MXPA00006575A

MXPA00006575A - Aryl fused azapolycyclic compounds

Info

Publication number: MXPA00006575A
Application number: MXPA/A/2000/006575A
Authority: MX
Inventors: Jotham Wadsworth Coe; Paige Roanne Palmer Brooks
Original assignee: Paige Roanne Palmer Brooks; Jotham Wadsworth Coe; Pfizer Products Inc
Priority date: 1997-12-31
Filing date: 2000-06-30
Publication date: 2001-06-26

Abstract

Compounds of formula (I) and their pharmaceutically acceptable salts, wherein R1, R2, R3 and n are defined as in the specification, intermediates in the synthesis of such compounds, pharmaceutical compositions containing such compounds and methods of using such compounds in the treatment of neurological and psychological disorders are claimed.

Description

COMPOUNDS AZAPOLICICL1COS CONDENSADOS CON ARILO BACKGROUND OF THE INVENTION This invention relates to azapolyclic compounds fused with aryl, as more specifically defined by formula I shown below. The compounds of formula I bind to specific nicotinic acetylcholine receptor sites present in neurons and are useful for modulating cholinergic function. Such compounds are useful in the treatment of inflammatory bowel disease (including, but not limited to, ulcerative colitis, pyoderma gangrenosum and Crohn's disease), irritable bowel syndrome, spastic dystonia, chronic pain, acute pain, sprue celiac, bursitis, vasoconstriction, anxiety, panic disorders, depression, bipolar disorder, autism, sleep disorders, time dsfase, amyotrophic lateral sclerosis (ALS), cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac arrhythmias, acid hypersecretion gastric, ulcers, pheochromocytoma, progressive supra-muscular paralysis, chemical dependencies and addictions (for example, dependence or additions to nicotine (and / or tobacco products), alcohol, benzodiazepines, barbiturates, opiates or cocaine ), cefalalgias, apoplexy, traumatic brain injury (TBI), obesity-compulsive disorder, psychosis, Huntington's Korea, d tardive iskkinesia, hyperkinesia, dyslexia, schizophrenia, multi-infarct dementia, age-related cognitive decline, epilepsy, including minor or minor epilepsy, senile dementia of Alzheimer's type (AD), Parkinson's disease (PD), hyperactivity disorder with attention deficit (ADHD) and Tourette's syndrome. The compounds of this invention can also be used in combination with an antidepressant, such as, for example, a tricyclic antidepressant or a selective serotonin reuptake inhibitor (SRI) antidepressant, to treat both cognitive decline and depression associated with AD, PD , stroke, Huntington's disease or traumatic brain injury (TBI); in combination with muscarinic agonists to stimulate central muscarinic and nicotinic receptors for the treatment, for example, of ALS, cognitive dysfunction, cognitive decline related to age, AD, PD, stroke, Huntington's disease, and TBI; in combination with neurotrophic factors, such as NGF to maximize cholinergic activation for the treatment, for example, of ALS, cognitive dysfunction, cognitive decline related to age, AD, PD, stroke, Huntington's disease and TBI; or in combination with agents that slow or stop AD, such as cognition enhancers, amyloid aggregation inhibitors, secretase inhibitors, tau kinase inhibitors, neuronal anti-inflammatory agents and therapy with estrogen-like agents. In the United States Patent Application 08 / 963,852 which was filed on November 4, 1997, other compounds that bind to nicotinic receptor sites of the neurons are mentioned. The above request belongs to the same owner as the present application and is presented here by reference in its entirety.

BRIEF DESCRIPTION OF THE INVENTION This invention relates to azapolycyclic compounds fused with aryl of the formula: wherein: R1 is hydrogen, (C? -C6) alkyl, unconjugated (C3-Ce) alkenyl, benzyl, XC (= O) R13 or -CH2CH2-O-alkyl (d-C4); R2 and R3 is independently selected from hydrogen, alkenyl, (C2-C6) alkenyl, (C2-C6) alkynyl, hydroxy, nitro, amino, halo, cyano, -SOq-alkyl (C? -C6), where is zero, one or two, alkylamino (C? -C6) -, [(C, -C6) alkyl] 2 amino-, -CO2R4, -CONR5R6, -SO2NR7R8, -C (= O) R13, -XC (= O ) R13, aryl-alkyl (Co-C3) - or aryl-alkyl (C0-C3) -O-, wherein said aryl is selected from phenyl and naphthyl, heteroaryl-(C0-C3) alkyl- or heteroaryl-alkyl (C0) -C3) -O-, wherein said heteroaryl is selected from aromatic rings of five to seven members containing from one to four heteroatoms selected from oxygen, nitrogen and sulfur, and X2- (C0-C6) alkyl- and X2alkoxy (C6-6) -alkyl (C0-Ce), where X2 is absent or X2 is alkylamino (C6C6) - or [alkyl ( C? - and where the alkyl (Co-C6) - or (C? -C6) -alkoxy (C0-C6) -alkyl- of said X2- (C0-C6) alkyl- and X2alkoxy (C? -C6) - alkyl (Co-C6) - contains at least one carbon atom, and where from one to three of the carbon atoms of said alkyl portions (C0-C6) - or (C? -C6) alkoxy-alkyl (Co-C6) ) - can optionally be replaced by an oxygen, nitrogen or sulfur atom, with the proviso that any two of such heteroatoms have to be separated by at least two carbon atoms, and where any of the alkyl portions of said alkyl (C0- C6.- or (C -? - C6) -alkoxy (C0-C6) alkoxy - may optionally be substituted with two to seven fluorine atoms, and where one of the carbon atoms of each of the alkyl portions of said aryl-alkyl (Co-C3) and said heteroaryl-alkyl (Co-C3) can optionally be replaced by an at as oxygen, nitrogen or sulfur, and wherein each of the above aryl and heteroaryl groups may be optionally substituted with one or more substituents, preferably from zero to two substituents, independently selected from (C? -C6) alkyl optionally substituted with one to seven fluorine atoms, optionally substituted with two to seven fluorine atoms, halo (for example chlorine, fluorine, bromine or iodine), alkenyl (C2-C6), alkynyl (C2-C6), hydroxy, nitro, cyano, amino alkylaminoCi-Cß), [(C 1 -C 6) alkyl] 2 amino-, -CO 2 R 4, -CONR 5 R 6, -SO 2 NR 7 R 8, -C (= O) R 13 and -XC (= O) R 13; or R2 and R3, together with the carbons to which they are attached, form a monocyclic carbocyclic ring of four to seven members, or a bicyclic carbocyclic ring of ten to fourteen members, which may be saturated or unsaturated, where from one to three of the non-condensed carbon atoms of said monocyclic rings, and from one to five of the carbon atoms of said bicyclic rings, which are not part of the benzene ring shown in formula I, can be optionally and independently replaced by a nitrogen, oxygen or sulfur, and wherein said monocyclic and bicyclic rings may be optionally substituted with one or more substituents, preferably from zero to two substituents in the case of the monocyclic rings and from zero to three substituents in the case of the bicyclic rings, which are select, independently, between alkyl (Co-C6) - or (C? -C6) alkoxy-alkyl (Co-C6) -, where the total number of carbon atoms does not exceed six and wherein any of the alkyl portions may be optionally substituted with one to seven fluorine, nitro, oxo, cyano, halo, (C2-C6) alkenyl, (C2-C6) alkynyl, hydroxy, amino, alkylaminoC C) -, [ alkyl (C? -C6)] 2 amino-, -CO2R4, -CONR5R6, -SO2NR7R8, -C (= O) R13 and -XC (= O) R13; each of R4, R5, R6, R7, R8 and R13 are independently selected from hydrogen and alkyl (C? -C6), or R5 and R6, or R7 and R8 together with the nitrogen to which they are attached, form a pyrrolidine, piperidine, morpholine, azetidine, piperizine, -N-alkyl (C? -C6) piperizine or thiomorpholine ring, or a thiomorpholine ring, where the ring sulfur is replaced with a sulfoxide or sulfone; and each X is, independently, alkylene (C? -C6); with the proviso that: (a) at least one of R1, R2 and R3 must be other than hydrogen, and (b) when R2 and R3 are hydrogen, R1 can not be hydrogen, alkyl (C? -C6) or (C3-C6) non-conjugated alkenyl; and pharmaceutically acceptable salts of such compounds. Examples of heteroaryl groups which may be each of R2 and R3 are the following: thienyl, oxazoyl, isoxazolyl, pyridyl, pyrimidyl, thiazolyl, tetrazolyl, isothiazolyl, triazolyl, imidazolyl, tetrazolyl, pyrrolyl and the following groups: wherein one of R9 and R18 is hydrogen or (C -? - C6) alkyl, and the other is a bond to the benzene ring of formula I. Examples of compounds of this invention are compounds of formula I and their pharmaceutically acceptable salts, wherein R2 and R3, together with the benzene ring of formula I, form a bicyclic ring system selected from the following: where R10 and R17 are independently selected from alkyl (Co-C6) - and alkoxy (C? -C6) -alkyl (Co-C6) -, where the total number of carbon atoms does not exceed six and where any of the alkyl portions may be optionally substituted with one to seven fluorine atoms, nitro, cyano, halo, amino, alkylamino (d-Ce), [alkyi-Ce-amino-, -CO2R4, -CONR5R6, -SO2NR7R8, -C (= O) R13, -XC (= O) R13, phenyl and monocyclic heteroaryl, wherein said heteroaryl is defined as R2 and R3 in the definition of the compounds of the formula I indicated above. Other embodiments of this invention relate to compounds of formula I and their pharmaceutically acceptable salts wherein R 2 and R 3, together with the benzene ring of formula I, form a bicyclic or tricyclic ring system selected from the following: where R10 and R17 are defined as indicated above and m is zero, one or two, and wherein one of the carbon atoms of ring A can optionally be replaced with oxygen or -N-alkyl (C-C6). Other embodiments of this invention relate to compounds of formula I and their pharmaceutically acceptable salts, wherein neither R2 nor R3 are attached to the benzene ring of formula I by an oxygen atom. Other embodiments of this invention relate to compounds of formula I and their pharmaceutically acceptable salts, wherein R 2 and R 3 do not form a bicyclic or tricyclic ring system together with the benzene ring of formula I. Other embodiments of this invention are refer to compounds of formula I, wherein one or both of R2 and R3 is -C (= O) R13, where R13 is alkyl (C? -C6). Additional embodiments of this invention relate to compounds of the formula I, wherein one or both of R2 and R3 is -C (= O) R13, where R13 is (C? -C6) alkyl or (C? -C3) alkyl ) optionally substituted with one to seven fluorine atoms. Other embodiments refer to compounds of the formula I, wherein one of R2 and R3 is CF3, fluorine, cyano or C2Fs- Other embodiments of this invention refer to compounds of the formula I in which R1 is not methyl. Examples of specific compounds of the formula I are the following: 6-methyl-5,7-dioxo-6,13-diazatetracycle hydrochloride [9.3.1.02 10.04'8] pentadeca-2 (10), 3,8-triene; 6-methyl-5-oxo-6,13-diazatetracycle hydrochloride [9.3.1.02'10.04,8] pentadeca-2 (10), 3,8-triene; 5,7-dimethyl-6-oxo-5,7,13-triazatetracyclo hydrochloride [9.3.1.02-10.04,8] pentadeca-2 (10), 3,8-triene; ,7-dioxo-6,13-diazatetracyclo hydrochloride [9.3.1.02 10.04'8] pentadeca-2 (10), 3,8-triene; 5-oxo-6,13-diazatetracycle hydrochloride [9.3.1.02'10.04 8] pentadeca-2 (10), 3,8-triene; 6-oxo-5,7,13-diazatetracycle hydrochloride [9.3.1.02'10.04 8] pentadeca-2 (10), 3,8-triene; 4,5-difluoro-10-aza-tricyclo [6.3.1.02'7] dodeca-2 (7), 3,5-triene hydrochloride; 5-fluoro-10-aza-tricyclo [6.3.1.02-7] dodeca-2 (7), 3,5-triene-4-carbonitrile hydrochloride; 4-ethynyl-5-fluoro-10-aza-tricyclo [6.3.1.02,7] dodeca-2 (7), 3,5-triene hydrochloride; 5-ethynyl-10-aza-tricyclo [6.3.1.02'7] dodeca-2 (7), 3,5-triene-4-carbonitrile hydrochloride; 5-chloro-10-aza-tricyclo [6.3.1.02,7] dodeca-2 (7), 3,5-triene-4-carbonitrile hydrochloride; 4-ethynyl-5-chloro-10-aza-tricyclo [6.3.1.02'7] dodeca-2 (7), 3,5-triene hydrochloride; 5-oxa-7-methyl-6-oxo-7,13-diazatetracyclo [9.3.1.02 10.04'8] hydrochloride pentadeca-2 (10), 3,8-triene; 4-fluoro-5-trifluoromethyl-10-aza-tricyclohydrochloride [6.3.1.02'7] dodeca-2 (7), 3,5-triene; 4-chloro-5-trifluoromethyl-10-aza-tricyclohydrochloride [6.3.1.02'7] dodeca-2 (7), 3,5-triene; 5-trifluoromethyl-10-aza-tricyclo [6.3.1.02'7] dodeca-2 (7), 3,5-triene-4-carbonitrile hydrochloride; 4-ethynyl-5-trifluoromethyl-10-aza-tricyclohydrochloride [6.3.1.02,7] dodeca-2 (7), 3,5-triene; 6-methyl-5-thia-5-dioxa-6,13-diazatetracycle hydrochloride [9.3.1.02'10.048] pentadeca-2 (10), 3,8-trine; hydrochloric acid, 7-d-methylamine-5-thia-5-d-ioxa-6, 13-d-iazatetracyclo [9.3.1.02,10.04 8] pentadeca-2 (10), 3,8-triene; 6,7-dioxa-5,8,14-triazatetracyclo hydrochloride [10.3.1.02'11.04 9] hexadeca-2 (11), 3, 9-triene; and 5,8-dimethyl-6,7-dioxa-5,8,14-triazatetracyclochloride [10.3.1.02'11.0, 9] hexadeca-2 (1 1), 3,9-triene. This invention also relates to compounds of the formula wherein P is hydrogen, methyl, COOR16, where R16 is alkyl (C-i-Cß), allyl, 2,2,2-trichloroethyl or alkyl (C? -C6); -C (= O) NR5R6, where R5 and R6 are defined as in formula I above; -C (= O) H, -C (= O) -alkio (C? -C6), where the alkyl portion may be optionally substituted with 1 to 3 halo atoms, preferably with 1 to 3 fluorine or chlorine atoms; benzyl or t-butoxycarbonyl (t-Boc); and R14 and R15 are independently selected from hydrogen, (C? -C6) alkyl optionally substituted with one to seven fluorine atoms; -C (= O) -alkyl (C-i-Cß), cyano, hydroxy, nitro, amino, -O-alkyl (C? -C6) or halo; with the proviso that R14 and R15 can not both be hydrogen when P is hydrogen, (C? -C6) alkyl or (C3-C6) non-conjugated alkenyl. Such compounds are useful as intermediates in the synthesis of the compounds of formula I. The invention also relates to a compound of the formula: wherein R2 and R3 were defined above; and P 'is COOR16, where R16 is allyl, 2,2,2-trichloroethyl or alkyl (C6C6); -C (= O) NR5R6, where R5 and R6 are defined as in claim 2; -C (= O) H, -C (= O) -alkyl (C-i-Cß), wherein the alkyl portion may be optionally substituted with 1 to 3 halo atoms, preferably with 1 to 3 fluorine or chlorine atoms; benzyl or t-butoxycarbonyl (t-Boc). Unless otherwise indicated, the term "halo", as used herein, includes fluorine, chlorine, bromine and iodine.

Unless otherwise indicated, the term "alkyl", as used herein, includes linear, branched or cyclic alkyl portions and may include linear and cyclic alkyl portions, as well as branched and cyclic portions. The term "alkoxy," as used herein, means "alkyl-O", wherein "alkyl" is defined as indicated above. The term "alkylene", as used herein, means an alkyl radical having two available binding sites (i.e., -alkyl-), wherein "alkyl" is defined as indicated above. Unless otherwise indicated, the term "one or more substituents", as used herein, refers to a number of one to the maximum number of possible substituents based on the number of available binding sites. The term "treatment", as used herein, refers to the reversal, alleviation, inhibition of the progress of, or prevention of the disorder or condition to which such term applies, or of one or more symptoms of such disorder or condition. . The term "treatment", as used herein, refers to the act of treating, as defined by "treatment" in the immediately preceding paragraph. The compounds of formula I may have optical centers and, therefore, may appear in different enantiomeric configurations. The invention includes all enantiomers, diastereomers and other stereoisomers of such compounds of formula I, as well as racemic mixtures and other mixtures thereof. The present invention also relates to all radiolabelled forms of the compounds of formula I. Preferred radiolabelled compounds of formula I are those in which radiolabels are selected from 3H, 11C, 14C, 8F, 123L and 125L. Such radiolabeled compounds are useful as research and diagnostic tools in pharmacokinetic studies of metabolism and in binding assays both in animals and in humans. The present invention also relates to a pharmaceutical composition for use in the reduction of nicotine addiction or to help to stop or reduce the use of tobacco in a mammal, including the human being, which comprises an amount of a compound of the invention. Formula I, or a pharmaceutically acceptable salt thereof, effective in reducing nicotine addiction or to help stop or reduce tobacco use, and a pharmaceutically acceptable carrier. The present invention also relates to a method for reducing nicotine addiction or for aiding or stopping or reducing the use of tobacco in a mammal, including a human, which comprises administering to said mammal an amount of a compound of formula I , or a pharmaceutically acceptable salt thereof, which is effective in reducing nicotine addiction or in helping to stop or reduce tobacco use.

The present invention also relates to a method of treating a disorder or condition selected from inflammatory bowel disease (including, but not limited to, ulcerative colitis, pyoderma gangrenosum and Crohn's disease), irritable bowel syndrome, dystonia. spastic, chronic pain, acute pain, celiac sprue, bursitis, vasoconstriction, anxiety, panic disorders, depression, bipolar disorder, autism, sleep disorders, jet lag, amyotrophic lateral sclerosis (ALS), cognitive dysfunction, hypertension, bulimia, anorexia , obesity, cardiac arrhythmias, gastric acid hypersecretion, ulcers, pheochromocytoma, progressive supramuscular paralysis, chemical dependencies and addictions (for example, dependence or additions to nicotine (and / or tobacco products), alcohol, benzodiazepines, barbiturates, opioids or cocaine), cephalalgias, stroke, traumatic brain injury (TBI), obsessive-compulsive disorder (OCD), psychosis, Huntington's disease, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia, multi-infarct dementia, cognitive decline related to age, epilepsy, including minor or small malignant epilepsy, senile dementia type Alzheimer (AD), Parkinson's disease (PD), attention deficit hyperactivity disorder (ADHD) and Tourette syndrome in a mammal, which comprises administering a mammal in need of such treatment an amount of a compound of the formula I or a pharmaceutically acceptable salt thereof, which is effective in the treatment of such disorder or condition.

The present invention also relates to a pharmaceutical composition for the treatment of a disorder or condition selected from inflammatory bowel disease (including, but not limited to, ulcerative colitis, pyoderma gangrenosum and Crohn's disease), bowel syndrome irritable, spastic dystonia, chronic pain, acute pain, celiac sprue, bursitis, vasoconstriction, anxiety, panic disorders, depression, bipolar disorder, autism, sleep disorders, jet lag, amyotrophic lateral sclerosis (ALS), cognitive dysfunction, hypertension, bulimia, anorexia, obesity, arrhythmias, cardiac, hypersecretion of gastric acid, ulcers, pheochromocytoma, progressive supramuscular paralysis, chemical dependencies and addictions (for example dependence or addictions to nicotine (and / or to tobacco products), to alcohol, to benzodiazepines, barbiturates, opioids or cocaine), headaches, stroke, traumatic brain injury (TBI), obsessive-compulsive disorder (OCD), psychosis, Huntington's disease, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia, multi-infarct dementia, age-related cognitive decline, epilepsy, including minor or minor epilepsy, senile dementia of Alzheimer's type (AD), Parkinson's disease (PD), attention deficit hyperactivity disorder (ADHD) and Tourette syndrome in a mammal, comprising an amount of a compound of the formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable vehicle.

The present invention also relates to a method for reducing nicotine addiction or for helping to stop or reduce the use of tobacco in a mammal, which comprises administering to said mammal an amount of a compound comprising an amount of a compound of the formula or a pharmaceutically acceptable salt thereof, which is effective in reducing nicotine addiction or in helping to stop or reduce tobacco use. The present invention also relates to a method for the treatment of a disorder or condition selected from inflammatory bowel disease (including, but not limited to, ulcerative colitis, pyoderma gangrenosum and Crohn's disease), irritable bowel syndrome Spastic dystonia, chronic pain, acute pain, celiac sprue, bursitis, vasoconstriction, anxiety, panic disorder, depression, bipolar disorder, autism, sleep disorders, jet lag, amyotrophic lateral sclerosis (ALS), cognitive dysfunction, hypertension, bulimia, anorexia, obesity, arrhythmias cardiac events, gastric acid hypersecretion, ulcers, pheochromocytoma, progressive supramuscular paralysis, chemical dependencies and addictions (for example, dependence or addiction to nicotine (and / or tobacco products), alcohol, benzodiazepines, barbiturates, opiates or cocaine), headaches, stroke, traumatic brain injury (TBI), obsessive-compulsive disorder (OCD), psychosis, Huntington's disease, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia, multi-infarct dementia, cognitive decline related to age, epilepsy, including minor or small malignant epilepsy, senile dementia of Alzheimer's type (AD), Parkinson's disease (PD), junk hyperactivity disorder with attention deficit (ADHD) and Tourette Syndrome in a mammal, which comprises administering to a mammal in need of such treatment an amount of a compound of the formula or a pharmaceutically acceptable salt thereof, which is effective in the treatment of the disorder or condition. This invention also relates to the pharmaceutically acceptable acid addition salts of the compounds of formula I. Examples of pharmaceutically acceptable acid addition salts of the compounds of formula I, the salts of hydrochloric acid, p-toluenesulfonic acid, of fumaric acid, citric acid, succinic acid, salicylic acid, oxalic acid, hydrobromic acid, phosphoric acid, methanesulfonic acid, tartaric acid, malate, di-p-toluoyl tartaric acid and acid mandélico.

DETAILED DESCRIPTION OF THE INVENTION Except where otherwise indicated, from R1 to R18, m, P and structural formula I of the reaction schemes and discussion shown below are defined as indicated above.

SCHEME 1 IB SCHEME 2 SCHEME 2 (continued) SCHEME 3 IB SCHEME 4 SCHEME 5 SCHEME 6 10 SCHEME 6 (continued) SCHEME 7 (ring A = present or (ring A = present or absent) absent) XII XIII / (ring A = present or absent) XIIIA (ring A = present or absent) XIV IG: (R2 and R3 form ring A) III: (ring A = absent FIGURE 8 XV XVI XVII F or (C1-C6) alkoxy) XIX XVIII XXI SCHEME 9 IL SCHEME 10 IQ Schemes 1-10 illustrate procedures for the synthesis of omponents of formula I.

