WO2015004304A1

WO2015004304A1 - Salts of pyridazino[2,3-a]pyrrolo[2,1-c]quinoxaline for the treatment of leishmania infections and diseases that involve the protein tyrosine phosphatase 1b

Info

Publication number: WO2015004304A1
Application number: PCT/ES2014/070568
Authority: WO
Inventors: Antonio JIMÉNEZ RUIZ; Kilian GUTIERREZ VIÑAS; David Moreno Mateos; Patricia SÁNCHEZ ALONSO; Ramón ALAJARÍN FERRÁNDEZ; Juan José VAQUERO LÓPEZ; Julio ÁLVAREZ-BUILLA GÓMEZ; Mercedes GRIERA MERINO; María Luisa DÍEZ MARQUÉS; Diego RODRÍGUEZ PUYOL; Manuel RODRÍGUEZ PUYOL
Original assignee: Universidad De Alcalá
Priority date: 2013-07-10
Filing date: 2014-07-10
Publication date: 2015-01-15
Also published as: ES2537221B2; ES2537221A1

Abstract

The invention relates to novel compounds of formula (I), to methods for preparing same, to the use thereof as growth inhibitors of the Leishmania parasite and/or as inhibitors of the protein tyrosine phosphatase 1B (PTP1B), to the use of the intermediate products that lead to said compounds for preparing a growth inhibitor of the Leishmania parasite and/or an inhibitor of PTP1B included in said formula, and to the use of the pharmaceutical compositions that contain said compounds for the treatment of diseases caused by infection with the Leishmania parasite and/or diseases in which the PTP1B is involved in the pathogenesis thereof.

Description

SIRES OF PIRIDAZINOr2,3-a1PIRROLOr2,1 -c1QUINOXALINIO FOR THE TREATMENT OF INFECTIONS BY LEISHMANIA AND DISEASES IN WHICH THE THYROSINE PHOSPHATE PROTEIN IS INVOLVED 1B

SECTOR OF THE TECHNIQUE

The present invention is related to the field of chemical synthesis of compounds that have structures of pyridazino [2,3-a] pyrrolo [2,1-c] quinoxalinium salts that are bioactive against the Leishmania parasite and that behave as inhibitors of PTP1 B.

STATE OF THE TECHNIQUE

Parasites of the genus Leishmania owe their name to W.B. Leishman, who developed the first parasite detection techniques in 1901. This parasite is the cause of leishmaniasis, a disease present in 22 countries of America and 66 nations of the old world, with special incidence in Southeast Asia, East Africa and Brazil. In Europe it is possible to find cases of infection in humans in 16 countries, including France, Italy, Greece, Malta, Spain and Portugal. The disease has several manifestations that, for the most part, depend on the species that causes the infection. Most of the cases correspond to the cutaneous form, which affects the skin of the patients, being responsible for severe disfigurements. However, the most relevant cases from the point of view of health correspond to the visceral form of the disease (LV), which causes thousands of deaths per year.

Approximately 60% of the cases of LV, also known as Kala-azar, occur in the Indian subcontinent (Bangladesh, India and Nepal), mainly among the poorest population in rural areas. The rest of the cases are located in East Africa (Ethiopia, Kenya and Sudan) and in Brazil. LV is caused by two different species, L. donovani and L. infantum, each with its own geographical distribution. L. infantum primarily infects children and immuno-suppressed individuals, while L. donovani infects individuals of all ages. It is estimated that about 50,000 deaths occur each year due to this disease and 500,000 new cases are recorded. Between the diseases caused by parasites, this death rate is only exceeded by malaria.

The dog is the main reservoir of the species causing LV. There is evidence that demonstrates a decrease in the incidence of the disease, both in dogs and children, as a result of a broad serological analysis of the dog population and the subsequent elimination of infected animals. However, this control strategy is considered as unacceptable and other measures leading to disease control in these animals would be desirable. Recent data show a very high incidence of infection in domestic dogs of the countries of the Mediterranean basin, being considered in fact one of the most frequent and lethal diseases among these animals (Solano-Gallego, L, P. Morell, et al. 2001 J. Clin. Microbiol. 39: 560-3).

The treatment of VL is based on the use of anti-Leishmania drugs and an aggressive control of any concomitant bacterial or parasitic infection, of possible anemias, hypovolemia and malnutrition. Pentavalent antimonials sodium stibogluconate and meglumine antimoniato have been the first line of treatment in many areas of the planet for more than 70 years. Antimonials are toxic drugs with frequent adverse effects such as cardiac arrhythmias, and acute pancreatitis. Patients under 2 years of age or older than 45 with advanced disease and / or severe malnutrition have a high risk of death during antimonial therapy as a result of their high cytotoxicity, slow action and / or complications of disease (Chappuis, F., S. Sundar, et al. 2007. Nat. Rev. Microbiol. 5 (1 1): 873-82).

Conventional Amphotericin B treatment has replaced antimonials in the treatment of LV in some areas, in which the failure rate of antimonials exceeds 60%. Fever, chills and rigor are almost universal effects of conventional Amphotericin B treatment and it is not uncommon to find adverse effects with serious risk to life such as the drop in blood potassium concentration, nephrotoxicity and even anaphylactic shocks after the first dose. In addition, this drug is expensive and its administration regimen is complicated (15 slow infusions on alternate days) (Chappuis, F., S. Sundar, et al. 2007. Nat. Rev. Microbiol. 5 (1 1): 873- 82). Despite the existence of some alternatives to these treatments, such as liposomal amphotericin B, miltefosine (a drug originally developed as an anti-tumor), paramomycin (aminoglycoside antibiotic), and Sitamaquine (8-aminoquinoline) There is still a great need to advance in the research and development of new drugs that improve the repertoire of available strategies for disease control.

Diabetes mellitus is an important and growing health problem in the world (Yach, D., et al. Nat. Med. 2006, 12, 62-6). Type 2 diabetes mellitus (type 2 diabetes), also known as non-insulin dependent diabetes mellitus, is a heterogeneous disorder, with both genetic and environmental factors that contribute to its development. The pathogenesis of type 2 diabetes involves multiple mechanisms that lead to hyperglycemia, considerably increased hepatic glucose production, decreased insulin secretion by β cells and reduced glucose uptake by skeletal muscle and adipose tissue (peripheral insulin resistance) . Type 2 diabetic patients have a substantially high risk of macrovascular disease including coronary heart disease and stroke, and microvascular disease including retinopathy, nephropathy and neuropathy.

Type 2 diabetes is a therapeutic field with a huge potential market. The increase in the number of patients has been estimated from 170-175 million in 2000 to over 230 million in 2030 (Wild, S., et al. Diab. Care 2004, 27, 1047-53; Yach, D., et al. Nat. Med. 2006, 12, 62-6). It is expected that most of this increase will occur in developed countries and India will be the country with the highest number of diabetic patients in 2030.

