TRICYCLIC COMPOUNDS WITH ANTIVIRAL ACTIVITY

TRICYCLIC COMPOUNDS AND METHOD OF TREATING HERPES VIRUS

FIELD OF THE INVENTION

The present invention relates to compounds possessing antiviral activity against viruses of the herpes family, or a composition containing them. These compounds provide a method for treating herpes viral infections, including condition caused by herpes simplex I such as cold sores, herpes simplex II such as genital herpes, as well as shingles caused by herpes zoster and infections caused by cytomegalovirus, Epstein Barr Virus.

BACKGROUND OF THE INVENTION

Various subfamilies of herpes viruses (Herpes viridae) exist: α-herpesvirinae, β-herpesvirinae, γ-herpesvirinae and cercopithecing Herpes virus I (B virus); some specific viruses are: Herpes simplex virus-1 (HSV-1), Herpes simplex virus-2 (HSV- 2), Cytomegalovirus (CMV), Varicella Zoster virus (VZV), Epstein-Barr virus (EBV), human herpes virus-6 (HHV-6), human herpes virus-7 (HHV-7), human herpes virus-8 (HHV) as well as others which may not yet be defined.

The incidence of infections by Herpes simplex virus is very high throughout the world. Serological studies showed that herpes viral infections affect a substantial percentage of the population. Reactivation of herpes virus infections may lead to recurrent infections. The risk of severe diseases increases with decreasing immunocompetence of the host. There is a pressing need for improved therapy for treating this disease. Currently, exclusive of vaccines, treatment involves primarily nucleoside drugs such as acyclovir, which target thymidine kinase and suffer from . development of resistance. SUMMARY OF THE INVENTION

The present invention provides a compound of the formula and its pharmaceutically acceptable salts, or the compound and its pharmaceutical composition having useful antiviral activity against viruses of the herpes family.

I wherein:

X = O, (CH₂)_m, S, SO, SO₂, NH, N s or a chemical bond;

Y = O, (CH₂)_m, S, SO, SO₂, NH, NR₈;

Z = N, NH, O, NHRs, NRg, S, SO, SO₂; n = an integer of from 0 to 2; m = an integer of 1,2, or 3;

Ri, R₂, R₃, R^ R₅ independently are hydrogen, halogen, hydroxyl, amino, mono or dialkylamino, cyano, nitro, alkyl groups (1-6 carbon atoms), alkoxy groups (1-6 carbon atoms), CF₃, OCF₃, aminoalkyl (1-6 carbon atoms), aminoaryl, Oaryl, or a heterocyclic ring having 5-7 atoms with 1-4 hetero atoms of N, O or S;

Ar = phenyl, substituted phenyl, benzoheterocyclic ring, substituted benzoheterocyclic ring, heterocyclic ring, or substituted heterocyclic ring, which have substitutions R; or R ; Rδ and R are independently hydrogen, alkyl group (1-6 carbon atoms), cycloalkyl (3- 12 carbon atoms), halogen, alkoxy, CF₃, aminoalkyl (1-6 carbon atoms), aminoaryl, or a heterocyclic ring of from 5-7 atoms with 1-4 heteroatoms of N, O or S; Re and R may also form a ring, optionally cycloalkyl or aryl or substituted aryl; Rs is hydrogen, alkyl (1-6 carbon atoms), cycloalkyl (3-12 carbon atoms), phenyl or substituted phenyl wherein the substituents are as defined above.

The invention also provides for a pharmaceutical composition for the treatment of infection or disease caused by a virus, optionally a Herpes virus which comprises an amount of the compound of Claim 1 sufficient to provide an antivirally effective dosage of the compound of Formula I and a pharmaceutically effective carrier.

The invention also provides for a method of treatment of infection or disease caused by a virus, optionally a Herpes virus which comprises administering to a subject in need of such treatment an effective antivirally dosage ofa composition of formula I.

DESCRIPTION OF PREFERRED EMBODIMENTS

The present invention pertains to anti viral compounds. Preferred compounds are as follows:

One preferred compound is:

Another preferred compound is:

IV

Another preferred compound is:

Another preferred compound is:

VI

Another preferred compound is:

substituted

Another preferred compound is:

₂, SH, CN, NO

₂, OCH

₃, OCH

₂CH

₂OH, NHCH

₃, or

N(CH₃)₂.

The term "cycloalkyl" means a hydrocarbon ring, which contains from 3 to 12 carbon atoms unless otherwise specified, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and adamantyl. Where possible, the cycloalkyl group may contain double bonds. The cycloalkyl ring may be unsubstituted or substituted by from 1 to 3 substituents selected from alkyl, cycloalkyl, alkoxy, thioalkoxy all as defined herein, hydroxy, thiol, nitro, halogen, amino, formyl, carboxyl, nitrile, -NH-CO-R, -CO-NHR-, -CO₂R, -COR, aryl, or heteroaryl wherein alkyl (R), aryl, and heteroaryl are defined as herein.

The term "alkoxy" having 1-6 carbon atoms means a Ci-C6 alkyl-O- group or radical wherein Ci-C₆ alkyl has the meaning as defined above. Illustrative examples ofa straight or branched alkoxy group or radical having from 1 to 6 carbon atoms, also known as a Ci - C₆ alkoxy, include methoxy, ethoxy, 1-propoxy, 2-propoxy, 1- butoxy, 2-butoxy, 2-methyl- 1-propoxy, and 1,1-dimethylethoxy, 1-pentoxy, 2- pentoxy, 3-pentoxy, 2,2-dimethylpropoxy, 1-hexoxy, 2-hexoxy, 3-hexoxy, and 4- methyl- 1 -pentoxy .

The term "thioalkoxy" having 1-6 carbon atoms means a Cι-C₆ alkyl-S- group or radical wherein Ci-Cβ alkyl has the meaning as defined above. Illustrative examples ofa straight or branched thioalkoxy group or radical having from 1 to 6 carbon atoms, also known as a Ci - C₆ thioalkoxy, include methylthio, ethylthio, 1- propylthio, 2-propylthio, 1-butylthio and 2-butylthio, 1-pentylthio, 2-pentylthio, 3- pentylthio, 2,2-dimethylpropylthio, 1-hexylthio, 2-hexylthio, 3-hexylthio, and 4- methyl- 1 -p entylthio .

The term "aryl" means an aromatic carbocyclic ring having from 6 to 10 carbon atoms. Illustrative examples of an aryl group or radical include phenyl, 1- naphthyl, and 2-napthyl. The aryl group may be unsubstituted or independently substituted by from 1 to 3 substituents selected, unless otherwise specified, from F, CI Br, I, OH, NH₂, SH, CN, NO₂, OCH₃, OCH₂CH₂OH, NHCH₃, orN(CH₃)₂.

The term "Oaryl" means an aryl-O- group or radical wherein aryl has the meaning as defined above. Illustrative examples of an Oaryl group or radical include phenoxy, 1-naphthyloxy, and 2-napthyloxy. Oaryl groups may be unsubstituted or independently substituted by from 1 to 3 substituents selected, unless otherwise specified, fromF, CI, Br, I, OH, NH₂, SH, CN, NO₂, OCH₃, OCH₂CH₂OH, NHCH₃, orN(CH₃)₂.

The term "halogen" means bromine, chlorine, fluorine or iodine.

The term "monoalkylamino" means an NH-alkyl group or radical wherein alkyl has the meaning as defined abve.

The term "dialkylamino" means an N-(alkyl)₂ group or radical wherein alkyl has the meaning as defined abve.

The term "aminoalkyl" having 1-6 carbon atoms means an H₂N-(Cι-C6 alkyl)- group or radical wherein Ci-C₆ alkyl has the meaning as defined above. The aminoalkyl group is a substituted Cι-C₆ alkyl group or radical containing at least one substituent which is NH₂.

The term "aminoaryl" means anH₂N-aryl- group or radical wherein aryl has the meaning as defined above. The aminoaryl group is a substituted aryl group or radical containing at least one substituent which is NH₂.

The term "carbocycle" means cycloalkyl as defined above.

The term "heteroatom" means a nitrogen, sulfur, or oxygen.

The term "heterocycle" means a heterocyclic radical which are 5-7 atoms having 1-4 heteroatoms and are selected from: fϊtran, pyrrole, thiophene, oxazole, isoxazole, thiazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, piperazine, piperidine, morpholine, thiomorpholine, oxolane, dioxane, sulfolane, unsubstituted or substituted by 1 to 2 substituents selected from alkyl as defined above. For heterocycles containing sulfur, the oxidized sulfur heterocycles containing SO or SO2 groups are also included.

The term "benzoheterocyclic ring" ("fused heterocycle") refers to a heterocycle that is adjoined at two consecutive positions with a phenyl ring or another heterocycle. such rings may include 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7~benzo[b]thienyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 5-, 6-, or 7-benzothiazolyl.

Some of the compounds of Formula I are capable of further forming pharmaceutically acceptable acid-addition and/or base salts. All of these forms are within the scope of the present invention.

Pharmaceutically acceptable acid addition salts of the compounds of Formula I include salts derived from nontoxic inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, hydrofluoric, phosphorous, and the like, as well as the salts derived from nontoxic organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihyrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinates suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. Also contemplated are salts of amino acids such as arginate and the like and gluconate, galacturonate (see, for example, Berge S.M., et al., "Pharmaceutical Salts," Journal of ^'Pharmaceutical Science, 1977;66:1-19.

The acid addition salt of said basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner.

Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are ,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine (see, for example, Berge, supra., 1977).

The base addition salts of said acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner. Certain of the compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms, are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.

Certain of the compounds of the present invention possess one or more chiral centers and each center may exist in the R(D) or S(L) configuration. The present invention includes all enantiomeric and epimeric forms as well as the appropriate mixtures thereof. Configuration drawn is most preferred.