Referring to scheme 1, the starting material of formula III is reacted with trifluoroacetic anhydride in the presence of pyridine, to form the compound of formula IV. This reaction is typically carried out in methylene chloride at a temperature from about 0 ° C to about room temperature. The compound of formula IV is then converted to the dinitro derivative of formula NA by the following procedure. The compound of formula IV is added to a mixture of 4 or more equivalents of trifluoromethanesulfonic acid (CF3SO2OH) and 2 to 3 equivalents of nitric acid, in a chlorinated hydrocarbon solvent such as chloroform, dichloroethane (DCE) or methylene chloride. The resulting mixture is allowed to react for about 5 to 24 hours. The two above reactions are generally carried out at a temperature ranging from about -78 ° C to about 0 ° C, for about 2 hours, and then allowed to warm to room temperature for the remaining time. Reduction of the compound of formula HA using procedures well known to those skilled in the art produces the compound of formula IIB. This reduction can be carried out, for example, using hydrogen and a palladium catalyst, such as palladium hydroxide, and carrying out the reaction in methanol at about room temperature. Referring to scheme 2, the compound of formula HA is converted to the corresponding compound in which the trifluoroacetyl protecting group is replaced by a t-Boc protective group (VIA) by the reaction first with an alkali metal hydroxide or carbonate or alkaline earth metal (or ammonium) and then the reaction of the product isolated from the above reaction with di-t-butyl dicarbonate. The reaction with the alkali metal or alkaline earth metal hydroxide or carbonate (or ammonium) is generally carried out in an aqueous alcohol, dioxane or tetrahydrofuran (THF) at a temperature from about room temperature to about 70 ° C, preferably to about 70. ° C, for about one to about 24 hours. The reaction of the deprotected isolated amine or of an acid addition salt of such an amine, from the above reaction, with di-t-butyl dicarbonate is preferably carried out in a solvent such as THF, dioxane or methylene chloride, a temperature from about 0 ° C to about room temperature. This reaction can be carried out in the presence or absence of a base. When the reactant is a salt of the amine, the use of a base is preferred. The resulting compound of formula VIA can be converted to the corresponding diamino derivative of formula VIB using the procedure described above to convert the dinitro compound of formula HA to the corresponding diamino compound of formula IIB: The conversion of the compound of formula VI B into the desired compound of formula VII can be made by reacting the compound of formula VIB with a compound of formula XXIIA wherein R10 is hydrogen, alkyl (C-pCe) optionally substituted with one or seven fluorine atoms, aryl-alkyl (Co-C3 ) wherein said aryl is selected from phenyl and naphthyl, or heteroaryl (C0-C3) alkyl wherein said heteroaryl is selected from aromatic rings of five to seven members containing from one to four heteroatoms selected from oxygen, nitrogen and sulfur, and wherein each of the above aryl and heteroaryl groups may be optionally substituted with one or more substituents, preferably of zero to two substituents, independently selected from alkyl (C-i-Cß) optionally substituted with one to seven fluorine atoms, (C 1 -C β) alkoxy optionally substituted with one to seven fluorine atoms and cyano. The preferred solvent for this reaction is a 10: 1 mixture of ethanol: acetic acid. The reaction temperature can vary between about 40 ° C and about 100 ° C. Preferably, it is about 60 ° C. Other suitable solvents include acetic acid, ethanol and isopropanol. Segelstein et al. Tetrahedron Lett., 1993 34, 1897, describe alternative methods for preparing compounds of the formula VII and the compound of the formula VIB. Removal of the t-Boc protecting group from the compound of formula VII produces the corresponding compound of formula I A. The protecting group can be removed using procedures well known to those skilled in the art. For example, the compound of formula VII can be treated with an anhydrous acid, such as hydrochloric acid, hydrobromic acid, methanesulfonic acid or trifluoroacetic acid, preferably hydrochloric acid in ethyl acetate, at a temperature of about 0 ° C. at about 100 ° C, preferably from about room temperature to about 70 ° C, for about one to 24 hours. The compound of formula VII can be converted into the corresponding compound of formula IB, by reacting it with a compound of formula R17Z, where R17 is defined as defined above R10 and Z is a leaving group, such as halo or sulfonate (e.g. , chlorine, bromine, mesylate or tosylate), in the presence of a base such as an alkali metal hydride, hydroxide or carbonate, preferably potassium hydroxide, in a polar solvent such as water, dimethyl sulfoxide (DMSO), THF or DMF, preferably a mixture of DMSO and water, and then removing the protecting group as described above. The reaction with R17Z is generally carried out at a temperature from about room temperature to about 100 ° C, preferably at about 50 ° C, for about 5 hours. Scheme 3 illustrates an alternative procedure for preparing compounds of the formula IB from the compound of the formula VIA. This process is the preferred process for making compounds of the formula IB wherein R17 is a bulky group, such as an aryl or heteroaryl containing group, or when R17 can not be attached, as illustrated in scheme 2, by alkylation or aryl substitution. Referring to scheme 3, the compound of formula VIA is reacted with the appropriate compound of formula R17NH2 in a polar solvent such as THF, DMF or DMSO, preferably THF, at a temperature from about room temperature to about 100 ° C, preferably at reflux temperature, for about four to eighteen hours. The resulting compound of formula XXIII is then converted to the corresponding compound of formula XXIV by reduction of the nitro group to an amino group, using methods well known to those skilled in the art. Such procedures have been mentioned above for the conversion of the compounds of the formula HA to a compound of the formula IIB in scheme 1 and have been exemplified in the experimental examples 12B and 18B. The closure of the imidazole ring can then be performed to form the corresponding compound of formula XXV, by reacting the compound of formula XXIV of the above reaction with a compound of the formula XXIIA wherein R10 is defined as indicated above, as described above for converting compounds of formula VI B to those of formula VII. Removal of the protecting group of the compound of formula XXV produces the corresponding compound of formula IB. This can be done using procedures well known in the art, for example, as described above to form compounds of the formula IA from the corresponding compounds of the formula VII. Scheme 4 illustrates a process for preparing compounds of formula IC, wherein R 10 and R 17 are as defined above.

Referring to scheme 4, the compound of formula VIB is reacted with a compound of the formula (adduct of sodium bisulfite and ethane dione) in water or other polar solvent, such as THF, DMF or DMSO, preferably a mixture of water and a solvent miscible with water such as THF, for about one to four hours. The reaction temperature may vary between about 40 ° C and about 100 ° C, and preferably it is about the reflux temperature. Alternatively, the compound of formula VIB can be reacted with a compound of the formula (double condensation reaction) in a polar solvent such as THF, water or acetic acid, preferably a mixture of water and THF. This ratio is typically carried out at a temperature of about 40 ° C to about 100 ° C, preferably at the reflux temperature, for about two to four hours. The desired quinoxoline of formula IC can then be formed by deprotecting the compound formed in any of the above reactions, using the procedure described above to convert a compound of formula VII to one of formula IA. Scheme 5 illustrates a process for preparing compounds of formula I wherein R2 and R3, together with the benzene ring to which they are attached, form a benzoxazole ring system. Such as compounds, wherein R 1 is hydrogen, is represented in scheme 5 as the chemical compound of formula IE. Referring to scheme 5, the compound of formula XXII, wherein Y is nitro, halo, trifluoromethanesulfonate or a diazonium salt, is reacted with potassium acetate or other alkali metal or alkaline earth metal carboxylate, in a solvent such as as dimethyl sulfoxide (DMSO), DMF or acetonitrile, preferably DMSO. Generally, this reaction is allowed to proceed for approximately 12-24 hours. Appropriate reaction temperatures vary between about 70 ° C and about 140 ° C. A temperature of about 100 ° C is preferred. The above reaction produces the compound of formula HIV, which can then be converted to the desired compound having the formula IE by the following procedure. First, the compound of formula HIV is reduced by reaction with hydrogen and a palladium or platinum catalyst, such as palladium hydroxide in methanol, at a temperature of from about 0 ° C to about 70 ° C, preferably at about room temperature, to form the corresponding amino derivative. The product of this reaction is then reacted with an acid chloride of the formula R10COCI or an acid anhydride of the formula (R10CO) 2O, wherein R10 is alkyl (C? -C6), or with a compound of the Formula R10C (OC2H5) 3, in an appropriate inert solvent such as decalin, chlorobenzene or xylenes. A mixture of xylenes is preferred. This reaction is typically carried out at a temperature of about 120-150 ° C, preferably at about 140 ° C. When R10COCI is used as the reagent, it is preferred to add a stoichiometric amount of triethylamine (TEA) or other organic tertiary amine base and a catalytic amount of pyridinium p-toluenesulfonic acid or pyridinium p-toluenesulfonate (PPT) to the reaction mixture. When R10C (OC2H5) 3 is used as a reagent, it is preferable to add a catalytic amount of PPT to the reaction mixture. Removal of the protective group of the trifluoroacetyl nitrogen produces the desired compound of the formula IE. This can be done using procedures well known to those skilled in the art, for example, by reacting the protected compound with a lower alkanol and an aqueous alkali metal or alkaline earth metal (or ammonium) hydroxide or carbonate, aqueous sodium carbonate, a temperature of about 50 ° C to about 100 ° C, preferably at about 70 ° C, for about two to six hours. Scheme 6 illustrates the preparation of compounds of the formula I wherein R1 is hydrogen and R2 and R3, together with the benzene ring to which they are attached, form a benzothiazole ring system. Referring to scheme 6, the compound of formula III is reacted with trifluoroacetic anhydride to form the corresponding compound in which the ring nitrogen is protected by a trifluoroacetic group and the compound with the resulting protected nitrogen is then reacted with two equivalents. of trifluoromethanesulfonic anhydride and one equivalent of nitric acid to form the corresponding compound of formula IX, wherein there is a single nitro substituent on the benzene ring. The reaction with trifluoroacetic acid is typically carried out in the presence of pyridine. The above two reactions are typically carried out in a solvent inert to the reaction, such as a chlorinated hydrocarbon solvent, preferably methylene chloride, at a temperature from about 0 ° C to about room temperature, preferably at about room temperature.

The above transformation can also be performed using other nitration procedures known to those skilled in the art. The reduction of the nitro group to an amine group can be carried out as described above to provide a compound of the formula IX '. The compound of the formula IX 'is then reacted with a halide or carboxylic acid anhydride of the formula R10COX or (R10CO) 2O wherein X is halo and R10 is hydrogen or alkyl (C? -C6), and pyridine, TEA or other tertiary amine b to form a compound of the formula X, which can then be converted to the desired compound having the formula XI by reaction thereof with the Lawesson reagent shown below.

The reaction with R10COX, where X is halo, or with (R10CO) 2O, is generally carried out at a temperature from about 0 ° C to about room temperature, preferably at about room temperature. The reaction with Lawesson's reagent is generally carried out in a reaction-inert solvent, such as benzene or toluene, preferably toluene, at a temperature from about room temperature to about the reflux temperature of the reaction mixture, preferably at about reflux temperature. The closing of the benzothiazole ring and the deprotection of the nitrogen to form the desired compound of formula IF can be carried out by reacting the compound of formula XI with potassium ferricyanide and sodium hydroxide, in a mixture of water and methanol (NaOH / H2O / CH3OH) , at a temperature of about 50 ° C to about 70 ° C, preferably at about 60 ° C for about 1.5 hours. Scheme 7 illustrates a process for preparing the compound of formula III, which is used as a starting material for the process of scheme 1, or a compound of formula IG, wherein R2 and R3 form a ring (marked with the letter "A" in the scheme), as defined above in the definition of the compounds of formula I. Referring to scheme 7, the compound of formula XII, wherein X1 and X2 are independently selected from chlorine, fluorine, bromine and iodine, but in which at least one of X1 and X2 is Br "or I", is reacted with cyclopentadiene in the presence of magnesium metal, in THF, dioxane or other ethereal solvent, at a temperature of about 100. ° C, preferably at about the reflux temperature, to form a compound of the formula XIII. Reaction of the resulting compound of formula XIII with N-methylmorpholine N-oxide (NMO) and osmium tetroxide in acetone at about room temperature yields the corresponding compound of formula XI 11 A. The compound having the formula XI HA then it is converted to the corresponding compound of formula XIV using the following procedure. First, the compound of formula XI HA is reacted with sodium periodate in a mixture of a chlorinated hydrocarbon, preferably dichloroethane (DCE) and water, or with lead tetraacetate in a chlorinated hydrocarbon solvent, at a temperature of about 0 ° C at about room temperature, to generate an intermediate dialdehyde or glycal. The product of this reaction is then reacted with benzylamine and sodium triacetoxyborohydride in a chlorinated hydrocarbon solvent at a temperature from about 0 ° C to about room temperature, preferably at about room temperature, to form the desired compound of formula XIV. Removal of the benzyl group from the compound of formula XIV yields the compound of formula III (when ring A is absent) or IG (when ring A is present). This can be done using procedures well known to those skilled in the art, for example, by optionally reacting the free base with one equivalent of hydrochloric acid (to form the corresponding acid addition salt), followed by hydrogen and palladium hydroxide in methanol. at about room temperature.

In the reductive amination step described above and throughout this document, alternatives to benzyl amine can also be used, such as ammonia, hydroxylamine, alkoxyamines, methylamine, allylamine and substituted benzylamines (eg, diphenylmethylamine and 2- and 4- substituted alkoxy benzylamines). They can be used in the form of free bases or in the form of their salts, preferably their acetate salts, and can be subsequently removed by the procedures described for each by TW Greene and GM Wuts, "Protective Groups in Organic Synthesis", 1991, John Wiley &; Sons, New York, NY. The procedure of scheme 7 can also be used to prepare compounds of the formula I wherein R2 and R3 do not form a ring and are not hydrogen, replacing the starting material of formula XII with the appropriate compound having the formula Schemes 8, 9 and 10 illustrate the processes for preparing compounds of formula I wherein R 1 is hydrogen and R 2 and R 3 represent a variety of different substituents, as defined above, but do not form a ring. Scheme 8 illustrates a variation of the procedure shown in scheme 7, which can be used to make a compound identical to that of formula III, with the exception that the benzene ring is substituted with a fluoro group or an alkoxy group (R.sub.18 on the scheme 8). This compound is represented in scheme 8 as the chemical structure 1 H. Referring to scheme 8, in which, for example, R18 is F, it is reacted 1,3-difluorobenzene with a strong base, such as an alkali metal dialkylamine or an alkali metal alkyl (or aryl) in an ether solvent, such as ethyl ether or THF, at a temperature below -50 ° C, followed by by inactivation with iodine or N-yodosuccinamide, to form 1,3-difluoro-2-iodobenzene. The 1,3-difluoro-2-iodobenzene compound (of structural formula XVI in scheme 8) is then converted to the compound of formula IH by a series of reactions (represented in scheme 8 as XVI? XVII? XVHI? XIX? IH) which are analogous to those in the series of reactions described above and illustrated in scheme 7 for converting the compounds of formula XIII to those of formula IG or III. The conversion of the compound of formula XVI into the compound of formula XVII can also be carried out by treating a mixture of the compound of formula XVI and cyclopentadiene with an alkyl lithium reagent, preferably n-butyl lithium, in an inert hydrocarbon solvent, such as petroleum ether or methyl cyclohexane, at a temperature from about -20 ° C to about room temperature, preferably at about 0 ° C. The compound of formula IH can then be converted into the corresponding protected nitrogen derivative of formula XX using the procedures described above, to synthesize the compound of formula IV of scheme 1. The nitration of the compound of formula XX using the procedure described above to prepare the compound of formula IX of scheme 6, it produces the compound of formula XXI in which the benzene ring is substituted with a fluorine group and another nitro or an alkoxy group and a nitro group. The compound of formula XXI can be used to make a variety of compounds of the formula I, wherein one of R2 and R3 is fluorine, using methods that are well known to those skilled in the art, for example, by first converting the nitro group to an amino group and converting the amino group to a variety of other substituents, as illustrated in scheme 10, and then removed the nitrogen protecting group. The compound of formula XXI acts as a regioisomeric functional equivalent of the compounds having HA, VIA and XXII formulas, since the fluorine atom of formula XXI reacts analogously to the nitro and y groups of the formulas HA, VIA and XXII and, therefore, thus, it can be subjected to the same series of reactions as described above for these last three compounds, providing an alternative means to prepare the products of such reactions. Similarly, the alkoxy group of formula XXI (R18 = alkoxy) can be converted to a hydroxyl group before or after the introduction of the nitro group, and can then be converted to isomeric products as described above. In addition, the trifluoromethanesulfonate salt of such hydroxy derivative can act as a Y group as described above.

The compounds of formula I wherein R2 = -O-alkyl (CrC6), alkyl (C? -C6) or aryl, wherein aryl is defined as indicated above in the definition of formula I, and R3 is H or one of the other substituents described above in the definition of formula I can be prepared as described above in Scheme 8 by replacing one of the fluorine atoms of the compound of formula XV or with -O- alkyl (C-i-Cß), alkyl (C? -C6) or aryl, respectively. Scheme 9 illustrates procedures for preparing compounds of the formula I in which: (a) R1 is hydrogen and R2 is R7R8NO2S-; (b) both R1 and R2 are chlorine; and (c) R1 is hydrogen and R2 is R13C (= O) -. These compounds are referred to in scheme 9, respectively, compounds of the formulas IJ, IK and IL. Referring to scheme 9, the compounds of formula IJ can be prepared by reacting the compound of formula IV with two or more equivalents of a halosulfonic acid, preferably chlorosulfonic acid, at a temperature from about 0 ° C to about room temperature. The reaction of the chlorosulfonic acid derivative thus formed with an amine having the formula R7R8NH, wherein R7 and R8 are as defined above, followed by removal of the nitrogen protecting group, yields the desired compound having the formula IJ . The compounds of formula IK can be prepared by reacting the compound of formula IV with iodine trichloride in a chlorinated hydrocarbon solvent, followed by removal of the nitrogen protecting group. The reaction with iodine trichloride is typically carried out at a temperature from about 0 ° C to about room temperature, and is preferably carried out at about room temperature. In a similar manner, the mono- or dibrominated or mono-or di-iodated analogues can be prepared by reaction of the IV compound with N-iodosuccinimide or N-bromosuccinimide in a trifluoromethanesulfonic acid solvent, followed by removal of the nitrogen protecting group. as described above. The reaction of the IV compound with an acid halide of the formula R 13 COCl or with an acid anhydride of the formula (R 13 CO) 2 O, with or without a reaction-inert solvent such as a chlorinated hydrocarbon solvent, preferably methylene chloride, in the presence of a Lewis acid such as aluminum chloride, at a temperature of from about 0 ° C to about 100 ° C, followed by the deprotection of nitrogen, produces the compound of formula IL. The reaction with the acid halide or the acid anhydride can be carried out using other known Lewis acids or other Friedel-Crafts acylation methods which are known in the art. The reactions described in this document in which NO2, - SO2NR7R8, -COR13, I, Br or Cl are introduced into the compound of formula IV, as represented in scheme 9 and described above, can be carried out on any analogous compound in which R2 is hydrogen, alkyl ( Ci-Cß), halo, (C? -C6) alkoxy or -NHCONR7R8, producing compounds of the formula I wherein R2 and R3 are defined as in the definition of the compounds of the formula I above. Compounds which are identical to those of the formula IL, but which retain the nitrogen protecting group, can be converted into the corresponding O-acyl-substituted compounds, ie those in which the -C (= O) R13 group of IL formula is replaced by a group -O-C (= O) R13, using Baeyer-Villiger procedures well known to those skilled in the art. The resulting compounds can be partially hydrolyzed, as described in Example 35, to produce the corresponding hydroxy-substituted compounds, and then alkylated to form the corresponding alkoxy-substituted compounds. Also, as described in example 36, such O-acyl substituted compounds can be used to prepare variably substituted benzoisoxazoles. Scheme 10 illustrates processes for making compounds of the formula I in which: (a) R 1 is hydrogen and R 2 is chlorine; (b) R1 is hydrogen and R2 is cyano; (c) R1 is hydrogen and R2 is amino; and (d) R1 is hydrogen and R2 is R13C (= O) N (H) -. These compounds are referred to in scheme 10, respectively, compounds of the formula IM, IN, IP and IQ. The compounds of the formula IM can be prepared from compounds of the formula IX ', by the generation of a diazonium salt with, for example, an alkali metal nitrite and a strong mineral acid (for example, hydrochloric acid, sulfuric acid and hydrobromic acid) in water, followed by the reaction with a copper halide salt, such as copper (I) chloride. Deprotection of nitrogen by the procedures described above yields the desired compound of formula IM. Alternative methods for the generation of diazonium salts may also be used, as is known and practiced by those skilled in the art. The above reaction is generally carried out at temperatures ranging from about 0 ° C to about 60 ° C, preferably at temperatures of about 60 ° C, for about 15 minutes to one hour. Reaction of the diazonium salt, prepared as described above, with potassium iodide in an aqueous medium, provides the analogous iodide derivative. This reaction is generally carried out at a temperature from about 0 ° C to about room temperature, preferably at about room temperature. The resulting compound or its analogous N-tert-butylcarbonate protected form can be used to prepare the corresponding cyano derivative by reaction with copper (I) cyanide and sodium cyanide in DMF, N, N-dimethylpropylurea (DMPU) or DMSO, preferably DMF , at a temperature of from about 50 ° C to about 180 ° C, preferably at about 150 ° C. Nitrogen deprotection as described above provides the desired compound of formula IM. The iodine derivative described above can also be used to access a variety of different substituents, such as aryl, acetylene and vinyl substituents, as well as the corresponding carbonyl esters and amides, by palladium and nickel catalyzed processes known to those skilled in the art. technique, such as Heck, Suzuki and Stille couplings and Heck carbilations. Nitrogen deprotection of the compound of formula IX 'provides the compound of the formula IP. The compound of formula IX 'can be reacted with an acyl group having the formula R 13 COCl or (R 13 CO) 2 O using the procedures described above, followed by deprotection of nitrogen to provide compounds of the formula IQ. In a similar manner, treatment of the protected amine with a compound having the formula R13SO2X, where X is chloro or bromo, followed by deprotection of nitrogen, provides the corresponding sulfonamide derivative. Other suitable amine protecting groups that can be used, alternatively, in the processes described throughout this document, include -COCF3, -COCCI3, -COOCH2CCI3, -COO-alkyl (C-? -C6) and -COOCH2C6H5. These groups are stable under the conditions described herein and can be eliminated by the procedures described for each in Greene's "Protective Groups in Organic Chemistry", mentioned above. In each of the reactions discussed above or illustrated in the schemes 1-10 above, the pressure is not critical unless otherwise indicated. Generally, pressures from about 0.5 atmospheres to about 5 atmospheres are acceptable, with ambient pressure being preferred for convenience reasons, i.e. about 1 atmosphere. The compounds of the formula I and their pharmaceutically acceptable salts (hereinafter, "the active compounds") can be administered via the oral, transdermal routes (for example, by the use of a patch), intranasal, sublingual, rectal, parenteral or topical. Transdermal and oral administration are preferred. These compounds are administered, most desirably, in doses ranging from about 0.25 mg to about 1500 mg per day, preferably between about 0.25 and about 300 mg per day in a single dose or in divided doses, although variations will necessarily occur depending on the weight and the condition of the subject to be treated and the particular administration route chosen. However, in the most desirable manner, a dosage level that is in the range of about 0.01 mg to about 10 mg per kg of body weight and per day is employed. However, variations may occur depending on the weight and condition of the persons to be treated and their individual responses to said medication, as well as the type of pharmaceutical formulation chosen and the period and interval of time during which such administration is being carried out. . In some cases, dosage levels lower than the lower limit of the aforementioned range may be more than adequate, while in other cases even higher doses will be used without causing any harmful side effects, provided that such larger doses are first divided into several doses. small to be administered throughout the day. The active compounds can be administered alone or in combination with pharmaceutically acceptable carriers or diluents by any of the several routes indicated above. More particularly, the active compounds can be administered in a wide variety of different dosage forms, for example, they can be combined with various inert pharmaceutically acceptable carriers in the form of tablets, capsules, transdermal patches, pills, troches, hard candies, powders, sprays, creams, ointments, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups and the like. Such carriers include diluents or solid fillers, sterile aqueous media and various non-toxic organic solvents. In addition, oral pharmaceutical compositions can be conveniently sweetened and / or flavored. In general, the active compounds are present in such dosage forms at dosage levels ranging from about 5.0% to about 70% by weight. For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine can be used, together with various disintegrants such as starch (preferably corn, potato or tapioca starch) and certain alginic acid. complex silicates, together with granulation binders such as polyvinyl pyrrolidone, sucrose, gelatin and gum arabic. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc can be used to form tablets.