Treatment strategies for type 2 diabetes include diet, exercise and pharmacotherapy. Clinically established therapies for type 2 diabetes include insulin and its analogues, and various oral hypoglycemic drugs such as sulfonylureas, metformin, α-glucosidate inhibitors (acarbose, miglitol), insulin secretagogues other than sulfonylureas (repaglinide, nateglinide), and derivatives thiazolidinedione (rosiglitazine, pioglitazone) acting by agonism of PPARy (Mathaei, R., et al. Endocrine Rev. 2000, 21, 585-618; Skyler, JSJ Med. Chem. 2004, 47, 41 13-7). These drugs act by different mechanisms to normalize blood glucose levels, but have a limited ability, both alone and in combination, to prevent the onset of complications of diabetes. In addition, each of the drugs mentioned generally has insufficient efficacy in addition to a number of adverse effects. For example, it is known that sulfonylureas, which have been the basis of oral treatment for 5 decades, are associated with a high rate of secondary failure and hypoglycemia. Glitazones improve glucose utilization without stimulating insulin release, but its use is associated with undesirable effects such as myocardial infarction risk, cardiac hypertrophy, liver toxicity and weight gain.

Taking into account that 90% of diabetes cases are cases of type 2 diabetes and that, in addition, currently available treatments are not very effective, there is a great clinical need and a wide potential market for new oral antidiabetic drugs that maintain the level Glycemic well controlled and prevent the complications of diabetes.

Tyrosine protein phosphatases (PTPs) are a broad family of signaling enzymes (Alonso, A., et al. Cell 2004, 117, 699-71 1) that play important roles in intracellular signal transduction processes through cell regulation of the level of tyrosine phosphorylation to control cell growth and differentiation, metabolism, cell migration, genetic transcription, ion channel activity, immune response, cell apoptosis and bone development (Hunter, C. Cell 2000, 100, 1 13 -27). The deregulated functioning of PTPs is responsible for many human diseases such as cancer (Blume-Jensen, P. Nature 2001, 411, 355-65), diabetes (Montalibet, J. Drug Discov. Today: Therap. Strateg. 2005, 2, 129-35), obesity (Cook, WS Developmental Cell 2002, 2, 385-7) and osteoporosis (Schiller, KRJ Cell Biochem. 2005, 96, 262-77).

Among the varied family of PTPs, PTP1 B activates c-Src in human breast cancer (Bjorge, JDJ Biol. Chem. 2002, 275, 41439-46) and also influences downregulation of insulin signaling by dephosphorylation of the insulin receptor including the insulin receptor substrate 1 (IRS-1) and the insulin receptor substrate 2 (IRS-2) (Walchli, SJ Biol. Chem. 2000, 275, 9792-96). Therefore, PTP1 B can be a useful target for diabetes and cancer, and PTP1 B inhibitors can be promising drugs to treat these diseases. In addition, considering that mice genetically deficient in PTP1 B are resistant to obesity, PTP1 B plays a critical role in the development of obesity (Klaman, LD Mol. Cell. Biol. 2000, 20, 5479-89). Despite the therapeutic potential of PTP1 B inhibitors against diabetes, obesity and cancer, it is difficult to develop selective PTP1 B inhibitors against other PTPs such as SHP, VHR, LAR, CD45 and cdc25D, due to structural homologies between PTPs (Cheng, A. Eur. J. Biochem. 2002, 269, 1050-9; Penninger, JMJ Nat. Immunol. 2001, 2, 389-96; Qu, CK Biochem. Biophys. Acta 2002, 1592, 297- 301; Hoffman, BT Curr. Pharm. Des. 2004, 10, 1 161-81). Specifically, because T-cell PTP (TCPTP) has an 80% homology with PTP1 B in the catalytic regions, non-selective inhibition causes severe side effects (Tiganis, TJ Biol. Chem. 1999, 274, 27768- 75; You-Ten, KEJ Exp. Med. 1977, 186, 683-93), although recently there are different opinions about PTP1 B and TCPTP co-ordinating regulating an insulin signaling process (Galic, S. Mol. Cell Biol. 2005, 25, 819-29).

The therapeutic potential of PTPs inhibitors, and PTP1 B in particular, for the treatment of human diseases has been extensively reviewed (Lee, K. Curr. Top. Med. Chem. 2003, 3, 797-807; Zhang, ZY Acc. Chem. Res. 2003, 36, 285-92; Hoft van Huijsduijnen, RHJ Med. Chem. 2004, 47, 4142-46; Dewan, PM Curr. Chem. Res. 2005, 12, 1 -22; Bialy, L. Angew. Chem. Int. Ed. 2005, 44, 3814-39; Zhang, ZY Curr. Opin. Chem. Biol. 2001, 5, 416-23; Burke, TR Biopolymers (Peptide Science) 1999, 47, 225 -41). Specifically, the structural biology, mechanism and inhibitors of PTP1 B (Taylor, Curr. Top. Med. Chem. 2003, 3, 759-82) as well as the approximation of small molecules to study the function of PTP1 have been reviewed B (Zhang, Methods, 2005, 31, 9-21) which introduced the initial strategies to find potent and selective PTP1 B inhibitors, the synthesis of cell permeable analogs for cell studies and the application of those inhibitors to dissect the role of PTP1 B in the insulin signaling pathway. The structural and biological characteristics of specific low molecular weight inhibitors of PTP1 B have been discussed in depth (Lee, S .; Wang, Q. Med. Res. Rev. 2007, 27, 553-73; Thareja, S .; Aggarwal , S .; Bardwaj, TR; Kumar, M. Med. Res. Rev. 2012, 32, 459-517), emphasizing the specificity of low molecular weight inhibitors of PTP1 B versus other PTPs. Some classes of these low molecular weight inhibitors include: thiazolidinediones, phosphotyryl peptidomimetics containing phosphorus, isothiazolidinones, Phosphotomimetics phosphotyrosyl with acid groups that do not contain phosphorus, biphenylbenzofurans and biphenylbenzothiophenes, vanadium compounds, ortho-oxalylamylbenzoic acids, 1,2-naphthoquinones, 3-formylchromones, pyridazine analogs, acetophenones, catholes, analogues; cinnamic acids and the like; peptidomimetics; metino-tetrasubstituted derivatives; diterpene pigments type abietano; natural products and their analogues, such as those extracted from roots of Broussonetia papyrifera, bark of Erythirna addisoniae, bark of Erythirna abyssinica, Cinnamomun cassaia, bark of Morus root, Siegesbeckia glaberscens, Acanthopanax koreanum, rhizomes of Astilbe koreana, Jugna rans Roots of Saussurealappa Clarke, Japanese Ardisia, Psydium Guiana, Steptomyces sp. MJ742-NF5, the sea sponge Hyrtios erectus, berberine or papaverine.

Although a wide range of research has recently been carried out on PTP1 B inhibitors, including mechanistic studies of inhibitors against PTP1 B, structure-activity relationships, synthetic and pharmacological studies, the structural homogeneity of the active center and secondary binding center of the family of PTPs makes the discovery of specific PTP1 B antagonist inhibitors for the development of drugs used in clinical trials still very interesting.