The compounds of the present invention can be prepared and administered in a wide variety of oral and parenteral dosage forms. Thus, the compounds of the present invention can be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally. Also, the compounds of the present invention can be administered by inhalation, for example, intranasally. Additionally, the compounds of the present invention can be administered transdermally. It will be obvious to those skilled in the art that the following dosage forms may comprise as the active component, either a compound of Formula I or a corresponding pharmaceutically acceptable salt of a compound of Formula I.

For preparing pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances, which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided active component.

In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

The powders and tablets preferably contain from five or ten to about seventy percent of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted, and the active component is dispersed homogeneously therein, as by stirring. The molten homogenous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing and thickening agents as desired.

Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or, synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.

Also included are solid form preparations, which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

The pharmaceutical preparation is preferably in unit dosage form. In such form the preparation is divided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

The quantity of active component in a unit dose preparation may be varied or adjusted from 0.1 mg to 100 mg preferably 0.5 mg to 100 mg according to the particular application and the potency of the active component. The composition can, if desired, also contain other compatible therapeutic agents.

In therapeutic use as antagonists of a virus, as agents for the treatment of infections caused by a virus or as agents for the treatment of diseases due to a virus, the compounds utilized in the pharmaceutical method of this invention are administered at the initial dosage of about 0.01 mg to about 100 mg/kg daily. A daily dose range of about 0.01-mg to about 10 mg/kg is preferred. The dosages, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated, the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages, which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired.

General procedure 1 (for Singleton synthesis):

Reductive amination of aryl amines with aldehydes or ketones.

Reagent 2 (1 eq.) was taken in a solvent (dichloromethane, 1,2-dichloroethane or tetrahydrofuran or diethyl ether) and to it reagent 1 (1 to 1.2 eq.) was added. To this solution cooled at 0°C was added a reducing agent (sodium cyanoborohydride or sodium triacetoxyborohydride) (1 to 2 eq.). To it a drop of acetic acid was added and kept under stirring at room temperature for 6 to 24 hours. The excess hydride was quenched by adding methanol. The reaction mixture was diluted with ethyl acetate and washed with saturated ammonium chloride solution, aqueous sodium bisulfite and brine; dried over anhydrous magnesium sulfuate or sodium sulphate. Organic layer was concentrated and crude product was purified by flash silica gel chromatography to afford the final product. The products were characterized by spectral data. The compounds synthesized using this procedure are shown in Table 4.

General procedure 2 for multiple, simultaneous solution phase synthesis (combinatorial chemistry synthesis):

To a 2-dram glass vial were added, by Tecan liquid handling robot, a solution of reagent 2 (0.05mmol) in trimethyl orthoformate (0.2ml) followed by reagent 1 (0.05mmol) in trimethyl orthoformate (0.2ml). The vial was capped and the reaction mixture was shaken at room temperature for 18 hours (overnight), then concentrated to dryness. To each vial was added, by Tecan™ liquid handling robot, 1,2- dichloroethane (1ml). Solid sodium triacetoxyborohydride (~23mg) was added manually to each vial. A a solution of acetic acid (0.05mmol) in dichloroethane (0.05ml) was added to each vial by Tecan™ liquid handling robot. The vial was again capped and the reaction mixture was shaken at room temperature for 18 hours (overnight). To the reaction mixture was added, by Tecan liquid handling robot, methanol (1ml). The reaction mixture was then transferred, by Tecan liquid handling robot, to be prewashed (That is washed with methanol (2ml) and dichloroethane (1ml)) BAKERBOND spe™ Aromatic Sulfonic Acid (SO₃H) disposable Extraction Columns. The columns were allowed to drain and then washed with methanol (2xlml) these solvents were discarded. The desired product was eluted from the column using a solution of 2M ammonia in methanol (3x1 ml) and concentrated to dryness in a tared 2-dram vial. The product was analyzed by LCMS (liquid chromotography mass spec).

General procedure 3 for multiple, simultaneous solution phase synthesis (combinatorial Chemistry synthesis):

To a 2-dram glass vial were added, by Tecan™ liquid handling robot, a solution of reagent 2 (0.05mmol) in N,N-dimethylformamide (0.1ml) followed by reagent 1 (0.05mmol) in N,N-dimethylformamide (0.1ml). Each vial was treated with trimethylorthoformate (0.2ml) by Tecan™ liquid handling robot. The vial was capped and the reaction mixture was shaken at room temperature for 18 hours (overnight), then concentrated to dryness. To each vial was added, by Tecan™ liquid handling robot, 1,2-dichloroethane (1ml). Solid sodium triacetoxyborohydride (~23mg) was added manually to each vial. A solution of acetic acid (0.05mmol) in 1,2- dichloroethane (0.05ml) was added to each vial by Tecan™ liquid handling robot. The vial was again capped and the reaction mixture was shaken at room temperature for 18 hours (overnight). To the reaction mixture was added, by Tecan™ liquid handling robot, methanol (1ml). The reaction mixture was then transferred, by Tecan™ liquid handling robot, to be prewashed (That is washed with methanol (2ml) and 1,2-dichloroethane (1ml)) BAKERBOND spe™ Aromatic Sulfonic Acid (SO₃H) disposable Extraction Columns. The columns were allowed to drain and then washed with methanol (2xlml) these solvents were discarded. The desired product was eluted from the column using a solution of 2M ammonia in methanol (3xlml) and concentrated to dryness in a tared 2-dram vial. The product was analyzed by LCMS (liquid chromatography mass spec).

General procedure 4 for multiple, simultaneous solution phase synthesis (combinatorial Chemistry synthesis):

To a 2-dram glass vial were added, by Tecan™ liquid handling robot, a solution of reagent 2 (0.05mmol) in methanol (0.2ml) followed by reagent 1 (0.2mmol) in methanol (0.2ml). To each vial was added, by Tecan™ liquid handling robot, a IN solution of sodium cyanoborohydride in methanol (0.2ml) and a 10% acetic acid in methanol (0.05ml) solution. The vial was capped and the reaction mixture was shaken at room temperature for 18 hours (overnight), then concentrated to dryness. The vial was again capped and the reaction mixture was shaken at room temperature for 18 hours (overnight). To the reaction mixture was added, by Tecan™ liquid handling robot, methanol (1ml). The reaction mixture was then transferred, by Tecan™ liquid handling robot, to be prewashed (That is washed with methanol (2ml) and 1,2- dichloroethane (1ml)) BAKERBOND spe™ Aromatic Sulfonic Acid (SO₃H) disposable Extraction Columns. The columns were allowed to drain and then washed with methanol (2xlml) these solvents were discarded. The desired product was eluted from the column using a solution of 2M ammonia in methanol (3xlml) and concentrated to dryness in a tared 2-dram vial. The product was analyzed by LCMS (liquid chromatography mass spec).

General procedure 5 for multiple, simultaneous solution phase synthesis (combinatorial Chemistry synthesis):

₃H) disposable Extraction Columns. The columns were allowed to drain and then washed with methanol (2xlml) these solvents were discarded. The desired product was eluted from the column using a solution of 2M ammonia in methanol (3xlml) and concentrated to dryness in a tared 2-dram vial. The product was analyzed by LCMS (liquid chromatography mass spec).

General procedure 6 for multiple, simultaneous solution phase synthesis (combinatorial Chemistry synthesis):

To a 2-dram glass vial were added, by Tecan™ liquid handling robot, a solution of reagent 2 (0.05mmol) in methanol (0.2ml) followed by reagent 1 (0.15mmol) in methanol (0.1ml). To each vial was added a IN solution of sodium cyanoborohydride in methanol (0.1ml) and a 10% acetic acid in methanol solution (0.05ml). The vial was capped and the reaction mixture was shaken at room temperature for 18 hours (overnight). To the reaction mixture was added, by Tecan™ liquid handling robot, methanol (1ml). The reaction mixture was then transferred, by Tecan™ liquid handling robot, to be prewashed (washed with methanol (2ml) and 1,2-dichloroethane (1ml)) BAKERBOND spe™ Aromatic Sulfonic Acid (SO₃H) disposable Extraction Columns. The columns were allowed to drain and then washed with methanol (2xlml) these solvents were discarded. The desired product was eluted from the column using a solution of 2M ammonia in methanol (3xlml) and concentrated to dryness in a tared 2-dram vial. The product was analyzed by LCMS (liquid chromatography mass spec).

General procedure 7 for multiple, simultaneous solution phase synthesis (combinatorial Chemistry synthesis):

To a 2-dram glass vial were added, by Tecan™ liquid handling robot, a solution of reagent 2 (0.05mmol) followed by reagent 1 in N,N-dimethylformamide (0.32ml) or methanol (0.2ml). The vials were then concentrated overnight to dryness. Each vial was treated by Tecan™ liquid handling robot with reagent 1 (0.15mmol) in methanol (0.1ml) and methanol (0.2ml). To each vial was added a IN solution of sodium cyanoborohydride in methanol (0.1ml) and a 10% acetic acid in methanol solution (0.05ml). The vial was capped and the reaction mixture was shaken at room temperature for 18 hours (overnight). To the reaction mixture was added, by Tecan™ liquid handling robot, methanol (1ml). The reaction mixture was then transferred, by Tecan™ liquid handling robot, to be prewashed (washed with methanol (2ml) and 1,2-dichloroethane (1ml)) BAKERBOND spe™ Aromatic Sulfonic Acid (SO₃H) disposable Extraction Columns. The columns were allowed to drain and then washed with methanol (2x1 ml) these solvents were discarded. The desired product was eluted from the column using a solution of 2M ammonia in methanol (3xlml) and concentrated to dryness in a tared 2-dram vial. The product was analyzed by LCMS (liquid chromatography mass spec). Synthesis of Compound 450: To dibenzofuran-2-yl-amine (0.91 g, 5 mmol) taken in dichloromethane (75 mL) was added ,α'-dibromo-ortho-xylene (1.85 g, 7 mmol) followed by triethylamine (3.03 g, 30 mmol). The reaction was stirred at room temperature for 24 hours. The solvents were evaporated and the residue was purified by flash silica gel chromatography to give the title compound (1.43 g).