Solid compositions of a similar type may also be employed as fillers in gelatin capsules; Preferred materials in this regard also include lactose or milk sugar, as well as high molecular weight polyethylene glycols. When aqueous suspensions and / or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring materials and, if desired, with emulsifying and / or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin and various combinations thereof. For parenteral administration, a solution of an active compound in sesame or peanut oil or in aqueous propylene glycol may be employed. Aqueous solutions should be suitably buffered (preferably at a pH greater than 8), if necessary, and the liquid diluent first made isotonic. These aqueous solutions are suitable for intravenous injection purposes. Oily solutions are suitable for intra-articular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is easily accomplished by conventional pharmaceutical techniques well known to those skilled in the art.

It is also possible to administer the active compounds topically, and this can be done by means of creams, patches, jellies, gels, pastes, ointments and the like, in accordance with conventional pharmaceutical practice.

Biological assay The efficacy of the active compounds in the suppression of nicotine binding to specific receptor sites is determined by the following procedure, which is a modification of the Lippiello, P.M. and Fernandes, K.G. (in The Binding of L-.3HlNicotine To A Single Class of High-Affinitv Sites in Rat Brain Membranes, Molecular Pharm. 29, 448-54. (1986)) and Anderson, D.J. and Arneric, S.P. (in Nicotinic Receptor Binding of 3H-Cvstesine, 3H-Nicotine and 3H-Methylcarboxylcholine in Rat Brain, European J. Pharm .. 253. 261-67 (1994)).

Procedure Male Sprague-Dawley rats (200-300 g) from Charles River were caged in groups, in hanging cages of stainless steel wire, and kept in a 12-hour light / dark cycle (light period 7 a.m. p.m). Rats received conventional Purina Rat Chow and water ad libitum. The rats were sacrificed by decapitation. The brains were removed immediately after decapitation. Membranes of brain tissue were prepared according to Lipiello's procedures and Fernandez (Molec Pharmacol). 29, 448-454, (1986) with some modifications. Whole brains were removed, rinsed with ice-cold buffer and homogenized at 0 ° C in 10 volumes of buffer (w / v) using a Brinkman Polytron ™ 6 facility for 30 seconds. The buffer consisted of 50 Mm Tris HCl with a pH of 7.5 at room temperature. The homogenate was sedimented by centrifugation (10 minutes); 50. 000 x g; 0 to 4 ° C. The supernatant was removed by pouring it and the membranes were gently resuspended with the Polytron and centrifuged again (10 minutes, 50,000 x g, 0 to 4 ° C). After the second centrifugation, the membranes were resuspended in assay buffer at a concentration of 1.0 g / 100 ml. The composition of the standard assay buffer was 50 mM Tris HCl, 120 mM NaCl, 5 mM KCl, 2 mM MgCl 2, 2 mM CaCl 2 and had a pH of 7.4 at room temperature. Routine tests of borosilicate glass test tubes were performed. The assay mixture typically consisted of 0.9 mg of membrane protein in a final incubation volume of 1.0 ml. Three sets of tubes were prepared, where the tubes in each series contained 50 μl of vehicle, blank or test compound, respectively. To each tube was added 200 μl of [3 H] -nicotine in assay buffer, followed by 750 μl of the membrane suspension. The final concentration of nicotine in each tube of 0.9 nM. The final concentration of cytisine in the blank was 1 μM. The vehicle consisted of deionized water containing 30 μl of 1 N acetic acid per 50 ml of water. The test compounds and cytisine were dissolved in vehicle.

The tests were started by shaking in a Vortex apparatus after the addition of the membrane suspension to the tube. The samples were incubated at a temperature of 0 to 4 ° C in a water bath stirred with ice. Incubations were terminated by rapid vacuum filtration through Whatman GF / B ™ glass fiber filters using a Brandel ™ multi-collector tissue harvester. After initial filtration of the test mixture, the filters were washed twice with ice-cold assay buffer (5 m each). The filters were then placed in counting vials and mixed vigorously with 20 ml of Ready Safe ™ (Beckman) before quantification of radioactivity. Samples were counted in a LKB Wallach Rackbeta ™ liquid scintillation counter with an efficiency of 40-50%. All determinations were made in triplicate.

Calculations The specific binding (C) to the membrane is the difference between the total binding in the samples that contained only vehicle and membrane (A) and the non-specific binding in the samples that contained the membrane and cytisine (B), that is, Specific binding = C = (A) - (B) The specific binding in the presence of the test compound (E) is the difference between the total binding in the presence of the test compound (D) and the non-specific binding (B), it is say, (E) = (D) - (B). % inhibition = (1 ((E) / (C)) per 100. The compounds of the invention that were tested showed Cl 50 values less than 10 μM The following experimental examples illustrate, but do not limit the scope of this invention .

EXAMPLE 1 10-Aza-tricyclo, 6.3.1.0 .2,7 '1dodeca-2,7, 5-triene A) 1,4-Dihydro-1,4-methano-naphthalene (Based in whole or in part on a) Witting, G .; Knauss, E. Chem. Ber. 1958, 91, 895. b) Muir, D. J .; Stothers, J. B. Can J. Chem. 1993, 71, 1920). Magnesium filings (36.5 g, 1.5 M) in anhydrous THF (250 ml) were stirred in a 3-neck round bottom flask, with 2 I capacity, dry and equipped with a 250 ml non-compensating addition funnel, with a nitrogen flow adapter (N2), a mechanical agitator and an efficient condenser equipped with a N2 flow adapter. The flask was stirred and heated to reflux by a removable heating jacket. 2-Fluorobromobenzene (2 g) was added followed by 1 ml of 3N ethylmagnesium bromide (EtMgBr in THF). A mixture of cyclopentadiene (94.4 g, 1.43 M, prepared by the procedure described in: Org, Syn Col. Vol. V 414-418) and bromofluorobenzene (250 g, 1.43 M) was introduced into the addition funnel, which was maintained. at 0 ° C in another flask with an ice bath, and transferred to the addition funnel through a cannula. Small portions (~ 1 ml) of the intimate mixture were introduced to aid initiation (~ 4x).

After ~ 15 minutes, the reaction started (exotherm and steam condensation), the heating jacket was removed and the content of the addition funnel was added dropwise at such a rate as to allow reflux to be maintained (1.5 hours). The heating jacket was reapplied and the reflux was maintained for 1.5 hours (100% TLC in hexanes Rf 0.67). The reaction was cooled to room temperature and quenched with H 2 O (500 mL) and cautiously with 1 N HCl (200 mL, which produces the evolution of H2 from the unconsumed Mg). To this mixture ~ 50 ml of concentrated HCl was added to dissolve the solids. Total addition / inactivation time ~ 1 hour. A saturated aqueous solution of sodium chloride (NaCl) (300 ml) was added and the hexanes were removed from the product until the active product was no longer removed to potassium permanganate (KMnO 4). (4 x ~ 250 ml). The combined organic layer was washed with saturated NaHCO3 solution (250 ml) and sodium bicarbonate Na SO4, dried and concentrated to an oil (~ 200 g). The product was distilled at 78-83 ° C @ 15 mm (131 g, 64%). (On page 419 of Fieser and Fieser, Vol. I, Reagents for Organic Synthesis, Wiley, NY., NY, 1967, an alternative processing is described).

B) 1, 2,3,4-Tetrahydro-1,4-methano-naphthalene-2,3-diol (Except in the processing procedure and the amount of OsO used, based on VanRheenen, V .; Cha, DY; Hartley, WM Org. Syn. 1988, 6, 342.) In a 2-neck, 3-neck round bottom flask equipped with a N2 flow adapter and a mechanical stirrer, 1,4-dihydro-1 was placed , 4-methano-naphthalene (79.5 g, 560 mmol) stirred in acetone (800 mL) and H2O (100 mL), and N-methyl morpholine N-oxide (67.5 g 576 mmol). To this mixture was added osmium tetroxide (OsO4) (15 ml of a 15 mol% solution of t-BuOH, 1.48 mmole, 0.26 mol%) and the mixture was stirred vigorously. After 60 hours, the reaction was filtered and the white product rinsed with acetone and dried with air (60.9 g). The mother liquors were concentrated to an oily solid: trituration with acetone, filtration and rinsing with acetone gave (27.4 g total 88.3 g, 89%). (TLC 50% EtOAc / hexanes Rf ~ 0.5). p.f. 176-177.5 ° C.

C) 10-Benzyl-10-aza-tricichlor6.3.1.02 71dodeca-2 (7) .3.5-triene (Based on Abdel-Magid, AF; Carson, KG; Harris, BD; Maryanoff, CA; Shah, RDJ Org Chem. 1996, 61, 3849; and Mazzocchi, PH; Stahly, BCJ Med. Chem. 1979, 22, 455). 1, 2,3,4-Tetrahydro-1,4-methano-naphthalene-2,3-diol (40 g, 227.3 mmol) was stirred in H2O (1050 mL) and 1,2-dichloroethane (DCE) ( 420 ml) in a 2 1 round bottom flask, under nitrogen and with a cold water bath (~ 10 ° C). To this solution were added sodium periodate (NalO) (51 g, 239 mmol) and triethylbenzyl ammonium chloride (Et3BnNCI) (50 g). The resulting mixture was stirred for 1 hour (slight initial exotherm), then the layers were separated and the aqueous layer was extracted with DCE (200 ml). The organic layer was washed with H 2 O (4 x 200 ml), or until no further reaction was observed in the starch iodide in the aqueous wash), and then dried through a cotton plug. To this was added benzyl amine (25.5 g 238.6 mmol), the mixture was stirred for 2 minutes and then immediately transferred to sodium triacetoxyborohydride NaHB (oAc) 3 / DCE (see below) for 10 minutes. In another 2 I round bottom flask, under nitrogen, NaHB (oAc) 3 (154 g, 0.727 mmol) in DCE (800 ml) was stirred magnetically at 0 ° C (ice bath). To this the above mixture was added for 10 minutes, without delay after mixing the dialdehyde and the amine. The resulting orange mixture was allowed to warm to room temperature and stirred for 30-60 minutes. The reaction was quenched by the careful addition of saturated sodium carbonate solution (Na2CO3) (~ 300 mL) first and the mixture was stirred for 1 hour (pH 9). The layers were separated and the aqueous layer was extracted with CH2Cl2 (2 x 300 mL). The organic layer was washed with a saturated aqueous NaCl solution (200 ml), dried by a cotton plug and then evaporated to a red oil. This was dissolved in a minimum of Et2O and filtered through a layer of silica (3 x 4 inches) (7.62 x 10.16 cm) eluting with 15% ethyl acetate.

(EtOAc) / hexanes + 1% of a 37% aqueous ammonium hydroxide solution (NH OH) to remove the initial red color. The concentration produced a light yellow oil (48.5 g, 194.8 mmol, 85.7%). (TLC 10% EtOAc / Rf hexanes 0. 75). 1 H NMR (400 MHz, CDCl 3) d 7.16 (m, 7 H), 6.89 (m, 2 H), 3.48 (m, 2 H), 3.08 (m, 2 H), 2.80 (d, J = 9.5 Hz, 2 H), 2.42 (d, J = 9.5 Hz, 2H), 2.27 (m, 1 H), 1.67 (d, J = 10.0 Hz, 1 H). APCI MS m / e 250.3 [(M + 1) *].

D) 10-Aza-tricyclo r6.3.1.02,71dodeca-2 (7) .3.5-triene (For an alternative synthesis, see: Mazzocchi, P.H., Stahly, B.C. J. Med. Chem. 1979, 22, 455). 10-Benzyl-10aza-tricyclo [6.3.1.02'7] dodeca-2 (7), 3,5-triene (70.65 g, 284 mmol) was stirred in EtOAc (250 mL) and treated with 3 N HCl in EtOAc (1.03 eq.) Slowly with cooling (ice bath). The resulting precipitate was filtered and rinsed with EtOAc. The solids were dissolved in MeOH (250 ml) in a Parr flask. To this was added Pd (OH) 2 (7 g of 20% w / C) and the mixture was stirred under 50-40 psi (344)., 737-275.79 kPa) of H2 for 24 hours or until TLC was made. The reaction was filtered through a pad of Celite and concentrated to an oily solid. This was distilled azeotropically with methanol (MeOH) (3x), then triturated with acetone, treated with ethyl ether (Et2O) until the product was precipitated and filtered. The concentration of the mother liquor and a second treatment gave an off-white solid (48.95 g, 251 mmol, 88%). (TLC MeOH at % / CH2Cl2 (NH3) Rf 0.2). 1 H NMR (400 MHz, CDCl 3) d 7.18 (m, 4 H), 2.97 (m, 4 H), 2.68 (d, J = 12.5 Hz, 2 H), 2.41 (m, 1 H), 1.95 (d, J = 11.0 Hz, 1 H). APCI MS m / e 160.2 [(M + 1) + J.

EXAMPLE 2 4-Fluoro-10-aza-tricyclohydrochloride_6.3.1.02'71dodeca-2 (7) .3.5-triene A) 6-Fluoro-1, 4-dihydro-1,4-methane-naphthalene (Eisch, JJ, Burlinson, NEJ Amer. Soc. 1976, 98, 753-761 Paquette, LA; Cottrell, DM; Snow, RAJ Amer. Chem. Soc, 1977, 99, 3723-3733.) Magnesium filings (0.66 g 27.2 mmol) in anhydrous THF (10 ml) were stirred in a 3-neck 75 ml flask flame-dried equipped with a funnel non-compensating addition with N2 flow adapter, a magnetic stirrer and an efficient condenser equipped with a N2 flow adapter. The flask was stirred and heated to reflux by a removable heating jacket. 2,5-difluorobromobenzene (0.1 g) was added followed by 3 N EtMgBr in THF (0.1 ml). An intimate mixture of cyclopentadiene (1.71 g, 25.9 mmoles) and 2,5-difluorobromobenzene (5.0 g, 25.9 mmoles) was introduced into the addition funnel. Small portions (~ 0.2 ml) of the intimate mixture were introduced to assist initiation (~ 4 x).

After ~ 15 minutes, the reaction had started (exotherm and vapor condensation) and heating was maintained when necessary during the addition of the addition funnel content. Then, the reaction was refluxed for 1 hour. The reaction was cooled to room temperature and quenched with H2O (20 ml) followed by an aqueous solution of 1 N HCl (20 ml) to dissolve the solids. A saturated aqueous solution of NaCl (30 ml) was added and the product was extracted with hexanes (4 x 25 ml). The combined organic layer was washed with saturated aqueous NaHCO3 solution (25 ml), dried (Na2SO4), filtered through a plug of silica rinsing with hexanes and concentrated to give an oil. Chromatography on silica gel eluting with hexanes provided an oil (780 mg, 19%). (TLC hexanes Rf 0.38). 1 H NMR (400 MHz, CDCl 3) d 7.10 (m, 1 H), 6.97 (d, J = 8.0 Hz, 1 H), 6.80 (sa, 1 H), 6.78 (sa, 1 H), 6.59 (m, 1 H), 3.87 (sa, 2H), 2.32 (d, J = 7.0 Hz, 1 H), 2.25 (d, J = 7.0 Hz, 1 H).

B) 6-Fluoro-1, 2,3,4-tetrahydro-1,4-methano-naphthalene-2,3-diol 6-Fluoro-1,4-dihydro-1,4-methano-naphthalene (680 mg, 4.22 mmoles) and N-methyl morpholine N-oxide (599 mg, 4.43 mmoles) in acetone (50 ml) and H2O (5 ml). To this was added a solution of OsO4 (0.2 ml, 2.5% by weight solution in T-BuOH, 0.02 mmol). After 72 hours, florisil (5 g) and saturated aqueous NaHSO 3 solution (3 ml) were added and the mixture was stirred for 1 hour. The florisil was filtered and the filtrate was concentrated to yield a crystalline product which was triturated with acetone and filtered (524 mg, 64%). 1 H NMR (400 MHz, CDCl 3) d 7.10 (dd, J = 8.0, 5.0 Hz, 1 H), 6.90 (dd, J = 8.0, 2.3 Hz, 1 H), 6.75 (ddd, J = 8.0, 8.0, 2.3 Hz), 3.79 (s, 2H), 3.18 (d, J = 1.5 Hz, 2H), 2.22 (d, J = 10.0 Hz, 1 H), 1.92 (dd, J = 10.0, 1.5 Hz, 1 Hz), GCMS m / e 194 (M +).

C) 10-Benzyl-4-fluoro-10-aza-trichloro6.3.1.0 -dododeca-2,7), 3,5-triene 6-fluoro-1, 2,3,4- were stirred vigorously. tetrahydro-1,4-methane-naphthalene-2,3-diol (524 mg, 2.68 mmol) and Et3NBnCI (10 mg) in dochloroethane (15 mg) and H2O (45 ml), then treated with sodium periodate (0.603 mg) 2.82 mmoles). After 1.5 hours, the layers were separated and the aqueous layer was extracted with DCE (2 x 20 ml). The combined organic layer was washed with H2O (4 x 20 ml) until no reaction was observed on the starch iodide paper and then with a saturated aqueous NaCl solution (20 ml). The organic layer was dried through a cotton plug, treated with benzyl amine (0.308 ml, 2.82 mmol), stirred for 2 minutes and then transferred to an addition funnel. This solution was added for -10 minutes to a cooled (0 ° C) and vigorously stirred mixture of NaHB (OAc) 3 (1.82 g, 8.58 mmol) in DCE (50 mL). After the addition was complete, the mixture was stirred without refrigeration for 2 hours. The mixture was quenched with a saturated aqueous solution of Na 2 CO 3 (100 ml) and stirred for 1 hour, then the layers were separated and the aqueous layer was extracted with CH 2 Cl 2 (3 x 30 ml). The combined organic layer was washed with saturated aqueous NaCl solution (50 ml), dried through a cotton plug and concentrated. Chromatography on silica gel provided an oil (520 mg, 80%). (TLC 2% acetone / CH2Cl2 Rf 0.40). 1 H NMR (400 MHz, CDCl 3) d 7.18 (m, 1 H), 6.88 (m, 2 H), 3.48 (s, 2H), 3.06 (m, 2H), 2.78 (m, 2H), 2.41 (m, 2H), 2.27 (m, 1 H), 1.69 (d, J = 10.5 Hz, 1 H).

D) 4-fluoro-10-aza-tricyclohydrochloride.6.3.1.02'71dodeca-2.7) .3.5-triene 10 benzyl-4-fluoro-10-aza-tricyclo [6.3.1.02'7] dodeca-2 (7), 3,5-triene (390 mg, 1461 mmol), ammonium formate (3.04 g 48.2 mmol) and 10% Pd (OH) 2 / C (30 mg) in MeOH (50 ml) were taken into reflux under N2 for 1.5 hours. Ammonium formate (1.0 g) was added and reflux continued for 0.5 hour. The reaction mixture was filtered through a pad of Celite that was rinsed with MeOH. The filtrate was concentrated. The residues were treated with saturated aqueous Na 2 CO 3 solution (30 ml) and the product was extracted with methylene chloride (CH 2 Cl 2) (3 x 25 ml). The organic layer was washed with saturated aqueous NaCl solution (50 ml), dried through a cotton plug and concentrated. The residue was treated with 2 N HCl MeOH (5 mL) and concentrated, then taken up in a minimum of MeOH and saturated with EÍ2O.

After stirring for 18 h, the white crystals were collected by filtration (86 mg, 28%). (TLC 5% MeOH / CH2Cl2 (NH3) Rf 0.27). (data for free base) 1 H NMR (400 MHz, CDCl 3) d 7.06 (m, 1 H), 6.83 (m, 2 H), 2.89 (m, 4 H), 2.61 (dd, J = 12.0 Hz, 2 H), 2.37 (m, 1 H), 1.87 (d, J = 11.5 Hz, 1 H). APCI MS m / e 178.2 [(M + 1) + j. (Salt HCl) p.f. 260-262 ° C.

EXAMPLE 3 4-Methyl-10-aza-tricichlorß.3.1.02 '1dodeca-2 _7) 3,5-triene hydrochloride The title compound was prepared by the procedure described in Example 1 and 2, from 2-fluoro-5-methyl-bromobenzene. (Data for the free base). 1 H NMR (400 MHz, CDCl 3) d 7.04 (d, J = 7.5 Hz, 1H), 6.99 (s, 1 H) 6.98 (d, J = 7.5 Hz, 1H), 2.98-2.90 (m, 4H), 2.63 (m, 2H), 2.35 (m, 1 H), 2.32 (s, 3H), 1.87 (d, J = 11.5 Hz, 1 H). APCI MS m / e 174.2 [(M + 1)]. (HCl salt) m.p. 254-255 ° C. Analysis Calculated for C12 H12 F3 HCl 1 / 3H2O: C, 53.44; H, 5.11; N, 5.19. Found: C, 53.73; H, 4.82; N, 5.15.

EXAMPLE 4 4-Trifluoromethyl-10-aza-tricyclohydrochloride, 6.3.1.02'71dodeca-2 7), 3,5-triene (See Grunewaid, G. L .; Paradkar, V. M., Pazhenchevsky, B .; Pleiss, M. A .; I left, D. J .; Seibel, W. L .; Reitz, T. J. J. Org. Chem. 1983, 48, 2321-2327. Grunewaid, G. L .; Markovinch, K. M .; Salí, D. J. J. Med. Chem. 1987, 30, 2191-2208). The title compound was prepared by the procedures described in Examples 1 and 2 from 2-fluoro-trifluoromethylbromobenzene. 1 H NMR (400 MHz, CD 3 OD) d 7.71 (s, 1 H), 7.64 (d, J = 8.0 Hz, 1 H), 7.57 (d, J = 8.0 Hz, 1 H), 3.46 (m, 4H), 3.21 (d, J = 12.5 Hz, 2H), 2.41 (m, 1 H), 2.16 (d, J = 1 1.5 Hz, 1 H). APCI MS m / e 228.2 [(M + 1) 4]. (Salt HCl) p.f. 244-246 ° C. Analysis Calculated for C12H12F3N HCl 1 / 3H2O: C, 53.44; H, . eleven; N, 5.19. Found: C, 53.77; H, 4.82; N, 5.18.

EXAMPLE 5 3-Trifluoromethyl-10-aza-tricyclohydrochloride_6.3.1.02'71dodeca-2, 7) .3.5-triene (Grunewaid, G. L .; Markovich, K. M., Sali, D. J. J. Med. Chem. 1987, 30, 2191-2208).

The title compound was prepared by the procedures described in Examples 1 and 2, from 2-fluoro-6-trifluoromethylbromobenzene. 1 H NMR (400 Mhz, CD 3 OD) d 7.65 (s, 2 H), 7.52 (m, 1 H), 3.65 (s at, 1 H), 3.49-3.43 (m, 3 H) , 3.20 (m, 2H), 2.42 (m, 1 H), 2.18 (d, j = 1 1.5 Hz, 1 H). APC MS m / e 228.2 [(M + 1) +]. (Salt HCl) p.f. 275-277 ° C.

