MXPA00001365A - 5,6-HETEROARYL-DIPYRIDO[2,3-b - Google Patents

Abstract

Disclosed are novel heteroaryl-dipyridoazepines. These are useful in the prevention or treatment of HIV infection.

Description

. ß-HETEROARLL-DIPIRID? r2.3-B: 3'.2'-FlAZEPINAS AND ITS USE IN THE PREVENTION OR TREATMENT OF HtV INFECTION Field of the invention. The invention relates to novel 5,6-heteroaryldipyrido [2,3-b: 3 ', 2'-fjazepines and their pharmaceutically acceptable salts, to methods for preparing these compounds, to the use of these compounds alone or in combination with other antiviral agents, immunomodulators, antibiotics, anti-infectives, or vaccines for the prevention or treatment of HIV infection, and to pharmaceutical compositions containing these compounds. BACKGROUND OF THE INVENTION The human disease, Acquired Immune Deficiency Syndrome (AIDS), is caused by the Human Immunodeficiency Virus (HIV), particularly the strain known as HIV-1. Like other viruses, HIV-1 can not replicate without seizing the biosynthetic apparatus of the host cell it infects. It makes this device produce the structural proteins that make up the viral progeny. These proteins are encoded by the genetic material contained in the infecting viral part, or virion. However, being a retro virus, the genetic material of HIV is RNA, not DNA as in the genome of the host cell. Therefore, viral RNA must first become DNA, and then be integrated into the genome of the host cell, in order that REF: 32353 host cell produces the viral proteins required. The conversion of RNA into real DNA- is raised by the enzyme reverse transcriptase (RT), which together with RNA is a component of the infecting virion. Reverse transcriptase has three known enzymatic functions; it acts as an RNA-dependent DNA-polymerase, as a ribonuclease and as a DNA-dependent DNA-pouser. By acting in the first place as an RNA-dependent DNA polymerase, RT forms a copy of the single-stranded DNA of the viral RNA. By acting as a ribon nuclease, RT releases the newly produced DNA from the original viral RNA and destroys the original RNA. Finally, by acting - like a DNA-dependent polymerase DNA, RT forms a second complementary DNA strand, using the first strand of DNA as a template. The two chains form double-stranded DNA, which is integrated into the genome of the host cell by another enzyme called integrase. Compounds that inhibit the enzymatic functions of HIV-1 reverse transcriptase will inhibit the replication of HIV-1 in infected cells. Said compounds are useful in the prevention or treatment of HIV-1 infection in human subjects as demonstrated by the known RT inhibitors: 3'-azido-3'-deoxythymidine (AZT), 2 \ 3'- dideoxyinosine (ddl) and 2 ', 3'-dideoxycytidine (ddC) and D4T, the only drugs approved so far for use in the treatment of AIDS and the AIDS-related Complex (ARC).

As with any antiviral therapy, the use of RT inhibitors in the treatment of AIDS ultimately leads to a virus that is less sensitive to the given drug. Resistance (reduced sensitivity) to these drugs is the result of mutations that take place in the reverse transcriptase segment of the pol gene. . The compounds of the present invention are very potent not only against the RT enzyme of the virus - wild-type (non-mutated), but are also effective against the reverse transcriptase of many mutant viruses that have been observed in patients who have been treated with RT inhibitors. Specifically, the compounds of the present invention are effective to inhibit the Y181C £ mutant in which the thyrotoxin (Y) at codon 181 has mutated to a cysteine residue (C) which has been the most commonly observed mutant in clinical studies after of therapy with many non-nucleoside reverse transcriptase inhibitors. The compounds are also effective-in contrast to other mutant enzymes observed that contain a single point mutation such as K103N, V106A, G190A, Y188C or P236L. Prior art K. D. Hargrave, J.R. Proudfoot, J. Adams, K.Grozinger, G. Schmidt,. Engel, G. Trummlitz and W. Eberlein, application for US Pat. No. 740,828 (1991); Karl D. Hargrave, John R. Proudfoot, Karl G. Grozinger, Ernest Cullen, Suresh R. Kapadia, Usha R. Patel, Victor U. Fuchs, Scott C. Mauldin, Jana Vitous, Mark L.