In the present invention, compounds 2a and 4a (Cheeseman, GWH; Tuck, BJ Chem. Soc. 1966, 852-5; Guillon, J .; Dallemagne, P .; Pfeiffer, B .; Renard, P .; Manechez, D .; Kervran, A .; Rault, S. Eur. J. Med. Chem. 1998, 33, 293), 2b (Cheeseman, GWH; Hawi, AA; Varvounis, GJ Heterocycl. Chem. 1985, 22, 423- 7), 2c (Campiani, G .; Morelli, E .; Gemma, S .; Nacci, V .; Butini, S .; Hamon, M .; Novellino, E .; Greco, G .; Cagnotto, A .; Goegan, M .; Cervo, L; Dalla Valle, F .; Fracasso, C; Caccia, S .; Mennini, TJ Med. Chem. 1999, 42, 4362-79), 2d, 2f, 4d and 4f (Guillon, J .; Grellier, P .; Labaied, M .; Sonnet, P .; Leger, J.-M .; Deprez-Poulain, R .; Forfar-Bars, I .; Dallemagne, P .; Lemaitre, N .; Pehourcq, F .; Rochette, J .; Sergheraert, C; Jarry, CJ Med. Chem. 2004, 47, 1997-2009), 2e (Campiani, G .; Nacci, V .; Corelli, F .; Anzini, M Synth. Commun. 1991, 21, 1567-76), 2f and 4g (Guillon, J .; Dallemagne, P .; Pfeiffer, B .; Renard, P .; Manechez, D .; Kervran, A .; Rault, S. Eur. J. Med. Chem. 1998, 33, 293; Campiani , G .; Morelli, E .; Gemma, S .; Nacci, V .; Butini, S .; Hamon, M .; Novellino, E .; Greco, G .; Cagnotto, A .; Goegan, M .; Cervo, L .; Dalla Valle, F .; Fracasso, C; Caccia, S .; Mennini, TJ Med. Chem. 1999, 42, 4362-79), 4e (Alleca, S .; Corona, P .; Loriga, M .; Paglietti, G .; Loddo, R .; Mascia, V .; Busonera, B .; La Colla, P. Fármaco 2003, 58, 639-50), 5th and 6th (Guillon, J .; Forfar, I .; Mamani-Matsuda, M .; Desplat, V .; Saliege, M .; Thiolat , D .; Massip, S .; Tabourier, A .; Leger, J.-M .; Dufaure, B .; Haumont, G .; Jarry, C; Mossalayi, D. Bioorg. Med. Chem. 2007, 15, 194-210; Cheeseman, GWH; Tuck, BJ Chem. Soc. 1966, 852-5) and compound 5d (Guillon, J .; Forfar, I .; Mamani-Matsuda, M .; Desplat, V .; Saliege, M .; Thiolat, D .; Massip, S .; Tabourier, A .; Leger, J.-M .; Dufaure, B .; Haumont, G .; Jarry, C; Mossalayi, D. Bioorg. Med. Chem. 2007, 15, 194-210) were prepared as described above.

Compounds 2a, 2f, 4a and 4g have been described as intermediates in the preparation of glucagon receptor antagonists. Compounds 2d, 2f, 4d and 4f have previously been prepared as intermediates of compounds with anti-malaria activity. Compound 2b has been used as an intermediate in the synthesis of 5,6-dihydropyrrile [1,2-a] -1,3,6-thiadiazocins. Compounds 2c, 2g, 4c and 4g are intermediates in the preparation of 5-HT3 receptor agonists. Compound 4e has been described as an intermediate in the synthesis of compounds with antiproliferative properties. Compounds 5a, 5d and 6a have been described as intermediates of products with anti-Leishmania activity.

Type 6 compounds with antiproliferative activity against cancer cells have been described (Pierre, F .; Regan, C; Chevrel, M.-C; Siddiqui-Jain, A .; Macalino, D .; Streiner, N .; Drygin, D .; Haddach, M .; O'Brien, SE; Rice, WG; Ryckman, DM Bioorg. Med. Chem. Lett. 2012, 22, 3327-31; Desplat, V .; Moreau, S .; Gay, A. ; Fabre, SB; Thiolat, D .; Massip, S .; Macky, G .; Godde, F .; Mossalayi, D .; Jarry, C; Guillon, JJ Enzyme Inhibit. Med. Chem. 2010, 25, 204- 15; Plasencia, C; Grande, F .; Oshima, T .; Cao, X .; Yamada, R .; Sánchez, T .; Aiello, F .; Garofalo, A .; Neamati, N. Cancer Biol. Ther. 2009, 8, 458-65), inhibitors of the multiresitence of bacteria to antibiotics (Vidaillac, C; Guillon, J .; Moreau, S .; Arpin, C; Lagardere, A .; Larrouture, S .; Dallemagne, P. ; Caignard, D.-H .; Quentin, C; Jarry, CJ Enzyme Inhibit. Med. Chem. 2007, 22, 620-31), anti-Leishmania (Guillon, J .; Forfar, I .; Desplat, V. ; Fabre, SB; Thiolat, D .; Massip, S .; Carrie, H .; Mossalayi, D .; Jarry, CJ Enzyme Inhibit. M ed. Chem. 2007, 22, 541-9; Guillon, J .; Forfar, I .; Mamani-Matsuda, M .; Desplat, V .; Saliege, M .; Thiolat, D .; Massip, S .; Tabourier, A .; Leger, J.-M .; Dufaure, B .; Haumont, G .; Jarry, C; Mossalayi, D. Bioorg Med. Chem. 2007, 15, 194-210), anti-Malaria (Guillon, J .; Grellier, P .; Labaied, M .; Sonnet, P .; Leger, J.-M .; Deprez-Poulain, R .; Forfar-Bars, I .; Dallemagne, P .; Lemaitre, N .; Pehourcq, F .; Rochette, J .; Sergheraert, C; Jarry, CJ Med. Chem. 2004, 47, 1997-2009; Guillon, J .; Mouray, E .; Moreau, S .; Mullie, C; Forfar, I .; Desplat, V .; Belisle-Fabre, S .; Pinaud, N .; Ravanello, F .; Le-Naour, A. ; Leger, J.-M .; Gosmann, G .; Jarry, C; Deleris, G .; Sonnet, P .; Grellier, P. Eur. J. Med. Chem. 2011, 46, 2310-26; Guillon, J .; Moreau, S .; Mouray, E .; Sinou, V .; Forfar, I .; Fabre, SB; Desplat, V .; Millet, P .; Parzy, D .; Jarry, C; Grellier, P. Bioorg. Med. Chem. 2008, 16, 9133-44) and Akt kinase inhibitors (Desplat, V .; Geneste, A .; Begorre, M.-A .; Fabre, SB; Brajot, S .; Massip, S .; Thiolat, D .; Mossalayi, D .; Jarry, C; Guillon, JJ Enzyme Inhibit. Med. Chem. 2008, 23, 648-58). On the other hand, the compounds of Formula I have not been described prior to this invention.