Synthesis of Compound 451: To dibenzofuran-2-yl-amine (0.91 g, 5 mmol) taken in dichloromethane (75 mL) was added phthaloyl dichloride (1.16 g, 6 mmol) followed by triethylamine (3.03 g, 30 mmol). The reaction was stirred at room temperature for 5 minutes. The reaction was quenched with sodium bicarbonate solution and the organic layer was separated. The crude product was purified by flash silica gel chromatography to give the title compound (0.51 g).

Synthesis of Compound 463: To compound 58 (0.25 g, 0.87 mmol) taken in tetrahydrofuran (10 mL) was added sodium hydride (60% in mineral oil, 0.035 g, 0.87 mmol). To it methyl iodide (0.25 g, 1.74 mmol) was added. The reaction was stirred at room temperature for 24 hours. The solvents were evaporated and the residue was purified by flash silica gel chromatography to give the title compound (0.18 g).

Deprotection of t-butyloxycarbonyl group: The general procedure for the removal of tert-butyoxycarbonyl (Boc) group is as follows : To the compound taken a flask was added hydrochloric acid in an appropriate solvent (dioxane, methanol, 1,2- dichloromethane and the reaction was kept under shaking for 5 to 18 hours. Removal of volatiles furnished the corresponding product.

Reagents 1 are shown in Table 1.

Table 1: Aldehydes/ketones (reagent 1) No. Reagent 1 (aldehydes/ketones)

1 o-tolualdehyde

2 meta-tolualdehyde

3 para-tolualdehyde 2-fluorobenzaldehyde

3-fluorobenzaldehyde

4-fluorobenzaldehyde

4-tert-butylb enzaldehyde α,α, -Trilfluoro-o-tolualdehyde α,α,α-Trilfluoro-m-tolualdehyde α, ,α-Trilfluoro-p-tolualdehyde o-anisaldehyde m-anisaldehyde p-anisaldehyde

Salicylaldehyde

3 -hy droxybenzaldehyde

4-hydroxybenzaldehyde

2-chlorobenzaldehyde

3 -chlorobenzaldehyde

4-chlorobenzaldehyde

3 -benzyloxybenzaldehyde

4-benzyloxybenzaldehyde

2,3 -dimethoxybenzaldehyde

2,4-dimethoxybenzaldehyde

2, 5 -dimethoxybenzaldehyde

2, 6-dimethoxyb enzaldehyde

3 ,4-dimethoxybenzaldehyde

3 , 5 -dimethoxybenzaldehyde l,4-Benzodioxan-6-carboxaldehyde

2,4-dimethylbenzaldehyde

2, 5-dimethylbenzaldehyde

2,3 -difluorobenzaldehyde

2,4-difluorobenzaldehyde

2, 5-difluorobenzaldehyde

2, 6-difluorobenzaldehyde

3 ,4-difluorobenzaldehyde

3 , 5 -difluorob enzaldehyde ,3,4-trifluorobenzaldehyde ,3,6-trifluorobenzaldehyde -fluoro-2-methylb enzaldehyde -fluoro-p-anisaldehyde -pyridinecarboxaldehyde

3 -pyridinecarboxaldehyde -pyridinecarboxaldehyde

4-pyridinecarboxaldehyde N-oxide

6-methyl-2-pyridinecarboixaldehyde

3-furaldehyde

2-furaldehyde

5-chloro-2-thiophenecarboxaldehyde

3 -thiophenecarboxaldehy de

2-thiophenecarboxaldehyde pyrrole-2-carboxaldehyde

1 -methyl-2-pyrrolecarboxaldehy de

1 -naphthaldehyde

2-naphthaldehyde

2-quinolinecarboxaldehyde

3-quinolinecarboxaldehyde

4-quinolinecarboxaldehyde indole-3 -carboxaldehyde

2-bromobenzaldehyde

2-chlorobenzaldehyde

2-ethoxybenzaldehyde

2-cyanobenzaldehyde

5-(2-chlorophenyl)furfural

5 -(3 -chlorophenyl)furfural

5 -(4-chlorophenyl)furfural

2-thiazolecarboxaldehyde

2-imidazolecarboxaldehyde

4(5)-imidazolecaboxaldehyde

5-nitro-2-thiophenecarboxaldehyde 2-nitrobenzaldehyde

4-formyluracil

4-acetoxybenzaldehyde

4-(dimethylamino)benzaldehyde

1 -acetyl-3 -indolecarboxaldehyde

4-bromo-2-thiophenecarboxaldehyde

Piperonal

3 -trifluoromethoxyb enzaldehyde

4-chloro-3 -nitro-benzaldehyde

Benzaldehyde

3 -benzyloxybenzaldehyde

3 -phenoxyb enzaldehyde

2-butanone >

2-Pentanone

3 -Methyl-2-butanone

Tetrahydrothiophene-3 -one

Tetrahydrothiopyran-4-όne

Cycloheptanone

Cyclooctanone

Cyclohexylmethylketone

4-Methyl-2-pentanone

3-Pentanone

3-Hexanone

4-Hydroxy-3 -methyl-2-butanon

2-Methoxyphenylacetone

4-nitrobenzaldehyde

4-(methylthio)benzaldehyde

Propionaldehyde

Isovaleraldehyde

3 -(methylthio)propional"dehyde

1 -phenyl-2-pentanone

Acetone .

Cyclopropyl methyl ketone 103 Cyclohexanone

104 n-tert-butoxycarbonyl-4-piperidone

105 3,3,5,5 -tetramethylcy clohexanone

106 1-decalone

107 4-cyclohexylcyclohexanone

108 2-norbornanone

109 4-tert-butylcyclohexanone

110 Cyclopentanone

111 2-adamantanone

112 Bicyclo[3,2, l]octan-2-one

113 1 , 1 -dioxo-tetrahydro-thiopyran-4-one

Reagent 2 (amines) used in the above general procedures are shown in Table 2:

Table 2:

No. Reagent 2 (amines)

1 Dibenzoftιran-2-yl-methyl-amine

2 8-fluoro-dibenzofuran-2-yl-amine

3 8-chloro-dibenzofuran-2-yl-amine

4 8-amino-dibenzofuran-2-ol

5 3 -methoxy-diebenzofijran-2-yl-amine

6 9H-Fluoren-3-yl-amine

7 9H-Fluorene-2-yl-amine

8 Dibenzofuran-4-yl-amine

9 Benzo[4,5]furo[2,3-H pyridin-3-yl-amine

10 9-Ethyl-9H-carbazol-3-ylamine

11 3-Amino-carbazole-9-carboxylic acid tert-butyl ester

12 Dibenzofiιran-2-yl-methyl-amine

13 Dibenzofiιran-2-yl-dimethyl-amine

14 Dibenzothiophene-2-yl-amine

15 Dibenzothiophene-3-yl-amine

16 6-Amino-l,2,3,4-tetrahydro-carbazole-9-carboxylic acid tert-butyl ester

17 Dibenzo[l,4]dioxin-2-yl-amine 18 Phenoxanthiin-3-yl-amine

19 10-Oxa-9-thia- 1 -aza-anthracen-3 -yl-amine

20 10H-Benzo-b]pyrido[2,3-e][l,4]oxazin-3-ylamine acetic acid, tert-butyl ester

21 Anthracen-2-yl-amine

22 10, 11 l-Dihydro-5H-diebnzo[b,f]azepin-3-yl-amine

23 6,7, 8,9-Tetrahydro-5H-carbazol-3 -yl-amine

24 7-Amino-l-aza-phenoxathiin

The compounds of Formula I include:

1 (l-Cyclopropyl-ethyl)-(2-methoxy-dibenzofuran-3-yl)-amine

2 Cyclopentyl-(9H-fluoren-2-yl)-amine

3 (1 -Cyclopropyl-ethyl)-(9H-fluoren-2-yl)-amine

4 N³-Cyclopentyl-N²,N²-dimethyl-9H-fluorene-2,3 -diamine

5 Isopropyl-(2-methoxy-dib enzofuran-3 -yl)-amine

6 (2-Methoxy-dibenzofuran-3 -yl)-(tetrahydro-thiopyran-4-yl)-amine

7 Cycloheptyl-(2-methoxy-dibenzofuran-3 -yl)-amine

8 (l-Ethyl-propyl)-(2-methoxy-dibenzofiiran-3-yl)-amine

9 sec-Butyl-(2-methoxy-dib enzofiιran-3 -yl)-amine

10 N²,N²-Dimethyl-N³-piperidin-4-yl-9H-fluorene-2,3 -diamine

1 1 N³-(l-Benzyl-butyl)-N²,N²-dimethyl-9H-fluorene-2,3-diamine

12 (9H-Fluoren-2-yl)-piperidin-4-yl-amine

13 (1 -Benzyl-butyl)-(9H-fluoren-2-yl)-amine

14 sec-Butyl-(9H-fluoren-2-yl)-amine

15 (1,1 -Dioxo-hexahydro-thiopyran-4-yl)-(2-methoxy-dib enzofuran-3 -yl)-amine

16 Dibenzofuran-2-yl-(3 ,3 , 5, 5-tetramethyl-cyclohexyl)-amine

17 (Decahydro-naphthalen- 1 -yl)-dibenzofuran-2-yl-amine

18 Adamantan-2-yl-dibenzofiιran-2-yl-amine

19 Bicyclohexyl-4-yl-dibenzofuran-2-yl-amine

20 Bicyclo[2.2. l]hept-2-yl-dibenzofuran-2-yl-amine

21 (4-tert-Butyl-cyclohexyl)-dibenzofuran-2-yl-amine

22 Bicyclo[3.2. l]oct-2-yl-dibenzofuran-2-yl-amine

23 Cyclopentyl-dibenzoflιran-2-yl-amine

24 Cyclohexyl-(2-methoxy-dibenzofuran-3 -yl)-amine Cyclohexyl-(9H-fluoren-2-yl)-amine Dibenzofuran-2-yl-bis-(3 -methylsulfanyl-propyl)-amine Dibenzofuran-2-yl-bis-(3 -methyl-butyl)-amine Dibenzofiιran-2-yl-dipropyl-amine N³-(l,l-Dioxo-hexahydro-thiopyran-4-yl)-N²,N²-dimethyl-9H-fluorene-2,3- diamine N³-Isoproρyl-N²,N²-dimethyl-9H-fluorene-2,3 -diamine N²,N²-Dimethyl-N³-(tetrahydro-thiopyran-4-yl)-9H-fluorene-2,3 -diamine N³-Cyclohexyl-N²,N²-dimethyl-9H-fluorene-2,3-diamine N³-Cycloheptyl-N²,N²-dimethyl-9H-fluorene-2,3 -diamine N³-(l -Ethyl-propyl)-N²,N²-dimethyl-9H-fluorene-2,3 -diamine N³-(l-Cycloρropyl-ethyl)-N²,N²-dimethyl-9H-fluorene-2,3-diamine N³-sec-Butyl-N²,N²-dimethyl-9H-fluorene-2,3 -diamine (9H-Fluoren~2-yl)-isopropyl-amine (9H-Fluoren-2-yl)-(tetrahydro-thiopyran-4-yl)-amine Cycloheptyl-(9H-fluoren-2-yl)-amine Dibenzofuran-2-yl-(l, l-dioxo-hexahydro-thiopyran-4-yl)-amine Dibenzofuran-2-yl-piperidin-4-yl-amine Dibenzofiιran-2-yl-isopropyl-amine Cyclohexyl-dibenzofuran-2-yl-amine (l-Cyclopropyl-ethyl)-dibenzofuran-2-yl-amine Dibenzofuran-3 -yl-( 1 , 1 -dioxo-hexahydro-thiopyran-4-yl)-amine Dibenzofuran-3 -yl-piperidin-4-yl-amine Dibenzofuran-3 -yl-isopropyl-amine Dibenzofuran-3 -yl-(tetrahydro-thiopyran-4-yl)-amine Cyclohexyl-dibenzofuran-3 -yl-amine Cycloheptyl-dibenzofuran-3 -yl-amine (4-Chloro-benzyl)-dibenzofuran-2-yl-amine (4-Chloro-3-nitro-benzyl)-dibenzofuran-2-yl-amine Dibenzofuran-2-yl-(3 -trifluoromethoxy-benzyl)-amine Benzo[l,3]dioxol-5-ylmethyl-dibenzofuran-2-yl-amine Dibenzofuran-2-yl-(2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-amine Dibenzofuran-2-yl-(3 , 5 -dimethoxy-benzyl)-amine Dibenzofuran-2-yl-(4-trifluoromethyl-benzyl)-amine Dibenzofuran-2-yl-(2-methyl-benzyl)-amine Dibenzofuran-2-yl-thiophen-3 -ylmethyl-amine Dibenzofuran-2-yl-(4-nitro-benzyl)-amine Dibenzofuran-2-yl-(4-methylsulfanyl-benzyl)-amine Dibenzofuran-2-yl-(4-methyl-b enzyl)-amine Benzyl-dibenzofuran-2-yl-amine (3 -Benzyloxy-benzyl)-dibenzofuran-2-yl-amine (1 -Benzyl-butyl)-dibenzofuran-2-yl-amine Dibenzofuran-2-yl-[2-(2-methoxy-phenyl)- 1 -methyl-ethylj-amine 3 -(Dibenzofuran-2-ylamino)-2-methyl-butan- 1 -ol Dibenzofuran-2-yl-(l-ethyl-butyl)-amine Dibenzo_furan-2-yl-(l -ethyl-propyl)-amine Dibenzofuran-2-yl-( 1 ,3 -dimethyl-butyl)-amine (l-Cyclohexyl-ethyl)-dibenzofuran-2-yl-amine Cyclooctyl-dibenzofuran-2-yl-amine Cycloheptyl-dibenzofuran-2-yl-amine Dibenzofuran-2-yl-(tetrahydro-thiopyran-4-yl)-amine Dibenzofuran-2-yl-(tetrahydro-thiophen-3 -yl)-amine Dibenzofuran-2-yl-(l,2-dimethyl-propyl)-amine Dibenzofuran-2-yl-(l-methyl-butyl)-amine sec-Butyl-dibenzofuran-2-yl-amine Benzofiιrp[3,2-b]pyridin-8-yl-(2-fluoro-benzyl)-amine Benzofuro[3,3-b]pyridin-8-yl-pyridin-4-ylmethyl-amine Benzofuro[3 ,2-b]pyridin-8-yl-(2-methyl-benzyl)-amine N-(2-Fluoro-benzyl)-N'-methyl-dibenzofuran-2,8-diamine N-Methyl-N'-quinolin-4-ylmethyl-dibenzofuran-2,8-diamine N-Methyl-N'-naphthanlen- 1 -ylmethyl-dibenzofuran-2, 8-diamine N-(4-Methanesulfonyl-benzyl)-N'-methyl-diebnzofuran-2,8-diamine N-Methyl-N' -pyridin-4-ylmethyl-dibensofuran-2, 8-diamine N-Methyl-N' -(2-methyl-benzyl)-dibenzofuran-2, 8-diamine Naphthanlen- 1 -ylmethyl-( 10H-phenothiazin-2-yl)-amine (4-Methanesulfonyl-benzyl)-(10H-phenothiazin-2-yl)-amine 90 (3 -Fluoro-2-methyl-benzyl)-(l 0-oxa-9-thia- 1 -aza-anthracen-6-yl)-amine