Behnke, Janice M. Klunder, Kollol Pal, Jerry W. Skiles, Daniel W. McNeil, Janice M. Rose, Grace Chow, Mark T. Skoog, Joe C. Wu, Günther Schmidt, Wolfhard W. Engel, Wolfgang G. Eberlein , Tracy D Saboe, Scot J. Campbell, Alan S. Rosenthal and Julian Adams, "Novel Non-Nucleoside Inhibitors of HIV-1 Reverse Transcriptase 1. Tricyclic Pyridobenzo- and Dipyridodiazepinones ", J. Med. Chem., 34, 2231 (1991), N. K. Terrett, D. Bojanic, J. R. Merson and P. T. Stephejí are, , 3 ', 6,?) Dipyrido. { 3, 2-b: 2 ', 3'-e] Q, 4) -diazepines: Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors with Greater Enzyme Affinity than Nevirapine. "Bioorg Med. Chem. Leftt 2, 1745 (1992). John R. Proudfoot *, Karl D. Hargrave, Suresh R. Kapadia. Usha R. Patel, Karl G. Grozinger, Daniel W. McNeil, Ernest Cu-lien, Mario Cardozo, Liang Tong, Terence A. Kelly, Janice Rose, Eva David, Scott c. Mauldin, Victor U. Fuchs, Jana Vitous, MaryAnn Hoer ann, Janice M. Klunder, Palayakotai Raghavan, Jerry W. Skiles, Philip Mui, Douglas D. Richman, John L. Sullivan, Cheng-Kon Shih, Peter Grob and Julian Adams . "Novel Non-Nucleoside Inh_i_ bitters of HIV-1 Reverse Transcriptase, 4.2-Substi tuted Dipyridodiazepinones are Potent Inhibitors of both Wild Type and Cysteine-181 HIV-1 Reverse Transcriptase Enzymes", J. Med. Chem. 38, 4830. (nineteen ninety five). Summary of the Invention. A first aspect of the invention comprises new dipyridof2,3-b: 3 ', 2' -fjazepines. They possess inhibitory activity against the RT of HIV-1 both wild type and mutant. A second aspect of the invention comprises methods for preparing these new compounds. A third aspect of the invention is a method for preventing or treating HIV-1 infection comprising administering, to a human being exposed to or infected by HIV-1, a prophylactically or therapeutically effective amount of one of the novel compounds cited above, either alone or in combination with other antiviral agents. A final aspect of the invention comprises pharmaceutical compositions suitable for the prevention or treatment of HIV-1 infection comprising the aforementioned compounds. Description of the invention In one of its aspects in terms of the composition of the material, the invention comprises dipyrid Q., 3-b: 3 ', 2' -fj azepines of formula I, formula II and formula III. p m wherein: in formula I, formula II and formula III, A and D are independently carbon (unsubstituted or optionally substituted with methyl, ethyl, isopropyl, vinyl, isopropenyl, ethynyl, halogen, nitro, cyano, amino, methylamino, dimethylamino, hydroxy, methoxy, mercapto or methylthio) or nitrogen, and B is sulfur, oxygen or nitrogen (unsubstituted or optionally substituted by methyl, ethyl, isopropyl, hydroxy or methoxy); and R. is a hydrogen atom, alkyl of 1 to 4 carbon atoms, fluoroalkyl of 1 to 4 carbon atoms and 1 to 3 fluorine atoms, cycloalkyl of 3 to 6 carbon atoms, oxetanyl, tert-butyl, tetrahydrofuran tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, alkylammonium or alkynylmethyl of 3 to 4 carbon atoms, alkyloxyalkyl or alkyltioalkyl of 2 to 3 carbon atoms, alkanoyl or alky1 (thiocarbonyl) of 2 to 5. carbon atoms, or cyanoalkyl of 2 to 3 carbon atoms. and, R 2 is a hydrogen atom, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, alkenyl or alkynyl of 2 to 6 carbon atoms, trihalsmethyl, hydroxyalkyl of 1 to 6 carbon atoms , alkyloxy or alkylthio of 2 to 6 carbon atoms, alkyloxyalkyl or alkylthioalkyl of 2 to 6 a t < or carbon monomers, pyrrolidinyl, pyrrolinyl, piperidinyl, mono- or di-alkylamino in which each alkyl moiety contains 1 to 3 carbon atoms, halogen, cyano, nitro or carboxyl, aryl (in which aryl is phenyl, pyridinyl, thienyl, furanyl, pyrroH, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl or isothiazolyl) which is unsubstituted or substituted by hydroxyl, amino, halogen, alkyl or alkyloxy of 1 to 3 carbon atoms, and R 3 is a hydrogen, methyl or halogen atom R. is a hydrogen, methyl, ethyl or halogen atom. R5 is a hydrogen, hydroxy, amino, hydroxymethyl or aminomethyl atom. A subgeneric aspect of the invention comprises compounds of formula I, formula II and formula III, wherein: in formula I, formula II and formula III, A and D are independently carbon (unsubstituted or optionally substituted by methyl, cyano or halogen) or nitrogen and B is sulfur or oxygen or nitrogen (not substituted or optionally substituted with methylo); and, R. is alkyl of 1 to 3 carbon atoms or cycloalkyl of 3 to 4 carbon atom; R 2 is a hydrogen atom, methyl, trihalomethyl, methoxy, pyrrolidinyl, pyrrolinyl, piperidinyl, dimethylamino, halogen, cyano, nitro or aryl (wherein aryl is phenyl, pyridinyl, -thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, oxazoli -lo, isoxazolyl, thiazolyl or isothiazolyl) which is either not substituted or substituted by methyl, methoxy, hydroxyl, amino or halogen. R- is a hydrogen atom, methyl, chlorine or bromine; R- is hydrogen or methyl. and, Re is a hydrogen atom, or A particular subgeneric aspect of the invention comprises compounds of formula I, formula II and formula III, wherein: in formula I, formula II and formula III, A and D are independently carbon or nitrogen, and B is sulfur, oxygen or nitrogen, and, R. is ethyl or cyclopropyl; R "is hydrogen, chloro or pyrazolyl, Rj and e are hydrogen; R »is hydrogen or methyl. Preferred compounds of formula I, formula II and form mule III are: 11-Ethyl-thienl [2 \ 3 ^ 6.5] d-pyrido [2,3-b: 3 \ 2 * - *? Azep na 11-Ethyl-thieni [3 ', 4': 6,5] dipyrido [2,3-b: 3,, 2'-f] azepine; 2-Chloro-11-ethyl-thienyl [2 ', 3,: 6,5] dipyrido [2,3-b: 3,, 2, -f] azepine; 2- (4-Pyrazolyl) -11-ethyl-thienyl [2,, 3,: 6,5] dipyrido [2,3-b: 3 ', 2'-f] azepine; 11-Ethyl-thiazolyl .d'ie.dJdipyridofS ^ -b ^ '. S'-flazepine; d-Ethyl-oxazolo ^ '.e.E.E.dipyridop.S-biS' ^ '-fjazepine; d-Ethyl-Cl ^^ diadiazole Q ^ S 'ß.SJdipiridQf S-feS' ^ '- ílazepina? -Bromo-d-etil-ÍI ^ .Stiadiazoloμ'.S'ie.SJdipiridop.S-biS' ^ '-? azepine; 6-Ethynyl-8-5thyl-. { 2,3) 5-Jadiazol Ql 4 5 ': 6.5 Jdipyrid Qi 3-, 3,, 2, -? A2epine; β-Phenylethyl-d-eti I ^ .Styladiazolo. S'ie.Sjdipiridop.S-b.-S '^' - flazepine; 11-Ethyl-oxazolyl. { 4 ', d ": 6, dJdipirido_ [3., 2-b: 2'., 3, -e.] Aze? Ina; and, The compounds of formula I, formula II and formula III, and their salts, can be prepared by known methods or their obvious modifications. The A-C methods, described below, are illustrative of the methods for preparing the com ponents. Method A The compounds of formula I, formula II, formula III - above in which A, B and D, and R. to Rg are as defined above, can be obtained by cyclizing compounds of formula IV, V and VI respectively .

IV VI wherein A, B and D, and R, to R, - are as defined above and Rfi is a fluoro or chloro substituent. These reactions are generally carried out in an inert atmosphere of argon or nitrogen, and in inert solvents, such as 1,4-dioxane or tetrahydrofuran and the like, at temperatures generally between room temperature and the boiling point of the solvent in the presence of a base, such as sodium hydride or sodium bistrimethyl-silylamide. Compounds of formula IV, formula V and formula VI above in which A, B and D, and R. to Rβ are as defined above, can be obtained from the compounds of formula VII, and formula VIII and formula IX . vp vm IX wherein A, B and D and R, and Rr are as defined above, and R is bromine or iodine, by reaction with a compound of formula X X wherein Rg is tributyltantan or trimethylene and R, R, R. and Rg are as defined above, in an inert solvent, such as tetrahydrofuran, dioxane, dimethylformamide or N-methyl-pyrrole idinone, a temperature between the ambient temperature and the boiling point of the solvent in the presence of a cata-lizer such as Pd (Ph3P) 2CI2 or Pd (Ph3P, or Pd (P aAsi ,.

The compounds of formula VII, formula VIII and formula IX can be obtained from the compounds of formula XI, -formula XII and formula XIII XI xp xm wherein A, B and D, and R, -, Rg and R-, are as defined above by reaction with a compound of formula XIV.

RrNH2 XIV where R. is as defined above. These reactions are generally carried out in an inert solvent, such as 1,4-dioxane or tetrahydrofuran, and the like, generally between room temperature and the boiling point of the dissolution In cases where the boiling point of XIV is less than the boiling point of the solvent, it may be advantageous to use a closed reaction vessel. The compounds of formula XI, formula XII and formula XIII can be obtained from the compounds of formula XV, formula XVI and formula XVII XV XVI xvp where A, B and D, and R? they are as defined above, by reaction with a compound of formula XVIII xvm wherein Rr, Rg and Rfi are as defined above, by reaction in an inert solvent, such as tetrahydrofuran, dioxji no, dimethylformamide or N-meti Ipirrol idinone, at a temperature between room temperature and boiling point of the solvent, in the presence of a catalyst, such as Pd (Ph_P)? C 12 or Pd (Ph3P) 4 or Pd (Ph3As) 4. .

The compounds of formula X and formula XVIII can be obtained from the compounds of formula XIX or formula XX by lithiation followed by reaction with the appropriate trialkyl halide following methods known in the literature.