EXAMPLE 6 3-Fluoro-10-aza-tricyclo.6.3.1.02 71dodeca-2 (7) .3.5-triene hydrochloride A) 2,6-Difluorovodobenzene (Roe, AM; Burton, RA; Willey, GL; Baines, MW; Rasmussen, ACJ Med. Chem. 1968, 1 1, 814-819. Tamborsky, C .; Solosky, EJ Org. Chem. 1966, 31, 746-749, Grunewaid, GL, Arrington, HS, Bartlett, WJ, Reitz, TJ, Sali, DJJ Med Chem. 1986, 29, 1972-1982.) 1,3-Difluorobenzene (57.05) was added. g, 0.5 M) in THF (75 ml) to a stirred solution at -78 ° C of n-butyl lithium (n-BuLi) (200 ml, 2.5 M / hexanes, 0.5 M) and THF (500 ml) under N2 . Controlling the speed of addition, the internal temperature was maintained below -70 ° C. The total time of addition was ~ 0.5 hours. The resulting suspension was stirred for a further 0.5 hours and then the dispersion was treated with a solution of iodine (126.9 g, 0.5 M) in THF (300 ml) at a rate which maintained an internal temperature below -70 ° C. After the addition was complete, the mixture was allowed to warm to room temperature, treated with H2O (100 ml) and 10% aqueous solution of Na2S2? 3. (100 ml) and stirred. The layers were separated and the aqueous layer was extracted with hexanes (2 x 250 ml). The combined organic layer was washed with 10% aqueous Na 2 S 2 O 3 solution (100 mL), H 2 O (100 mL), saturated aqueous NaCl solution (100 mL), dried (Na2S4), filtered and concentrated to give a yellow oil (106.5 g). Distillation at ~1 -5 mm and at ~80 ° C produced a light yellow oil (89.5 g, 75%). 1 H NMR (400 MHz, CDCl 3) d 7.30 (m, 1 H), 6.87 (m, 2 H), GCMS m / e 240 (M +).

B) 5-Fluoro-1,4-dihydro-1,4-methano-naphthalene A solution of 2,6-difluoroiodobenzene (5.0 g, 20.8 mmol) and cyclopentadiene (2.07 g, 31.3 mmol) was stirred at 0 ° C in P ether (70 ml, 40-46 ° C) under N2 and treated with n-BuLi (8.74 ml, 2.5 M in hexanes, 21.8 mmol) dropwise over 10 minutes. The reaction was stopped after 15 minutes by the addition of aqueous 1 N HCl solution and the product was extracted with hexanes (3 x 50 ml). The combined organic layer was washed with H2O (50 ml), saturated aqueous NaCl solution (50 ml), dried (MgSO4), filtered and evaporated. Chromatography on silica gel gave the product as an oil (1.5 g, 45%). (TLC hexanes Rf 0.55). 1 H NMR (400 Mhz, CDCl 3) d 7.08 (ddd, J = 7.0, 1.0, 0.8 Hz, 1 H), 6.96 (ddd, J = 8.5, 8.3, 7.0 Hz, 1 H), 4.25 (sa, 1 H), 3.98 (sa, 1 H), 2.36 (ddd, J = 7.2, 1.7, 1.7 Hz, 1 H), 2.30 (ddd, J = 7.2, 1.7, 1.5 Hz , 1 HOUR). GCMS m / e 160 (M +) C) 3-Fluoro-10-aza-tricyclohydrochloride [6.3.1.027dodeca-2 (7) .3.5-triene The title compound was prepared by the procedures described in examples 2B, C and D from fluoro-1, 4-dihydro-1,4-methane-naphthalene. 1 H NMR (400 Mhz, CD 3 OD) d 7.36 (ddd, J = 8.3, 7.3, 5.0 Hz, 1 H), 7.21 (d, J = 7.3 Hz, 1 H), 7.07 (t, J = 8.3 Hz, 1 H), 3.62 (sa, 1 H), 3.42-3.30 (m, 3H), 3.21 (m, 2H), 2.38 (m, 1 H), 2, 12 (d, J = 11.5 Hz, 1 H). APCI MS m / e 178.4 [(M + 1)]. p.f. 269-271 ° C.

EXAMPLE 7 4-Nitro-10-azatricichlorß.3.1.Q2,7dodoca-2 (7), 3,5-triene hydrochloride A) 1- (10-Aza-tricyclo6.3.1.027dodeca-2 (7) .3.5-trien-10-in-2,2,2-trifluoro-ethanone The hydrochloride salt of 10-aza-tricyclo [6.3.1.02] was stirred , 7] dodeca-2 (7), 3,5-triene (12.4 g, 63.9 mmol) in CH2Cl2 (200 mL) This mixture was cooled (ice bath) and treated with pyridine (12.65 g, 160 mmol) followed by trifluoroacetic anhydride (TFAA) (16.8 g, 11.3 ml, 80 mmol) in an addition funnel for 10 minutes.After ~ 3 hours, the solution was poured into 0.5N aqueous HCl (200 ml) and the layers were The aqueous layer was extracted with CH2CI (3 x 50 ml) and the combined organic layer was washed with 0.5N aqueous HCl (50 ml, H2O (2 x 50 ml) and saturated aqueous NaHCO3 solution (50 ml). The solution was dried through a cotton plug, then diluted with ~ 3% EtOH and filtered through a 2 inch (5.08 cm) silica layer eluting with ~ 3% EtOAc / CH2Cl2. a clear oil that crystallized to give white needles (15.35 g 60.2 mmol, 94%). (TLC 30% EtOAc / hexanes Rf 0.53). 1 H NMR (400 Mhz, CDCl 3) d 7.18 (m, 4 H), 4.29 (da, J = 12.6 Hz, 1 H), 3.84 (da, J = 12.6 HZ, 1 H), 3, 51 (dd, J = 12.6, 1.5 Hz, 1 H), 3.21 (sa, 1 H), 3.10 (sa, 1 H), 3.10 (day, J = 12.6 Hz, 1 H), 2.37 (m, 1 K), 1, 92 (d, J = 10.8 Hz, 1H). GCMS m / e 255 (M +). p.f. 67-68 ° C.

B) 1- (4-Nitro-10-aza-tricichlor6.3.1.02'7dodeca-2 (7), 3,5-trien-10-n-2,2,2-trifluoroethanone (Based on the procedure described by Coon, CL; Blaucher, WG; Hill, MEJ Org. Chem. 1973, 25, 4243) To a solution of trifluoromethanesulfonic acid (2.4 ml, 13.7 mmol) in CH2Cl2 (10 ml) stirred at 0 ° C, nitric acid was added slowly (0.58 ml, 27.4 mmoles) generating a white precipitate.After 10 minutes, the resulting mixture was cooled to -78 ° C and treated with 1- (10-aza-tricyclo [6.3.1.12'7] dodeca-2 ( 7), 3,5-trin-10-yl) -2,2,2-trifluoro-ethanone (3.5 g, 13.7 mmol) in CH2Cl2 (15 mL) dropwise from an addition funnel for 5 minutes The reaction was stirred at -78 ° C for 30 minutes, and then warmed to 0 ° C for 1 hour.The reaction mixture was poured onto vigorously stirred ice (100 g) .The layers were separated and the aqueous layer was extracted with CH2CI2 (3 x 30 ml) The organic layers were combined and washed with H2O (3 x 30 ml). The combined organic layer was washed with saturated aqueous NaHCO 3 solution (20 ml) and H 2 O (20 ml), then dried through a cotton plug and concentrated to give an orange oil which solidified after a standing period (4.2 g). Chromatography afforded the pure product as a crystalline solid (3.2 g, 78%). (TLC 30% EtOAc / Rf hexanes 0.23). 1 H NMR (400 MHz, CDCl 3) d 8.12 (d a, J = 8.0 HZ, 1 H), 8.08 (s a, 1 H), 7.37 (d a, J = 8.0 Hz, 1 H), 4.38 (d a, J = 12.6 Hz, 1 H), 3.94 (d a, J = 12.6 Hz, 1 H), 3.59 (d a, J = 12.6 Hz, 1 H), 3.43-3.35 (m, 2 H), 3.18 (d a, J = 12.6 Hz, 1 H), 2.48 (m, 1 H), 2.07 (d, J = 10.8 Hz, 1 H). GCMS m / e 300 (M).

C) 4-Nitro-10-azatricichlor6.3.1.027dododeca-2 (7), 3,5-triene hydrochloride. 1- (4-Nitro-10-aza-tricyclo [6.3.1.02'7] dodeca-2 (7 ), 3,5-trien-10-yl) -2,2,2-trifluoro-ethanone (182 mg, 0.61 mmol) with Na 2 CO 3 (160 mg, 1.21 mmol) in MeOH (3 mL) and H 2 O (1 mL) ) at 70 ° C for 18 hours. The mixture was concentrated, water was added and the product was extracted with CH2Cl2. The organic layer was extracted with 1N aqueous HCl (2 x 20 ml) and the aqueous layer was basified to pH-10 with Na2CO3 (s) and the product was extracted with CH2Cl2 (3 x 30 ml). The organic layer was dried through a cotton plug and concentrated to an oil. This was dissolved in MeOH and treated with 1N HCl MeOH, concentrated to yield solids which were recrystallized from MeOH / Et2O yielding the product as a white solid (73 mg, 50): (TLC % MeOH / CH2Cl2 (NH3) Rf 0.38). 1 H NMR (400 MHz, DMSO-d 6) d 8.21 (s, 1 H), 8.18 (dd, J = 8.0, 2.0 Hz, 1 H), 7.59 (d, J = 8.0 Hz, 1 H), 3.43 (s a, 2H), 3.28 (m, 2H), 3.07 (dd, J = 13.0, 13. 0 Hz, 2H), 2.24 (m, 1 H), 2.08 (d, J = 1 1.5 Hz, 1 H). APCI MS m / e 205.1 [(M + 1) *] p.f. 265-270 ° C.

EXAMPLE 8 4-Amino-10-azatricichlor6.3.1.0 ldodeca-2 (7), 3,5-triene hydrochloride 4-Nitro-10-azatricyclo [6.3.1.02'7] dodeca-2 (7), 3,5-triene (500 mg, 2.08 mmol) in 1,4-dioxane (40 ml) was stirred and treated with solution Na2CO3 saturated aqueous solution (15 ml). To this mixture was added di-t-butyl dicarbonate (1.8 g, 8.31 mmol). After stirring for 18 hours, the reaction was treated with H2O (50 ml), extracted with CH2CI2 (4 x 30 ml), dried through a cotton plug and concentrated to give an oil (500 mg, 91% ). This oil (500 mg, 1.64 mmol) was dissolved in MeOH (30 ml), treated with 10% Pd / C (~50 mg) and hydrogenated under an atmosphere of H2 (45 psi) (1 atm). hour. The mixture was filtered through a pad of Celite and concentrated to a clear oil (397 mg, 88%).

This oil (50 mg, 0.18 mmol) was stirred in 3 N HCl in EtOAc (3 ml) for 2 hours and then concentrated to give a white solid (25 mg, 56%). 1 H NMR (400 MHz, DMSO-d 6) d 7.38-7.10 (3H), 3.60 (s a, 2H), 3.25 (m, 2H), 2.98 (m, 2H), 2.18 (m, 1 H), 1.98 (d, J = 1 1.5 Hz, 1 H). APC MS m / e 175.1 [(m + 1) +] p.f. 189-192 ° C.

EXAMPLE 9 Ni-p-azatricichlorß.3.1.02 71dodeca-2 (7) .3.5-trien-4- illacetamide hydrochloride A) 1- (4-Amino-10-aza-tricyclo6.3.1.0271dodeca-2 (7) .3.5-trien-10-yl) -2.2.2-trifluoroethanone The hydrogenation of 1- (4-nitro- 10-aza-tricyclo [6.3.1.02,7] dodeca-2 (7), 3l5-trien-10-yl) -2,2,2-trifluoride-ethanone (2.0 g, 6.66 mmole) under an H 2 atmosphere (40 psi) (275.79 kPa) and 10% Pd / C (200 mg) in MeOH for 1.5 hours, filtration through Celite and concentration gave a yellow oil (1.7 g). (TLC 50% EtOAc / hexanes Rf 0.27). 1 H NMR (400 MHz, CDCl 3) d 6.99 (m, 1 H), 6.64 (br s, 1 H), 6.57 (m, 1 H), 4.25 (m, 1 H), 3 , 82 (m, 1 H), 3.50 (m, 1 H), 3.17-3.07 (m, 3H), 2.35 (m, 1H), 1, 90 (d, J = 10.8 Hz, 1 H). GCMS m / e 270 (M +).

B) N- (10-Trifluoroacetyl-10-aza-tricyclo [6.3.1.02'71dodeca-2 (7), 3,5-trien-4-ip-acetamide) 1- (4-amino-10-aza-tricyclo [ 6.3.1.02'7] dodeca-2 (7), 3,5-trien-10-yl) -2,2,2-trifluoro-ethanone (850 mg, 3.14 mmol) in CH2Cl2 (5 ml), was treated with triethylamine (0.53 ml, 3.76 mmol) and acetyl chloride (0.23 ml, 3.2 mmol) and then stirred for 18 hours Conventional treatment with NaHCO3 produced an oil which was chromatographed to yield a clear oil (850 g, 87%). (50% EtOAc / hexanes Rf 0.28).

C) N1-l10-azatricichlor6.3.1.02 hydrochloride 7dodeca-2 (7) .3,5-trien-4-iOacetamide N- (10-trifluoroacetyl-10-aza-tricyclo [6.3.1.02'7] was stirred dodeca-2 (7), 3,5-trien-4-yl) -acetamide (100 mg, 0.32 mmol) with Na 2 CO 3 (70 mg, 0.64 mmol) in MeOH (10 mL) and H 2 O (2 mL) at 70 ° C for 18 hours. The mixture was concentrated, water was added and the product was extracted with EtOAc. The organic layer was extracted with 1 N aqueous HCl (3 x 20 ml) and the acid layer was washed with EtOAc (2 x 20 ml). The aqueous layer was basified to pH ~10 with Na2CO3 (s) and the product was extracted with EtOAc (3 x 20 ml). The organic layer was dried (sodium sulfate (Na 2 SO 4)) and concentrated to an oil. This material was dissolved in MeOH and treated with 3N HCl in EtOAc (3 mL), concentrated and recrystallized from MeOH / Et2O to give a solid (40 mg, 50%). 1 H NMR (400 MHz, DMSO-d 6) d 9.98 (s, 1 H), 9.02 (m a, NH), 7.65 (s, 1 H), 7.55 (sa, NH), 7.38 (d, J = 8.0 Hz, 1 H), 7.20 (d, J = 8.0 Hz, 1 H), 3.33 (m, 4H), 2.96 (m, 2H), 2.13 (m , 1 H), 2.00 (s, 3H), 1, 96 (d, J = 10.5 Hz, 1 H).

APCI MS m / e 217.2 [(M + 1) "*]. P., 225-230 ° C.

EXAMPLE 10 6-Methyl-5-thia-7,13-diazatetrachlorchlor9.3.1.02 10.0481pntadeca- 2 (10), 3,6,8-tetraene hydrochloride A) N- (10-Trifluoroacetyl-10-aza-trichloro6.3.1.027dodeca-2 (7) .3.5-trien-4-yl) thioacetamide N- (10-trifluoroacetyl-10-aza-tricyclo [ 6.3.1.02,7] dodeca-2 (7), 3,5-trien-4-yl) -acetamide (850 mg, 2.72 mmol) and 2,4-bis (4-methoxyphenyl) -1, 3-dithia- 2,4-diphosphoethane-2,4-disulfide (Lawesson's reagent) (1.1 g, 2.72 mmol) in toluene (10 ml) and the mixture was refluxed for 1.5 hours. After cooling the reaction, it was treated with EtOAc / saturated aqueous NaHCO3 solution. The organic layer was dried (Na2SO4), filtered, concentrated and chromatographed on silica gel to produce the product (410 mg, 44%). (50% EtOAc ai / Hexanes Rf 0.38).

B) 6-Methyl-5-thia-7,13-diazatetracichlor9.3.1.02,10.04 hydrochloride 81 pentadeca-2 (20) .3,6,8-tetraene The above oil, 2,2,2-trifluoro-N- (10-) trifluorothioacetyl-10-aza-tricyclo [6.3.1.02,7] dodeca-2 (7), 3,5-trien-4-yl) -thioacetamide, (360 mg, 1.05 mmol), was dissolved in MeOH (10 mL) and 1 N NaOH (5 mL) and added to potassium ferricyanide (K3Fe (CN) 6) (1.72 g, 5.23 mmol) in H2O (10 mL). This mixture was heated at 60 ° C for 1.5 hours, cooled, concentrated and treated with EtOAc / H2O. This material was stirred in dioxane (20 ml) and treated with H2O (50 ml) and Na 2 CO 3 until a pH of 10 was obtained. To this was added di-t-butyl dicarbonate (436 mg, 2.0 mmol) and the mixture was stirred for 18 hours. The reaction was concentrated, treated with H2O and extracted with CH2Cl2. The product was chromatographed (silica 30% EtOAc / hexanes Rf 0.41) producing an oil (100 mg). The above product was treated with 3N HCl / EtOAc (3 mL), heated to reflux for -15 minutes and then concentrated to a solid that was azeotropically distilled with CH 2 Cl (2x). These solids were dissolved in a minimum amount of MeOH, then saturated with Et 2 O and stirred. The resulting white crystalline powder was collected by filtration (40 mg, 14%). H NMR (400 MHz, DMSO-d6) d 9.46 (s, NH), 7.65 (s, 1 H), 7.82 (s, 1 H), 7.65 (ma, NH), 3.36 (m, 2H), 3.24 ( m, 2H), 3.02 (m, 2H), 2.76 (s, 3H), 2.23 (m, 1 H), 2.06 (d, J = 10.8 Hz, 1 H). APCI MS m / e 231, 1 [(M + 1) 4]. p.f. 183-184 ° C.

EXAMPLE 11 4.5-Dinitro-10-aza-tricichlor6.3.1.02.71dodeca-2.7), 3,5-triene A) 1-.4,5-Dnitro-10-aza-trichloride [6.3.1.02-71dodeca-2 (7) .3.5-trien-10-¡n-2.2.2-trifluoride -etanone (Based on the procedure described in Coon, CL; Blucher, WG; Hill, MEJ Org. Chem. 1973, 25, 4243. For an additional example of related nitration, see: Tined, H., Ishitobi, H .; Irie, T., Tsushima, TJ Am. Chem. Soc. 1969, 91, 4512). To a solution of trifluoromethanesulfonic acid (79.8 ml, 902.1 mmol) in CH2Cl2 (550 ml) stirred at 0 ° C, nitric acid (19.1 ml, 450.9 mmol) was slowly added generating a white precipitate. After 10 minutes, 1- (10-aza-tricyclo [6.3.1.02] was added dropwise, 7] dodeca-2 (7), 3,5-trien-10-yl) -2,2,2-trifluoro-ethanone (50 g, 196 mmol) in CH 2 Cl 2 (300 ml) from an addition funnel for 30 minutes. minutes The reaction was stirred at 0 ° C for 2.5 hours and then stirred at room temperature for 24 hours. The reaction mixture was poured into a vigorously stirred mixture of H2O (500 ml) and ice (400 g). The layers were separated and the aqueous layer was extracted again with CH2Cl2 (3 x 300 ml). The organic layers were combined and washed with H2O (3 x 300 ml). The combined aqueous layers were back extracted with CH2Cl2 (2 x 100 mL). The organic layers were combined and washed with saturated aqueous NaHCO3 solution (200 ml) and H2O (200 ml), then dried through a cotton plug and concentrated to produce solids. Trituration with EtOAc / hexanes produced off-white solids that were filtered and dried (52 g, 151 mmol, 77%). The mother liquor was chromatographed to give 4.0 g more for a total of 56.0 g (82.8%). (TLC 50% EtOAc / hexanes Rf 0.29). 1 H NMR (400 MHz, CDCl 3) d 7.77 (s, 1 H), 7.75 (s, 1 H), 4.39 (d a, J = 13.0 Hz, 1 H), 3.98 (day, J = 13.0 Hz, 1 H), 3.65 (d, J = 13.0 Hz, 1 H), 3.49 (sa, 1 H), 3.44 (sa, 1 H) , 3.24 (day, J = 12.6 Hz, 1 H), 2.53 (m, 1 H), 2.14 (d, J = 1 1.5 Hz, 1 H). GCMS m / e 345 (M +).

B) 4.5-Dinitro-10-aza-trichloro6.3.1.02'7dodeca-2 (7), 3.5-triene met 1- (4,5-dinitro-10-aza-tricyclo [6.3.1.02 , 7] dodeca-2 (7), 3,5-trien-10-yl) -2,2,2-trifluoro-ethanone (3.7 g, 10.7 mmoles) and Na2CO3 (2.3 g, 21.4 mmoles) in MeOH (50 ml) and H2O (20 ml), and then the mixture was refluxed for 18 hours. The reaction was cooled, concentrated, treated with H 2 O, extracted with CH 2 Cl 2 (3 x 50 mL) and then dried through a cotton plug. After concentration, the residue was chromatographed to give brown solids. (1.9 g, 71%). (TLC 5% MeOH / CH2Cl2 (NH3) Rf 0.36). 1 H NMR (400 MHz, CDCl 3) d 7.69 (s, 2 H), 3.17 (sa, 2 H), 3.1 1 (d, J = 12.6 Hz, 2 H), 2.53 (m, 1 H), 2.07 (d, J = 11.0 Hz, 1 H). GCMS m / e 249 (M +).

EXAMPLE 12 6-Methyl-7-propyl-5,7-13-triazatetracichlor9.3.1.02'10.04,81 pentadeca-2 (10), 3,5.8-tetraene hydrochloride A) 4,5-Dinitro-10-aza-tricyclo3.3.1.027dodeca-2 (7) .3.5-trine-10-carboxylic acid tert-butyl ester 4,5-dinitro-10- was stirred aza-tricyclo [6.3.1.02'7] dodeca-2 (7), 3,5-triene, (1.9 g, 7.6 mmoles) in 1,4-dioxane (75 ml) and treated with saturated aqueous Na 2 CO 3 solution ( 10 ml). To this mixture was added di-t-butyl dicarbonate (3.31 g, 15.2 mmol). After stirring for 6 hours, the reaction was treated with H2O (50 ml) and extracted with EtOAc (4 x 25 ml), dried (Na2SO4), filtered, concentrated and chromatographed to give the product (1.9 g, 71%). (TLC 30% EtOAc / hexanes (NH3) Rf 0.58). 1 H NMR (400 MHz, CDCl 3) - 7.77 (br s, 1 H), 7.72 (br s, 1 H), 4.08 (br, 1 H), 3.92 (br, 1 H), 3.39 (br, 1 H), 3.27 (sa, 1 H), 3.25 (m, 1 H), 3.18 (m, 1 H), 2.46 (m, 1 H), 2.02 (d, J = 1 1.0 Hz, 1 H).

B) 4,5-Diamino-10-aza-tricyclo [6.3.1.02,71dodeca-2 (7) .3,5-triene-10-carboxylic acid tert-butyl ester 4,5-dinitro- 10-aza-tricyclo [6.3.1.02,7] dodeca- 2 (7), 3,5-triene-10-carboxylic acid (1.9 g, 5.44 mmole) in MeOH under an atmosphere of H2 (45 psi) (310.26 kPa) on 10% Pd / C (100 mg) for 1.5 hours, then filtered through a pad of Celite and concentrated to give white solids (1.57 g, 100%). (TLC 5% MeOH / CH2Cl2 (NH3) Rf 0.14).

C) 6-Methyl-5,7,13-triazatetracyclic tert-butyl ester [9.3.1.02'10.04'8lpentadeca-2 (10) .3,5,8-tetraene-13-carboxylic acid (For the conditions, see: Segelstein , BE; Chenard, BL; Macor, JE; Post, RJ Tetrahedron Lett., 1993, 34, 1897). 4,5-Diamino-10-aza-tricyclo [6.3.1.02'7] dodeca-2 (7), 3,5-triene-10-carboxylic acid tert-butyl ester (700 mg, 2.42 mmol) was dissolved in EtOH (10 ml) and acetic acid (HOAc) (1 ml) and treated with 1-ethoxyethylamine mononitrile (329 mg, 2.42 mmol). The resulting mixture was heated to 60 ° C and stirred for 18 hours. The reaction was cooled, concentrated, treated with H2O and saturated aqueous Na2CO3 solution, extracted with EtOAc (3 x 50 mL) and then dried (Na2SO4). After filtration and concentration, the residue was chromatographed to give brown solids (247 mg, 36%). (TLC 5% MeOH / CH2Cl2 (NH3) Rf 0.28).

