromatography to provide the title compound. MS calculated for C12H12CIN02 + H: 240, observed: 240. Example 56 Separation of Enantiomers for the Selected Compounds of the Invention. The following compounds were separated into their respective enantiomers using a Chiral Pak AD-RH chiral column of 10 millimeters x 250 millimeters.

The following procedure was used to evaluate the representative compounds of the present invention as 5HT2c receptor agonists. The results of this assay are stipulated in Table 1. Cell Culture HEK 293 EBNA cells expressing the human 5HT2c receptor (VSV isoform, Burns et al., NATURE 387: 30308, 1997) were cultured in DMEM containing 10% dialyzed fetal bovine serum. percent, 9 micrograms / milliliter of blasticidin, at 37 ° C in an atmosphere with 5 percent C02.

Mobilization of Calcium HEK 293 EBNA cells expressing the human 5HT2c receptor (2x10 / well) were seeded in 384-well black collagen-coated plates and incubated overnight at 37 ° C in an atmosphere of 5% C02. / 95 percent. After removing the medium, the cells were treated with HBSS regulator (137 mM NaCl, 5.4 mM KCI, 5.5 mM glucose, 20 mM Hepes, pH 7.5, MgCl22.1 mM, 0.3 mM CaCl, MgSO40.02 mM, NaHCO3. 0 mM, and KH2P040.64 mM) containing the dye Calcium3 (Molecular Device, CA), probenecid 2.5 mM, and pluronic acid 0.08 percent, for 60 minutes, according to the manufacturer's instructions. Compounds that were solubilized in 100 percent dimethyl sulfoxide were diluted in Ringers CsCI buffer (CsCI 58.3 mM, 5.4 mM KCI, 5.5 mM glucose, 20 mM Hepes, pH 7.5, 2.1 mM MgCl2, 1.2 mM CaCl2), such that the final dimethyl sulfoxide concentration did not exceed 5 percent. 5HT was used as a positive control. Ligand-induced calcium release and consequent fluorescence were measured in a Fluorometric Imaging Plate Reader Reader (FLIPR, Molecular Device, CA). Data Analysis All data were analyzed by non-linear least squares curve fitting using the Prism 4.0 software. The stimulus of the calcium-induced fluorescence agonist in FLIPR was adjusted to the response to the sigmoidal dose using the equation Y = Background + (Upper Part-Background) / (1 + 10A ((LogEC50-X))), where X is the logarithm of the concentration of the compounds, and Y is the fluorescent response.

Example 5-HT2C EC50 Molecule Number (hVSV, μ?) , Enantiomer 2 < 0.1 , Enantiomer 2 > 10 , Enantiomer 2 < 1 , Enantiomer 1 < 1, Enantiomer 2 < 1 , Enantiomer 1 < 0.1, Enantiomer 2 < 0.1

Claims (5)

1. A compound of the formula: wherein: Ri is selected from the group consisting of H, halogen, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, perhaloalkyl, CN, N (R6) 2, SR6, CON (R6) 2, NR6COR7, NR6C02R7, S02N (R6) 2, NR6S02R7, aryl, heteroaryl, alkyl of 1 to 10 carbon atoms-aryl, and alkyl of 1 to 10 atoms carbon-heteroaryl; and when m + n = 1, R can also be OR6 or OCOR7; R2, R3, and R4 are independently selected from the group consisting of H, halogen, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, per-halo -alkyl, CN, OR6, N (R6) 2, SR6, OCOR7, CON (R6) 2, NR6COR7, NR6C02R7, S02N (R6) 2, NR6S02R7, aryl, heteroaryl, alkyl of 1 to 10 carbon atoms-aryl, and alkyl of 1 to 10 carbon atoms-heteroaryl, or R2 and R3, together with the ring to which they are attached, form a carbocyclic or heterocyclic ring of 5 to 7 members; R5 is selected from the group consisting of H, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, per-haloalkyl, CN, QR6, N (Re) 2, SR6, OCOR7, CON (R6) 2, NR6COR7, NR6C02R7, NR6S02R7, aryl, heteroaryl, alkyl of 1 to 10 carbon atoms-aryl, and alkyl of 1 to 10 carbon atoms-heteroaryl, or R4 and R5, together with the ring to which they are attached, form an aryl or heteroaryl ring of 6 to 8 members; R5a is H; or R5 and R5a, taken together, form a cyclopropane ring; R6 is selected from the group consisting of H, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, perhaloalkyl, alkyl of 1 to 10 carbon atoms-O-alkyl of 1 to 10 carbon atoms, aryl, heteroaryl, alkyl of 1 to 10 carbon atoms-O-aryl, alkyl of 1 to 10 carbon atoms-O-heteroaryl, alkyl of 1 to 10 carbon-aryl atoms, and alkyl of 1 to 10 carbon atoms-heteroaryl; and R7 is selected from the group consisting of alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, perhaloalkyl, alkyl of 1 to 10 atoms carbon-O-alkyl of 1 to 10 carbon atoms, aryl, heteroaryl, alkyl of 1 to 10 carbon atoms-O-aryl, alkyl of 1 to 10 carbon atoms-O-heteroaryl, alkyl of 1 to 10 atoms carbon-aryl, and alkyl of 1 to 10 carbon atoms-heteroaryl; with the understanding that, if R i, R 2, R s, and R a are H, then R 3 and / or R 4 must be H, and pharmaceutically acceptable salts thereof.