Method B The compounds of formula IV, formula V and formula VI above, in which A, B and D, and R ~ a Rg, are as defined above, can be obtained from the compounds of formula XXI, formula XXII and formula XXIII XXI XXII XXIII wherein A, B and D, and R £ a Rβ are as defined hap anteSs by reaction with a compound of formula XIV RrNH2 XIV The compounds of formula I, formula II and formula III can be administered in a single dose or in divided doses by oral, parenteral or topical routes. A suitable oral dosage for a compound of formula I, formula II and formula III would be in the range of about 0.5 mg to 1 gal day. A preferred oral dosage for a compound of formula I, formula II and formula III would be in the range of about 100 mg to 800 mg per day. In parenteral formulations, a suitable dosage unit may contain from 0.1 to 250 mg of said compounds, preferably 1 mg to 200 mg, after topical administration, formulations containing 0.01 to 1% active ingredient are preferred. However, it should be understood that the pharmaceutical administration will vary from patient to patient and the dosage of any particular patient will depend on the criteria of the physician, who will use it as a criterion to determine an appropriate dosage, the size and condition of the patient as well as the patient's response to the drug. When the compounds of the present invention are for oral administration, they can be administered as medicaments in the form of pharmaceutical preparations containing them in association with a pharmaceutical excipient carrier material. patible Said excipient material may be an inert organic or inorganic material suitable for oral administration. Examples of such excipient materials are water, gelatin, talc, starch, magnesium stearate, gum arabic, vegetable oils, polyalkylene glycols, petroleum jelly and the like. The pharmaceutical preparations can be made conventionally and the finished dosage forms can be solid dosage forms, for example, tablets, dragees, capsules and the like, or liquid dosage forms, for example solutions, suspensions, emulsions and the like. The pharmaceutical preparations can be subjected to conventional pharmaceutical operations, such as sterilization. In addition, the pharmaceutical preparations may contain conventional adjuvants, such as preservatives, stabilizers, emulsifiers, aroma enhancers, wetting agents, buffers, salts for varying the osmotic pressure and the like. The solid excipient material that can be used includes, for example, starch, lactose, mannitol, methylcellulose, microcrystalline cellulose, talc, silica, calcium phosphate dibasic and high molecular weight polymers (such as polyethylene glycol.) For parenteral use, a compound of formula I, formula II and formula III can be administered in an aqueous or non-aqueous solution, suspension or emulsion in an oil or a mixture of pharmaceutically acceptable liquids, which may contain - bacteriostatic agents, antioxidants, preservatives, buffers or other solutes which render the solution isotonic with blood, thickening agents, suspending agents or other pharmaceutically acceptable ingredients. Additives of this type include cluyen, for example, tartrate, citrate and acetate buffers, ethanol, propylene glycol, polyethylene glycol, complexing agents (such as EDTA), antioxidants (such as sodium bisulfite, sodium metabisulfite and ascorbic acid), high weight polymers. Molecular (such as liquid poly (ethylene oxides)) for viscosity regulation and polyethylene derivatives of sorbitol anhydrides. Preservatives such as benzoic acid, methyl- or propi-1-paraben, benzalkonium chloride or other quaternary ammonium compounds may also be added if necessary. The compounds of this invention can also be administered in the form of solutions for nasal application, and may contain, in addition to the compounds of this invention, suitable buffers, tonicity adjuvants, microbiological preservatives, antioxidants and viscosity increasing agents in an aqueous vehicle. . Examples of agents used to increase the viscosity are polyvinyl alcohol, cellulose derivatives, polyvinylpyrrolidone, polysorbates or glycerin. Added microbial preservatives may include benzene chloride, thiol, chlorobutanol or phenylethyl alcohol.

In addition, the compounds provided by the invention can be administered in the form of a suppository. As stated above, the compounds provided by the invention inhibit the enzymatic activity of the HIV-1 RT. Based on assays of these compounds, as described below, it is known that they inhibit the RNA-dependent DNA-polymerase activity of HIV-1 RT. It is known (data not shown) that they also inhibit the DNA-polimery DNA-dependent activity of the HIV-1 RT. Using the Reverse Transcriptase (RT) Assay described below, compounds can be assayed for their ability to inhibit the activity of the DNA-polymerase dependent on the RNA of the HIV-1 RT. Certain specific compounds described in the examples below will also be tested. The results of this test appear in Table I below. TRANSCRI TEST REVERSE TEST (RT) Test Theory. Among the enzymes encoded by the Human Immunodeficiency Virus (HIV-1) is a reverse transcriptase (1), so-called because it transcribes a copy of DNA from an RNA template. This activity can be measured quantitatively in a cell-free enzyme assay, which has been described previously (2), and which is based on the observation that reverse transcriptase can use a synthetic template [poly r (C) primed with d (G)] to transcribe a 3 chain of DNA precipitable with acids and radiolabeled using H-d GTP as a substrate. The assay described below uses the wild-type enzyme (WT), which is the predominant form of the enzyme. enzyme observed in patients infected with HIV-1. The use of the mutant RT enzyme (Y181C, prepared by site-directed mutagenesis in which the tyrosine residue in codon 181 has been replaced by a cysteine residue) and-analogous test conditions, allows to evaluate the efficacy of the compounds to inhibit this mutant enzyme. Materials: a) Preparation of the wild-type enzyme. The reverse transcriptase enzyme from the LAV strain of the Human Immunodeficiency Virus (HIV-1) (1) was isolated from the bacterial strain JM109 (3) which expresses the p-DNA clone BRTprt1 + (2) which is under the control of the lac promoter in the expression vector pIBI2l (4). A one-night culture grown in 2XYT medium (37 ° C, 225 rpm) (5) supplemented with 100 μg / ml ampicillin for positive selection at a 1:40 dilution in M9 medium supplemented with 10 μg / ml is inoculated. of thiamine, 0.5% casamino acids and 50 μg / ml ampicillin (5). The culture is incubated (37 ° C, 225 rpm) until it reaches a D0540 of 0.3-0.4. At that time, the inhibitor of the IPTG repressor (isopropi 1- ß-D-thiogalactopyranoside) is added at 0.5 mM and the mixture is incubated for a further 2 hours. The bacteria settle, they are resuspended in a buffer of 50mM Tris, 0.6mM EDTA, 0.375M NaCl, and are digested by addition of lysozyme (1 mg / ml) for 30 minutes on ice. The cells are lysed by addition of 0.2% NP-40 and brought to 1M NaCl. After separation of the insoluble residues by centrifugation, the protein is precipitated by the addition of 3 volumes of saturated aqueous ammonium sulfate. The enzyme is sedimented, resuspended in RT buffer (50mM Tris, pH 7.5, 1mM EDTA, 5mM DTT, 0.1% NP-40, 0.1M NaCl and 50% glycerol) ) and stored at -70 ° C for later use, b) Composition of the mother-reaction mixture concentrated twice. Mother solution Concentration of the reagent mixture twice Tris 1MpH 7.4 100m Dithiothreitol 1M 40mM NaCl 1M 120mM Nonidet P-40 1% 0.1% MgCM 4mM [poly r (C) / oligo d (G * j (d: 1) 2 μg / ml 3H-dGTP (81 μM) 0.6 μM Assay Procedure The concentrated mother-of-two-reaction mixture is divided into aliquots and stored at -20 ° C.