91 (2-Fluoro-2-methyl-benzyl)-(l 0-oxa-9-thia- 1 -aza-anthracen-6-yl)-amine

92 (10-Oxa-9-thia- 1 -aza-anthracen-6-yl)-qinolin-4-ylmethyl-amine

93 Naphthalene-l-ylmethyl-(10-oxa-9-thia-l-aza-anthracen-6-yl)-amine

94 (4-Methanesulfonyl-benzyl)-(10-oxa-9-thia-l-aza-anthracen-6-yl)-amine

95 (10-Oxa-9-thia- 1 -aza-anthracen-6-yl)-pyridin-4-ylmethyl-amine

96 (2-Methyl-benzyl)-(l 0-oxa-9-thia- 1 -aza-anthracen-6-yl)-amine

97 Anthracen-2-yl-quinolin-4-ylmethyl-amine

98 Anthracen-2-yl-(4-methanesulfonyl-benzyl)-amine

99 Anthracen-2-yl-pyridin-4-ylmethyl-amine

100 Anthracen-2-yl-(2-methyl-benzyl)-amine

101 Dibenzo[b,e][l,4]-dioxin-2-yl-(2-fluoro-benzyl)-amine

102 Dibenzo[b,e][l,4]dioxin-2-yl-(2-fluoro-benzyl)-amine

103 Dibenzo[b,e][l,4]fioxin-2-yl-quinolin-4-ylmethyl-amine

104 Dibenzo [b, e] [ 1 ,4]fioxin-2-yl-naphthalen- 1 -ylmethyl-amine

105 Dibenzo [b, e] [ 1 ,4]fioxin-2-yl-(4-methanesulfonyl-b enzyl)-amine

106 Dibenzo[b,e][l,4]fioxin-2-yl-pyridin-4-ylmethyl-amine

107 8-(3-Fluoro-2-methyl-benzylamino)-dibenzofuran-2-ol

108 8-(2-Fluoro-benzylamino)-dibenzofiιran2-ol

109 8-(4-Methanesulfonyl-benzylamino)-dibenzofuran-2-ol

1 10 8-[(Pyridin-4-ylmethyl)-amino]-dibenzofuran-2-ol

1 11 8-(2-Methyl-benzylamino)-dibenzofuran-2-ol

112 (8-Chloro-dibenzofuran-2-yl)-(2-fluoro-benzyl)-amine

1 13 8-Chloro-dibenzofuran-2-yl)-naphthalen- 1 -ylmethyl-amine

114 8-Chloro-dibenzofiιran-2-yl)-(4-methanesulfonyl-benzyl)-amine

115 (4-Methanesulfonyl-benzyl)-(6,7,8,9-tetrahydro-5H-carbazol-3-yl)-amine

116 Pyridin-4-ylmethyl-(6,7,8,9-tetrahydro-5H-carbazol-3-yl)-amine

117 Benzofuro[3,2-b]pyridin-8-yl-(3-fluoro-2-methyl-benzyl)-amine

118 Dibenzofuran-2-yl-quinolin-4-ylmethyl-amine

119 Dibenzofuran-2-yl-quinolin-2-ylmethyl-amine

120 (4-Dimethylamino-benzyl)-(8-fluoro-dibenzofiιran-2-yl)-amine

121 Dibenzofuran-2-yl-(4-dimethylamino-benzyl)-amine

122 Diebnzofuran-2-yl-(5-nitro-thiophen-2-ylmethyl)-amine 123 Dibenzofiιran-2-yl-thiazol-2-ylmethyl-amine

124 Benzyl-(8-fluoro-dibenzofuran-2-yl)-amine

125 N-(-3-Methoxybenzyl)-N'-methyl-dibenzofuran-2,8-diamine

126 N-(3,5-Dimethoxy-benzyl)-N'-methyl-dibenzofuran-2, 8-diamine

127 N- 4-tert-Butyl-benzyl)-N'-methyl-dibenzofiιran-2,8-diamine

128 N-Benzyl-N' -methyl-dibenzofuran-2, 8-diamine

129 2-[(8-Methylamino-dibenzofuran-2-ylamino)-methyl]-benzonitrile

130 (4-Methoxy-benzyl)-phenoxathiin-3 -yl-amine

131 (8-Chloro-dibenzofuran-2-yl)-(3 -methoxy-benzyl)-amine

132 (3 -Methoxy-b enzyl)-phenoxathiin-3 -yl-amine

133 (3,5 -Dimethoxy-b enzyl)-phenoxathiin-3 -yl-amine

134 (3 -Fluoro-4-methoxy-benzyl)-phenoxathiin-3 -yl-amine

135 (4-tert-Butyl-benzyl)-phenoxathiin-3 -yl-amine

136 Benzyl-phenoxathiin-3 -yl-amine

137 (2-Ethoxy-benzyl)-phenoxathiin-3-yl-amine

138 (8-Chloro-dibenzofuran-2-yl)-(3,5-dimethoxy-benzyl)-amine

139 (8-Chloro-dibenzofuran-2-yl)-(3-fluoro-4-methoxy-benzyl)-amine

140 Benzyl-(8-chloro-dibenzofuran-2-yl)-amine

141 (9H-Fluoren-2-yl)-(4-methoxy-benzyl)-amine

142 (8-Chloro-dibenzofuran-2-yl)-thiazol-2-ylmethyl-amine

143 (9H-Fluoren-2-yl)-(3 -methoxy-benzyl)-amine

144 (3,5-Dimethoxy-benzyl)-(9H-fluoren-2-yl)-amine

145 (9H-Fluoren-2-yl)-(3-fluoro-4-methoxy-benzyl)-amine

146 (4-tert-Butyl-benzyl)-(9H-fluoren-2-yl)-amine

147 Benzyl-(9H-fluoren-2-yl)-amine

148 (9H-Fluoren-2-yl)-thiazol-2-ylmethyl-amine

149 (2-Ethoxy-benzyl)-(9H-fluoren2-yl-amine

150 Dibenzofuran-4-yl-(4-methoxy-benzyl)-amine

151 2-[(8-Chloro-dibenzofuran-2-ylamino)-methyl]-benzonitrile

152 Dibenzofiιran-4-yl-(3-methoxy-benzyl)-amine

153 Dibenzofuran-4-yl-(3 , 5-dimethoxy-benzyl)-amine

154 Dibenzofuran-4-yl-(3-fluoro-4-methoxy-benzyl)-amine

155 (4-tert-Butyl-benzyl)-dibenzofiιran-4-yl-amine 156 Dibenzofuran-4-yl-(2-ethoxy-benzyl)-amine

157 N-(4-Methoxy-benzyl)-N' -methyl-dibenzofuran-2, 8-diamine

158 (8-Chloro-dibenzofuran-2-yl)(4-methoxy-benzyl)-amine

159 (8-Chloro-dibenzofiiran-2-yl)-(2-ethoxy-benzyl)-amine

160 Dibenzof_uran-4-yl-(2,4-dimethyl-benzyl)-amine

161 N-Methyl-N'-thiophen-3-ylmethyl-dibenzofuran-2,8-diamine

162 N-Methyl-N'-pyridin-2-ylmethyl-dibenzofuran-2, 8-diamine

163 (2-Bromo-benzyl)-phenoxathiin-3 -yl-amine

164 Phenoxathiin-3 -yl-quinolin-4-ylmethyl-amine

165 Phenoxathiin-3 -yl-thiophen-3 -ylmethyl-amine

166 (3 -Methyl-pyridin-2-ylmethyl)-phenoxathiin-3 -yl-amine

167 Phenoxathiin-3 -yl-pyridin-3 -ylmethyl-amine

168 Phenoxathiin-3 -yl-pyridin-2-ylmethyl-amine

169 (8-Chloro-dibenzofuran-2-yl)-thiophen-3 -ylmethyl-amine

170 (2-Bromo-benzyl)-(9-ethyl-9H-carbazol-3-yl)-amine

171 (8-Chloro-dibenzofuran-2-yl)-(3 -methyl-pyridin-2-ylmethyl)-amine

172 (9-Ethyl-9H-carbazol-3 -yl)-thiophen-3 -ylmethyl-amine

173 (5-Chloro-thioρhen-2-ylmethyl)-(9-ethyl-9H-carbazol-3-yl)-amine

174 (9-Ethyl-9H-carbazol-3 -yl)-pyridin-3 -ylmethyl-amine

175 (2-Bromo-benzyl)-(9H-fluoren-2-yl)-amine

176 (8-Chloro-dibenzofuran-2-yl)-pyridin-4-ylmethyl-amine

177 (9H-Fluoren-2-yl)-quinolin-2-ylmethyl-amine

178 (9H-Fluoren-2-yl)-thiophen-3 -ylmethyl-amine

179 (9H-Fluoren-2-yl)-(3-methyl-pyridin-2-ylmethyl)-amine

180 (9H-Fluoren-2-yl)-pyridin-4-ylmethyl-amine

181 (9H-Fluoren-2-yl)-pyridin-3 -ylmethyl-amine

182 (9H-Fluoren-2-yl)-pyridin-2-ylmethyl-amine

183 (8 -Chloro-dibenzofuran-2-yl)-pyridin-3 -ylmethyl-amine

184 Dibenzofuran-4-yl-quinolin-4-ylmethyl-amine

185 Dibenzofuran-4-yl-quinolin-2-ylmethyl-amine

186 Dibenzofuran-4-yl-thiophen-3 -ylmethyl-amine

187 Dibenzofuran-4-yl-(3-methyl-pyridin-2-ylmethyl)-amine

188 Dibenzofuran-4-yl-pyridin-4-ylmethyl-amine 189 Dibenzofuran-4-yl-ρyridin-3 -ylmethyl-amine

190 Dibenzofuran-4-yl-ρyridin-2-ylmethyl-amine

191 (2-Bromo-benzyl)-(8-chloro-dibenzofuran-2-yl)-amine

192 (8-Chloro-dibenzofuran-2-yl)-pyridin-2-ylmethyl-amine

193 N-Methyl-N'-(2,3,6-trifluoro-benzyl)-dibenzofuran-2,8-diamine

194 N-Methyl-N'-(2,3 ,4-trifluoro-benzyl)-dibenzofuran-2, 8-diamine

195 N-(2, 6-Difluoro-benzyl)-N'-methyl-dibenzofuran-2, 8-diamine

196 N-(2, 5-Difluoro-benzyl)-N'-methyl-dibenzofuran-2, 8-diamine

197 N-(2,4-Difluoro-benzyl)-N'-methyl-dibenzofuran-2,8-diamine

198 N-(2,3-Difluoro-benzyl)-N'-methyl-dibenzofuran-2,8-diamine

199 N-(2,5-Dimethyl-benzyl)-N'-methyl-dibenzofuran-2,8-diamine

200 N-(2,4-Dimethyl-benzyl)-N'-methyl-dibenzofuran-2,8-diamine

201 N-(2,3-Dihydro-benzo[l,4]dioxin-6-ylmethyl)-N'-methyl-dibenzofuran-2,8- diamine

202 (3 -Fluoro-2-methyl-benzyl)-phenoxathiin-3 -yl-amine

203 (8-Chloro-dibenzofuran-2-yl)-(2,3,6-trifluoro-benzyl)-amine

204 Phenoxathiin-3-yl-(2,3,6-trifluoro-benzyl)-amine

205 Phenoxathiin-3 -yl-(2,3 ,4-trifluoro-benzyl)-amine

206 (2, 6-Difluoro-benzyl)-phenoxathiin-3 -yl-amine

207 (2, 5-Difluoro-benzyl)-phenoxathiin-3 -yl-amine

208 (2, 4-Difluoro-benzyl)-phenoxathiin~3 -yl-amine

209 (2,3 -Difluoro-benzyl)-phenoxathiin-3 -yl-amine

210 (2,4-Dimethyl-benzyl)-phenoxathiin-3 -yl-amine

211 (2,3 -Dihy dro-benzo [1,4] dioxin-6-ylmethyl)-phenoxathiin-3 -yl-amine

212 Benzo[b]thiophen-5-yl-(3-fluoro-2-methyl-benzyl)-amine

213 (8-Chloro-dibenzofuran-2-yl)-(2,3,4-trifluoro-benzyl)-amine

214 (8-Chloro-dibenzofuran-2-yl)-(2,6-difluoro-benzyl)-amine

215 (8-Chloro-dibenzofuran-2-yl)-(2,5-difluoro-benzyl)-amine

216 (8-Chloro-dibenzofuran-2-yl)-(2,4-difluoro-benzyl)-amine

217 (9-Ethyl-9H-carbazol-3 -yl)-(3 -fluoro-2-methyl-benzyl)-amine

218 (8-Chloro-dibenzofuran-2-yl)-(2,3 -difluoro-benzyl)-amine

219 (9-Ethyl-9H-carbazol-3-yl)-(2,3,6-trifluoro-benzyl)-amine

220 (9-Ethyl-9H-carbazol-3 -yl)-(2,3 ,4-trifluoro-benzyl)-amine 221 (2,6-Difluoro-benzyl)-(9-ethyl-9H-carbazol-3-yl)-amine

222 (2,5-Difluoro-benzyl)-(9-ethyl-9H-carbazol-3-yl)-amine

223 (2,4-Difluoro-benzyl)-(9-ethyl-9H-carbazol-3 -yl)-amine

224 (2,3 -Difluoro-benzyl)-(9-ethyl-9H-carbazol-3 -yl)-amine

225 (2,5-Dimethyl-benzyl)-(9-ethyl-9H-carbazol-3-yl)-amine

226 (2,4-Dimethyl-benzyl)-(9-ethyl-9H-carbazol-3 -yl)-amine

227 (2,3-Dihydro-benzo[l,4]dioxin-6-ylmethyl)-(9-ethyl-9H-carbazol-3-yl)-amine

228 (9H-Fluoren-2-yl)-(3 -fluoro-2-methyl-benzyl)-amine

229 (8-Chloro-dibenzofuran-2-yl)-(2, 5-dimethyl-benzyl)-amine

230 (9H-Fluoren-2-yl)-(2,3,6-trifluoro-benzyl)-amine

231 (9H-Fluoren-2-yl)-(2,3,4-trifluoro-benzyl)-amine

232 (2,5-Difluoro-benzyl)-(9H-fluoren-2-yl)-amine

233 (2,4-Difluoro-benzyl)-(9H-fluoren-2-yl)-amine

234 (2,3 -Difluoro-benzyl)-(9H-fluoren-2-yl)-amine

235 (2,5-Dimethyl-benzyl)-(9H-fluoren-2-yl)-amine

236 (2,4-Dimethyl-benzyl)-(9H-fluoren-2-yl)-amine

237 (2,3-Dihydro-benzo[l,4]dioxin-6-ylmethyl)-(9H-fluoren-2-yl)-amine

238 (8-Chloro-dibenzofuran-2-yl)-(2,4-dimethyl-benzyl)-amine

239 Dibenzofuran-4-yl-(2,5-dimethyl-benzyl)-amine

240 Dibenzofuran-4-yl-(3 -fluoro-2-methyl-benzyl)-amine

241 N-(3 -Fluoro-2-methyl-benzyl)-N'-methyl-dibenzofiιran-2, 8-diamine

242 (8-Chloro-dibenzofuran-2-yl)-(3 -fluoro-2-methyl-benzyl)-amine

243 (8-Chloro-dibenzofuran-2-yl)-(2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-amine