DESCRIPTION OF THE INVENTION

In a first aspect the invention is related to new compounds that have Formula I:

(l)

where Ri, R ₂ and R 3 can be any of the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, carbocycle or heterocycle, aromatic or heteroaromatic; chlorine, bromine or iodine; preferably R ₁ is selected from hydrogen, chlorine, bromine or iodine; and / or preferably R ₂ and R 3 are hydrogen;

where R ₅ , R ₆ , R7 and Rs can be any of the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, carbocycle or heterocycle, aromatic or heteroaromatic; fluorine, chlorine, bromine or iodine; nitro; thiol; thioether (RS-) where the substituent R may be equal to any of the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, carbocycle or heterocycle, aromatic or heteroaromatic; ether (RO-) where the substituent R has been defined above; primary, secondary (RNH-) or tertiary (R'R "N-) amino where the substituents R 'and R" in the nitrogen may be the same or different, and may be hydrogen or any of the group indicated for R; primary (RCONH-), secondary (RCONR'-) or tertiary (RCONR'R "-) acylamino where the radical R of the acyl group can be hydrogen or any of the group indicated for R and the substituents R 'and R" have been defined previously; hydroxy; acyloxy (RCOO-) where the radical R of the acyl group can be hydrogen or any of the group indicated for R; (RCO-) acyl where the radical R acyl group can be hydrogen or any of the group indicated for R; primary, secondary (R'NHCO-) or tertiary (R "R'NCO-) carboxamide where the substituents R 'and R" in the nitrogen may be any of the group indicated for R; alkoxycarbonyl (ROCO-) where the substituent R in the oxygen may be equal to any of the group indicated for R; carboxy; preferably R ₅ and Rs are hydrogen; and / or preferably R6 is selected from chlorine, bromine, iodine, hydrogen fluorine, (C1-C4) alkyl optionally substituted by at least one halogen group, preferably the halogen group is fluorine, chlorine, bromine or iodine and more preferably is substituted by three fluorine groups forming the group -CF3, RO-, where R is preferably (C1-C4) alkyl; and / or preferably R ₇ is selected from (C1-C4) alkyl, chlorine, bromine, iodine, fluorine and hydrogen;

where Rg and R10 can be the same or different and any one to choose between hydrogen, alkyl, aryl or heteroaryl;

and where Rg and R10 can also be part of a saturated, carboaromatic or heteroaromatic carbocyclic ring; preferably they are the same and are selected from (C1-C4) alkyl, hydrogen or are part of the same carboaromatic ring; Y

where Y is mesitylenesulfonate, chlorine, bromine, iodine or any pharmaceutically acceptable anion.

The term "alkyl" refers, in the present invention, to saturated, linear or branched hydrocarbon chains having 1 to 10 carbon atoms, for example, methyl, ethyl, π-propyl, / -propyl, π-butyl , ferc-butyl, sec-butyl, n-pentyl, n-hexyl, etc. Preferably the alkyl group has between 1 and 6 carbon atoms, more preferably between 1 and 4. The alkyl groups may be optionally substituted by one or more substituents such as alkynyl, alkenyl, halo, hydroxy, alkoxy, carboxyl, cyano, carbonyl, acyl, alkoxycarbonyl, amino, nitro or mercapto. The halogen group is fluorine, chlorine, bromine or iodine. Preferably the alkyl group is substituted by at least one halo group and more preferably it is substituted by three fluorine groups forming the group -CF ₃ .

The term "alkenyl" refers, in the present invention, to unsaturated, linear or branched hydrocarbon chains, having 2 to 10 carbon atoms, preferably 2 to 6, and containing one or more double carbon-carbon bonds and which may optionally contain some triple bond, for example, vinyl, 1-propenyl, allyl, isoprenyl, 2-butenyl, 1, 3-butadienyl, etc. Alkenyl radicals may be optionally substituted by one or more substituents such as alkyl, alkynyl, halo, hydroxy, alkoxy, carboxyl, cyano, carbonyl, acyl, alkoxycarbonyl, amino, nitro or mercapto.

The term "alkynyl" refers to radicals of hydrocarbon chains, linear or branched, of 2 to 10 carbon atoms, preferably 2 to 6, and which contain at least one or more triple carbon-carbon bonds and which may optionally contain some double bond, for example, ethylino, propynyl, butynyl, etc. Alkynyl radicals may be optionally substituted by one or more substituents such as alkyl, alkenyl, halo, hydroxy, alkoxy, carboxyl, cyano, carbonyl, acyl, alkoxycarbonyl, amino, nitro or mercapto.

The term "aryl" or "aromatic carbocycle" or "carboaromatic" refers, in the present invention, to aromatic rings, single or multiple, having between 5 and 18 carbon atoms in the ring part, such as but without be limited to, phenyl, naphthyl, diphenyl, indenyl, phenanthryl, fluorenyl or anthracil. Preferably the aryl group has 5 to 12 carbon atoms and more preferably the aryl group is a phenyl or an acenaphite. The aryl radicals may be optionally substituted in any of their positions by one or more substituents or two substituents forming a condensed aryl cycle and are independently selected from among them such as alkyl, alkenyl, alkynyl, O-alkyl, O, halogen, hydroxyl, amino or carboxylic acid.

The term "heteroaryl" or "heteroaromatic" refers to an aryl, as defined above, which contains at least one non-carbon atom, such as S, N, or O, forming part of the aromatic ring.

"Cycloalkyl" or "carbocycle" refers to a stable monocyclic radical or 3 to 10-membered bicyclic, which is saturated or partially saturated, and which only consists of carbon and hydrogen atoms, such as cyclohexyl or adamantyl.

"Cycloalkenyl" and "cycloalkynyl" refer to a cycloalkyl group or a carbocycle with at least one double or triple bond, respectively, formed part of the cycle.

The term "heterocycle" refers to a cycloalkyl, cycloalkenyl or cycloalkynyl, as defined above, which contains at least one atom other than carbon, such as S, N, or O, forming part of the cycle.