It is stable and thawed for use in each trial. This enzyme assay has been adapted to a 96-well microtiter plate system, and has been described previously (6). Tris buffer (50mM, pH7.4), vehicle (diluted solvent to match the dilution of the compound), or -compounds in the vehicle in 96 p_o ciliate microtiter plates (10 μl / well) are distributed.; 3 wells / compound). The RT enzyme of HIV-1 is thawed, diluted in 50 mM Tris, pH 7.4, so that 15 μl of the diluted enzyme contains 0.001 unit (one unit is the amount of enzyme that transforms 1 micromol of substratum). per minute at 25 ° C) and 15 μl per well are distributed. 20 μl of EDTA 0.12-0.5M are added to the first three wells of the microtiter plate. EDTA forms chelates with Mg ** present and prevents reverse transcription. This group serves as a base polymerization that is subtracted from the other groups. To all the wells, 25 μl of the reaction mixture is added -concentrated twice and the assay is carried out incubating at room temperature for 60 minutes. The assay is terminated by pre-precipitating the DNA in each well with 50 μl of 10% trichloroacetic acid (TCA) (10% w / v) in sodium pyrophosphate (1% w / v). The microtiter plate is incubated for 15 minutes at 4 ° C and the precipitate is fixed on glass fiber paper nQ 30 (Schleicher &Schuell) using a Skatron semiautomatic collector. The filters are then washed with more TCA (5%) containing sodium pyrophosphate (1%), rinsed with ethanol aqueous (70%), dried and transferred to scintillation vials (6). Each vial receives 2 ml of scintillation cocktail and is counted in a Beckman beta counter. The calculation of the inhibition percentage is as follows Average test value per CPM - Average control value per CPM x 100% inhibition Average control value per CPM References: 1 Benn, S., et al., Science 230: 949,1985 2. Farmerie, W.G. et al., Science 236: 305, 1987 3. Yanisch-Perron, C, Viera, J., and Messing, J., Gene 33: 103, 1985 4. International Biotechnologies, Inc., New Haven, CT 06535 . Maniatis, T, Frítsch, E.F., and J. Sambrook, comp. Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, 1982 6. Spira, T., et al. J. Clinical Microbiology, 25:97, 1987.