D) 6-Methyl-7-propyl-5,7-13-triazatetracichlor9.3.1.02 10.04, 81 pentane-2 (10) .3.5.8-tetraene-13-carboxylic acid tert-butyl ester (For conditions , see: Pilarski, B. Liebigs Ann. Chem. 1983, 1078). 6-Methyl-5,7,13-triazatetracyclo [9.3.1.02'10.04'8] pentadeca-2 (10), 3,5,8-tetraene-13-carboxylic acid tert -butyl ester (80 mg, 0.267 mmoles) in 50% aqueous solution of NaOH (3 ml) and DMSO (1 ml) and then treated with 1-iodopropane (0.03 ml, 0.321 mmol). This mixture was heated at 40 ° C for 2 hours, then cooled, treated with H2O and extracted with EtOAc. The organic layer was washed with H2O (3x), then dried (Na2SO4), filtered and concentrated to an oil (90 mg, 0.253 mmol). (TLC 5% MeOH / CH2Cl2 (NH3) Rf 0.15).

E) 6-Methyl-7-propyl-5.7.13-triazatetrachlorchlor9.3.1.02 0.048lpentadeca-2 (10), 3,5,8-tetraene hydrochloride 6-Methyl-7-tert-butyl ester was dissolved propyl-5,7,13-triazatetracyclo [9.3.1.02,10.04,8] pentadeca-2 (10), 3,5,8-tetraene-13-carboxylic acid (90 mg, 0.253 mmol) in 3 N HCl in EtOAc (5%). ml) and heated at 100 ° C for 0.5 hours. The mixture was cooled, concentrated, suspended in EtOAc and filtered to give a white solid (25 mg, 34%). 1 H NMR (400 MHz, DMSO-d 6) d 9.56 (s, 1 H), 7.91 (s, 1 H), 7.83 (ma, NH), 7.74 (s, 1 H), 4.38 (m, 2H), 3.48 (m, 2H), 3.32 (m, 2H), 3.10 (m, 2H), 2.87 (s, 3H), 2.28 (m, 1 H), 2.15 (d, J = 1 1.0 Hz, 1 H), 1.85 (m, 2H), 0.97 (m, 3H). p.f. 147-150 ° C.

EXAMPLE 13 5.7.13-Triazatetracichlor Hydrochloride 9.3.1.02 10.0481 Pentadeca-2 (10) .3.5.8-Tetraene A) Tert-butyl ester of 5,7,13-triazatra-tetrachloro3.3.1.02"l0.04 81 pentadeca-2 (10) .3,5,8-tetraene-13-carboxylic acid (For the conditions, see: Segelstein , BE; Chenard, BL; Macor, JE; Post, RJ Tetrahedron Lett., 1993, 34, 1897). 4,5-Diamino-10-aza-tricyclo-tert-butyl ester [6.3.1.02'7] was dissolved. dodeca-2 (7), 3,5-triene-10-carboxylic acid (1.0 g, 3.45 mmol) in EtOH (10 ml) and HOAc (1 ml) and treated with ethoxymethylene-malonitrile (421 mg, 3.45 mmol). The resulting mixture was heated to 60 ° C and stirred for 18 hours, the reaction was cooled, concentrated, treated with H 2 O and saturated aqueous Na 2 CO 3 solution, extracted with EtOAc (3 x 50 ml) and then dried (Na 2 SO 4). After filtration and concentration, the residue was chromatographed to give brown solids (580 mg, 56%). (TLC 5% MeOH / CH 2 Cl 2 (NH 3) Rf 0.28).

B) 5.7.13-triazatetracyclohydrochloride [9.3.1.02 10.04 81-pentadeca-2 (10), 3,5,8-tetraene The tert-butyl ester of 5,7,13-triazatetracycle ^ .SI. O ^^. O ^^ pentadeca1 OJ.Sdd-tetraeno-IS-carboxylic acid was converted to the title compound by the procedures described in Example 12E. 1 H NMR (400 MHz, D 2 O) d 8.95 (s, 1 H), 7.67 (s, 2 H), 3.45 (s a, 2H), 3.31 (d, J = 12.5 Hz, 2H), 3.13 (d, J = 12.5 Hz, 2H), 2.30 (m, 1 H), 1.99 (d, J = 11.5 Hz, 1 H). APCI MS m / e 200.1 [(M + 1) *]. p.f. > 250 ° C.

EXAMPLE 14 7-Methyl-5.7.13-triazatetracichlorhydrochloride9.3.1.02'10.04 B1pentadeca- 2 (10) .3,5.8-tetraene Using the procedures described in Example 12D, the 5,7,13-triazatetracyclo tert-butyl ester [9.3.1.02 'l0.04'8] pentadeca-2 (10), 3,5,8-tetraene was converted -13-carboxylic acid in the title compound, by reaction with iodomethane followed by deprotection as described in Example 12E. 1 H NMR (400 MHz, D 2 O) d 8.97 (s, 1 H), 7.71 (s, 1 H), 7.67 (s, 1 H), 3.94 (s, 3 H), 3.48 (m, 2 H), 3.33 (d, J = 12.2 Hz, 2H), 3.14 (d, J = 12.2 Hz, 2H), 2.34 (m, 1 H), 2.03 (d, J = 11.5 Hz, 1 H). APCI MS m / e 214.2 [M + 1) *].

EXAMPLE 15 6-Methyl-5.7.13-triazatetracichlor9.3.1.02 Hydrochloride 10.04'81Pentadeca- 2 (10., 3,5,8-tetraene) The 6-methyl-5,7,13-triazatetracyclo [9.3.1.02,10.04'8] pentadeca-2 (10), 3,5,8-tetraene-13-carboxylic acid tert-butyl ester was converted into the compound of the title by the procedures described in example 12E. 1 H NMR (400 MHz, DMSO-d 6) d 9.40 (ma, NH), 7.77 (ma, NH), 7.70 (s, 1 H), 3.44 (m, 2H), 3.30 (m, 2H), 3.05 (da , J = 11.0 Hz, 2H), 2.79 (s, 3H), 2.23 (m, 1 H), 2.10 (d, J = 10.8 Hz, 1 H). GCMS m / e 213.5 (M +).

EXAMPLE 16 6.7-Dimethyl-5.7.13-triazatetracycle_9.3.1.02 10.0481 pentadeca-2 (10) .3.5.8-tetraene hydrochloride Using the procedures described in Example 12D, the 6-methyl-5,7,13-triazatetracyclic tert-butyl ester was converted to a .sup.12.sup.-O.sup. carboxylic acid in the title compound by reaction with iodomethane followed by deprotection as described in Example 12E. 1 H NMR (400 MHz, DMSO-d 6) d 9.52 (s, NH), 7.84 (s, 1 H), 7.82 (m, NH), 7.72 (s, 1 H), 3.90 (s, 3 H), 3.45 ( m, 2H), 3.28 (m, 2H), 3.04 (m, 2H), 2.82 (s, 3H), 2.23 (m, 1 H), 2.12 (d, J = 11 .0 Hz, 1 H). APCl MS m / e 228.2 [M + 1 )*]. p.f. 225-230 ° C.

EXAMPLE 17 7-Propyl-5.7.13-triazatetracyclohydrochloride .9.3.1.02'10. 04'81 pentadeca-2 (10) .3.5.8-tetraene Using the procedures described in Example 12D, the t-butyl ester of 5,7,13-triazatetracyclo [9.3.1.02'10.04,8] pentadeca-2 (10), 3,5,8-tetraeo-13 acid was converted -carboxylic acid in the title compound by reaction with iodopropane followed by deprotection as described in example 12E. 1 H NMR (400 MHz, DMSO-d 6) d 9.52 (s.1 H), 9.45 (sa.NH), 7.97 (s.1 H), 7.85 (s.1 H), 7.83 (ma.NH), 4.43 (m.2H), 3.49 (m.2H), 3.33 (m.2H), 3.08 (m.2H), 2.28 (m.1 H), 2.15 (dJ = 1 1.0Hz.1 H), 1.92 (m .2H), 0.93 (m.3H). APCl MS m / e 242.2 [(M + 1) +]. P.f.170-171 ° C (up.).

EXAMPLE 18 7-Butyl-5,7,13-Triazatetracycle_9.3.1.02 Hydrochloride 0.0481Pentadeca- 2 (10), 3.58-tetraene A) 4-Butylamino-5-nitro-10-aza-tricyclo [6.3.1.02 71dodeca-2 (7), 3,5-triene-10-carboxylic acid tert-butyl ester For the conditions, see; Senskey, M.D .; Bradshaw, J.D .; Tessier, C.A .; Youngs, W.J. Tetrahedron Lett. 1995, 36, 6217.) The tert-butyl ester of 4,5-dinitro-10-aza-tricyclo [6.3.1.02,7] dodeca-2 (7), 3,5-triene-10-carboxylic acid (500 mg, 1.43 mmol) and 1-butylamine (1.42 ml, 14.3 mmol) in THF (5 ml) and stirred for 4 hours. The mixture was diluted with EtOAc (50 ml) and washed with H2O (3x30 ml), then dried (Na2SO4), filtered and concentrated to an oil. This oil was passed through a silica gel filter column to remove the initial impurities eluting with 30% EtOAc / hexanes (510 mg, 1.41 mmol, 99%).

B) 4-Butylamino-5-amino-10-aza-tricyclo6.3.1.027dodeca-2 (7) .3.5-triene-10-carboxylic acid tertiary ester Tert-butyl ester of 4-butyl acid -butylamino-5-nitro-10-aza-tricyclo [6.3.1.02,7] dodeca-2 (7), 3,5-triene-10-carboxylic acid (460 mg, 1.27 mmol) with ammonium formate (850 mg, 12.7 mmoles) and 10% Cd (OH) 2 (50 mg) in MeOH (20 ml), refluxed for 1 hour and then filtered through a pad of Celite and concentrated. The solids were treated with saturated aqueous Na 2 CO 3 solution), extracted with CH 2 Cl 2 (3x30 ml) and dried by filtration through a cotton plug to give an oil (400 mg, 100%).

C) 7-Butyl-5,7,13-triazatetracichlor9.3.1.02 10-04 8lpentadeca-2 (10), 3,5,8-tetraene-13-carboxylic acid tert-butyl ester Tert-butyl ester was dissolved of 4-butylamino-5-amino-10-aza-tricyclo- [6.3.1.027] dodeca-2 (7), 3,5-triene-10-carboxylic acid (440 mg, 1.27 mmol) in EtOH (20 ml) and HOAc (2 ml) and treated with ethoxymethylenemalononitrile (168 mg, 1.52 mmol). The resulting mixture was heated to 60 ° C and stirred for 18 hours. The reaction was cooled, concentrated, treated with H2O and saturated aqueous Na2CO3 solution, then extracted with EtOAc (3x50 mL) and dried (Na2SO). After filtration and concentration, the residue was chromatographed to give a yellow oil. (400 mg, 89%). (TLC 5% MeOH / CH2Cl2 (NH3) Rf 0.70).

D) 7-Butyl-5.7.13-triazatetracichlorhydrate 9.3.1.02 10.04 81-pentadeca-2 (10) .3.5.8-tetraene The 7-butyl-5,7,13 tert-butyl ester was converted -triazatetracyclo [9.3.1.02,10.04,8] pentadeca-2 (10), 3,5,8-tetraene-13-carboxylic acid in the title compound by the procedures described in example 12E. 1 H NMR (400 MHz, DMSO-d 6) d 9.93 (br.NH), 9.68 (1 H), 7. 99 (s.1 H), 7.92 (ma.NH), 7.87 (s.1 H), 4.50 (m.2H), 3.49 (m.2H), 3.30 (m.2H), 3. 08 (m.2H), 2.26 (m.1 H), 2.15 (d.J = 11.0 Hz.1 H), 1.88 (m.2H), 1.32 (m.2H), 0. 82 (t, J = 7.0 Hz.3H). APCl MS m / e 256.2 [(M + 1) +]. P.f. 204-208 ° C.

EXAMPLE 19 7-Isobutyl-5.7.13-triazatetracyclocycle 9.3.1.02 10.0481 pentadeca-2 (10..3.5.8-tetraene) The 4,5-dinitro-10-aza-tricyclo6.3.1.02,7] dodeca-2 (7), 3,5-triene-10-carboxylic acid ester and isobutylamine in the title compound were converted. using the procedures described in example 18A-D. 1 H NMR (400 MHz, CDC13) d 7.74 (s.1 H), 7.52 (s.1 H), 7.14 (s.1 H), 3.90 (dd, J = 7.5.2.0 Hz, 2H), 3.04-2.97 (m, 4H), 2.70 (dd, J = 12.8.2.3 Hz), 2.42 (m, 1 H), 2.19 (m, 1 H), 1.98 (d, J = 10.5 Hz, 1 H), 0.93 (m , 6H). APCl MS m / e 256.2 [(M + 1) "*"]. p.f. 147-150 ° C (up.).

EXAMPLE 20 6-Methyl-7-isobutyl-5.7.13-triazatetracichlor9.3.1.02'10.04 Hydrochloride 81petadeca-2 (10) .3.5.8-tetraene A) 6-Methyl-7-isobutyl-5,7,13-triazatetracyclo [9.3.1.02 10.04-8-formaldehyde-2 (10), 3.5.8-tetraene-13-carboxylic acid tert-butyl ester 4-amino-5-isobutylamino-10-aza-tricyclo [6.3.1.02,7] dodeca-2 (7), 3,5-triene-10-carboxylic acid (250 mg, 0.74 mmol) of Example 19B was dissolved in EtOH (10 ml) and HOAc (2 ml) and processed with 1-ethoxyethylene-malononitrile (1 18 mg, 0.87 mmol). The reaction proceeded as in example 18c (18h) and was treated in a similar manner to give the product (TLC 3% MeOH / CH2C12 (NH3) Rf 0.57).

B) 6-Methyl-7-isobutyl-5.7.13-triazatetracyclo-hydride [9.3.1.02 10.04 81 pentadeca-2 (10), 3,5.8-tetraene The 6-methyl-7-tert-butyl ester was converted isobutyl-5,7,13-triazatetracyclo [9.3.1.02'10.04'8] pentadeca-2 (10), 3,5,8-tetraene-13-carboxylic acid in the title compound by the procedures described in example 12E. APCl MS m / e 270.3 [M + 1) +]. Pf. 129-130 ° C (up.).

EXAMPLE 21 7-Phenyl-5.7.13-Triazatetracyclor9.3.1, 02.10.0481Pentadeca- 2 (10) .3.5.8-tetraene Hydrochloride Using the procedures described in Example 18A, the 4,5-dinitro-10-aza-tricyclo [6.3.1.02,7] dodeca-2 (7), 3,5-triene-10-tert-butyl ester was converted -carboxylic and aniline in the tert-butyl ester of 4-phenylamino-5-nitro-10-aza-tricyclo [6.3.1.02'7] dodeca-2 (7), 3,5-triene-10-carboxylic acid at 75 ° C for 4 hours, in the coupling stage. Then, this was converted to the title compound using the procedures described in Examples 18B, C and D. 1HRMN (400 MHz.DMSO-de) d 9.08 (1 H), 7.78-7.57 (m, 7H), 3.47- 3.00 (m, 6H), 2.23 (m, 1 H), 2.09 (d, J = 1 1.5 Hz, 1 H) .APCI MS m / e 276.2 [(m + 1) +]. Pf 210-213 ° C EXAMPLE 22 6-Methyl.7-phenyl-5.7.13-triazatetracichlor9.3.1.02 0- (T'a1pentadeca-2 (10) .3.5,8-tetraene Hydrochloride Using the procedures described in Example 21 and Example 20, the 4,5-dinitro-10-aza-tricyclo [6.3.1.02,7] dodeca-2 (7), 3-tert-butyl ester was converted, 5-triene-10-carboxylic acid and aniline in the title compound. 1 H NMR (400 MHz, DMSO-d 6) d 7.79 (s.1 H), 7.73-7.56 (m, 5H), 7. 32 (s, 1 H), 3.46-2.99 (m, 6H), 2.66 (s, 3H), 2.23 (m, 1 H), 2.08 (d, J = 11.0 Hz, 1 H).

APCl MS m / e 290.2 [(M + 1) +]. P.f. > 250 ° C.

EXAMPLE 23 7-Neopentyl-5.7.13-triazatetracyclohylohydrate, 9.3.1.02'9.0481 pentadeca- 2 (10) .3.5.8-tetraene Using the procedures described in examples 18A-D, the 4,5-dinitro-10-aza-tricyclic [6.3.1.02'7] dodeca-2 (7), 3,5-triene-10-tert-butyl ester was converted. carboxylic acid and neopentylamine in the title compound. Precursor t-Boc GCMS m / e 369 (M +). (salt HC1) p.f. > 250 ° C EXAMPLE 24 6-Methyl-7-neopentyl-5,7,13-triazatetracyclo-9.3.1.02'10.04'81 pentadeca-2 (10) .3.5.8-tetraene hydrochloride Using the procedures described in Examples 21 and 20, the 4,5-dinitro-10-aza-tricyclo [6.3.1.02,7] dodeca-2 (7), 3,5-triene tert-butyl ester was converted -10-carboxylic acid and neopentylamine in the title compound. 1 H NMR (400 MHz, DMSO-d 6) d 7.31 (s, 1 H), 7.27 (s, 1 H), 7. 02 (sa, NH), 4.41 (t, J = 13.0 Hz, 2H), 3.90 (s, 3H), 3.47-3.26 (m, 6H), 2.20 (m, 1 H), 2. 00 (d, J = 1 1.5 Hz, 1 H), 0.90 (s, 9H). Precursor t-Boc APCl MS m / e 384. 2 [(M + 1) +]. P.f. > 250 ° C.

EXAMPLE 25 6.7-Dimethyl-5.8.14-trlazatetraciclop hydrochloride 0.3.1.02 11.0491hexadeca- 2 (11) .3.5.7.9-pentane (Based on the following procedure: Jones, R. G .; McLaughlin, K.C .; Org. Syn. 1963, 4, 824. b) Ehrlich, J., Bobert, M.T.J. Org. Chem. 1947, 522.) The 4,5-diamino-10-aza-tricyclo [6.3.1.02'7] dodeca-2 (7), 3,5-triene-10-carboxylic acid tert-butyl ester was heated. (100 mg, 0.35 mmol) at 80 ° C in H2O (5 ml). To this butane 2,3-dione (0.034 ml, 0.38 mmol) was added under N2 for 2 hours. The reaction was cooled to room temperature and extracted with EtOAc (3 x 40 mL). The combined organic layer was washed with H2O (2 x 30 ml), dried (Na2SO4), filtered, concentrated and chromatographed on silica gel to provide an oil (120 mg, 100%). The oil was dissolved in 2 N HC1 in MeOH (5 mL), heated to reflux for 30 minutes and then concentrated. Recrystallization from MeOH / Et2O afforded white powder (150 mg, 43%). (TLC EtOAc Rf 0.14). 1 H NMR (400 MHz, DMSO-d 6) d 7.85 (S, 2h, 3.50 (HS, 2h), 3.32 (d, J = 12.5 Hz, 2H), 3.10 (d, J = 12.5 Hz, 2H), 2.64 (s.6H), 2.24 (m, 1 H), 2.13 (d, J = 1 1.0 Hz, 1 H). Precursor t-Boc APCl MS m / e 340.3 [(M + 1) 4].

EXAMPLE 26 Hydrochloride of 5.8.14-triazatetracycloH 0.3.1.02 11,049l-hexadeca- 2 (11) .3.5.7.9-pentane A) 1 -, 4,5-Diamino-10-aza-tricyclo6.3.1.027dodeca-2 (7), 3,5-trien-10-n-2,2,2, -trifluoroethanone Hydrogenated 1- (4, 5-dinitro-10-aza-tricyclo [6.3.1.02,7] dodeca-2 (7)) 3,5-trien-10-yl) -2,2,2-trifluoro-ethanone (3.0 g, 8.70 mmol) in MeOH (30 ml) under H2 (45 psi) (310.26 kPa) over Pd (OH) 2 (300 mg of 20% w / w, 10% by weight). After 2.5 hours, the reaction was filtered through a pad of celite and rinsed with MeOH (30 ml). The solution was concentrated to give a light brown oil which crystallized (2.42 g 96%). (TLC 10% MeOH / CH2Cl2Rf0.56). APCl MS m / e 286.2 [(M + 1) +]. p.f. 129-131 ° C.

B) 1- (5,8,14-triazatetracyclo [10.3.1.02 11.04 9l-hexadeca-2 (11) .3.5.7.9-pentaeno) -2,2.2-trifluoro-ethanone. It was stirred 1- (4,5-diamino) -10-aza-tricyl [6.3.1.02,7] dodeca-2 (7), 3,5-trien-10-yl) -2,2,2-trifluoro-ethanone (500 mg, 1.75 mmol) in THF ( 2 ml). This mixture was treated with H2O (2 ml) and with the hydrated addition compound of glyoxal and sodium bisulfite (931 mg, 3.50 mmol), and then stirred at 55 ° C for 2.5 hours. The reaction was cooled to room temperature and extracted with EtOAc (3 x 40 mL). The combined organic layer was washed with H2O (2 x 30 ml), dried (Na2SO), filtered, concentrated and chromatographed on silica gel to yield an off-white powder (329 mg, 60%). (TLC EtOAc al % / hexanes Rf 0.40). p.f. 164-166 ° C.

C) Hydrochloride of 5.8.14-triazatratraciclop? 3,1.02-11.04 9-hexadeca-2 (11), 3,5,7,9-pentaene 1 - (5,8,14-triazatetracyclo) was suspended [10.3.1.02 11.04'9] -hexadeca-2 (11), 3,5,7,9-pentane) -2,2,2-trifluoro-ethanone (320 mg, 1.04 mmol) in MeOH (2.0 ml) and was treated with Na2CO3 (221 mg, 2.8 mmol) in H2O (2.0 ml). The mixture was heated at 70 ° C for 2 hours, then concentrated, treated with H2O (20 ml) and extracted with CH2C12 (3 x 10 ml). The organic layer was dried through a cotton plug and concentrated to give a light yellow oil (183 mg, 83%) which solidified upon standing (mp 138-140 ° C). This material was dissolved in MeOH (10 ml), treated with 3 M HCl / EtOAc (3 ml), concentrated and azeotropically distilled with MeOH (2 x 20 ml) to give solids which were recrystallized from MeOH / Et2O producing the product in the form of a white solid (208 mg, 97%). (TLC 5% MeOH / CH2C12 (NH3) Rf 0.26). 1 H NMR (400 MHz, CD 3 OD) d 8.94 (s, 2 H), 8.12 (s, 2 H), 3.70 (m, 2H), 3.54 (d, J = 12.5 Hz, 2H), 3.35 (d, J = 12.5 Hz, 2H), 2.49 (m, 1 H), 2.08 (d, J = 11.0 Hz, 1 H). GCMS m / e 21 1 (M +). p.f. 225-230 ° C.