The cycloalkyl, cycloalkenyl, cycloalkynyl or heterocycle radicals can be optionally substituted in any of their positions by one or more substituents and can be independently selected from alkyl, alkenyl, alkynyl, O-alkyl, O, halogen, hydroxy, amino or carboxylic acid. a preferred embodiment the compounds of the invention are selected from 7-bromo-2,3,10,1 1-tetramethylpyrididazino [2,3- a] pyrrolo [2,1-c] quinoxal-13-inium mesylethenesulfonate, bromide of 7-bromo-10-chloro-2,3-diethylpyridazino [2,3-a] pyrrolo [2,1-c] quinoxal-13-inium; 7-Bromo-10,1-1-dimethylpyrididazino [2,3-a] pyrrolo [2,1-c] quinoxal-13-inium mesitylenesulfonate; 10-Chloro-2,3-diethylpyridazino [2,3-a] pyrrolo [2,1-c] quinoxal-13-inium bromide; 2,3-dimethylpyridazino [2,3-a] pyrrolo [2,1-c] quinoxal-13-inium mesitylenesulfonate; 2,3,10,1 1-tetramethylpyrididazino [2,3-a] pyrrolo [2,1-c] quinoxal-13-inium mesitylenesulfonate;

2,3,1 1 -trimethylpyridazino [2,3-a] pyrrolo [2,1-c] quinoxal-13-inium mesitylenesulfonate; 2,3-dimethyl-1-1-methoxypyridazino [2,3-a] pyrrolo [2,1-c] quinoxal-13-inium mesitylenesulfonate; 2,3-dimethyl-1-1-trifluoromethylpyridazino [2,3- a] pyrrolo [2,1-c] quinoxal-13-inium mesitylenesulfonate; 10-Chloro-2,3-dimethylpyridazino [2,3-a] pyrrolo [2,1-c] quinoxal-13-inium mesitylenesulfonate; 10,1 1-dichloro-2,3-dimethylpyridazino [2,3-a] pyrrolo [2,1-c] quinoxal-13-inium mesitylenesulfonate; acenaphth mesitylenesulfonate [1 ', 2': 3,4] pyridazino [2,3-a] pyrrolo [2,1-c] quinoxal-9-inium; 10,1 1-dimethylpyrididazino [2,3-a] pyrrolo [2,1-c] quinoxal-13-inium mesitylenesulfonate; 10-chloropyridazino [2,3-a] pyrrolo [2,1-c] quinoxal-13-inium mesitylenesulfonate; and 2,3-diethyl-10,1-1-dimethylpyridazino [2,3-a] pyrrolo [2,1-c] quinoxal-13-inium mesitylenesulfonate.

In a second aspect the invention is related to a method of preparing the compounds of Formula I. In a third aspect, the invention is also related to the use of said compounds of Formula I to inhibit the growth of the Leishmania parasite, which constitutes a new tool with importance both from a medical and veterinary point of view.

In a fourth aspect the invention is also related to the use of said compounds of Formula I for the treatment of infections caused by the Leishmania parasite. Leishmaniasis is a disease that primarily affects vertebrates, that is, both in humans or vertebrate animals, such as marsupials, canids, rodents or primates.

There are several types of leishmaniasis depending on the type of organs that are affected by this disease and that are: visceral leishmaniasis (LV), which is mainly caused by two species L. donovani and L. infantum, cutaneous leishmaniasis (LC) or mucous leishmaniasis or mucocutaneous (CML). Given the similarity of the different Leishmania species, the compounds of the invention are used for the treatment of any type of leishmaniasis.

In a fifth aspect the invention is also related to the use of the compounds of Formula I for the preparation of a pharmaceutical composition for the treatment of infectious diseases caused by Leishmania. The present invention relates to a pharmaceutical composition comprising at least one of the compounds of the invention, together with a pharmaceutically acceptable carrier. The use of said composition for the treatment of infectious diseases will be in a therapeutically effective amount.

The pharmaceutically acceptable adjuvants and vehicles that can be used in said compositions are the adjuvants and vehicles known to those skilled in the art and commonly used in the elaboration of therapeutic compositions.

The compounds of the invention, their pharmaceutically acceptable salts, prodrugs and / or solvates, as well as the pharmaceutical compositions containing them, can be used together with other drugs, or active ingredients, additional to provide a combination therapy. Said additional drugs may be part of the same pharmaceutical composition or, alternatively, they may be provided in the form of a separate composition for simultaneous or non-simultaneous administration to that of the composition. Pharmaceutical comprising a compound of Formula I or a prodrug, solvate, derivative or a pharmaceutically acceptable salt thereof.

In a sixth aspect the invention is also related to the use of said compounds of Formula I to inhibit PTP1 B.

In a seventh aspect the invention is also related to the use of said compounds of Formula I for the treatment of diseases in which PTP1 B is involved.

More specifically, the present invention is related to the field of chemical synthesis of new compounds and their use as inhibitors of PTP1 B, which are useful in the treatment or prevention of diseases in which it is known that PTP1 B is involved. in the pathogenesis. As inhibitors of phosphatase activity and, in particular, as inhibitors of PTP1 B, the new compounds of the present invention can be used for the treatment of insulin resistance, glucose intolerance, obesity, diabetes mellitus, hypertension and ischemic diseases. of large and small blood vessels, conditions that accompany type 2 diabetes including dyslipidemia, for example, hyperlipidemia and hypertriglyceridemia, atherosclerosis, vascular restenosis, irritable bowel syndrome, pancreatitis, fat cell cancer and carcinomas such as liposarcoma, and other disorders where Insulin resistance is indicated. In addition, the compounds of the present invention can be used for the treatment of cancer, osteoporosis, neurodegenerative and infectious diseases, and diseases involved with inflammation and the immune system.

The present invention also concerns the use of the compounds of the invention for use in the treatment of renal insufficiency (diabetic and non-diabetic), diabetic nephropathy, glomerulonephritis, glomerular sclerosis, primary renal disease proteinuria, diabetic retinopathy, all types of heart failure including acute and chronic congestive heart failure, left ventricular dysfunction and hypertrophic cardiomyopathy, diabetic cardiac myopathy, ventricular and supraventricular arrhythmias, atrial fibrillation and atrial palpitation, angina pectoris (both unstable and stable), myocardial infarction and its sequelae , ischemia / reperfusion injury, harmful vascular restoration including vascular restenosis, treatment of other vascular disorders such as migraines, peripheral vascular disease and Raynaud's disease, sclerosis multiple, cerebral infarction, spinal cord injury, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and polyglutamine diseases such as Huntington and spinocerebellar ataxia, infectious diseases including leishmaniasis, diseases involved in inflammation and the immune system and diseases involved in muscle degeneration.

In an eighth aspect the invention is also related to that of the compounds of Formula I for the preparation of a pharmaceutical composition for the treatment of diseases in which PTP1 B is involved.

The present invention relates to a pharmaceutical composition comprising at least one of the compounds of the invention, together with a pharmaceutically acceptable carrier, may optionally comprise another active ingredient. The use of said composition for the treatment of infectious diseases will be in a therapeutically effective amount.

The compounds of the invention, their pharmaceutically acceptable salts, prodrugs and / or solvates, as well as the pharmaceutical compositions containing them, can be used together with other drugs, or active ingredients, additional to provide a combination therapy. Said additional drugs may be part of the same pharmaceutical composition or, alternatively, they may be provided in the form of a separate composition for simultaneous or non-simultaneous administration to the pharmaceutical composition comprising a compound of Formula I or a prodrug, solvate, derivative or a pharmaceutically acceptable salt thereof.

In the sense used in this description, the term "therapeutically effective amount" refers to the amount of the agent or compound capable of developing the therapeutic action determined by its pharmacological properties, calculated to produce the desired effect and, in general, will be determined, among other causes, due to the characteristics of the compounds, including the age, condition of the patient, the severity of the disorder or disorder, and the route and frequency of administration.