TABLE 1 Ex. N! RT test (WT) RT test (Y181C)% inh. (1 μM)% inh (1 μM) 1. 96 90 2. 97 91 3. 92 68 4. 94 52 . 89 36 6. 91 58 7. 83 46 8. 72 32 9. 91 70 10. 72 12 11. 84 25 12. 96 89 Examples: The following examples further illustrate the present invention and allow others skilled in the art to understand it - more completely However, it should be understood that the invention is not limited to the particular examples given below. Ex emp l o 1 8-Ethyl-thienylf3 ', 4': 6.d1DÍDÍridof2.3-b: 3, .2, -f1azepina (a) 2-Fluoro-3-tributi lestanni Ipyridine. To a mixture of lithium diisopropylamide (1.5M in cloxane, 43 ml) and tetrahydrofuran (60 ml) cooled to -70 ° C, 2-fluoropyridine (6.0 ml) was added at a rate such that the temperature remained stable. below -70 ° C. After 1.5 hours ,tributyltin chloride (15ml) was added, and the mixture was allowed to warm to room temperature. The mixture was diluted with hexane, washed with water, dried, filtered and evaporated. Chromatography of the residue on silica gel (cyclohexane / ethyl acetate 98/2) gave 2-f luoro-3-tributi lestanni Ipyridine (17 g). (b) 3-Bromo-4- (2-fluoropyridin-3-yl) thiophene. A mixture of 2-fluoro-3-tributi lestanni lpi ridine (1.9 g), 3,4-dibromothiophene (1.5 g) and Pd (Ph3P) 2C 1"(0. 175 g) in N-meti Ipi Nonane (7.5 ml), in a closed tube, was heated at 100 ° C for 16 hours. The mixture was cooled and stirred with aqueous potassium fluoride for 6 hours. The mixture was diluted with ethyl acetate, washed with water, dried, filtered and eva pored. The residue was fractionated by chromatography to give 3-bromo -4- (2-f luoropyridin-3-yl) thiophene (0.35 g), m.p. 48-50 ° C. (c) 3-bromo-4- (2-ethylaminopyridin-3-yl) thiophene. A solution of 3-bromo-4- (2-f luoropyridin-3-yl) thiophene (0.344 g) and ethylamine (0.2 g) in dioxane (1 ml), in a closed tube, was heated to 100 °. C for four days. The mixture was cooled, diluted with ethyl acetate, washed with water, dried, filtered and evaporated. The residue was fractionated by chromatography to give 3-bromo-4- (2-ethylaminopyridin-3-yl) thiophene (0.316 g) as an oil. (d) 3- (2-Fluoropyridin-3-yl) -4- (2-ethylaminopyridin-3-yl) thiophene. A mixture of 3-bromo-4- (2-ethylaminopyridin-3-yl) thiophene (0.31 g), 2-f luoro-3-tributyltantan Ipyridine (0.507 g) and Pd (Ph, P) 2Cl2 (0.035 g) in N-meti Ipirrol idinone (3 ml), in a closed tube, was heated at 100 ° C for 17 hours. The mixture was cooled and tetrabutylammonium fluoride (1M in tetrahydrofuran, 1 ml) was added. After one day, the mixture was diluted with ethyl acetate, washed with water, dried, filtered and evaporated. The residue was fractionated by chromatography to give 3- (2-f luoropyridin-3-yl) -4- (2-ethylaminopyridin-3-yl) thiophene (0.077 g), m.p. 127-129 ° C. (E) 8-Eti-1-thienyl [3 ', 4': 6, dj dipi rido 2, 3-b: 3 ', 2' -f] azepine. To a solution of 3- (2-f luoropyridin-3-i 1) -4- (2-eti lanp nopyridin-3-yl) thiophene (0.021 g) in tetrahydrofuran (1.5 ml) was added bi strimeti 1 if 1 i 1 potassium amide (0.5M in toluene) until no yellow color appeared when adding more reagent. The mixture was stirred for 5 minutes, ethanol was added, it was diluted with ethyl acetate, washed with water, dried, filtered and evaporated. The residue was fractionated by chromatography to give 8-ethylthienyl j ', 4': 6, dj dipyrido [2,3-b: 3 ', 2'-f) azepine, m.p. 140-142 ° C. Example 2. 6-Chloro-8-35-thienyl £ 3 ', 4': 6,?] Dipyrido f2, 3-b: 3 ', 2' -fj azepine (a) 2,6-Dichloro-3-tributylstannilpyridine. To a mixture of lithium diisopropylamide (1.5M in cyclohexane, 9.0 ml) and tetrahydrofuran (20 ml), cooled to -70 ° C, 2,6-dichloropyridine (2.0 g, 13.5 mmol) in tetrahydrofuran (25 ml) was added, keeping the temperature below -60 ° C. The mixture was stirred for 30 minutes, tributyltin chloride (3.7 ml, 13.5 mmol) was added dropwise and the mixture was allowed to warm to room temperature. Acetate of ethyl was added and the mixture was washed with water, dried, filtered and evaporated. Chromatography of the residue on silica gel (eluent, 36 ethyl acetate / hexane) gave 2,6-dichloro -3-tributylstannaylpyridine (4.0 g). (^ e-Chloro-ß-ethyl-tiepiltS '. ^ -. T.Sldipiridol? .S-b-a'.Z'-nazepip A mixture of 3-bromo-4- (2-ethylaminopyridin-3-yl) thiophene [synthesis described above] (0.757 g), 2,6-dichloro-3-tributylstannilpyridine (1.331 g), triphenylarsine (0.261 g) and trisdibenzylideneacetone-dipalladium (0.092 g) in N-methylpyrrolidinone (3 ml) was heated at 100 C for 48 hours. Tetrabutylammonium fluoride (IM in ethahydrofuran, 3 ml) was added. After two hours, the mixture was diluted with ethyl acetate, washed with water, dried, filtered and evaporated. The residue was fractionated by chromatography to give 3- (2,6-dichloropyridin-3-yl) -4- (2-eethylaminopyridin-3-yl) thiophene 90.059 g) which was used directly in the next step. To a solution of 3- (2,6-dichloropyridin-3-yl) -4- (2-ethylaminopyridin-3-yl) -iophene (0.059 g) in tetrahydrofuran (2 ml) was added sodium hexamethyldisilazide (1 molar) in tetrahydrofuran, 1 ml). After 20 minutes, the reaction was quenched with methanol, diluted with ethyl acetate, washed with water, dried, filtered and evaporated. The residue was fractionated by chromatography to give 6-chloro-8-ethyl-thienyl-p ', 4'; 6, f] di p i r ido [2, 3-b:, 3 ', 2' -fjazepine (0.024 g), p.f.139-141 ° C. Example 3 6- (Pyrazol-4-yl) -8-ethyl-thienyl [3,, 4l: 6,5] dipyridoC2,3-b: 3l, 2l-f? azepine A mixture of 6-chloro-8-eti'I-thieni 1 [j3 ', 4': 6, 5-dimido (2,3-b: 3 ', 2'-f] azepine (0.024 g), triethylamine ( , 3 g), trimeti Isi 1 i laceti (0.158 g), copper iodide (l) (0.0021 g) and Pd (Ph3P) 2Cl2 (0.0046 g) was heated in a closed tube at 85 ° C for 24 hours The mixture was diluted with hexane / ethyl acetate, washed with water, dried, filtered and evaporated. duo was fractionated by chromatography to give 6- (trimeti Isi 1 i letini 1) -8-ethyl-thienyl 3 ', 4': 6, d) dipyrido 2, 3-: 3 ', 2' -f] azepine which was used directly in the next reaction. 6- (TrimethylH sil i letini l) -8-ethyl-thienyl- (3 ', 4': 6,5) ipyridojj, 3-b-3 ', 2'-f] aze pine was dissolved in ethereal diazomethane ( 2M, 0.5 ml). The mixture was stirred for 28 hours, evaporated to dryness, taken up in tetrahydrofuran and tetrabutylammonium fluoride (1M in tetrahydrofuran, 0.5 ml) was added. After 5 minutes, the mixture was diluted with ethyl acetate, washed with water, dried, filtered and evaporated. The residue was fractionated by chromatography to give 6- (pyrazol-4-yl) -8-ethyl-thienylj ', 4': 6, d] dipyride, 3-b: 3 ', 2'-f] azepine (0.011 g) , pf 250-252 ° C. Example 4: 8-Et i 1 - 1 -meti I -t ieni 1 Q '': 6, jdipi ridoj, 3-b: 3 ', 2' -fjazepine Example 5: 8-ethi 1 - 1, 3-dimeti 1-tieni 1 fß ', 4': 6, ¿] dipi rido 2, 3-b: 3 ', 2', fjazepine To a solution of 8-ethi 1-beni 1 ', 4': 6,5-Jipipyride, 3-b: 31, '-] azepine (0.025 g) in tetrahydrofuran (2 ml) cooled to 78 ° C, lithium diisopropylamide was added (1.5M in cyclohexane, 0.1 ml). After 10 minutes, iodomethane (2 drops) was added and the mixture allowed to warm to room temperature. The mixture was diluted with ethyl acetate, washed with water, dried, filtered and evaporated. The residue was dissolved in tetrahydrofuran (2ml) cooled to -78 ° C, and lithium diisopropylamide (1.5M in cyclohexane, 0.1ml) was added. After 10 minutes, iodomethane (0.05 ml) was added and the mixture was allowed to warm to room temperature. The mixture was diluted with ethyl acetate, washed with water, dried, filtered and evaporated. The residue was fractionated by HPLC to give 8-et i 1-1 -met i 1 -t ieni 1 [31, 4 ' , 2 '-fjazepine (0.010 g), m.p. 106-108 ° C and 8-et i 1 - 1, 3-d imet i 1 -ti in i 1 [* 3 ', 4': 6, 5¡ d i pi r i? J. , 3-b: 3 ', 2'-) azepine (0.003 g), m.p. 176- 178 ° C. Example 6 B (a) 3-Bromo-2- (2-f luoropi ridin-3- i 1) thiophene. A mixture of 2,3-dibromothiophene (2.86 g), 2-f luoro-3-tributylstannyl pyridine (3.93 g), Pd (Ph_P) 2C 12 (0, 153 g) in N-methy Ipyrrolidone (25 ml) was heated at 75 ° C under argon durají te 3.5 hours. Tetrabutylammonium fluoride (1M in tetrahydrofuran, 10 ml) was added and the mixture was stirred for 3 hours. The mixture was diluted with ethyl acetate, washed with water, dried, filtered and evaporated. Chromatography of the residue on silica gel gave 3-bromo-2- (2-f 1 uoropyrid n-3- i 1) thiophene (1.07 g) as an oil. (b) 3-Bromo-2- (2-eti laminopyridin-3-yl) thiophene.

A mixture of 3-bromo-2- (2-f luoropyridin-3-yl) thiophene (0.47 g) and ethylamine (0.4 g) in dioxane (2 ml) in a closed tube was heated to 100 ° C. for 2 days. The mixture was diluted with ethyl acetate, washed with water, dried, filtered and evaporated to give 3-bromo-2- (2-ethylaminopyridin-3-yl) thiophene (0.45 g) (c) 3- (2-fluoropyridin-3-yl) -2- (2-ethylaminopyridin-3-yl) thiophen A mixture of 3-bromo-2- (2-ethi laminopyridin-3-yl) thiophene (0.085 g), 2-f luoro-3-tributylstannane Ipyridine (0.26 g) and Pd (Ph3 P) 2C12 (0 , 014 g) in N-met i iprol idinone (2 ml) was heated at 75 ° C under argon for 1 day. The mixture was diluted with ethyl acetate, washed, dried, filtered and evaporated. The residue was chromatographed to give 3- (2-f luoropi-ridin-3-i 1) -2- (2-ethylaminopyridin-3-yl) thiophene (0.028 g), m.p. 86-89 ° C. (d) 8-Ethyl-thienyl Q1, 3 ': 6.djdipyridop, 3-b: 3', 2'-f] azepine. To a solution of 3- (2-f luoropyridin-3-i 1) -2- (2-ethy laphopyridin-3-yl) thiophene (0.028 g) in tetrahydrofuran (1.5 ml) was added KHMDS (0, 5M in toluene, 0.5 ml). The mixture was quenched with methanol and evaporated to dryness. The residue was fractionated by preparative thin layer chromatography to give 8-ethyl-thienylp ', 3": 6, d] dipyrido [2, 3-b: 3', 2'-fjazepine (0.006 g), mp 158-160 ° C.