EXAMPLE 27 14-Methyl-5,814-triazatetracyclo chloride 10.3.1.02'11.0 91 hexadeca-2 (11) .3.5.7.9-pentane ,8,14-Triazatetracyclo [10.3.1.02,11.04 9] -hexadeca-2 (11), 3,5,7,9-pentaene (207 mg, 0.98 mmol) was treated with 37% aqueous formalin solution ( 1 ml) and formic acid (1 ml), then heated at 80 ° C for 1 hour. The reaction was poured into water, made basic (NaOH, pH ~ 11) and extracted with EtOAc. The organic layer was dried (Na2SO4), concentrated and chromatographed on silica gel to yield a yellow solid. This material was stirred in MeOh (2 mL) and treated with 3 N EtOAc HCl (2 mL). After concentration, the solids were recrystallized from MeOH / Et2O producing the product as a white solid (70 mg, 27%). (2% MeOH / CH2C12 (NH3) Rf 0.47). 1 H NMR (400 MHz, CDC13) d 8.71 (s, 2 H), 7.80 (s, 2 H), 3.37 (s, 2 H), 3.03 (m, 2 H), 2.47 (m, 2 H), 2.32 (m, 1 H ), 2.18 (sa, 3H), 1.84 (d, J = 11.0 Hz, 1 H). APCl MS m / e 226.2 [(M + 1) +]. p.f. > 250 ° C.

EXAMPLE 28 5-Oxa-7 Hydrochloride. 13-diazatetracycle-r9.3.1.02'10. 04,81 pentadeca-2 (10., 3,6,8-tetraene) A) 2,2,2-Trifluoro-1- (4-hydroxy-5-nitro-10-aza-tricichlor6.3.1.02 71-doceca-2 (7), 3,5-trin-10-yl) ) -etanone 1- (4, 5-dithro-10-aza-tricyclo [6.3.1.02, 7] dodeca-2 (7), 3,5-trien-10-yl) -2I2) 2-trifluoro-ethanone (900 mg, 2.61 mmole) and potassium acetate (KOAc) (2.6 g, 26.1 mmole) in DMSO (10 ml) and the mixture was heated with stirring at 100 ° C for 16 hours. The mixture was cooled and diluted with H2O (50 ml), then extracted with 80% EtOAc / hexanes (6 x 25 ml). The organic layer was washed with H2O (3 x 20 ml), dried (Na2SO4), filtered, concentrated and purified by chromatography to give an oil (575 mg, 70%). (TLC 50% EtOAc / hexanes (NH3) Rf 0.56).

B) 2,2,2-Trifluoro-1 - (4-hydroxy-5-amino-10-aza-tricyclo [6.3.1.027 ldodeca-2 (7). 3.5-trien-10-yl) -ethanone 2,2,2-Trifluoro-1- (4-hydroxy-5-nitro-10-aza-tricyclo [6.3.1.02'7] dodeca-2 (7) was hydrogenated, 3,5-trien-10-yl) -etone (575 mg, 1.82 mmol) in MeOH under an atmosphere of H2 at (45 psi) (310.26 kPa) over 10% Pg / C (80 mg) for 1.5 hours , then filtered through a pad of Celite and concentrated until white solids were obtained (450 mg, 86%). (TLC 5% MeOH / CH2C12 (NH3) Rf 0.6). 1 H NMR (400 MHz, CD 3 OD) d 6.67-6.59 (m, 2 H), 4.12 (m, 1 H), 3. 73 (m, 1 H), 3.73 (m, 1 H), 3.51 (m, 1 H), 3.07 (m, 2H), 2.24 (m, 1 H), 1.94 (d, J = 10.5 Hz, 1 H). GCMS m / e 286 (M +).

C) 2,2.2-Trifluoro-1- (5-oxa-7,13-diazatetracycle T9.3.1.02 10. 04 81 pentadeca-2 (10). 3,6,8-tetraene) -etonone (Goldstein, SW Dambek, PJJ Het Chem. 1990, 27, 335.) 2,2,2-Trifluoro-1- (4-hydroxy-5-amino-10-aza-tricyclic met) [6.3.1.02,7] dodeca-2 (7), 3,5-trien-10-yl) -ethanone (150 mg, 0.524 mmol), trimethyl orthoformate (0.19 ml, 1.73 mmol), pyridinium- p-toluenesulfonic (PPTS, 18 mg, 0.07 mmol) and xylenes (10 ml) under nitrogen and stirred at 135 ° C for 18 hours. The mixture was cooled, treated with H2O and extracted with EtOAc. The extracts were dried (Na 2 SO 4), filtered, concentrated and purified by chromatography to give an oil (10 mg, 71%). (TLC EtOAc 20% / hexanes Rf 0.40).

D) 5-Oxa-7,13-diazatetracyclo-r9.3.1.02 10.0481 pentedeca-2 (10), 3,6,8-tetraene hydrochloride 2,2,2-trifluoro-1- (5-oxa) -7,13-diazatetraciclo- [9.3.1.02 10.04'8] pentadeca-2 (10), 3,6,8-tetraene) -ethanone (110 mg, 0.37 mmol) in MeOH (5 ml) and was treated with Na2CO3 (78 mg, 0.74 mmol) in H2O (2 ml). The stirred mixture was heated at 80 ° C for 2 hours, concentrated to give solids, diluted with H2O and extracted with EtOAc (3 x 40 mL). The product was extracted into aqueous 1 N HCl solution (2 x 40 ml), which was washed with EtOAc and then neutralized with saturated aqueous Na 2 CO 3 solution at pH-10. The product was extracted with EtOAc (3 x 40 ml). , dried (Na2SO4), concentrated and chromatographed on silica gel producing an oil. (TLC % MeOH / CH2C12 (NH3) Rf 0.19). The oil was dissolved in MeOH and treated with 3N HCl in EtOAc (4 mL), then concentrated, stirred at a minimum of CH2C12 and saturated with hexanes. After 18 hours, the product was collected by filtration (55 mg, 63%). 1 H NMR (400 MHz CD3OD) d 8.47 (s, 1 H), 7.70 (s, 1 H), 7.65 (s, 1 H), 3.41 (m, 2 H), 3.30 (m, 2 H), 3.10 (d, J = 12.5 Hz 2H), 2.47 (m, 1 H), 2.15 (d, J = 1 1.0 Hz, 1 H). APCl MS m / e 201.03 [(M + 1) +].

EXAMPLE 29 ß-Methyl-5-oxa-7.13-diazatetracichlor9.3.1.02 10.04'81 pentane-2 (10), 3,6,8-tetraene hydrochloride A) 2,2.2-Trifluoro-1- (6-methyl-5-oxa-7,13-diazatetracyclo- 9.3.1.02-10.04-8lpentadeca-2 (10) .3,6,8-tetraene) -ethanone They met 2,2,2-trifluoro-1- (4-hydroxy-5-amino-10-aza-tricyclo [6.3.1.02,7] dodeca-2 (7), 3,5-trien-10-yl) -ethanone (150 mg, 0.524 mmol), triethyl orthoacetate (0.34 ml, 1.83 mmol), pyridinium-p-toluenesulfonic acid (PPTS, 20 mg, 0.08 mmol) and xylenes (10 ml) under nitrogen and the mixture was stirred at 135 °. C for 18 hours. Treatment, isolation and purification as in Example 28C provided the title compound (90 mg, 55%).

B) 6-Methyl! -5-oxa-7,13-diazatetracic! O- [9.3.1.02 10.04 8lpentadeca-2 (10) .3,6,8-tetraene hydrochloride. 2,2,2-trifluoro-1- was stirred. (6-methyl-5-oxa-7,13-diazatetracyclo- [9.3.1.02,10.04,8] pentadeca-2 (10), 3,6,8-tetraene) -ethanone (90 mg, 0.30 mmol) in MeOH (5 ml) and treated with Na2CO3 (61 mg, 0.58 mmol) in H2O (2 ml). The stirred mixture was heated at 80 ° C for 2 hours, concentrated until solids were obtained, diluted with H2O and extracted with EtOAc (3 x 40 ml). The solution was dried (Na 2 S 4), concentrated and chromatographed on silica gel to produce an oil. (TLC 10% MeOH / CH2C12 (NH3) Rf 0.18). 1 H NMR (free base) (400 MHz, CDC13) d 7.40 (s, 1 H), 7.26 (s, 1 H), 3.02-2, 98 (m, 4H), 2.72 (d, J = 12.8 Hz, 2H ), 2.59 (s, 3H), 2.46 (m. 1 H), 1.98 (d, J = 10.5 Hz, 1 H). The oil was dissolved in MeOH and treated with 3N HCl in EtOAc (4 mL), then concentrated, stirred at a minimum of CH2C12 and saturated with hexanes. After 18 hours, the product was collected by filtration (10 mg, 13%). APCl MS m / e 215.2 [(M + 1) +]. p.f. > 250 ° C.

EXAMPLE 30 2-Fluoro-N- (5-hydroxy-10-aza-tricyclo rß.3.1.02 71dodeca-2 (7), 3,5-trien-4-yl) -benzamide hydrochloride 2,2,2-Trifluoro-1- (4-hydroxy-5-amino-10-aza-tricyclo [6.3.1.02,7] dodeca-2 (7), 3,5-trien-10 was combined -yl) -etone (150 mg, 0.524 mmol), 2-fluorobenzoyl chloride (0.07 ml, 0.576 mmol), pyridinium-p-toluenesulfonic acid (PPTS, 20 mg, 0.08 mmol), pyridine (0.046 ml, 0.576 mmoles) and xylenes (5 ml) under nitrogen and stirred at 135 ° C for 18 hours, after 24 hours, more PPTS (50 mg) was added and the material was stirred at 135 ° C for a further 24 hours. The above treatment afforded the crude product (145 mg, 0.375 mmol), which was mixed with Na2CO3 (s) (80 mg, 0.75 mmol) in MeOH (5 mL) and H2O (2 mL) and heated to reflux. After 3 hours, the reaction was cooled and diluted with water, then extracted with CH2C12 (4 x 40 ml), dried through a cotton plug and then chromatographed to remove the initial impurities (5% MeOH). / CH2C12 (NH3)). The crude material was treated with excess 3 N HCl in EtOAc and concentrated, then dissolved in a minimum of MeOH and the solution was saturated with Et 2 O and stirred. After stirring for 4 hours, the product was collected by filtration (85 mg, 68%). 1 H NMR (400 MHz, CD 3 OD) d 7.99 (m, 2 H), 7.59 (m, 1 H), 7.36 7.23 (m, 2 H), 6.82 (s, 1 H), 2.99 (m, 4 H), 2.78 (m , 2H), 2.35 (m, 1 H), 1.96 (d, J = 10.5 Hz, 1 H). APCl MS m / e313.1 [(M + 1) *]. P.F. 125-130 ° C (up.) EXAMPLE 31 4-Chloro-10-azatricyclohydrate rß.3.1.02'71 dodeca-2 (7), 3,5-triene A) 1 - (4-Chloro-10-aza-tricyclo T6.3.1.0271dodeca-2 (7) .3.5-trien-10-yl ^^^ - trifluoro-ethanone Copper (I) chloride (CuCl) was prepared as follows: CuSO4 (4.3 g) and NaCl (1.2 g) were dissolved in hot H2O (14 ml) Sodium bisulfite (NaOH) (690 mg) was dissolved in H2O (7 ml) and added to the solution hot acid for 5 minutes The precipitated white solids were filtered and washed with water, 1- (4-amino-10-aza-tricyclo [6.3.1.02,7] dodeca-2 (7), 3.5- was dissolved trien-10-yl) -2,2,2-trifluoro-ethanone (460 mg, 1.7 mmol) in H 2 O (2 ml) and concentrated HCl solution (1 ml), then cooled to 0 ° C and it was treated dropwise with a solution of sodium nitrite (NaNO2) (275 mg) in (1 ml) To the resulting solution was added CuCl (202 mg, prepared as described above, 2.04 mmol) in concentrated HCl solution. (2 ml) for 10 minutes (gas evolution is observed) The resulting solution was heated at 60 ° C for 15 minutes, Then it was cooled to room temperature and extracted with EtOAc (4 x 30 ml). After drying over Na2SO4, the solution was filtered and concentrated to give an oil which was filtered through a silica layer to remove the starting material eluting with 50% EtOAc / hexanes to produce an oil (470 mg, 95% ).

B) 4-Chloro-10-azatricyclohydrochloride [6.3.1.0271dodeca-2 (7) .3.5-triene They were heated to reflux 1 - (4-chloro-10-aza-tricyclo [6.3.1.02l7] dodeca -2 (7), 3,5-trin-10-yl) -2,2,2-trifluoro-etona (470 mg, 1.62 mmol) and Na 2 CO 3 (344 mg, 3.24 mmol) in MeOH (30%). ml) and H2O (10 ml). After 2 hours, the reaction was cooled and diluted with water, then extracted with EtOAc (4 x 40 ml), dried (Na2SO), filtered and concentrated to give a yellow oil. The crude material was treated with excess 3 N HCl in EtOAc and concentrated, then dissolved in a minimum of CH 2 Cl 2 and the solution was saturated with hexanes and stirred. After stirring for 4 hours, the product was collected by filtration (155 mg, 42%). 1 H NMR (free base) (400 MHz, CDCl 3) d 7.15 (m, 2 H), 7.09 (d, J = 8.0 Hz, 1 H), 3.00-2.94 (m, 4 H), 2.68 (m, 2 H), 2.38 (m, 1 H), 1.92 (d, J = 10.5 Hz, 1 H). 1 HOUR). NMR (HCl salt) (400 MHz, DMSO-d6) d 7.30-7.20 (m, 3H), 3.30-3.15 (m, 6H), 2.37 (m, 1 H), 1.89 (d, J = 11.0 Hz, 1 H). APCl MS m / e 194.1 [(M + D - EXAMPLE 32 Cyanide Hydrochloride 10-Azatricyclo Rß.3.1.0 ~ 2.7 ~ 1dodeca-2 (7) .3.5-trien-4-yl A) 1 - (4-Iodo-10-aza-tricyclo [6.3.1.02 71dodeca-2 (7) .3, 5-trien-10-yl) -trifluoro-ethone 1- (4-amino-10-aza-tricyclo [6.3.1.02'7] dodeca-2 (7), 3,5-trien-10-yl) was dissolved -2,2,2-trifluoro-ethanone (500 mg, 1.85 mmol) in HO (5 ml) and concentrated solution of H2SO4 (0.5 ml), then cooled to 0 ° C and treated dropwise with a solution of sodium nitrite (NaNO2) (140 mg, 2.04 mmol) in H2O (2 ml). Potassium iodide (460 mg, 2.78 mmol) in a 1 N H2SO4 solution (0.5 ml) was added over 10 minutes (the reaction turned dark red). The resulting solution was warmed to room temperature and stirred for 18 hours. The reaction was quenched with NaHSO3 and water (pH 2.5) and then extracted with EtOAc (4 x 30 mL). After drying (Na2SO4), the solution was filtered and concentrated to give a yellow oil which was chromatographed on silica gel producing a yellow oil. (260 mg, 37%). (TLC 30% EtOAc / hexanes Rf 0.70). (with an amount of 5.4 g proceeding as indicated above, 5 g, 67% was produced).

B) 4-iodo-10-aza-tricyclo [6.3.1.02,71 dodeca-2- (7), 3,5-triene-10-carboxylic acid tert-butyl ester 1- (4-iodo-10 -aza-tricyclo [6.3.1.02-7] dodeca-2 (7), 3,5-triten-10-yl) -2,2,2-trifluoro-ethanone (5 g, 13.1 mmol) and saturated aqueous solution 37% NH 4 OH (50 ml) in MeOH (250 ml) for 2 hours, then the mixture was concentrated and azeotropically distilled with MeOH (2 x 50 ml). The resulting product was stirred in 1,4-dioxane (75 ml) and treated with a saturated solution of Na 2 CO 3 (15 ml). To this was added di-t-butyl dicarbonate (5.71 g, 26.2 mmol). After stirring for 18 hours, the reaction was treated with H2O (50 ml) and extracted with CH2Cl2 (4 x 30 ml), dried (Na2S4), filtered, concentrated and chromatographed on silica gel ( TLC 20% EtOAc / hexanes) providing the product as an oil (4.9 g, 98%).

C) 4-Cyano-10-aza-tricyclo [6.3.1.0271 dodeca-2 (7) .3,5-triene-10-carboxylic acid tert-butyl ester (Using the procedures described in: House, HO; Fischer, WFJ Org. Chem., 1969, 3626). CuCN (108 mg, 1.21 mmol) and NaCN (59 mg, 1.21 mmol) in dry DMF (6 mL) were combined and heated to 150 ° C under N2. The solution occurred in 20 minutes. To this was added tert-butyl ester of 4-iodo-10-aza-tricyclo [6.3.1.02-7] dodeca-2 (7), 3,5-triene-10-carboxylic acid (232 mg, 0.6 mmol) in DMF (3.5 ml) and the mixture was stirred for 18 hours at 150 ° C. The reaction was cooled and diluted with saturated aqueous solution to 50% NaCI and extracted with 50% EtOAc / hexanes (3 x 30 ml). After drying (Na2SO), filtration and concentration, the product was isolated by chromatography (86 mg, 50%). (TLC EtOAc 20% / hexanes Rf 0.28).

D) 10-azatricic cyanide hydrochloride or [6.3.1.0 ~ 2.7 ~ 1dodeca-2.7), 3.5-trin-4-Ho The tert-butyl ester of 4-cyano-10-aza-tricyclic acid was treated [6.3.1.02-7] dodeca-2 (7), 3,5-triene-10-carboxylic acid with 3 N HCl in EtOAc (6 ml) and heated to reflux for 2 hours, then concentrated and dissolved in a minimum of MeOH that was saturated with Et 2 O and stirred for 18 hours. The product was collected by filtration (49 mg, 73%). 1 H NMR (400 MHz, DMSO-d 6) d 9.66 (br s, NH, 7.86 (br s, NH) 7. 74-7.70 (m, 2H), 7.49 (d, J = 7.5 Hz, 1 H), 3.33-2.97 (m, 6H), 2.17 (m, 1 H), 2.01 (d, J = 11.0 Hz, 1 H ). GCMS m / e 184 (M +). p.f. 268-273 ° C.

EXAMPLE 33 3- (10-Azatricichlor6.3.1.02 71dodeca2 (7), 3,5-trien-4-in-5-methyl-1,2,4-oxadiazole hydrochloride 4-Cyano-10-aza-tricyclo [6.3.1.02-7] dodeca-2 (7), 3,5-triene-10-carboxylic acid tert-butyl ester (300 mg, 1.1 mmol) in EtOH was stirred ( 10 ml). To this were added hydroxylamine hydrochloride (382 mg, 5.5 mmol) and NaOH (242 mg, 6.05 mmol) and the mixture was heated to reflux.

After 45 minutes, the reaction was cooled, diluted with H2O and extracted with EtOAc. The organic layer was dried (Na2SO4) and concentrated to yield a yellow solid (110 mg, 0.35 mmol). This solid was dissolved in pyridine (1 ml), treated with acetyl chloride (0.33 ml, 0.415 mmol) and heated to 110 ° C for 18 hours. The reaction was cooled, treated with H2O and extracted with EtOAc. The organic extracts were washed with water and saturated aqueous NaCl solution, dried (Na2SO4) and concentrated. Chromatography on silica gel yielded the product (50 mg, 0.15 mmol). (EtOAc al % / hexanes Rf 0.18). This product was treated with 2N HCl in MeOH (10 mL), heated at 70 ° C for 1 hour, cooled, concentrated and recrystallized from MeOH / ET2O affording the product (15 mg). APCl MS m / e 242.2 [(M + lfi.

EXAMPLE 34 1- (10-azatricichlorß.3.1.0271dodeca 2 (7) .3.5-trien-4-yl.-1-ethanone hydrochloride A) 1-, 4-Acetyl-10-aza-trichloride [6.3.1.027 ldodeca-2 (7) .3.5-trien-10-yl) -2,2,2-trifluoro-ethanone They were dissolved 1- (10-aza-tricyclo [6.3.1.0 -7] dodeca-2 (7), 3,5-trien-10-ii) -2,2,2-trifluoro-ethanone (253 mg, 1.0 mmol) and AcCl ( 0.68 ml, 10 mmol) in DCE (3 ml) and the mixture was treated with aluminum chloride (AICI3) (667 mg, 5.0 mmol). The resulting yellow mixture was stirred for 30 minutes, then poured onto ice and saturated aqueous solution of NaHCO3. After stirring for 20 minutes, the mixture was extracted with CH2CI2 (3 x 30 ml). The organic layer was dried through a cotton plug and then concentrated to give an orange-yellow oil (255 mg, 86%).

B) 4-Acetyl-10-aza-tricyclo [6.3.1.02-7dodeca-2 (7) .3,5-trinene-10-carboxylic acid tert -butyl ester 1- (4-acetyl) -10-aza-tricyclo [6.3.1.02-7] dodeca-2 (7), 3,5-trien-10-yl) -2,2,2-trifluoro-ethanone (1.3 g, 4.37 mmol) and aqueous solution NH4OH 37% (10 ml) in MeOH (30 ml) for 3 hours, the mixture was then concentrated and azeotropically distilled with MeOH (2 x 50 ml). (This product could be converted to the HCl salt directly: see the following example). The resulting product was stirred in 1,4-dioxane (20 ml) and treated with saturated aqueous Na 2 CO 3 solution (5 ml). To this was added di-t-butyl dicarbonate (1.91 g, 8.74 mmoles). After stirring for 2 hours, the reaction was treated with H 2 O (50 ml), extracted with CH 2 Cl 2 (4 x 30 ml), dried (Na 2 SO 4), filtered, concentrated and chromatographed to yield an oil (1.3 g, 100%). (TLC 40% EtOAc / hexanes Rt 0.56).

C) 1- (10-Azatricyclo [6.3.1.02-71dodeca-2 (7) .3,5-trien-4-i!, -1-ethanone hydrochloride The tert-butyl ester of 4-acetyl- 10-aza-tricyclo [6.3.1.02-7] dodeca-2 (7), 3,5-trien-10-carboxylic acid (190 mg, 0.63 mmol) with excess 3N EtOAc HCl, warmed to 70 ° C for 1 hour and then concentrated and dissolved in a minimum of MeOH The resulting solution was saturated with Et 2 O and stirred.After 18 hours, the white crystalline product was collected by filtration (81 mg, 54%) 1 H NMR (400 MHz, DMSO-d 6) d 9.75 (br s, NH), 7.89 (s, 1 H), 7.88 (d, J = 8.0 Hz, 1 H), 7.74 (sa, NH), 7.44 (d , J = 8.0 Hz, 1 H), 3.33 (sa, 2H), 3.22 (s, a, 2H), 3.00 (ma, 2H), 2.54 (s, 3H), 2.17 (m, 1 H), 2.02 ( d, J = 11.0 Hz, 1 H) GCMS m / e 201 (M +), mp 198-202 ° C.

EXAMPLE 35 Hydrochloride of 1 Q-azatricilorß.3.1.0271dodeca-2 (7) .3.5-trien-4-ol A) 10-Fluoroacetyl-10-aza-trichloro6.3.1.027dodeca-2 (7), 3,5-trien-4-yl ester of acetic acid. 1- (4-acetyl-10-aza- tricyclo [6.3.1.02.7] dodeca-2 (7), 3,5-trien-10-yl) -2,2,2-trifluoro-ethanone (2.5 g, 8.41 mmol) and 3-chloroperoxybenzoic acid ( m-CPBA) (7.5 g, 42 mmol) in CH2Cl2 (20 mL) and the mixture was heated at 40 ° C for 18 hours. The mixture was cooled to room temperature, then treated with dimethylsulfide (Me2S) (3 mL, 40.8 mmol) and stirred for 24 hours. The resulting mixture was poured into ice and saturated aqueous Na 2 CO 3 solution (100 ml) and then extracted with Et 2 O. (4 x 40 ml). The organic layer was washed with saturated aqueous solution of Na 2 CO 3 (3 x 40 ml), then dried (Na 2 SO 4), filtered and concentrated to yield an oil (1.83 g, 69%). TLC EtOAc Rf 0.80).