244 (2,5-Dimethoxy-benzyl)-phenoxathiin-3-yl-amine

245 (2,3 -Dimethoxy-b enzyl)-phenoxathiin-3 -yl-amine

246 (2-Chloro-benzyl)-phenoxathiin-3 -yl-amine

247 (2-Methoxy-benzyl)-phenoxathiin-3 -yl-amine

248 (2-Methyl-benzyl)-phenoxathiin-3 -yl-amine

249 Anthracen-2-yl-(2-chloro-benzyl)-amine

250 Anthracen-2-yl-(2-fluoro-benzyl)-amine

251 Dibenzo [1,4] dioxin-2-yl-(2,3 -dimethoxy-benzyl)-amine

252 (2-Chloro-benzyl)-dibenzo[l,4]dioxin-2-yl-amine

253 2-(Dibenzo[l,4]dioxin-2-ylaminomethyl)-phenol 254 Dibenzo[l,4]dioxin-2-yl-(2-methoxy-benzyl)-amine

255 2-[(9-Ethyl-9H-carbazol-3-ylamino)-methyl]-phenol

256 (9-Ethyl-9H-carbazol-3 -yl)-(2-fluoro-benzyl)-amine

257 (9-Ethyl-9H-carbazol-3 -yl)-(2-methyl-benzyl)-amine

258 (2-Chloro-benzyl)-(9H-fluoren-2-yl)-amine

259 2-[(9H-Fluoren-2-ylamino)-methyl]-phenol

260 (9H-Fluoren-2-yl)-(2-methoxy-benzyl)-amine

261 (9H-Fluoren-2-yl)-(2-trifluoromethyl-benzyl)-amine

262 (9H-Fluoren-2-yl)-(2-fluoro-benzyl)-amine

263 Dibenzofuran-4-yl-(2,5-'dimethoxy-benzyl)-amine

264 Dibenzofuran-4-yl-(2,3 -dimethoxy-benzyl)-amine

265 2-(Dibenzofuran-4-ylaminomethyl)-phenol

266 Dibenzofuran-4-yl-(2-methoxy-benzyl)-amine

267 (2,5-Dimethoxy-benzyl)-(3-methoxy-dibenzofuran-2-yl)-amine

268 (2,3 -Dimethoxy-benzyl)-(3 -methoxy-dibenzofuran-2-yl)-amine

269 (2-Methoxy-benzyl)-(3 -methoxy-dibenzofiιran-2-yl)-amine

270 Dibenzofuran-2-yl-(2, 5-dimethoxy-benzyl)-amine

271 Dibenzofuran-2-yl-(4-methoxy-benzyl)-amine

272 (2-Bromo-benzyl)-dibenzofuran-2-yl-amine

273 (8 -Fluoro-dibenzofuran-2-yl)-(3H-imidazol-4-ylmethyl)-amine

274 2-[(8-Fluoro-dibenzofuran-2-ylamino)-methyl]-benzonitrile

275 (2-Ethoxy-benzyl)-(8-fluoro-dibenzofuran-2-yl)-amine

276 (8-Fluoro-dibenzofuran-^:2-yl)-(4-methylsulfanyl-benzyl)-amine

277 (2-Bromo-benzyl)-(8-fluoro-dibenzofi_ιran-2-yl)-amine

278 (8-Fluoro-dibenzofuran-2-yl)-quinolin-4-ylmethyl-amine

279 (8-Fluoro-dibenzofuran-2-yl)-quinolin-2-ylmethyl-amine

280 Dibenzofuran-2-yl-naphthalen- 1 -ylmethyl-amine

281 (8-Fluoro-dibenzofuran-2-yl)-naphthalen-2-ylmethy 1-amine

282 (8-Fluoro-dibenzofuran-2-yl)-naphthalen- 1 -ylmethyl-amine

283 Dibenzofuran-2-yl-(2-nitro-benzyl)-amine

284 Dibenzoj[_uran-2-yl-(3H-imidazol-4-ylmethyl)-amine

285 2-(Dibenzofuran-2-ylaminomethyl)-benzonitrile

286 Dibenzofuran-2-yl-(2-ethoxy-benzyl)-amine 287 Dibenzofuran-2-yl-(3 -trifluoromethyl-benzyl)-amine

288 (4-tert-Butyl-benzyl)-dibenzofuran-2-yl-amine

289 Dibenzofuran-2-yl-(3 -fluoro-benzyl)-amine

290 (2,5-Dimethoxy-benzyl)-(8-fluoro-dibenzofuran-2-yl)-amine

291 (2,3 -Dimethoxy-benzyl)-(8-fluoro-dibenzofuran-2-yl)-amine

292 (4-Benzyloxy-benzyl)-(8-fluoro-dibenzofuran-2-yl)-amine

293 (3 -Benzyloxy-benzyl)-(8-fluoro-dibenzofiιran-2-yl)-amine

294 (4-Chloro-benzyl)-(8-fluoro-dibenzofuran-2-yl)-amine

295 (3 -Chloro-benzyl)-(8-fluoro-dibenzofuran-2-yl)-amine

296 (2-Chloro-benzyl)-(8-fluoro-dibenzofuran-2-yl)-amine

297 4-[(8-Fluoro-dibenzofuran-2-ylamino)-methyl]-phenol

298 3-[(8-Fluoro-dibenzofuran-2-ylamino)-methyl]-phenol

299 Dibenzofuran-2-yl-(2-fluoro-benzyl)-amine

300 (8-Fluoro-dibenzofuran-2-yl)-(4-methoxy-benzyl)-amine

301 (8-Fluoro-dibenzofuran-2-yl)-(3 -methoxy-benzyl)-amine

302 (8-Fluoro-dibenzofuran-2-yl)-(2-methoxy-benzyl)-amine

303 (8-Fluoro-dibenzofuran-2-yl)-(4-trifluoromethyl-benzyl)-amine

304 (8-Fluoro-dibenzofuran-2-yl)-(3 -trifluoromethyl-benzyl)-amine

305 (4-tert-Butyl-benzyl)-(8-fluoro-dibenzofuran-2-yl)-amine

306 (4-Fluoro-benzyl)-(8-fluoro-dibenzofuran-2-yl)-amine

307 (3 -Fluoro-benzyl)-(8-fluoro-dibenzofuran-2-yl)-amine

308 (2-Fluoro-benzyl)-(8-fluoro-dibenzofuran-2-yl)-amine

309 (8-Fluoro-dibenzofuran-2-yl)-(4-methyl-benzyl)-amine

310 (8-Fluoro-dibenzofuran-2-yl)-(3 -methyl-benzyl)-amine

311 Dibenzofiιran-2-yl-(2,6-dimethoxy-benzyl)-amine

312 Dibenzofuran-2-yl-(2,4-dimethoxy-benzyl)-amine

313 Dibenzofuran-2-yl-(2,3 -dimethoxy-benzyl)-amine

314 (4-Benzyloxy-benzyl)-dibenzofuran-2-yl-amine

315 Dibenzofiιran-2-yl-(3 -methyl-b enzyl)-amine

316 (3 -Chloro-benzyl)-dibenzofuran-2-yl-amine

317 3-(Dibenzofuran-2-ylaminomethyl)-phenol

318 (2-Chloro-benzyl)-dibenzofixran-2-yl-amine

319 Dibenzo&ran-2-yl-(3 -methoxy-benzyl)-amine 320 Dibenzofuran-2-yl-(2-methoxy-benzyl)-amine

321 (9H-Fluoren-2-yl)-(2-methyl-benzyl)-amine

322 Dibenzofuran-4-yl-(2-methyl-benzyl)-amine

323 (8-Chloro-dibenzofuran-2-yl)-(2-methyl-benzyl)-amine

324 (2-Methyl-benzyl)-(10H-phenothiazin-2-yl)-amine

325 Dibenzo[b,e][l,4]dioxin-2-yl-(2-methyl-benzyl)-amine

326 Dibenzofuran-2-yl-(2, 6-difluoro-benzyl)-amine

327 Dibenzofuran-2-yl-(2,5-difluoro-benzyl)-amine

328 Dibenzofuran-2-yl-(2,4-difluoro-benzyl)-amine

329 Dibenzofuran-2-yl-(2,3 -difluoro-benzyl)-amine

330 (8-Fluoro-dibenzofuran-2-yl)-thiophen-2-ylmethyl-amine

331 Dibenzofuran-2-yl-(2,5-dimethyl-benzyl)-amine

332 (8-Fluoro-dibenzofuran-2-yl)-thiophen-3 -ylmethyl-amine

333 (8-Fluoro-dibenzofuran-2-yl)-furan-2-ylmethyl-amine

334 (8-Fluoro-dibenzofuran-2-yl)-furan-3 -ylmethyl-amine

335 (8-Fluoro-dibenzofuran-2-yl)-(6-methyl-pyridin-2-ylmethyl)-amine

336 (8-Fluoro-dibenzofuran-2-yl)-(4-methanesulfonyl-benzyl)-amine

337 (8-Fluoro-dibenzofuran-2-yl)-pyridin-4-ylmethyl-amine

338 (8-Fluoro-dibenzofuran-2-yl)-pyridin-3 -ylmethyl-amine

339 (8-Fluoro-dibenzofuran-2-yl)-pyridin-2-ylmethyl-amine

340 (8-Fluoro-dibenzofuran-2-yl)-(3 -fluoro-4-methoxy-benzyl)-amine

341 Dibenzofuran-2-yl-(2,4-dimethyl-benzyl)-amine

342 (8-Fluoro-dibenzofuran-2-yl)-(3 -fluoro-2-methyl-benzyl)-amine

343 (8-Fluoro-dibenzofuran-2-yl)-(2,3,6-trifluoro-benzyl)-amine

344 (8-Fluoro-dibenzofuran-2-yl)-(2,3 ,4-trifluoro-benzyl)-amine

345 (3 , 5-Difluoro-benzyl)-(8-fluoro-dibenzofuran-2-yl)-amine

346 (3 ,4-Difluoro-benzyl)-(8-fluoro-dibenzofuran-2-yl)-amine

347 (3 , 5-difluoro-benzyl)-(8-fluoro-dibenzofuran-2-yl)-amine

348 (2,6-Difluoro-benzyl (2,.5-Difluoro-benzyl)-(8-fluoro-dibenzofuran-2-yl)-amine