Example 7 8-Ethyl-thiazolo. { 4 ', 5': 6.5] dipyridoC2,3-b: 3 ', 2'-fjazepine (a) 2-chloro-3-p2-cl oropi ridin-3-i) acetyl) pyridine. A mixture of 2-chloropyridone-3-carboxaldehyde (0.132 mol) and trimethy cyanide Isi 1 ilo (13.1 g) was stirred at 50-60 ° C for 4 hours in the presence of zinc iodide (10 mg) and COI Stay overnight at room temperature. The mixture was diluted with tetrahydrofuran (70 ml) and the lithium idide (1.5M in cyclohexane 130ml) in tetrahydrofuran (130ml) was slowly added to a solution of diisopropy (keeping the temperature below -65). ° C. After 30 minutes, 2-chloro-3-chloromethyl Ipi ridine (21.4 g) in tetrahydrofuran (20 ml) was slowly added. After stirring at -70 ° C for 30 minutes the mixture was allowed to warm to room temperature. Water was added and the mixture was extracted with methylene chloride. The organic phase was dried, filtered and evaporated. Chromatography of the residue on silica gel (ethyl acetate / hexane 1/1) dio2-chloro-3-i. { 2-chloro-pyridin-3-yl) acetyl] pyridine (27 g) in the form of an oil. 2-Chloro-3- [2-bromo-2- (2-chloropyridin-3-yl) acetyl] pyridine. To a solution of bromine (0.125 g) in acetic acid (1 m 1) was slowly added a solution of 2-chloro-3-r (2-chloropyridin-3-yl) acetyl pyridine (0.21 g) in acetic acid (5 ml). The mixture was stirred overnight at room temperature. The mixture was diluted with water and extracted with methylene chloride. The organic phase was dried (Na2SO4), filtered tro and evaporated. The residue was purified by chromatography on silica gel (ethyl acetate / hexane) to give chloro-3-bromo- (2-chloropyridin-3-yl) acetyl] pyridine (0.224 g). (b) 4,5-di- (2-chloropyridin-3-yl) -2-aminothiazole. A solution of 2-chloro-2-bromo-2- (2-chloropyridin-3-yl) acetyl-pyridine (0.170 g) and thiourea (0.040 g) in ethanol (5 ml) was heated to 70-75 ° C. for 2 hours. The solvent was evaporated and the residue was recrystallized from ethanol to give 4, 5-di- (2-chloropyridin-3-yl) -2-aminothiazole (0.030 g), m.p. 273-274 ° C (c) 4, 5-di (2-chloropyridin-3-yl) thiazole. To a solution of 4,5-di- (2-chloropyridin-3-yl) -2-amino-thiazole (0.060 g) in tetrahydrofuran (5 ml) was added butyl nitrite (0.060 g). The mixture was refluxed for 3 hours. Butyl nitrite was added and heating was continued for 2 hours. The solvent was evaporated and the residue fractionated by chromatography on silica gel to give 4,5-di- (2-chloropyridin-3-yl) thiazole (0.03d g) as a solid. (d) 4- £ 2- (4-methoxybenzyllamino) pyridin-3-ifj-5- (2-chloropyridin-3-yl) thiazole. A mixture of 4,5-di- (2-chloropyridin-3-yl) thiazole (0.047 g), 4-methoxybenzyl sheet (0.021 g) and diisopropylethylamine (0.025 g) in xylene was heated in a closed tube at 130 ° C. C for 4 days. The solvent was evaporated and the residue was fractionated by chromatography to give 4- 2- (4-methoxybenzyllamino) pyridin-3-i fj -5- (2-chloropyridin-3-yl) thiazole (0.015 g). (e) 8- (4-methoxybenzyl) -thiazolo [4,, 5,: 6,5] dipyrido [2,3-b: 3,, 2, -f] azepine.