Said therapeutic composition may be prepared in the form of a solid form or aqueous suspension, in a pharmaceutically acceptable diluent. The therapeutic composition provided by this invention may be administered by any appropriate route of administration, for which said composition will be formulated in the pharmaceutical form appropriate to the route of administration chosen. In a particular embodiment, administration of the therapeutic composition provided by this invention is performed orally, topically, rectally or parenterally (including subcutaneously, intraperitoneally, intradermally, intramuscularly, intravenously, etc.). A review of the different pharmaceutical forms of drug administration and of the excipients necessary to obtain them can be found, for example, in the "Galician Pharmacy Treaty", C. Faulí i Trillo, 1993, Luzán 5, S.A. Ediciones, Madrid, or other habitual or similar ones of the Spanish and United States Pharmacopoeias.

Throughout the description and the claims the word "comprises" and its variants are not intended to exclude other technical characteristics, additives, components or steps. For those skilled in the art, other objects, advantages and features of the invention will be derived partly from the description and partly from the practice of the invention. The following examples are provided by way of illustration, and are not intended to be limiting of the present invention.

The compounds of the invention can be prepared from the pyrroloquinoxalines 6 which can be prepared as indicated in Figure 1. The reaction of o-nitroanilines 1 with 2,5-dimethoxytetrahydrofurans 3 in acetic acid at reflux makes it possible to prepare 1 - (2-nitrophenyl) pyrroles 2. These compounds thus prepared are subjected to a reduction process with hydrazine or tin dichloride to synthesize 2- (pyrrol-1-yl) anilines 4. Heating of these anilines with acetic anhydride in acetic acid at reflux leads to 2- (pyrrol-1-yl) anilides 5. Subsequently the anilides are treated with a dehydrating agent to choose between P ₂ 0 ₅ , POCI ₃ , POBr ₃ , PCI ₃ , PBr ₃ , PCI ₅ or SOCI ₂ to produce cyclisation to pyrroloquinoxalines 6. These pyrroloquinoxalines are subsequently used for the synthesis of compounds of this invention having the Formula I that can be achieved by the reactions indicated in the example Illustrative of Figure 2. Especially preferred compounds are described in the examples of this invention and the methods for preparing the compounds of Formula I comprise:

a) transform pyrroloquinoxalines 6

where Ri, F½ and R3 can be any of the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, carbocycle or heterocycle, aryl or heteroaryl;

where R ₄ can be any of the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, carbocycle or heterocycle, aryl or heteroaryl;

where R ₅ , R ₆ , R7 and Rs can be any of the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, carbocycle or heterocycle, aryl or heteroaryl; fluorine, chlorine, bromine or iodine; nitro; thiol; thioether (RS-) where the substituent R may be equal to any of the group indicated for R ₄ except hydrogen; ether (RO-) where the substituent R may be equal to any of the group indicated for R ₄ except hydrogen; primary, secondary (RNH-) or tertiary (RR'N-) amino where the substituents R and R 'in the nitrogen may be equal to any of the group indicated for R ₄ except hydrogen; primary (RCONH-), secondary (RCONR'-) or tertiary (RCONR'R "-) acylamino where the radical R of the acyl group may be equal to any of the group indicated for R ₄ and the substituents R 'and R" in the nitrogen may be equal to any of the group indicated for R ₄ except hydrogen; hydroxy; acyloxy (RCOO-) where the radical R of the acyl group can be equal to any of the group indicated for R; (RCO-) acyl where the radical R acyl group may be equal to any of the group indicated for R ₄ ; primary, secondary (RNHCO-) or tertiary (RR'NCO-) carboxamide where the substituents R and R 'in the nitrogen may be equal to any of the group indicated for R ₄ except hydrogen; alkoxycarbonyl (ROCO-) where the substituent R in the oxygen may be equal to any of the group indicated for R ₄ except hydrogen; or carboxy,

in halopirroloquinoxalines 7i

where X is any to choose between chlorine, bromine or iodine;

wherein R2 and R3 can be any of the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, carbocycle or heterocycle, aryl or heteroaryl;

and where R ₄ , R5, R6, R7 and Rs have been defined above,

by reaction with an N-halosuccinimide.

and / or in halopyrrinoquinoxalines 72

where X is any to choose between chlorine, bromine or iodine;

where R1 and R3 can be any of the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, carbocycle or heterocycle, aryl or heteroaryl;

and where R ₄ , R5, R6, R7 and Rs have been defined above,

by reaction with an N-halosuccinimide;

and / or in 7z halopyrroloquinoxalines

where X is any to choose between chlorine, bromine or iodine; where Ri and R2 may be any of the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, carbocycle or heterocycle, aryl or heteroaryl;

and where R ₄ , R ₅ , R6, R7 and Rs have been defined above;

by reaction with an N-halosuccinimide;

b) transform halopyrrinoquinoxalines 7i

where X, R2, R3, R4, R5, R6, R7 and Rs have been defined above;

in aminoquinoxalinium salts 81

STS- where X, R ₂ , R3, R ₄ , R5, R6, R7 and Rs have been defined above;

and where Y can be any one to choose between mesitylenesulfonate or any pharmaceutically acceptable anion;

by reaction with hydroxylamine O-mesitylenesulfonate (MSH);

or hydroxylamino-O-sulfonic acid (HOSA);

or 0- (2,4-dinitrophenyl) hydroxylamine

c) transforming halopirroloquinoxalinas _{July 2}

where X, R1, R3, R ₄ , R5, R6, R7 and Rs have been defined above;

in aminoquinoxalinium salts 8 ₂

STS- where X, Ri, R3, R ₄ , R5, R6, R7 and Rs have been defined above;

by reaction with hydroxylamine O-mesitylenesulfonate (MSH);

or hydroxylamino-O-sulfonic acid (HOSA);

or 0- (2,4-dinitrophenyl) hydroxylamine.

d) transform 7z halopyrrinoquinoxalines

where X, R1, R ₂ , R ₄ , R5, R6, R7 and Rs have been defined above;

in aminoquinoxalinium salts 83

where X, R1, R ₂ , R ₄ , R5, R6, R7 and Rs have been defined above;

by reaction with hydroxylamine O-mesitylenesulfonate (MSH);

or hydroxylamino-O-sulfonic acid (HOSA);

or 0- (2,4-dinitrophenyl) hydroxylamine.