2. A compound as in claim 1, wherein Ri is alkyl of 1 to 5 carbon atoms, halogen, CF3, aryl, heteroaryl, or H; R2, R3, and R are independently alkyl of 1 to 5 carbon atoms, -0-R6, halogen, CF3, aryl, heteroaryl, or H; or R2 and R

3. together with the ring to which they are attached, they form an aryl or heteroaryl ring of 5 to 7 members; R5 is alkyl of 1 to 5 carbon atoms, -OR6, or alkene of 2 to 6 carbon atoms; and R6 is alkyl of 1 to 5 carbon atoms or H. 3. A compound as in claim 1, selected from the group consisting of: 5-methoxy-8-methyl-1, 2,3,3a, 8 , 8a-hexahydro-indene- [1,2-c] -pyrrole; 5-hydroxy-8-methyl-1, 2,3,3a, 8,8a-hexahydro-indene- [1,2-c] -pyrrole; 5-methoxy-6-chloro-8-methyl-1, 2,3,3a, 8,8a-hexahydro-indene- [1,2-c] -pyrrole; 5-hydroxy-6-chloro-8-methyl-1, 2,3,3a, 8,8a-hexahydro-indene- [1,2-cl-pyrrole; 6-chloro-8-methyl-1, 2,3,3a, 8,8a-hexahydro-indene- [1,2-c] -pyrrole; 5- (4-Fluoro-benzyloxy) -6-chloro-8-methyl-1, 2,3,3a, 8,8a-hexahydro-indene- [1,2-c] -pyrrole; 5-benzyloxy-6-chloro-8-methyl-1, 2,3,3a, 8,8a-hexahydro-indene- [1,2-c] -pyrrole; 5- (2-Fluoro-benzyloxy) -6-chloro-8-methyl-1, 2,3,3a, 8,8a-hexahydro-ndeno- [1,2-c] -pyrrole; 5- (3-Fluoro-benzyloxy) -6-chloro-8-methyl-1, 2,3,3a, 8,8a-hexahydro-indene- [1,2-c] -pyrrole; 1,2,3,3a, 8,8a-hexahydro-ndene- [1,2-c] -pyrrolidone; 6-chloro-1,2,3,3a, 8,8a-hexahydro-enane- [1,2-c] -pyrrolidone; 6,7-dichloro-8-methyl-1, 2,3,3a, 8,8a-hexahydro-indene- [1,2-c] -pyrrole; 4,5-dimethoxy-6-chloro-8-methyl-1, 2,3,3a, 8,8a-hexahydro-indene- [1,2-c] -pyrrole; 4,6-dichloro-5-methoxy-8-methyl-1, 2,3,3a, 8,8a-hexahydro-indene- [1,2-c] -pyrrole; and 6- (2,6-difluoro-phenyl) -1,2,3,3a, 8,8a-hexahydro-indene- [1,2-c] -pyrrole.

4. A pharmaceutical composition, which comprises at least one compound of claim 1, and a pharmaceutically acceptable carrier.

5. A method for the treatment of a disease, disorder, and / or condition in a patient in which the modulation of a 5-HT2c function is desired, which comprises administering an effective amount of at least one compound of the claim 1, to a patient in need of such treatment.