B) 2,2.2-Trifluoro-1-.4-hydroxy-10-aza-tricyclol6.3.1.02 71dodeca-2 (7) .3.5-trien-10-yl) -ethanone 10-trifluoroacetyl was stirred -10-aza-tricyclo- [6.3.1.02 7] dodeca-2 (7), 3,5-trien-4-yl acetic acid ester (900 mg, 2.87 mmol) in MeOH (20 ml) and saturated aqueous solution NaHCO3 (15 ml) for 48 hours. The mixture was concentrated, diluted with H2O, extracted with CH2Cl2 (3 x 20 ml) and then dried through a cotton plug. Chromatography on silica gel yielded the pure product (420 mg, 54%). (TLC 5% MeOH / CH 2 Cl 2 Rf 0.44). 1 H NMR (400 MHz, CDCl 3) d 7.05 (m, 1 H), 6.70 (m, 1 H), 6.62 (m, 1 H), 4.32 (m, 1 H), 3.84 (m, 1 H), 3.48 (m, 1 H), 3.21 (sa, 1 H), 3.16 (sa, 1 H), 3.09 (m, 1 H), 2.38 (m, 1 H), 1.97 (d, J = 1 1.0 Hz, 1 H).

C) 10-azatricichlorochloride 6.3.1.0 2 /; 7H? Dodeca-2 (7) .3.5-trien-4 ol 2,2,2-trifluoro-1- (4-hydroxy-10-aza) -trip [6.3.1.02 7] -dodeca-2 (7), 3,5-trien-10-yl) -ethanone (50 mg, 0.184 mmol) in MeOH / H2O (3/1, 5 ml), was treated with Na2CO3 (s) (40 mg, 0.369 mmol) and heated to 65 ° C for 2 hours. The mixture was concentrated, diluted with H 2 O, extracted with CH 2 Cl (3 x 20 ml) and then dried through a cotton plug. Filtration through a plug of silica gel produced an oil (MeOH al % / CH 2 Cl 2) which was treated with 3 N HCl in EtOAc (3 mL), then concentrated, dissolved in a minimum of MeOH which was saturated in Et 2 O and stirred. After 18 hours, the white crystalline product was collected by filtration (10 mg, 25%). 1 H NMR (400 MHz, CDOD 3) d 7.16 (d, J = 8.0 Hz, 1 H), 6.80 (d, J = 2.0 Hz, 1 H). 6.72 (dd, J = 8.0, 2.0 Hz, 1 H), 3.32-3.28 (4H), 3.09 (dd, J = 14. 5, 12.0 Hz, 2H), 2.32 (m, 1H), 2.03 (d, J = 11.0 Hz, 1H). APCl MS m / e 176. 2 [(M + 14]. P.f.308 (dec.) C.

EXAMPLE 36 7-Methyl-5-oxa-6.13-diazatetracyclo-r9.3.1.02-10.0481 Pentadeca-2.4 (8) .6.9-tetraene Hydrochloride A) 1- (4-Acetyl-5-hydroxy-10-aza-tricyclo- [6.3.1.027dodeca-2- (7) .3.5-trin-10-yl) -2,2.2-trifluoro-ethanone combined 10-trifluoroacetyl-10-aza-trichloro [6.3.1.027] dodeca-2- (7), 3,5-trien-4-yl acetic acid ester (800 mg, 2.55 mmol) with AICI3 (1.0 g, 7.65 mmoles) and the mixture was heated at 170 ° C for 2 hours. The mixture was cooled and treated with aqueous 1N HCl solution (20 ml), extracted with EtOAc and dried (Na2SO4). Chromatography yielded an oil (190 mg, 24%). (TLC EtOAc Rf 0.75%). 1 H NMR (400 MHz, CDCl 3) d 12.58 (s, 0.5 H), 12.52 (s, 0.5H), 7. 53 (s, 1 H) 6.86 (s, 1 H), 4.33 (m, 1 H), 3.91 (m, 1 H), 3.56 (m, 1 H9, 3.28 (sa, 1 H), 3.24 (sa, 1 H), 3.14 (m, 1 H), 2.35 (m, 1 H), 1.97 (day, J = 1 1.1 Hz, 1 H).

B) 2,2,2-Trifluoro-1-, 4-hydroxy-5- (1-hydroxy-ethyl-ethyl) -10-aza-tricyclo6.3.1.02 7dodeca-2,7) .3.5-trien-10 -ill-ethanone 1 - (4-acetyl-5-hydroxy-10-aza-tricyclo- [6.3.1.02-7] dodeca-2 (7), 3,5-trin-10-yl) ) -2,2,2-trifluoro-ethanone (190 mg, 0.605 mmol), hydroxylamine HCl (99 mg, 1.21 mmol) and NaOAc (118 mg, 1.21 mmol) in MeOH (4 mL) and H2O (1 mL) and the mixture was heated at 65 ° C for 18 hours. The mixture was cooled, diluted with H2O and extracted with EtOAc, which was dried (Na2SO4), filtered and concentrated to yield a yellow oil (177 mg, 93%).

C) 2,2,2-Trifluoro-7-methyl-5-oxa-6,13-diazatetracyclo-r9.3.1.02-10.04 8lpentadeca-2.4 (8) .6,9-tetraene-ethanone The above oil, 2 > 2,2-trifluoro-1- [4-hydroxy-5- (1-hydroxyimino-ethyl) -10-aza-tricyclo [6.3.1.02-7] dodeca-2 (7), 3,5-trien-10- il] -ethanone (177 mg, 0.54 mmol) was stirred in DCE (3 mL), treated with triethylamine (0.4 mL, 2.8 mmol) and acetic anhydride (Ac2O) (0.3 mL, 2.8 mmol), and then stirred for 18 hours. The reaction was treated with H2O and extracted with EtOAc. The extracts were dried (Na2SO4), filtered and concentrated to give a yellow oil which was dissolved in anhydrous DMF (3 ml) and treated with NaH at 60% in oil (32 mg, 1.08 mmol). After stirring for 18 hours, more 60% NaH in oil (3mg) was introduced and the mixture was stirred for 2 hours. The reaction was quenched with H2O (5 mL) and extracted with EtOAc at 80% / hexanes (3 x 30 ml). The organic layer was washed with H2O (3 x 20 ml), dried (Na2S4), filtered and concentrated and chromatographed to yield an oil. (40% EtOAc / hexanes Rf 0.56).

D) 7-Methyl-5-oxa-6,13-diazatetracyclohydrochloride-r9.3.1.02-10.04 8lpentadeca-2.4 (8) .6.9-tetraene Using the procedures described in Example 9C, 2 was converted, 2,2-trifluoro-7-methyl-5-oxa-6,13-diazatetracyclo [9.3.1.02-10.048] -pentadeca-2,4 (8), 6,9-tetraene-ethanone in the title compound. This was treated with 3N HCl in EtOAc (3 mL), concentrated and dissolved in a minimum of CH 2 Cl 2 which was saturated with hexanes and stirred. After 18 hours, the white crystalline product was collected by filtration (18 mg, 13% of the total). 1 H NMR (400 MHz, DMSO-d 6) d 7.72 (s, 1 H), 7.63 (s, 1 H), 3.42-2.98 (m, 6 H), 2.50 (s, 3 H), 2.23 (m, 1 H) , 2.08 (d, J = 10.5 Hz, 1 H). APCl MS m / e 215.2 [(M + 1) + j.

EXAMPLE 37 4-, 2-Methyl-2H-pyrazole-3-ii) -10-aza-tricichlor6.3.1.0271dodeca- 2- (7) Hydrochloride. 2.5-triene and 4- (1-methyMH-pyrazol-3-yl) -10-aza-tricyclo-6.3.1.0271dodeca-2 (7) .3.5-triene hydrochloride They were heated at 140 ° C for 18 hours 1- (4-acetyl-10-aza-tricyclo [6.3.1.02-7] dodeca-2- (7), 3,5-triene-10-yl) -2.2 , 2-trifluoro-ethanone (1.0 g, 3.3 mmole) and dimethylformamide dimethylacetal (DMF-DMA) (4.0 g, 33.6 mmoles). After cooling, a crystalline precipitate was filtered and rinsed with EtOAc (690 mg, 58%). The above solid, 3-dimethylamino-1- (10-trifluoroacetyl-10-aza -tricicothe.SI-O -dodeca ^ ^ JSd-triene ^ -i -propenone, (200 mg, 0.56 mmole) was dissolved in EtOAc (2). ml) and treated with 5 N HCl in EtOH (0.1 ml) followed by methyl hydrazine (0.6 mmol) The resulting mixture was heated at 70 ° C for 4 hours.The mixture was cooled, diluted with water, extracted with EtOAc, dried (Na2SO4) and concentrated, chromatography on silica gel yielded a 3/1 mixture of regioisomeric products (130 mg, 68%). (50% TLC EtOAc / Rf 0.40 hexanes). 130 mg, 0.388 mmol) and Na2CO3 (s) (82 mg, 0.775 mmol) were stirred in MeOH (10 ml) and H2O (5 ml) for 18 hours, after cooling, the reaction was diluted with water, extracted with CH2CI2, dried through a cotton plug and concentrated The product was purified by chromatography on silica gel and concentrated to an oil.The salt was generated with 2N HCl in MeOH, concentrated and recrystallized in MeOH / EtOAc yielding a 3/1 mixture of regioisomeric pyrazoles (85 mg, 58%). (5% MeOH / CH2Cl2 (NH3) Rf 0.25). Precursor of TFA APCl MS m / e 336.2 [(M + 1) +].

EXAMPLE 38 4,5-Dichloro-IO-azatricyclohydrochloride .6.3.1.0 2'.7 '?, Dodeca-2 (7). 2.5-triene A) 1- (4,5-Dichloro-10-aza-tricyclo .6.3.1.02-7dodeca-2 (7) .3.5-trien-10-yl) -2.2.2-trifluoro-ethanone (Based on Campigne, E Thompson, WJ Org. Chem. 1950, 72 (629) .It was stirred 1 - (10-aza-tricyclo [6.3.1.02 7] dodeca-2 (7), 3,5-trien-10-yl) - 2,2,2-trifluoro-ethanone (539 mg, 2.1 mmol) in CH2Cl2 (5 mL) and treated with ICI3 (s) (982 mg, 4.21 mmol) The resulting orange solution was stirred for 0.5 hours, poured in saturated aqueous NaHSO 3 solution (25 ml), extracted with CH 2 Cl 2 (3 x 25 ml), dried through a cotton plug and concentrated to give an oil (570 mg, 84%) (TLC 50% EtOAc). % / hexanes Rf 0.62).

B) 4,5-dichloro-10-azatricichlor6.3.1.02 71dodeca-2 hydrochloride (7), 3,5-triene. 1- (4,5-Dichloro-10-aza-tricyclo [6.3.1.02-7] dodeca-2 (7), 3,5-trien-10-yl) 2 was stirred. , 2,2-trifluoro-ethanone (570 mg, 1.75 mmol) in MeOH (25 ml) and treated with NaCO3 (s) (5 g, 47 mmol) in MeOH (25 ml) and treated with Na2CO3 (s). ) (5 g, 47 mmol) in H2O (5 ml). The stirred mixture was heated at 70 ° C for 4 hours, concentrated until solids appeared, diluted with H2O and extracted with EtOAc (3 x 40 mL). The product was extracted into aqueous 1 N HCl solution (2 x 40 ml), which was washed with EtOAc, then neutralized with saturated aqueous Na 2 SO 3 solution until pH-10. The product was extracted with CH 2 Cl 2 (3 x 40 ml) , filtered through a cotton plug and concentrated to an oil (400 mg, 100%). The oil was dissolved in MeOH, treated with 3 N HCl in EtOAc (4 mL) and concentrated, then dissolved in a minimum of MeOH which was saturated with Et 2 O and stirred for 18 hours. The product was collected by filtration (210 mg, 45%). (TLC 50% EtOAc / hexanes (NH3) Rf 0.08). 1 H NMR (400 MHz, DMSO-d 6) d 7.58 (s, 2 H), 3.33-2.97 (m, 6 H), 2.18 (m, 1 H), 1.99 (d, J = 10.5 Hz, 1 H). 13 C NMR (100 MHz, DMSO-d 6) d 141.02, 130.60, 126.58, 45.54, 40.55, 38.30, GCMS m / e 227, 229 (M +). p.f. 283-291 ° C.

EXAMPLE 39 N4, N4-Dimethyl-10-azatricichlor6.3.1.02 71dodeca-2 (7) .3.5-triene-4-sulfonamide hydrochloride A) 10-Trifluoroacetyl-10-aza-tricyclochloride .6.3.1.02 71dedeca-2 (7), 3,5-triene-4-sulfonyl Chloride 1- (10-aza-tricyclo [6.3.1.02-7] dodeca-2 (7), 3,5-trien-10-yl) -2,2,2-trifluoro-ethanone (530 mg, 2.1 mmol) to chlorosulfonic acid (2 mL, 30 mmol) and the mixture was stirred for 5 minutes. The mixture was quenched with ice, extracted with EtOAc, dried (Na 2 S 4), filtered and concentrated to give an oil (640 mg, 87%). (TLC EtOAc at 30 / hexanes Rf 0.15).

B) Hydrochloride of N4, N4-dmethyl-10-azatricichlor6.3.1.02 71dodeca-2 (7). 3,5-triene-4-sulfonyl. 10-Trifluoroacetyl-10-aza-tricyclo [6.3.1.02-7] dodeca-2 (7), 3,5-triene-4-sulfonyl chloride ( 320 mg, 0.9 mmol) in THF (10 ml) and the mixture was treated with 40% Me 2 NH / H 2 O (1.5 ml). After 10 minutes, the mixture was concentrated and chromatographed on silica gel (TLC 30% EtOAc / hexanes Rf 0.31) to yield an oil (256 mg, 78%). This material was dissolved in MeOH (6 ml) and NH OH (2 ml) and stirred for 18 hours. The mixture was concentrated and azeotropically distilled in MeOH (3x). The resulting oil was dissolved in MeOH and treated with 3 N HCl in EtOAc (4 mL), concentrated and dissolved in a minimum of MeOH, which was saturated with Et 2 O and stirred for 18 hours. The product was collected by filtration in the form of a white powder (163 mg, 59%). (TLC 10% MeOH / CH2Cl2 (NH3) Rf 0. 54). 1 H NMR (data, free base) (400 MHz, CDCl 3) d 7.64 (m, 2 H), 7.41 (d, J = 8.0 Hz, 1 H), 3.30 (m, 2 H), 3.20 (d, J = 12.5 Hz , 2H), 3.07 (dd, J = 12.5, 2.2 Hz, 2H), 2.69 (s, 6H), 2.45 (m, 1 H), 2.00 (d, J = 1.0 Hz, 1 H). 13 C NMR (100 MHz, CDCl 3) d 128.43, 124.16, 122.75, 46.67, 46.55, 42.11, 39.44, 37.81. GCMS m / e 266 (M +). (HCl salt data) 1 H NMR (400 MHz, DMSO-d 6) d 7.68-7.52 (3 H), 3.38 (m, 2 H), 3.24 (m, 2 H), 3.04 (m, 2 H), 2.58 (s, 6 H) , 2.22 (m, 1 H), 2.04 (d, J = 1 1.0 Hz, 1 H). GCMS m / e 266 (M +). Analysis Calculated for C 13 H 18 N 2 O 2 HCl: C, 51.56; H, 6.32; N, 9.25. Found: C, 51.36; H, 6.09; N, 9.09.

EXAMPLE 40 4- (1-pyrrolidinyl sulfoniP-10-azatriciclo.6.3.1.02 71dodeca- 2,7) .3.5-triene hydrochloride The pyrrolidine analogue was prepared from 10-trifluoroacetyl-10-aza-tricyclo [6.3.1.02-7] dodeca-2 (7), 3,5-triene-4-sulfonyl chloride (320 mg, 0.9 mmol) as in the coupling step described in the example 39B with the substitution of pyrroline. The TFA product was isolated in the form of an oil (314 mg, 89%). Deprotection and conversion to the salt as in Example 39B produces a white powder (189 mg, 63%). (TLC MeOH at % / CH2Cl2 (NH3) Rf 0.60). (TLC 50% EtOAc / hexanes Rf 0.65). 1 H NMR (400 MHz, CDCl 3) d 7.66 (d, J = 8.0 Hz, 1 H), 7.64 (s, 1 H), 7.37 (d, J = 8.0 Hz, 1 H), 3.30-3.15 (m, 8H ), 3.00 (m, 2H), 2.39 (m, 1 H), 1.98 (d, J = 1 1.5 Hz, 1 H), 1.72 (m, 4H). 13 C NMR (100 MHz, CDCl 3) d 146.91, 144.08, 136.65, 127.90, 124.18, 122.36, 50.43, 47.87, 46.80, 46.63, 42.1 1, 39.63, 25.10. APCl MS m / e 293 [(M + 1) *]. (HCl salt data) 1 H NMR (400 MHz, DMSO-d 6) d 9.78 (br s, NH), 8.1 (br s, NH), 7.73 (d, J = 1.5 th Hz, 1 H), 7.66 (dd, J = 8.0, 1.5 Hz, 1 H), 7.53 (d, J = 8.0 Hz, 1 H), 3.39-3.01 (10 H), 2.21 (m, 1 H), 2.04 (d, J = 11.0 Hz, 1 H ), 1.66 (m, 4H). GCMS m / e 292 (M +). Analysis calculated for C13H- | 8N2O2HCM / 2MeOH: C, 54.07; H, 6.47; N, 8.51. Found: C, 53.98, H, 6.72; N, 8.12.

EXAMPLE 41 5,13-Diazatetracichlor Hydrochloride 9.3.1.02 7.0481-pentadeca-2,4 (8), 9-trien-6-one (The title compound was prepared following the procedures described in Quallich, GJ, Morrissey, PM Synthesis 1993, 51-53, treating the tert-butyl ester of 4,5-dihitro-10-aza-tricyclic acid [6.3.1.0 2.7 ] -1dedeca-2 (7), 3,5-triene-10-carboxylic acid as an equivalent to give an ortho fluoro phenyl radical). 1 H NMR (400 MHz, DMSO-d 6) d 10.42 (s, NH), 9.88 (s a, NH), 7. 52 (sa, 1 H), 7.15 (sa, 1 H), 7.15 (s, 1 H), 6.79 (s, 1 H), 3.41 (d, J = 5.0 Hz, 2 H), 3.35-3.13 (m, 4H), 2.93 (m, 2H), 2.12 (m, 1 H), 1.95 (d, J = 11.5 Hz, 1 H).

APCl MS m / e 215.2 [(M + 1) +].

EXAMPLE 42 6-Oxo-5-oxa-7.13-diazatetracichlor9.3.1.02 10.0481Pentadeca- 2 (10) .3.6.8-tetraene Hydrochloride (For references, see: Nachman, R. J. J. Het Chem, 1982, 1545). 2,2,2-Trifluoro-1- (4-hydroxy-5-amino-10-aza-tricyclo [6.3.1.02-7] dodeca-2 (7), 3,5-trien-10-yl) was stirred Etonone (317 mg, 1.11 mmol) in THF (10 ml) was treated with carbonyldiimidazole (269 mg, 1.66 mmol) and heated at 60 ° C for 18 hours. The mixture was concentrated, diluted with CH2Cl2 (50 mL) and washed with 1 N aqueous HCl solution (3x10 mL). The organic layer was dried through a cotton plug, concentrated and chromatographed on silica gel (50% EtOAc / hexanes) to provide an oil (130 mg). This material was converted to the title compound by the procedures described in Example 9C. 1 H NMR (400 MHz, DMSO-d 6) d 11.78 (s, NH), 9.56 (s a, NH), 7. 63 (s a, NH), 7.24 (s, 1 H), 7.07 (s, 1 H), 3.26 (s a, 2 H), 3.16 (t a, J = 9.5 Hz, 1 H), 2.93 (s a, 1 H), 2.18 (m, 1 H), 1.97 (d, J = 11.0 Hz, 1 H). APCl MS m / e 217.2 KM + 1) 1.

EXAMPLE 43 3-Trifluoromethyl-10-aza-tri-chloro6.3.1.0271dodeca-2 (7) .3.5-triene hydrochloride (see Grunewaid, G.L., Paradkar, V.M., Pazhenchevsky, B .; Pleiss, M.A .; I left, D.J .; Seibel, W.L .; Reitz, T. J. J. Org. Chem. 1983, 48, 2321-2327. Grunewaid, G. L .; Markovich, K.M .; Salí, D. J. J. Med. Chem. 1987, 30, 2191-2208). The title compound was prepared by the procedures described in Examples 1 and 2 from 2-fluoro-6-trifluoromethylbromobenzene. 1 H NMR (400 MHz, CD 3 OD) d 7.67-7.50 (3 H), 3.65 (s a, 1 H), 3. 49-3.42 (m, 2H), 3.29 (s, 1 H), 3.28-3.16 (m, 2H), 2.42 (m, 1 H), 2.18 (d, J = 11.5 Hz, 1H). APCl MS m / e 228.2 [(M + 1) + j. (HCl salt) m.p. 275-277 ° C. Analysis calculated for C 12 H 12 F 2 N-HCl 1 / 3H 2 O: C, 53.44; H, 5.11; N, 5.19.

Found: C, 53.73, H, 4.83; N, 5.16.

EXAMPLE 44 3-Phenyl-10-aza-tricichlorß.3.1.02 hydrochloride 7dodeca-2 (7., 3,5-triene) A) 5-Fluoro-1,4-dihydro-1,4-methano-naphthalene and 5-iodo-1,4-dihydro-1,4-methano-naphtha ene (Eisch, J.J.; Burlinson, N. E. J. Amer. Chem. Soc. 1976, 98, 753-761. Paquette, L. A .; Cottrell, D. M .; Snow, R. A. J. Amer. Chem. Soc. 1977, 99, 3723-3733). Magnesium filings (9.37 g, 385 mmol) in anhydrous THF (1000 ml) were stirred in a 2-neck, 2 1 flask, flame-dried, equipped with an uncompensated addition funnel, with a flow adapter. N2, a magnetic stirrer and an efficient condenser equipped with a N2 flow adapter. The flask was stirred and heated to reflux by means of a removable heating jacket. 2,6-Difluoro-iodobenzene (0.3 g) was added followed by 3 N EtMgBr in THF (0.3 ml). An intimate mixture of cyclopentadiene (24.24 g, 367 mmoles) and 2,6-difluoro-iodobenzene (88.0 g, 367 mmoles) was introduced into the addition funnel. Small portions (~ 1 ml) of the intimate mixture were introduced to assist initiation (~ 4x).

After -15 minutes, the reaction was started (exotherm and vapor condensation) and the heating was maintained when necessary during the addition of the addition funnel content. Then, the reaction was refluxed for-1 hour (no MP by GCMS).

The reaction was cooled to room temture and quenched with H2O (200 ml) followed by an aqueous solution of 1 N HCl (200 ml) to dissolve the solids. The product was extracted with hexanes (4 x 150 ml). The combined organic layer was washed with saturated aqueous NaHCO3 solution (150 ml), dried (Na2S4), filtered through a silica plug with rinsing with hexanes and concentrated to give an oil (70 g). Chromatography on silica gel eluting with hexanes yielded two batches (9.0 and 21.0 g) containing mainly 5-iodo-1,4-dihydro-1,4-methano-naphthalene. (TLC hexafanos Rf 0. 63).