e) transform aminoquinoxalinium salts 81

STS- where X, Y, R ₂ , R3, R ₄ , R5, R6, R7 and Rs have been defined above;

in the pyrimidopyrroloquinoxalinium salts 9i

MSTS- where R ₉ and R 10 can be any one of choice between hydrogen, alkyl, aryl or heteroaryl;

and where Rg and R10 can also be part of a saturated, carboaromatic or heteroaromatic carbocyclic ring;

by reaction with a 1,2-diketone of general formula

where Rg and R10 have been defined above,

in the presence of a base to choose between triethylamine and sodium acetate,

f) transform amino uinoxalinium salts 82

STS- where X, Y, R1, R3, R ₄ , R5, R6, R7 and Rs have been defined above;

in pyrimidopyrroloquinoxalinium salts 9 ₂

MSTS- where X, Y, Ri, R3, R ₄ , R5, R6, R7, Rs, R9 and R10 have been defined above; by reaction with a 1,2-diketone of general formula

where Rg and R10 have been defined above,

in the presence of a base to choose between triethylamine and sodium acetate,

g) transform aminoquinoxalinium salts 83

where X, Y, R1, R2, _R4, R5, R6, R7 and Rs are defined above;

in pyrimidopyrroloquinoxalinium salts 93

where X, Y, R1, R2, _R4, R5, R6, R7, Rs, R9 and R10 are defined above; by reaction with a 1,2-diketone of general formula,

where Rg and R10 have been defined above,

in the presence of a base to choose between triethylamine and sodium acetate,

h) transform pyrroloquinoxalines 6

where Ri, R ₂ and R 3 can be any of the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, carbocycle or heterocycle, aryl or heteroaryl;

and wherein _R4, R5, R6, R7 and Rs are defined above;

in the aminoquinoxalinium salts 10

STS- where Y, R1, R ₂ , R ₄ , R5, R6, R7 and Rs have been defined above;

by reaction with hydroxylamine O-mesitylenesulfonate (MSH);

or hydroxylamino-O-sulfonic acid (HOSA);

or 0- (2,4-dinitrophenyl) hydroxylamine.

i) transform aminoquinoxalinium salts 10

STS- where Y, R1, R ₂ , R3, R ₄ , R5, R6, R7 and Rs have been defined above;

in pyrimidopyrroloquinoxalinium salts 11

MSTS- where Y, Ri, R2, R3, R4, R5, R6, R7, Rs R9 and R10 have been defined above; by reaction with a 1,2-diketone of general formula

where Rg and R10 have been defined above,

in the presence of a base to choose between triethylamine and sodium acetate.

Another aspect of the invention relates to the use of an intermediate selected from the compounds of formula 6, 7, 7, ₂ , 7, ₃ , 81, 82, 83 or 10 described above to prepare a compound of formula (I).

Another aspect of the invention relates to the compound of formula 6 described above, except for the compounds when: R ₁ R ₂ , R ₃ , R 5, R 6, R 7 and Rs are hydrogen and R ₄ is methyl; and when R ₁ R ₂ , R ₃ , R 5, R 7 and Rs are hydrogen, R ₄ is methyl and R 6 is methoxy. In a preferred embodiment, the compound of formula 6 is selected from: 4,7-dimethylpyrrolo [1,2-a] quinoxaline; 4,7,8-trimethylpyrrolo [1,2-a] quinoxaline; 7-trifluoromethyl-4-methylpyrrolo [1,2-a] quinoxaline; 8-chloro-4-methylpyrrolo [1,2-a] quinoxaline; and 7,8-dichloro-4-methylpyrrolo [1,2-a] quinoxaline.

Another aspect of the invention relates to any of the compounds of formula 7i, 7 ₂ , 73, 81, 8 ₂ or 83 described above, Preferably the compounds are selected from: 1-bromine-4,7,8-trimethylpyrrolo [1, 2- a] quinoxaline; 1-Bromo-8-chloro-4-methylpyrrolo [1,2-a] quinoxaline; 3-Bromo-4,7,8-trimethylpyrrolo [1,2-a] quinoxaline; 1,2-dibromo-4,7,8-trimethylpyrrolo [1,2-a] quinoxaline; 2-Bromo-8-chloro-4-methylpyrrolo [1,2-a] quinoxaline; 5- amino-1-bromo-4,7,8-trimethylpyrrolo [1,2-a] quinoxal-5-inio mesylenesulfonate or 5- amino-1-bromo-8-chloro-4-methylpyrrolo [1, 2-a] quinoxal-5-inium.

Another aspect of the invention relates to a compound of formula 10 described above except when R ₁ R ₂ , R ₃ , R 5, R 6, R 7 and Rs are hydrogen and R ₄ is methyl. Preferably the compound is selected from: 5-amino-4,7-dimethylpyrrolo [1,2-a] quinoxal-5-inium mesitylenesulfonate; 5-amino-4,7,8-trimethylpyrrolo [1,2-a] quinoxal-5-inium mesitylenesulfonate; 5-amino-4-methyl-7-methoxypyrrolo [1,2-a] quinoxal-5-inium mesitylenesulfonate; 5-amino-7-trifluoromethyl-4-methylpyrrolo [1,2-a] quinoxal-5-inium mesitylenesulfonate; 5-amino-8-chloro-4-methylpyrrolo [1,2-a] quinoxal-5-inium mesitylenesulfonate; and 5-amino-7,8-dichloro-4-methylpyrrolo [1,2-a] quinoxal-5-inium mesitylenesulfonate.

DESCRIPTION OF THE FIGURES

Figure 1.- View of the structure of new compounds of Formula I

Figure 2.- Scheme showing an example of synthesis of pyrrolo [1, 2- a] quinoxalines

Figure 3.- Scheme representing an example of synthesis of new compounds of Formula I.

Figure 4.- IC50 in amastigotes of L. Infantum and in THP-1, index of selectivity (IS), percentage of inhibition and IC50 against PTP1 B of the new compounds of Formula I.

MODE OF REALIZATION

The invention will now be illustrated by tests carried out by the inventors, which show the specificity and effectiveness of the compounds of the invention.

Synthesis of 2-nitrophenyl-1H-pyrroles

To a solution of the corresponding aniline (1 eq.) In acetic acid (3 mL / mmol) is added, dropwise, 2,5-dimethoxytetrahydrofuran (1.1 eq.). The reaction mixture is heated at reflux for the indicated time. Subsequently, it is cooled and concentrated to dryness. The reaction crude is dissolved in AcOEt (1.5 mL / mmol) and washed with a saturated solution of NaHCO ₃ (3 x 0.78 mL / mmol), NaCl (sat) (3 x 0.78 mL / mmol ) and dried with anhydrous MgSO ₄ . It is filtered and concentrated to dryness. The residue is purified by silica gel chromatography using the eluent indicated in each case.

Example 1. Preparation of 1 - (2-nitrophenyl) pyrrole (Compound 2a, Figure 1) From 2-nitroaniline 1a (4.47 g; 32.3 mmol), heating at reflux for 1.5 hours, purifying and eluting with a hexane / AcOEt mixture (4: 1).

Solid red. Rto .: 4.41 g; 72% Mp: 56 ° C {Lit. 55 ° C). ¹ H-NMR (200 MHz, CDCI ₃ ): δ 7.83 (dd, 1H, J = 8.3 Hz, J = 1.5 Hz); 7.64 (td, 1H, J = 7.6 Hz, J = 1.7 Hz); 7.45 (m, 2H); 6.78 (t, 2H, J = 2.1 Hz); 6.30 (t, 2H, J = 2.1 Hz) ppm. HRMS (ESI ⁺ ) m / e: calculated for C10H9N2O2 [M + H] ⁺ : 189.0664; Found: 189.0672.