To a solution of 4- Jj2- (4-methoxybenzyllamino) pyridin-3-ylJ-5- (2-chloropyridin-3-yl) thiazole (0.045 g) in tetrahydrofuran (10 ml) was added bistrimeti 1-si 1 sodium starch (1M in tetrahydrofuran, 1.1 ml). The reaction mixture was stirred for 0.5 hour. The solvent was evaporated, the residue was taken up in methylene chloride, washed with water, dried (Na ?SO0), filtered and evaporated. The residue was fractionated by chromatography on silica gel to give 8- (4-methoxybenzyl) -thiazol (4 ', 5': 6, 5 dipyrido [2,3-b: 3 ', 2'-f] azepine as an oil (0.320 g) (f) Tiazolo [(41, 5 ': 6.5 dipyrid, 3-b: 3', 2'-jazepine) A solution of 8- (4-methoxybenzyl) -thiazoloH4 ', 5 ': 6, 5J dipyridor2, 3-b: 3', 2'-fjazepine (0.32 g) in trifluoric acid was left at room temperature for 3 hours.The mixture was diluted with water and It was extracted with methylene chloride, the organic phase was dried, filtered and evaporated to give tiazolium, 5 ': 6, 5J dipyrido-2,3-b-3', 2"-fjazepipa crystalline (0.21 g), mp 212-213 ° C (g) 8-Ethyl-thiazolo [V, 5 '; 6, djdi pi rido, 3-b-3', 2 '- Jazepine To a solution of thiazolo (_4', 5 ': 6, 5J dipyrido (2, 3-b: 3', 2'-fjazepine (0.09 g) in dimethylformamide (6 ml) was added sodium hydride (0.033 g). Ethyl iodide (0.degree. 15 g) and the mixture was stirred for 2 hours.The solvent was evaporated and the The residue was fractionated by chromatography giving 8-Ethyl-thiazolo ', 5': 6, 5-Dipirido [2, 3-b: 3 ', 2' -] azepine (0.085 g), pFl 167-168 ° C. Example 8 8-Ethyl-oxazoloC4 ', 5': 6,5] dipyrido 2,3-b-3 ', 2'- £ 3azepine (a) 4,5-di- (2-chloropyridin-3-yl) -2-aminooxazole. A solution of 2-chloro-2- (2-bromo-2- (2-chloropyridin-3-yl) acetyl] pyridine (0.062 g) and urea (0.054 g) in dimethylformamide (4 ml) was heated to 105 ° C. The solvent was evaporated and the residue was diluted with methylene chloride, washed with water, dried, filtered and evaporated.The residue was fractionated by chromatography on silica gel to give 4, d-di- (2). -cl2 ropyridin-3-yl) -2-aminooxazole (0.030 gj, pf243-244 ° C. (b) 4, d-di- (2-chloropyridin-3-yl) oxazole. To a solution of 4.5 -di- (2-chloropyridin-3-y1) -2-amino-oxazole (0.030 g) in tetrahydrofuran (3 ml) was added butyl nitrite (0.033 g) .The mixture was refluxed for 3 hrs. The solvent was evaporated and the residue was fractionated by chromatography to give 4,5-d- (2-c-loropyridin-3-yl) oxazole (0.010 g) as a solid, mp 157-158 ° C. (cJd ^ -methoxybenz -oxazolo. S're.djdipiri op.Sb ^ '^' - flazepine A mixture of 4,5-di- (2-chloropi idin-3-yl) oxazole (0.120 g) and -methoxybenzamine (0.270 g) and diisopropylethylamine (0.100 g) in xylene (10 ml) a closed tube was heated at 130 ° C for 4 days.The solvent was evaporated and the residue was fractionated by chromatography to give 8- (4-methoxybenzene). 1) -oxazolo ', 5': 6, 5Jdipiri_ , 2 '- azepine. A solution of 8- (4-methoxybenz 1) -oxazolo ', 5': 6, 5J dipyrido .S-brS ', 2'-} azepine (0.030 g) in trifluoroacetic acid Ethyl (3ml) was left at room temperature for 1 hour. The solvent was evaporated yielding oxazolo- (4 ', 5': 6, d] dipyridor2,3-b: 3'2'-f3azepine (0.030 g). (E) 8-Ethyl-oxazolo (4 ', 5': 6, d] dipyrido, 3-b: 3 ', 2' -2 azepine, to a solution of oxazolo ', 5': 6, 5J dipyridoij !, 3-b: 3 ', 2'-fJazepine (0.030 g) in dimethylformamide (3 ml) was added sodium hydride (0.030 g), ethyl iodide (0.100 g) was added and the mixture was stirred for 2 hours.The solvent was evaporated and the residue was fractionated by chromatography on silica gel giving 8-eti 1-oxazoloj? ', 5': 6, 3-b: 3 ', 2' - jazepine (0.031 g), m.p. 167-168 ° C. Example 9 8-Ethyl- (1, 2,3) thiadiazolo [4 ', 5': 6,5] dipyridor2,3-b: 3,, 2l-r | azepine ' (a) 4,5-di- (2-chloropyridin-3-yl) -1, 2, 3-t i adi azole. A mixture of (2-chloropyridin-3-y1) methi 1- (2. Loropyri-din-3-yl) ketone (0.273 g), ethyl carbazate (0.103 g) and p-toluenesulfonic acid monohydrate (, 010 g) in toluene 2 ml) was heated at 110 ° C for 3 hours. The mixture was evaporated to dryness and the residue was taken up in thionyl chloride, 3ml, and heated at 70 ° C for 1 hour. The mixture was added cautiously to aqueous potassium carbonate and extracted with ethyl acetate. The organic phase was dried, filtered and evaporated. Chromatography of the residue on silica gel 4, 5-di- (2-c lo ropyridin-3-yl) -1,2,3-thiadiol azol (0.269 g), m.p. 146-148 ° C. (b) 4- (2-chloropyridin-3-yl) -5- (2-ethylaminopyridin-3-yl) -1,2,3-t-aiadiolol. A mixture of 4,5-di- (2-c loropi-ridi n-3-i 1) -1,2,3-thi-adi-a-zol (1.823 g) and ethylamine (0.61 g) in dioxane (9 ml) it was heated at 105 ° C in a closed tube for 3 days. The mixture was diluted with ethyl acetate, washed with water, dried, filtered and evoked pore. Chromatography of the residue on silica gel gave 4- (2-chloropyridin-3-yl) -5- (2-ethylaminopyridin-3-yl) -1,2,3-thiadia-zol (1.243 g) as an oil. (c) 8-Ethyl- (1, 2,3) thiadiazole. { 4 ', 5': 6, d] dipyride, 3-b: 3 ', 2'-fJ azepine. To a solution of 4- (2-chloropyridin-3i 1) -5- (2-ethi lami-nopyridin-3-y1) -1,2,3-thiadiazole (0.700 g) in tetrahydrofuran (5 ml) was added bistrimeti Isi 1 i potassium lamidide (0.5M in toluene, 3.5 ml). After 10 minutes the mixture was diluted with ethyl acetate, washed with water, dried, filtered and evaporated. Chromatography of the residue on silica gel gave 8-ethyl- (1,2,3) thiadiazolo4 ', 5': 6, d] dipyrwido [2, 3-b: 3 ', 2'-f3aze-pina ( 0.453 g), pf 194-196 ° C. Example 10 6-Bromo-8-ethyl- (1, 2,3) thiadiazolo [4'.5l: 6,5] dipyrido [2,3-b: 3l, 2'-azepine. (a) 4- (2-chloropyridin-3-yl) -5- (2-ethylamino-5-bromo-pi ridin-3-y1) -1, 2,3-thiadiazole. To a solution of 4- (2-chloropyridin-3-y1) -5- (2-eti lami-nopyridin-3-yl) -l, 2,3-thiazole (0.324 g) in acetic acid (4 ml) containing sodium acetate (0.098 g) was added dropwise a solution of bromine (0.185 g) in acetic acid (1 ml). After After 5 minutes, the mixture was diluted with ethyl acetate, washed with aqueous potassium carbonate, dried, filtered and evaporated. Chromatography of the residue on silica gel (ethyl acetate / hexane / chloroform 1/3 / 0.5 gave 4- (2-chloropyridin-3-y1) -5- (2-ethylamino-5-bromo-pyridine -3-yl) -1, 2, 3-thiadiazole (0.329 g) (b) 5-Bromo-8-ethyl- (1,2,3) thiadiazolo { V, 5 ': 6, dj dipir ido [ 2, 3-b: 3 ', 2' -fjazepine To a solution of 4- (2-chloropyridin-3-i 1) -5- (2-eti lami no-d-bromo-pyridin-3-i 1 ) -1, 2, 3-thiadiazole (0.292 g) in tetrahydrofuran (3 ml) was added bi strimet i 1 si 1 i potassium lamidide (0.5M in toluene, 2.0 ml) After 10 minutes The mixture was diluted with ethyl acetate, washed with water, dried, filtered and evaporated.The residue was crystallized from hexane / chlorofor or to give 5-bromo-8-ethyl- (1, 2, 3) thiadiazole. - ', 5': 6, djdipir idof2, 3-b: 3 ', 2'-fJazepine (0.215 g) Example 11 6-Etini 1 -8-ethyl- (1, 2, 3) ti adiazole or 4 ', 5': 6.dJdipiridoC ?, 3-b: 3 ', 2'-fjazepina A mixture of 5-bromo-8-eti l- (1, 2,3) tiadiazolo ^ 1, 5 ': 6, 5j dipi r_ do [2,3-b: 3', 2 '-fjazepine (0.198 g ), Pd (Ph3P) 2 Cl2 (0.015 g), Cul (0.005 g), trimethylsilylacetylene (0.12 g) and triethylamine (2 ml) in dimethylformamide (1 ml) was heated at 100 ° C in a closed tube for 1 hour . The mixture was diluted with ethyl acetate, washed with water, dried, filtered and evaporated. Chromatography of the residue on silica gel (ethyl acetate / hexane / methylene chloride 1 / 0.2 / 0.2) gave 6-tr imet i 1 si 1 i let ini 1 -8-eti 1 (1, 2, 3) ti a-diazolo ', 5': 6, d] dipyrido 2,3-b: 3-, 2'-f) azepine (0.202 g). This product was taken up in tetrabutylammonium fluoride (1M in -tetrahydrofuran, 2 ml) and left at room temperature for 1.5 hours. The mixture was diluted with ethyl acetate, washed with water, dried, filtered and evaporated. Chromatography of the residue on silica gel (methylene chloride) gave 6-ethynyl-8-eti 1- (1, 2,3) thiadiazolo [V, 5 ': 6, d] dipyrido (5, 3-b: 3 ', 2'-] azepj na (0.124 g), mp 200-202 ° C. Example 12 6-Phenylethyl-8-ethyl- (1,2,3) thiadiazoloot, 5': 6, d. dipyridofj, 3-b: 3 ', 2'-fjazepine.