349 (2,4-Difluoro-benzyl)-(8-fluoro-dibenzofuran-2-yl)-amine

350 (2,3 -Difluoro-benzyl)-(8-fluoro-dibenzofuran-2-yl)-amine

351 (2,5-Dimethyl-benzyl)-(8-fluoro-dibenzofuran-2-yl)-amine

352 (2,4-Dimethyl-benzyl)-(8-fluoro-dibenzofuran-2-yl)-amine 353 (2,3-Dihydro-l,4-benzodioxin-6-ylmethyl)-(8-fluoro-dibenzofuran-2-yl)-amine

354 (3,5-Dimethoxy-benzyl)-(8-fluoro-dibenzofuran-2-yl)-amine

355 Dibenzofuran-2-yl-furan-2-ylmethyl-amine

356 Dibenzofuran-2-yl-furan-3 -ylmethyl-amine

357 Dibenzofuran-2-yl-(6-methyl-pyridin-2-ylmethyl)-amine

358 Dibenzofuran-2-yl-(4-methanesulfonyl-benzyl)-amine

359 Dibenzofuran-2-yl-pyridin-4-ylmethyl-amine

360 Dibenzofiιran-2-yl-pyridin-3 -ylmethyl-amine

361 Dibenzofuran-2-yl-pyridin-2-ylmethyl-amine

362 Dibenzofiιran-2-yl-(3 -fluoro-4-methoxy-benzyl)-amine

363 Dibenzofiιran-2-yl-(3 -fluoro-2-methyl-benzyl)-amine

364 Dibenzo&ran-2-yl-(2,3,6-trifluoro-benzyl)-amine

365 Dibenzofuran-2-yl-(2,3 ,4-trifluoro-benzyl)-amine

366 Dibenzofuran-2-yl-(3,5-difluoro-benzyl)-amine

367 Dibenzofuran-2-yl-(3 ,4-difluoro-benzyl)-amine

368 Dibenzofuran-2-yl-(3 ,4-dimethoxy-benzyl)-amine

369 Dibenzofiιran-2-yl-methyl-(2-methyl-benzyl)-amine

370 Dibenzothiohen-2-yl-(2,4-dimethyl-benzyl)-amine

371 (4-tert-Butyl-benzyl)-dibenzothiohen-2-yl-amine

372 (2-Chloro-benzyl)-dibenzothiohen-2-yl-amine

373 Dibenzothiohen-2-yl-(2,6-difluoro-benzyl)-amine

374 Dibenzothiohen-2-yl-(2,3,6-trifluoro-benzyl)-amine

375 Dibenzothiohen-2-yl-(2-fluoro-benzyl)-amine

376 B enzyl-dib enzothiohen-2-yl-amine

377 Dibenzothiohen-2-yl-(4-methoxy-benzyl)-amine

378 Dibenzothiohen-2-yl-(2,3 -dimethoxy-benzyl)-amine

379 Dibenzothiohen-2-yl-(2,5-difluoro-benzyl)-amine

380 Dibenzothiohen-2-yl-(3 -methoxy-benzyl)-amine

381 Dibenzothiohen-2-yl-(2,3 ,4-trifluoro-benzyl)-amine

382 (-2-Bromo-benzyl)-dibenzothiohen-2-yl-amine

383 Dibenzothiohen-2-yl-(2,3 -dihydro- 1 ,4-benzodioxin-6-ylmethyl)-amine

384 Dibenzothiohen-2-yl-(3 -fluoro-4-methoxy-benzyl)-amine

385 Dibenzothiohen-2-yl-(2,5-dimethyl-benzyl)-amine 386 Dibenzothiohen-2-yl-thiophen-3 -ylmethyl-amine

387 Dibenzothiohen-2-yl-naphthalene-l-ylmethyl-amine

388 Dibenzothiohen-2-yl-(2-trifluoromethyl-benzyl)-amine

389 Dibenzothiohen-2-yl-naphthalen-2-ylmethyl-amine

390 Dibenzothiohen-2-yl-(2-ethoxy-benzyl)-amine

391 (10, 1 l-Dihydro-5H-dibenz[b,f]azepin-2-yl)-(3-fluoro-2-methyl-benzyl)-amine

392 (10, 1 l-Dihydro-5H-dibenz[b,f]azepin-2-yl)-(2-methyl-benzyl)-amine

393 (10, 1 l-Dihydro-5H-dibenz[b,f]azepin-2-yl)-(2,4-dimethyl-benzyl)-amine

394 (4-tert-Butyl-benzyl)-( 10, 11 -dihydro-5H-dibenz[b,f| azepin-2-yl)-amine

395 (2-Chloro-benzyl)-(10, 1 l-dihydro-5H-dibenz[b,f]azepin-2-yl)-amine

396 (2,6-Difluoro-benzyl)-(10, 1 l-dihydro-5H-dibenz[b,f]azepin-2-yl)-amine

397 (10, 1 l-Dihydro-5H-dibenz[b,f]azepin-2-yl)-(2,3,6-trifluoro-benzyl)-amine

398 (10, 1 l-Dihydro-5H-dibenz[b,fjazepin-2-yl)-(2-fluoro-benzyl)-amine

399 (10, 1 l-Dihydro-5H-dibenz[b,f]azepin-2-yl)-(3,5-dimethoxy-benzyl)-amine

400 Benzyl-(10,1 l-dihydro-5H-dibenz[b,f]azepin-2-yl)-amine

401 (10, 1 l-Dihydro-5H-dibenz[b,f]azepin-2-yl)-(4-methoxy-benzyl)-amine

402 (10, 1 l-Dihydro-5H-dibenz[b,f]azepin-2-yl)-(2,3-dimethoxy-benzyl)-amine

403 (2, 5-difluoro-benzyl)-(l 0, 11 -dihydro-5H-dibenz[b,f] azepin-2-yl)-amine

404 (10, 1 l-Dihydro-5H-dibenz[b,fjazepin-2-yl)-(3-methoxy-benzyl)-amine

405 (10, 1 l-Dihydro-5H-dibenz[b,f]azepin-2-yl)-(2,3,4-trifluoro-benzyl)-amine

406 (2-Bromo-benzyl)-(10, 1 l-dihydro-5H-dibenz[b,f]azepin-2-yl)-amine

407 (2,3-Dihydro-l,4-benzodioxin-6-ylmethyl)-(10, 1 l-dihydro-5H- dibenz[b,f]azepin-2-yl)-amine

408 (10, 1 l-Dihydro-5H-dibenz[b,f]azepin-2-yl)-(3-fluoro-4-methoxy-benzyl)-amine

409 (10, 1 l-Dihydro-5H-dibenz[b,f|azepin-2-yl)-(2,5-dimethyl-benzyl)-amine

410 (10, 1 l-Dihydro-5H-dibenz[b,f]azepin-2-yl)-thiophen-3 -ylmethyl-amine

411 (10, 1 l-Dihydro-5H-dibenz[b,f]azepin-2-yl)-naphthalen-l-ylmethyl-amine

412 (10,1 l-Dihydro-5H-dibenz[b,fjazepin-2-yl)-(2-trifluoromethyl-benzyl)-amine

413 (10, 1 l-Dihydro-5H-dibenz[b,f]azepin-2-yl)-naphthalen-2-ylmethyl-amine

414 (10, 1 l-Dihydro-5H-dibenz[b,f]azepin-2-yl)-(2-ethoxy-benzyl)-amine

415 (3-Fluoro-2-methyl-benzyl)-(10H-phenothiazin-2-yl)-amine

416 (2,4-Dimethyl-benzyl)-(10H-phenothiazin-2-yl)-amine

417 (4-tert-Butyl-benzyl)-(10H-phenothiazin-2-yl)-amine 418 (2-Chloro-benzyl)-(10H-phenothiazin-2-yl)-amine