B) 5-Iodo-1, 2,3,4-tetrahydro-1,4-methano-naphthalene-2,3-diol 5-iodo-1,4-dihydro-1,4-methano-naphthalene was stirred (20). g) and N-methyl morpholine N-oxide (17.61 g, 130 mmol) in acetone (90 ml) and H2O (13 ml). To this was added a solution of OsO4 (0.2 ml, 2.5% by weight solution of t-BuOH, 0.02 mmol). After 144 hours, florisil (5 g) and saturated aqueous NaHSO 3 solution (3 ml) were added and the mixture was stirred for 0.5 hour. The mixture was filtered through a pad of Celite and the filtrate was concentrated to yield an oil which was purified by chromatography on silica gel, eluting with a gradient of hexanes to 100% EtOAc to yield a yellow solid (13.73 g). APCl MS m / e 301.1 [(M + 1) + triene 5-iodo-1, 2,3,4-tetrahydro-1,4-methano-naphthalene-2,3-diol (8.33 g, 27.6 mmol) and Et3NBnCI (10 mg) in dichloroethane (25 ml) were vigorously stirred. and H2O (75 ml), and the mixture was then treated with sodium odate (6.17 g, 29.0 mmol). After 1.5 hours, the layers were dried and the aqueous layer was extracted with H2O (4 x 30 ml) until no reaction was observed on the starch iodide pa and then with saturated aqueous NaCl solution (30 ml). The organic layer was dried through a cotton plug, treated with benzylamine (3.16 ml, 29.0 mmol), stirred for 2 minutes and then transferred to an addition funnel. This solution was added for -10 minutes to a vigorously stirred and cooled mixture (0 ° C) of NaHB (OAc) 3 (18.72 g, 88.0 mmol) in DCE (150 mL). After the addition was complete, the mixture was stirred without cooling for 2 hours. The mixture was quenched with saturated aqueous Na 2 CO 3 solution (100 ml) and stirred for 1 hour, then the layers were separated and the aqueous layer was extracted with CH 2 Cl 2 (3 x 50 ml). The combined organic layer was washed with saturated aqueous NaCl solution (50 ml), dried through a cotton plug and concentrated. Chromatography on silica gel yielded an oil (6.3 g, 61%) (TLC 5% EtOAc / hexanes Rf 0.10). 1 H NMR (400 MHz, CDCl 3) d 7.61 (d, J = 8.0 Hz, 1 H), 7.28-7.22 (m, 3 H), 7.13 (d, J = 8.0 Hz, 1 H), 6.98-6.94 ( m, 3H), 3.58 (AB dd, J = 14.2 Hz, 2H), 3.26 (sa, 1 H), 3.21 (sa, 1 H), 3.04 (day, J = 10.2 Hz, 1 H), 2 , 83 8d a, J = 10.2 Hz, 1 H), 2.47 (d, J = 10.0 Hz, 1 H), 2.39 (d, J = 10.0 Hz, 1 H) 2.43 (m, 1 H), 1. 72 (d, J = 10.5 Hz, 1 H). APCl MS m / e 376.0 [(M + 1) +]. trieno (For a discussion, see: Miyaura, N., Suzuki, A. Chem. Rev. 1995, 95, 2457-2483.) 10-benzyl-3-iodo-10-aza-tricyclo [6.3.1.02-] was combined. 7] -dodeca-2 (7), 3,5-triene (375.3 mg, 1.0 mmol), potassium acetate (785 mg, 8.0 mmol) and phenyl boronic acid (183 mg, 1.5 mmol) in 10/1 EtOH / H2O (5 ml). The mixture was degassed (3 cycles of vacuum / N2), treated with tetrakis (triphenylphosphine) palladium (0) (57.5 mg, 0.05 mmol) and heated at 90 ° C for 18 hours. The reaction was cooled, diluted with H2O and extracted with Et2O (3 x 50 mL). The organic layer was washed with brine (50 ml), dried (MgSO), filtered and concentrated to yield an oil (180 mg, 55%). (TLC EtOAc 4% / hexanes Rf 0.18). GCMS m / e 325 (M) +.

E) 3-phenyl-10-aza-tricichlor6.3.2.027dododeca-2 (7), 3,5-thienohydrochloride 10-benzyl-3-phenyl-10-aza-tricyclo [6.3.1.027] dodeca-2 ( 7), 3,5-triene in the title compound using the conditions described in example 2D. (TLC 10% MeOH / CH2Cl2 (NH3) Rf 0.30). (Data for the free base). 1 H NMR (400 MHz, CDCl 3) d 7.46-7.15 (8H), 3.17 (s a, 1 H), 3.01 (m, 2H), 2.93 (d J = 13.0 Hz, 1 H), 2.72 (dd, JH = 10.5 2.5 Hz, 1 H), 2.63 (dd, J = 10.5, 2.5 Hz, 1 H), 2.63 (dd, J = 10.5, 2.5 Hz, 1 H), 2.41 (m, 1 h), 1.91 (D, j = . 5 Hz, 1 H). APCl MS m / e 236.2 [(M + 1) +]. (Salt HCl) p.f. 262-265 ° C. Analysis Calculated for C17H? 7N.NCM / 3H2O; C, 73.26; H, 6.86; N, 5.19. Found: C, 73.50; H, 6.77; N, 5.04.

EXAMPLE 45 3-Hydroxy-1 Oaza-tricyclo.6.3.1.02 71dodeca-2- (7) .3,5-triene hydrochloride A) 10-Benzyl-3-boronic acid-10-aza-tricyclof6.3.1.02 71dodeca-2 (7) .3.5-triene 10-Benzyl-3-iodo-10-aza-tricyclo [6.3. 1.02"7] dodeca-2 (7), 3,5-triene (3.0 g, 7.99 mmol) in anhydrous THF (40 ml) at -78 ° C under nitrogen and treated dropwise with n-BuLi (3.84 ml of a 2.5 M solution in hexanes, 9.59 mmoles.) After 10 minutes, tri-isopropyl borate (4.61 mL, 20.0 mmol) was added dropwise.After -0.5 h, the reaction was poured into a saturated aqueous solution. NaHCO3, stirred for 5 minutes, extracted with EtOAc (3 x 50 ml) and concentrated The residue was dissolved in 30% Et2O / hexanes and extracted with aqueous 1N NaOH solution (4 x 50 ml) The combined aqueous base layers were treated with concentrated HCl to obtain a pH of 8 and extracted with EtOAc (4 x 25 ml), dried (Na 2 SO 4) and purified, chromatography on silica gel eluting first with 3% EtOAc. % / hexanes to remove the non-polar components and then with 5% MeOH / CH2Cl2 yielded the title compound.

(TLC 25% EtOAc / hexanes Rf 0.60).

B) 10-Benzyl-3-hydroxy-10-aza-tricichlor6.3.1.0 2.7l -, - dodeca-2 (7), 3.5 triene 10-benzyl-3-boronic acid-10-aza- tricycle [6.3.1.02'7] -2 (7), 3,5-triene (140 mg, 0.48 25 mmol) in THF (5 ml), treated with N-methylmorpholine N-oxide (64.5 mg, 0.48 mmol) ) and refluxed for 1 hour. The reaction was concentrated and chromatographed on silica gel to provide the product. (TLC 25% EtOAc / hexanes Rf 0.18). 1 H NMR (400 MHz, CDCl 3) d 7.18-7.15 (3 H), 7.04 (dd, J = 8.0, 7.0 Hz, 1 H), 6.95 (m, 2 H), 6.75 (d, J = 7.0 Hz, 1 H) , 6.59 (dd, J = 8.0, 1.0 Hz, 1 H), 3.53 (sa, OH), 3.51 (AB d, J = 14.0 Hz, 2H), 3.28 (sa, 1 H), 3.06 (sa, 1 H) ), 2.91 (dd, J = 8.5, 1.5 Hz, 1 H), 2.79 (ddd, J = 8.5, 1.5 Hz, 1 H), 2.42 (d, J = 1 1.0 Hz, 1 H), 2.39 (d, J = 1 1.0 Hz, 1 H), 2.23 (m, 1 H), 1.65 (d, J = 10.5 Hz, 1 H). APCl MS m / e 266.5 [(M + 1) "].

C) 3-Hydroxy-10-aza-tricyclo- [6.3.1.0 .2.7l-1dodeca-2 (7) .3.5-triene hydrochloride. 10-Benzyl-3-hydroxy-10-aza-tricyclo [6.3. 1.02 7] dodeca-2 (7), 3,5-triene (160 mg, 0.60 mmol) in the title compound by the procedures described in example 1 D. 1 H NMR (400 MHz, CDCl 3) d 7.15 (dd, J = 8.0, 7.5, 1 H), 6.84 (d, J = 7.5 Hz, 1 H), 6.76 (d, J = 8.0 Hz, 1H), 3.51 (sa, 1 H), 3.33-3.25 (3H), 3.16 (d, J = 12.0 Hz, 1 H), 3.09 (d, J = 12.0 Hz, 1 H), 2.29 (m, 1 H), 2.02 (d, J = 11.0 Hz, 1 H). APCl MS m / e 175.8 [(M + 1) 4]. HCl salt) m.p. 253-255 ° C.

EXAMPLE 46 4,5-difluoro-10-aza-trichlorohydrochloride6.3.1.0 2".7 '! -dodeca-2 (7) .3.5-triene The title compound was prepared by the procedures described in Examples 1 and 2, from 2,4,5-trifluorobromobenzene. 1 H NMR (400 MHz, CDCl 3) d 7.31 (t, J = 8.5 Hz, 2 H), 3.48-3.13 (6 H), 2.38 (m, 1 H), 2.11 (d, J = 11.5 Hz, 1 H). APCl MS m / e 196.2 [(M + 1)]. (Salt HCl) p.f. 301-303 ° C. Analysis calculated for C11HHF2N.HCI.I / 6H2O: C, 56.30; H, 5.30; N, 5.97. Found: C, 56.66; H, 5.41; N, 5.96.

EXAMPLE 47 6-Ethyl-5-oxa-6,13-diazatetraciclof9.3.1.02 10.0481 pentadeca- 2 (10), 3,6,8-tetraene hydrochloride 2,2,2-Trifluoro-1- (4-hydroxy-5-amino-10-aza-tricyclo [6.3.1.02-7] dodeca-2 (7), 3,5-trien-10-yl) was converted -ethanone and propionyl chloride in the title compound, following the procedures described in Example 30 and in Goldstein, SW; Dambeck, P.J.J. Het. Chem. 1990, 27, 335. 1 H NMR (400 MHz, CD 3 OD) d 7.64 (s, 1 H), 7.62 (s, 1 H), 3.48 (d, J = 2.5 Hz, 2H), 3.41 (d, J = 12.0 Hz, 2H), 3.20 (2H), 3.01 (q, J = 7.5 Hz, 2H), 2.45 (m, 1 H), 2.17 (d, J = 11.5 Hz, 1 H), 1 .42 (t, J = 7.5 Hz, 3H). APCl MS m / e 229.2 [(M + 1) 1.

EXAMPLE 48 6-Isopropyl-5-oxa-7,13-diazatetracichlor9.3.1.02 10.04 hydrochloride 81 pentadeca-2 (10), 3.6.8-tetraene 2,2,2-Trifluoro-1- (4-hydroxy-5-amino-10-aza-tricyclo [6.3.1.02 7] dodeca-2 (7), 3,5-trien-10-yl was converted ) -etanone and isobutyryl chloride in the title compound, following the procedures described in example 47. (TLC 25% EtOAc / hexanes Rf 0.14). 1 H NMR (400 MHz, CD 3 OD) d 7.65 (2H), 3.49 (sa, 2H), 3.41 (d, J = 12.0 Hz, 2H), 3.33-3.19 (3H), 2.45 (m, 1 H), 2.18 ( d, J = 1 1.5 Hz, 1 H), 1.45 (d, J = 7.0 Hz, 6H). APCl MS m / e 243.2 [(M + 1) *]. (HCl salt) m.p. 249-251 ° C.

EXAMPLE 49 6-Benzyl-5-oxa-7,13-diazatetrachlorohydrate 9.3.1.02 10.04 81 pentadeca-2 (10), 3,6,8-tetraene hydrochloride 2,2,2-Trifluoro-1- (4-hydroxy-5-amino-10-aza-tricyclo [6.3.1.02'7] dodeca-2 (7), 3,5-trien-10-yl) was converted -ethanone and phenyl-acetyl chloride in the title compound, following the procedures described in Example 47. 1 H NMR (400 MHz, CD 3 OD) d 7.63 (s, 1 H), 7.58 (s, 1 H), 7.36- 7.24 (5H), 4.29 (s, 2H), 3.46 (d, J = 2.5 Hz, 2H), 3.39 (d, J = 12.0 Hz, 2H), 3.18 (2H), 2.42 (m, 1 H), 2.15 (d, J = 1 1.5 Hz, 1 H). APCl MS m / e 291.2 [(M + 1) *]. Having described the invention as above, the content of the following claims is declared as property.

Claims

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of the formula wherein R1 is hydrogen, (C -? - C6) alkyl, (C3-C6) non-conjugated alkenyl, benzyl, XC (= O) R13 or -CH2CH2-O-alkyl (C? -C4); R2 and R3 are independently selected from hydrogen, alkenyl, (C2-C6) alkenyl, (C2-C6) alkynyl, hydroxy, nitro, amino, halo, cyano, -SOq-alkyl (Ci-Cß), where q is zero, one or two, alkylamino (d-Cß) -, [(C 1 -C 6) alkyl] 2 amino-, -CO 2 R 4, -CONR 5 R 6, -SO 2 NR 7 R 8, -C (= O) R 13, -XC (= O ) R13, aryl (C0-C3) alkyl or aryl-alkyl (Co-C3) -O-, wherein said aryl is selected from phenyl and naphthyl, heteroaryl-alkyl (Co-C3) - or heteroaryl-alkyl (Co -C3) -O-, wherein said heteroaryl is selected from aromatic rings of five to seven members containing from one to four heteroatoms selected from oxygen, nitrogen and sulfur, and X2- (C0-C6) alkyl- and X2alcoxy (C) ? -C6) -alkyl (Co-C6), where X2 is absent or X2 is alkylamino (C? -Ce) - or [(C? -C6)] 2 amino- alkyl, and where the alkyl portions (C0- C6) - or (C? -C6) alkoxy -alkyl (Co-C6) - of said X2- (C0-C6) alkyl- and X2alkoxy (C? -C6) -alkyl (C0-C6) - contains the minus one carbon atom, and where from one to three of the carbon atoms These alkyl (Co-C6) - or alkoxy (CrC6) -alkyl (Co-C6) - may optionally be replaced by an oxygen, nitrogen or sulfur atom, with the proviso that any two such heteroatoms have to be be separated by at least two carbon atoms, and where any of the alkyl portions of said alkyl (Co-C6) - or (C? -C6) alkoxy-(C0-C6) alkyl- may be optionally substituted with two to seven fluorine atoms, and wherein one of the carbon atoms of each of the alkyl radicals of said aryl-alkyl (Co-C3) and said heteroaryl-alkyl (Co-C3) can be optionally replaced by an oxygen, nitrogen or sulfur, and wherein each of the above aryl and heteroaryl groups may be optionally substituted with one or more substituents, preferably from zero to two substituents, independently selected from (C? -C6) alkyl optionally substituted with one to seven fluorine atoms, alkoxy (C? -Ce) optionally substituted with two to seven fluorine atoms, halo (for example chlorine, fluorine, bromine or iodine), alkenyl (C2-C6), alkynyl (C2-C6), hydroxy, nitro, cyano, aminoalkylamino (C? -C6) [alkyl (CrC6)] 2 amino-, -CO2R4, -CONR5R6, -SO2NR7R8, -C (= O) R13 and -XC (= O) R13; or R2 and R3, together with the carbons to which they are attached, form a monocyclic carbocyclic ring of four to seven members, or a bicyclic carbocyclic ring of ten to fourteen members, which may be saturated or unsaturated, where from one to three the non-condensed carbon atoms of said monocyclic rings, and from one to five of the carbon atoms of said bicyclic rings, which are not part of the benzene ring shown in formula I, can be optionally and independently replaced by a nitrogen, oxygen or sulfur, and wherein said monocyclic and bicyclic rings may be optionally substituted with one or more substituents, preferably from zero to two substituents in the case of the monocyclic rings and from zero to three substituents in the case of the bicyclic rings, which are selected , independently, between (C0-C6) alkyl or (C -? - C6) alkoxy -alkyl (Co-C6) -, where the total number of carbon atoms does not exceed six and wherein any of the alkyl portions may be optionally substituted with one to seven fluorine atoms, nitro, oxo, cyano, halo, alkenyl (Co-C6), alkynyl (C2-C6), hydroxy, amino, alkylamino (CrC6) - [alkyl (CrC6)] 2 amino-, -CO2R4, -CONR5R6, -SO2NR7R8, -C (= O) R13 and -XC (= O) R13; wherein R4, R5, R6, R7, R8 and R13 are independently selected from hydrogen and alkyl (C? -C6), or R5 and R6, or R7 and R8 together with the nitrogen to which they are attached, form a ring of pyrrolidine, piperidine, morpholine, azetidine, piperizine, -N-alkyl (C? -C6) piperizine or thiomorpholine, or a thiomorpholine ring, where the ring sulfur is replaced with a sulfoxide or sulfone; and each X is, independently, alkylene (C? -C6); with the proviso that: (a) at least one of R1, R2 and R3 must be other than hydrogen, and (b) when R2 and R3 are hydrogen, R1 can not be hydrogen, alkyl (C? -C6) or (C3-C6) non-conjugated alkenyl; or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1, wherein R2 and R3, together with the benzene ring of formula I, form a bicyclic ring system selected from the following: where R10 and R17 are independently selected from alkyl (Co-C6) - or (C? -C6) alkoxy-alkyl (Co-C6) -, where the total number of carbon atoms does not exceed six and where any of the alkyl radicals may be optionally substituted with one to seven fluorine atoms; Nitro, cyano, halo, amino, alkylamino (C -? - C6), [alkyD-CeJj ^ mino-, -CO2R4, - CONR5R6, SO2NR7R8, -C (= O) R13, -XC (= O) R13, phenyl and monocyclic heteroaryl, wherein said heteroaryl is selected from five to seven membered aromatic rings containing from one to four heteroatoms selected from oxygen, nitrogen and sulfur, and wherein R 4, R 5, R 6, R 7, R 8 and R 13 are as defined in claim 1.

3. A compound according to claim 1, wherein R2 and R3, together with the benzene ring of formula I, do not form a bicyclic or tricyclic ring system.

4. A compound according to claim 1, wherein one or both of R2 and R3 are -C (= O) R13 where R13 is alkyl (d-Ce).

5. - A compound according to claim 1, wherein one of R2 and R3 is -COR13, wherein R13 is (C6) alkyl or (C3) alkyl optionally substituted with one to seven fluorine atoms.

6. A compound according to claim 1, wherein one of R2 and R3 is CF3, fluorine, cyano or C2F.

7. A pharmaceutical composition for use in reducing the addition to nicotine or to help to stop or reduce the use of tobacco in a mammal, comprising an amount of a compound according to claim 1 which is effective in reducing addition to nicotine or to help stop or reduce the use of tobacco, and a pharmaceutically acceptable vehicle.

8. The use of a compound according to claim 1 in the manufacture of a medicament for reducing nicotine addiction or for helping to stop or reduce tobacco in a mammal.

9. A pharmaceutical composition for the treatment of a disorder or condition selected from inflammatory bowel disease (including, but not limited to, ulcerative colitis, pyoderma gangrenosum and Crohn's disease), irritable bowel syndrome, spastic dystonia , chronic pain, acute pain, celiac sprue, bursitis, vasoconstriction, anxiety, panic disorders, depression, bipolar disorder, autism, sleep disorders, jet lag, amyotrophic lateral sclerosis (ALS), cognitive dysfunction, hypertension, bulimia, anorexia, obesity , cardiac arrhythmias, gastric acid hypersecretion, ulcers, pheochromocytoma, progressive supramuscular paralysis, chemical dependencies and addictions (for example, dependence or additions to nicotine (and / or tobacco products), alcohol, benzodiazepines, barbiturates , to opiates or cocaine), cephalalgias, stroke, traumatic brain injury (TBI), psychos is, Huntington's disease, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia, multi-infarct dementia, decrease in minor or small-group epilepsy, senile dementia of Alzheimer's type (AD), Parkinson's disease (PD), attention deficit hyperactivity disorder (ADHD) and Syndrome Tourette in a mammal, comprising an amount of a compound according to claim 1 which is effective in the treatment of such disorder or condition and a pharmaceutically acceptable carrier.

10. The use of a compound according to claim 1 in the manufacture of a medicament for treating a disorder or condition selected from inflammatory bowel disease (including, but not limited to, ulcerative colitis, gasogenic pyoderma and disease) de Crohn), irritable bowel syndrome, spastic dystonia, chronic pain, acute pain, celiac sprue, bursitis, vasoconstriction, anxiety, panic disorders, depression, bipolar disorder, autism, sleep disorder, jet lag, amyotrophic lateral sclerosis ( ALS), cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac arrhythmias, hypersecretion of gastric acid, ulcers, pheochromocytoma, progressive supramuscular paralysis, chemical dependencies and addictions (for example, dependence or additions to nicotine (and / or tobacco products), alcohol, benzodiazepines, barbiturates, opioids or cocaine), headache, stroke, traumatic brain injury (TBI), psychosis, Huntington's disease, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia, multi-infarct dementia, cognitive decline related to age, epilepsy, including minor epilepsy or small malignant, senile dementia of Alzheimer's type (AD), Parkinson's disease (PD), attention deficit hyperactivity disorder (ADHD) and Tourette syndrome in a mammal.

11.- A compound of the formula wherein P is hydrogen, methyl, COOR16, where R16 is alkyl (C -? - C6), allyl or 2,2,2-trichloroethyl; -C (= O) NR5R6, where R5 and R6 are defined as in the formula I above; -C (= O) H, -C (= O) -alkyl (C? -C6), wherein the alkyl radical may be optionally substituted with 1 to 3 halo atoms, preferably with 1 to fluorine or chlorine atoms; benzyl, t-butoxycarbonyl (t-Boc) or trifluoroacetyl; and R14 and R15 are independently selected from hydrogen, (C-i-C) alkyl optionally substituted with one to seven fluorine atoms; -C (= O) -alkyl (C? -C6), cyano, hydroxy, nitro, amino, -O-alkyl (C? -C6) and halo; with the proviso that R 14 and R 5 can not both be hydrogen when P is hydrogen, (Ci-Cß) alkyl or (C 3 -C β) alkenyl non-conjugated.

12. - The use of a compound of the formula or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for reducing nicotine addiction or for helping to stop or reduce tobacco in a mammal. 13.- The use of a compound of the formula or a pharmaceutically acceptable salt thereof; in the manufacture of a medicament for treating a disorder or condition selected from inflammatory bowel disease (including, but not limited to, ulcerative colitis, pyoderma gangrenosum and Crohn's disease), irritable bowel syndrome, spastic dystonia, pain chronic, acute pain, celiac sprue, bursitis, vasoconstriction, anxiety, panic disorders, depression, bipolar disorders, autism, sleep disorders, jet lag, amyotrophic lateral sclerosis (ALS), cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac arrhythmias, gastric acid hypersecretion, ulcers, pheochromocytoma, progressive supramuscular paralysis, chemical dependencies and addictions (for example, dependence or addiction to nicotine (and / or tobacco products), alcohol, benzodiazepines, barbiturates, to opiates to cocaine), cephalalgias, stroke, traumatic brain injury (TBI), psychosis, Core Huntington's disease, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia, multi-infarct dementia, age-related cognitive decline, epilepsy, including minor or small malignant epilepsy, senile dementia of Alzheimer's type (AD), Parkinson's disease (PD), attention deficit hyperactivity disorder (ADHD) and Tourette syndrome in a mammal. 14.- A compound of the formula wherein R2 and R3 are as defined in claim 1; and P 'is COOR16, where R16 is allyl, 2,2,2-trichloroethyl or alkyl (C6C6); -C (= O) NR5R6 where R5 and R6 are defined as in claim 1; -C (= O) H, -C (O = O) alkyl (Ci-Cß) where the alkyl radical may be optionally substituted with 1 to 3 halo atoms, preferably with 1 to 3 fluorine or chlorine atoms; benzyl or t-butoxycarbonyl (t-Boc).