A mixture of 6-etini 1-8-eti l- (1, 2,3) thiadiazolo 4 ', 5': 6, 5jd ipi r_ do [2,3-b: 3 *, 2 * -f] azepine ( 0.103 g), iodobenzene (0.440 g), Pd (Ph3P) 2C12 (0.016 g), Cul (0.017 g), and triethylamine (1 ml) in dimethyl-formamide (1 ml) was heated at 100 ° C in a closed tube. for 2 hours. The mixture was diluted with ethyl acetate, washed with water, dried, filtered and evaporated. Chromatography of the residue on silica gel (methylene chloride) gave 6-phenyletini 1-8-ethyl- (1,2,3) thiadiazolo- -, 5 ': 6, d-dipyrido 2, 3-b: 3- , 2 * -flazepine (0.061 g). A mixture of this product and 10% Pd / C (0.066 g) in ethanol (15 ml) was hydrogenated in a Parr apparatus for 22 hours. The catalyst was removed by filtration and the solvent was evaporated. Fractionation of the residue by preparative thin layer chromatography (developer, methylene chloride) gave 6-Phenylethyl-8-ethyl- (1,2,3) thiadiazolo [4-, 5 ': 6, Q dipyrido [2,3- b: 3 ', 2'-f] azepine (0.011 g).

EXAMPLE? Capsules or tablets The compound of Example 1 was mixed in a powder mixture with the previously mixed excipient materials as identified above with the exception of the lubricant. The lubricant was then mixed and the resulting mixture compressed into tablets or filled into hard gelatin capsules.

EXAMPLE B Parenterates Solutions The excipient materials were mixed with water and then the compound of Example 1 was added. Mixing was continued until the solution was clear. The pH of this solution was adjusted to 3.0 and then filtered into the appropriate vials or ampoules and sterilized in an autoclave.

EXAMPLE C Nasal Solutions The excipient materials were mixed with water and then the compound of Example 1 was added and the mixing was continued until the solution was clear. The pH of this solution was adjusted to 4.0 and then filtered in appropriate vials or ampoules. It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (3)

R E I V I N D I C A C I O N S Having described the invention as above, the content of the following claims is claimed as property: 1. A compound of formula I, formula II or formula III. m caracerizado because; in formula I, formula II and formula III, A and D are carbon (unsubstituted or optionally substituted by methyl, ethyl, -isopropyl, vinyl, isopropenyl, ethynyl, halogen, nitro, -cyano, amino, methylamino, dimethylamino, hydroxy, methoxy, mercapto) or methylthio) or nitrogen, and B is oxygen , sulfur or nitrogen (unsubstituted or optionally substituted by methyl, ethyl, isopropyl, hydroxy or methoxy): and R. is a. hydrogen atom, alkyl of 1 to 4 carbon atoms fluoroalkyl of 1 to 4 carbon atoms and 1 to 3 fluorine atoms cycloalkyl of 3 to 6 carbon atoms, oxetanyl, thietanyl, tetrahydrofuran, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, alkenylmethyl or alkynylmethyl of 3 to 4 ato We are carbon, alkyloxyalkyl or alkylthioalkyl of 2 to 3 carbon atoms, alkanoyl or alky1 (thiocarbonyl) of 2 to 5 carbon atoms, or cyanoalkyl of 2 to 3 carbon atoms. R? is a hydrogen atom, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, alkenyl or alkynyl of 2 to 6 carbon atoms, trihalometloyl, hydroxyalkyl of 1 to 6 carbon atoms, alkyloxy or alkylthio of 2 to 6 carbon atoms, alkyloxyalkyl or alkylthioalkyl of 2 to 6 carbon atoms, pyrrolidinyl, pyrrolinyl, piperidinyl, mono- or dialkylamino in which each alkyl residue contains 1 to 3 carbon atoms, halogen, cyano , nitro or carboxyl, aryl (in which aryl is pyridinyl, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl or isothiazolyl) which is unsubstituted or substituted by hydroxy, amino, halogen, alkyl or Alkyloxy of 1 to 3 carbon atoms. R3 is a hydrogen atom, methyl or halogen; R. is a hydrogen atom, methyl, ethyl or halogen; R5 is a hydrogen atom, hydroxy, amino hydroxymethyl or aminomethyl; or one of its pharmaceutically acceptable salts. 2. A compound of formula I, formula II or formula III, co mo has been described in claim 1, characterized in that; in formula I, formula II and formula III, A and D are carbon (unsubstituted or optionally substituted with methyl, cyano halogen) or nitrogen, and B is sulfur, oxygen or nitrogen (not -5 substituted or optionally substituted with methyl) R .. is methyl, ethyl, propyl, isopropyl, propenyl, propynyl, cyclopropyl or cyclobutyl; and R 2 is a hydrogen atom, methyl, trihalomethyl, methoxy, pyrrolidinyl, pyrrolinyl, piperidinyl, dimethylamino, halogen, cyano, nitro or aryl (wherein aryl is phenyl, pyridinyl, -thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl or isothiazolyl) which is either unsubstituted or substituted by methyl, methoxy, hydroxyl, ap? no or halogen; d R3 R. and R5 are hydrogen; or one of its pharmaceutically acceptable salts. 3. A compound of formula I, formula II or formula III, as described in claim 1, caraqado-zado crqus; in formula I, formula II and formula III, A and D are carbon or nitrogen and B is sulfur, oxygen or nitrogen, or R. is ethyl or cyclopropyl; and R2 is hydrogen, chloro or pyrazole; R3 R, are hydrogen; d and R5 is hydrogen, amino or phenylethyl; or one of its pharmaceutically acceptable salts; 4._ a compound characterized because it is selected from the group consisting of: 11-Ethyl-thienyl [2 \ 3 ^ 6; 5-dipyrido [2,3-b: 3 *, 2 * -f] azepine; 11-Ethyl-thienyl [3, 14,: 6 > 5] (iipyridi2> 3-b: 3, f2, -fla2? Pina; -chloro-11-ethyl-thienyl [2 ', 3,: 6, d] dipyrido [2,3-b: 3, , 2, -f] azepine; - (4-Pyrazolyl) -11-ethyl-thienyl [2,, 3 ': 6, d] dipyrido [2,3-b: 3,, 2, -f] azepine; 11-Ethyl-thiazolyl [4 \ d ^ 6, d] d; pyrido [3,2-b: 2 ', 3 * -qazepine; 1-Et-

1-oxazole] [4 \ 5" : 6, d] dipyrido [2,3-b: 3 \ 2'-e] azepine, and 11-Ethylthiadiazolyl-S-pyrididyl-3'-a lazipine; or one of its pharmaceutically acceptable salts.

2- (4-Pyrazolyl) -11-ethyl-thienyl [2 \ 3,: 6, d] dipyrido [2,

3-b: 3 \ 2'-f] azepine. 6. - A method for preventing or treating the infection by iWf-lf sacsckErxz? O or perqué cpipaxte adranistrar to \ n be hunax) expiesto HEV-1 or infected by it, a prophylactic or therapeutically effective amount of a compound of formula I, formula II or formula III as described in claims 1,2,3,4 or 5, or a pharmaceutically acceptable salt thereof. 1.- A pharmaceutical composition suitable for preventing or inhibiting ipheracin per HIV-1, chaining, etc.) if it catches an ero-phylactic or therapeutically effective amount of a compound of formula I, formula II or formula III, as described in the reivin 1, 2, 3, 4 or 5, or one of its acceptable pharmaceutically acceptable salts, and a pharmaceutically acceptable excipient.