419 (2,6-Difluoro-benzyl)-(10H-phenothiazin-2-yl)-amine

420 (10H-Phenothiazin-2-yl)-(2,3 ,6-trifluorobenzyl)-amine

421 (2-Fluoro-benzyl)-( 10H-phenothiazin-2-yl)-amine

422 (3,5 -Dimethoxy-b enzyl)-( 10H-phenothiazin-2-yl)-amine

423 Benzyl-(10H-phenothiazin-2-yl)-amine

424 (4-Methoxy-benzyl)-(10H-phenothiazin-2-yl)-amine

425 (2, 5 -Difluoro-benzyl)-( 10H-phenothiazin-2-yl)-amine

426 (10H-Phenothiazin-2-yl)-(2,3,4-trifluoro-benzyl)-amine

427 (2,3-Dihydro-l,4-benzodioxin-6-ylmethyl)-(10H-phenothiazin-2-yl)-amine

428 (3 -Fluoro-4-methoxy-benzyl)-( 10H-phenothiazin-2-yl)-amine

429 (2, 5-Dimethyl-benzyl)-( 10H-phenothiazin-2-yl)-amine

430 (10H-Phenothiazin-2-yl)-thiophen-3 -ylmethyl-amine

431 (10H-Phenothiazin-2-yl)-(2-trifluoromethyl-benzyl)-amine

432 (9H-Carbazol-3 -yl)-(3 -fluoro-2-methyl-benzyl)-amine

433 (9H-Carbazol-3 -yl)-(2-methyl-benzyl)-amine

434 (9H-Carbazol-3 -yl)-(2,4-dimethyl-benzyl)-amine

435 (4-tert-Butyl-benzyl)-(9H-carbazol-3-yl)-amine

436 (9H-Carbazol-3 -yl)-(2-chloro-benzyl)-amine

437 (9H-Carbazol-3 -yl)-(2, 6-difluoro-benzyl)-amine

438 (9H-Carbazol-3-yl)-(2,3,6-trifluoro-benzyl)-amine

439 (9H-Carbazol-3-yl)-(3,5-dimethoxy-benzyl)-amine

440 (9H-Carbazol-3 -yl)-(2,3 -dimethoxy-benzyl)-amine

441 (9H-Carbazol-3-yl)-(2,5-difluoro-benzyl)-amine

442 (9H-Carbazol-3 -yl)-(2,3 ,4-trifluoro-benzyl)-amine

443 (9H-Carbazol-3 -yl)-(2,3-dihydro- 1 ,4-benzodioxin-6-ylmethyl)-amine

444 (9H-Carbazol-3-yl)-(2,5-dimethyl-benzyl)-amine

445 (9H-Carbazol-3 -yl)-naphthalen- 1 -ylmethyl-amine

446 (9H-Carbazol-3 -yl)-naphthalen-2-ylmethyl-amine

447 Dibenzofuran-2-yl-bis-(2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-amine

448 Dibenzofuran-2-yl-bis-thiophen-3 -ylmethyl-amine

449 Dibenzofuran-2-yl-(4-phenoxy-benzyl)-amine

450 2-Dibenzofuran-2-yl-2,3 -dihydro- IH-isoindole 451 2-Dibenzofiιran-2-yl~ lH-isoindole- 1 ,3 -dione

452 Dibenzofuran-2-yl-(4-trifluoromethoxy-benzyl)-amine

453 Dibenzofuran-2-yl-(2-methoxy-benzyl)-amine

454 Dibenzofiιran-2-yl-(3 -phenoxy-benzyl)-amine

455 Dibenzofuran-2-yl-methyl(2-methyl-benzyl)-amine

456 Dibenzofuran-2-yl-( 1 -phenyl-butyl)-amine

457 Dibenzofiιran-2-yl-phenethyl-amine

458 Dibenzofiιran-2-yl-(l-phenyl-ethyl)-amine

EXAMPLES

* Analysis was done by LCMS. Number shown is M+l. In all cases mass shown agrees with the expected mass for the compound shown.

The following compounds were prepared according to the general procedure 1 :

Antiviral activity assays:

Screening assays: Anti-herpes simplex virus- 1 (HSV) activity is determined in a yield reduction assay utilizing a recombinant HSV (HSV US3 : : pgC-lacZ) which expresses E. coli β-galactosidase (β-gal) under the control of an HSV late gene promoter (Fink, D.J.; Sternberg, L.R.; Weber, P.C.; Mata, M.; Goins, W.F.; Glorioso, J.C. Human Gene Therapy 3:11-19, 1992). Vero (African Green Monkey kidney) cells are infected at a multiplicity of infection of 0.01 with the virus, and serial dilutions of the compound in dimethyl sulfoxide (DMSO) are added. The final concentration of DMSO in all wells is 1%. DMSO is added to control wells. The infection is allowed to proceed for 2 days at which time the β-gal activity in cell lysates is measured. Activity in wells containing compound is compared to control wells and percent inhibition determined. The EC₅₀ is defined as the concentration of drug that produces a 50% reduction in β-gal production relative to control wells.

Anti-human cytomegalovirus (HCMV) activity is determined in a yield reduction assay utilizing a recombinant HCMV (RC256) that produces β-gal (Spaete, R.R.; Mocarski, E.S. Proceedings of the National Academy of Sciences USA 84:7213-7217, 1987). Primary human diploid fibroblasts (HFF cells) are infected at an moi of 0.01 withRC256, and serial dilutions of the compound inDMSO are added. The final concentration of DMSO in all wells is 1%. The infection is allowed to proceed for 7 days at which time the β-gal activity in cell lysates is measured. Activity in wells containing compound is compared to control wells and percent inhibition determined. The EC₅₀ is defined as the concentration of compound that produces a 50% reduction in β-gal production relative to control wells. TC₅₀ is defined as concentration of compound that produces cytotoxicity in 50% of uninfected cells.

Secondary yield reduction assays: To determine the activity of compounds against HSV, Vero cells are plated in 6 well dishes at a density of 5 x 10⁵ cells/well. Cells are infected at a multiplicity of infection of 0.01 with HSV (strain Synl7+). 30μL of one of six threefold serial dilutions of test compound inDMSO is added to each well at the time of infection. The plates are returned to a 37°C incubator and the infection allowed to proceed for 2 days. Aliquots of the supernatant are harvested, and the virus titer determined. Vero cells in 24 well plates are infected with threefold serial dilutions of supernatant. The virus is allowed to adsorb to the monolayer for 1.5 hours, after which it is aspirated and replaced with growth medium containing 0.5% methylcellulose. Plaques are allowed to develop for 5 days, at which time the medium aspirated and the monolayer stained with crystal violet. The plaques are enumerated under low power magnification. Percent inhibition is determined by comparison with the titer from cells infected in the presence of DMSO alone.

To determine the activity of compounds against CMV, HFF cells, plated in 24 well plates at 1 x 10⁵ cells/well, are infected with CMV (strain AD 169) at an moi of 0.01. 10 μL of one of six threefold dilutions of test compound in DMSO is added to each well at the time of infection. The plates are returned to a 37°C incubator and the infection allowed to proceed for 7 days. Aliquots of the supernatant of infected cells are harvested and the virus titer determined. HFF cells in 24 well plates are infected with threefold serial dilutions of supernatant. The virus is allowed to adsorb to the cells for 2 hours, at which time the inoculum is aspirated and replaced with growth medium containing 0.5% methylcellulose. The plaques are allowed to develop for 7- 10 days, at which time the medium is aspirated and the monolayer stained with crystal violet. The plaques are enumerated under low power magnification. Percent inhibition is determined by comparison with the titer from cells infected in the presence of DMSO alone.

Cellular toxicity assays: Cellular toxicity is measured in HFF cells. Cells are plated in 96 well plates at IxlO⁴ cells/ well. Serial dilutions of compounds are added to the wells in DMSO, with the final concentration of DMSO in all wells at 1%, in a total volume of 200μL. The plates are maintained in a 37°C incubator for 7 days. 50μL of a solution of XTT (sodium~3'[l-(phenyl-amino-carbonyl)-3,-tetrazolium]-bis(bis(4- methoxy-6-nitro)-benzene sulfonic acid hydrate) (3 x 10^"4 mg/ml) is added to each well, and the plates returned to the incubator for 4 hours, after which the A₄50 (absorbance at wavelength of 450 nm) for each well is measured in a plate reader. (Roehm, N.W., et al J. Immunol. Meth. 142:257-265, 1991). Toxicity is determined by comparison of the OD (optical density) ofa well containing compound to the OD of wells contaimng DMSO only.

The effect of test compounds on cellular DNA synthesis is measured in a ¹⁴C- thymidine incorporation assay, utilizing scintillation proximity assay technology. Cells are plated at 2 x 10⁴ cells/well in Amersham Cytostar 96 well scintillating microplates. The following day, serial dilutions of test compounds in DMSO are added to the wells, along with 0. lμCi/well of [methyl-¹⁴C]-thymidine (specific activity 50-62mCi/mmol). The plates are counted immediately in a μBeta scintillation counter (Wallac), to determine background, then placed in a 37°C incubator for 7 days. The plates are removed from the incubator at intervals and the thymidine incorporation into the cellular DNA determined by scintillation counting. Percent inhibition is determined by comparing ¹⁴C incorporation in wells containing test compound to incorporation in wells containing DMSO only.

Table 3 contains the results of the antiviral efficacy (HSV: EC₅₀, TC50 and Tl) screening results, where Tl is the therapeutic index (TC50 EC.50).

TABLE 3 Antiviral Efficacy in a Yield Reduction Assay (HSV-1) Antiviral Efficacy (Vero Cells) Example ~EC₅Q (μM) TC₅₀ (μM) Tl (EC₅₀/ TC₅₀^

60 0.5 >100 >200

57 0.81 >100 >124

56 0.7 >100 >143

208 0.26 >100 >385

217 0.32 >100 >313

139 0.4 >100 >250

150 0.85 >100 >118

93 1.3 >100 >77

Reference 0.2 >100 >500 Agent (Acyclovir)

Table 4 contains the results of the antiviral efficacy (HSV: EC50, TC50 and Tl) screening results, where Tl is the therapeutic index (TC₅₀ EC50). TABLE 4 Antiviral Efficacy in a Yield Reduction Assay (CMV)

Antiviral Efficacy (HFF Cells)

Example EC50 (μM) TC₅₀ (μM) TI (EC₅o/ TC₅

61 2.9 >100 >35

57 1.7 >100 >59

65 3.0 >100 >33

60 1.3 >100 >77

Reference 2.6 >100 >39

Agent

(Ganciclovir)

Tables 3 and 4 indicates that the compounds of the present invention have good to excellent activity in HSV infected cells from HSV pathogenecity at μM to sub-μM concentrations.

While the forms of the invention herein disclosed constitute presently preferred embodiments, many others are possible. It is not intended herein to mention all of the possible equivalent forms or ramifications of the invention. It is understood that the terms used herein are merely descriptive, rather than limiting, and that various changes may be made without departing from the spirit or scope of the invention.