Example 2. Preparation of 1- (4-methyl-2-nitrophenyl) pyrrole (Compound 2b, Figure 1)

From 4-methyl-2-nitroaniline 1b (4.34 g; 28.5 mmol), heating the reaction mixture at reflux for 50 minutes, purifying and eluting with hexane / AcOEt (9: 1).

Orange oil Rto .: 4.77 g; 83% ¹ H-NMR (200 MHz, CDCI3): δ 7.64 (s, 1H); 7.43 (dd, 1 H, J = 8.1 Hz; J = 1.3 Hz); 7.33 (d, 1 H, J = 8.1 Hz); 6.75 (t, 2H, J = 2.1 Hz); 6.33 (t, 2H, J = 2.1 Hz); 2.45 (s, 3 H) ppm. ¹³ C-NMR (50 MHz, CDCI ₃ ): δ 144.8; 138.3; 133.7; 131.5; 127.6; 124.8; 121.2 (2C); 110.5 (2C); 20.7 ppm HRMS (ESI ⁺ ) m / e: calculated for C11H11N2O2 [M + H] ⁺ : 203.0821; Found [M + H] ⁺ : 203.0816.

Example 3. Preparation of 1- (4,5-dimethyl-2-nitrophenyl) pyrrole (Compound 2c, Figure 1)

From 4,5-dimethyl-2-nitroaniline 1c (4.02 g; 24.2 mmol), heating for 45 minutes, purifying and eluting with hexane / AcOEt (4: 1).

Solid brown. Rto .: 5.13 g; 98% Mp: 58-59 ° C (Lit: 60-61 ° C). ¹ H-NMR (200 MHz, CDCI3): 57.66 (s, 1 H); 7.19 (s, 1 H); 6.74 (t, 2H, J = 2.1 Hz); 6.31 (t, 2H, J = 2.1 Hz); 2.34 (s, 6H) ppm. ¹³ C-NMR (50 MHz, CDCI ₃ ): 5143.2; 136.8; 132.0; 128.9; 125.7; 121.4 (2C); 110.5 (2C); 110.4; 19.8; 19.3 ppm HRMS (ESI ⁺ ) m / e: calculated for C12H13N2O2 [M + H] ⁺ : 217.0977; Found: 217.0970.

Example 4. Preparation of 1- (4-methoxy-2-nitrophenyl) pyrrole (Compound 2d, Figure 1)

From 4-methoxy-2-nitroaniline 1d (4.09 g; 24.3 mmol), maintaining heating for 3 hours, purifying and eluting with hexane / AcOEt (4: 1). Solid red. Rto .: 4.75 g; 97% Mp: 56-58 ° C (Lit: 57 ° C). ¹ H-NMR (200 MHz, CDCI ₃ ): δ 7.35 (m, 2H); 7.14 (dd, 1 H, J = 8.5 Hz, J = 2.9 Hz); 6.72 (t, 2H, J = 2.1 Hz); 6.31 (t, 2H, J = 2.1 Hz); 3.88 (s, 3H) ppm. ¹³ C-NMR (75 MHz, CDCI3): δ 158.6; 145.9; 129.3; 127.3; 121.7 (2C); 119.1; 110.3 (2C); 109.4; 56.1 ppm HRMS (ESI ⁺ ) m / e: calculated for C11H11N2O3 [M + H] ⁺ : 219.0770; Found: 219.0763.

Example 5. Preparation of 1- (4-trifluoromethyl-2-nitrophenyl) pyrrole (Compound 2e, Figure 1)

From 4-trifluoromethyl-2-nitroaniline 1e (3.94 g; 19.1 mmol), heating for 1 hour, purifying and eluting with hexane / AcOEt (9: 1) and subsequent micro distillation under reduced pressure (128 ° C / 2 mm Hg).

Brown oil Rto .: 2.92 g; 60% ¹ H-NMR (200 MHz, CDCI3): 58.09 (d, 1H, J = 1.3 Hz); 7.89 (dd, 1 H, J = 8.5 Hz, J = 1.3 Hz); 7.60 (d, 1 H, J = 8.5 Hz); 6.79 (t, 2H, J = 2.1 Hz); 6.39 (t, 2H, J = 2.1 Hz) ppm. HRMS (ESI ⁺ ) m / e: calculated for CnH ₇ F3N2O2 [M + H] ⁺ : 257.0532; Found: 257.0608.

Example 6. Preparation of 1- (5-Chloro-2-nitrophenyl) pyrrole (Compound 2f, Figure 1)

From 5-chloro-2-nitroaniline 1f (4.09 g; 23.7 mmol), heating the reaction mixture at reflux for 1.5 hours, purifying and eluting with a hexane / AcOEt mixture (9: 1) .

Solid red. Rto .: 4.82 g; 92% Mp: 75-76 ° C (Lit: 73 ° C). ¹ H-NMR (200 MHz, CDCI3): δ 7.81 (d, 1 H, J = 8.5 Hz); 7.46 (d, 1 H, J = 2.1 Hz); 7.41 (dd, 1 H, J = 8.5 Hz, J = 2.1 Hz); 6.76 (t, 2H, J = 2.1 Hz); 6.35 (t, 2H, J = 2.1 Hz) ppm. ¹³ C-NMR (50 MHz, CDCI3): 5143.0; 139.2; 135.3; 127.8; 127.5; 126.2; 121.1 (2C); 111.6 (2C) ppm. HRMS (ESI ⁺ ) m / e: calculated for C10H ₇ N2O2CI [M + H] ⁺ : 223.0269; Found: 223.0276.

Example 7. Preparation of 1- (4,5-dichloro-2-nitrophenyl) pyrrole (Compound 2g, Figure 1)

From 4,5-dichloro-2-nitroaniline 1g (2.13 g; 10.3 mmol), heating for 4 hours, purifying and eluting with hexane / AcOEt (9: 1). Solid red. Rto .: 2.61 g; 99% Mp: 71 -72 ° C (Lit. 70 ° C). ¹ H-NMR (200 MHz, CDCI ₃ ): δ 7.98 (s, 1 H); 7.57 (s, 1 H); 6.73 (t, 2H, J = 2, 1 Hz); 6.36 (t, 2H, J = 2, 1 Hz) ppm. ¹³ C-NMR (50 MHz, CDCI3): 5 142.9; 137.7; 133.3; 131.5; 129, 1; 126.5; 121, 1 (2C); 1 1 1, 7 (2C) ppm. HRMS (ESI ⁺ ) m / e: calculated for C10H7N2O2CI2 [M + H] ⁺ : 256.9885; Found: 256.9888.

Synthesis of 2- (pyrrol-1-yl) anilines

Method A: A solution of nitroarene (1 eq.) In ethanol (4.6 mL / mmol) is added, dropwise, on a suspension of Pd / C (10%) (0.05 eq.) In HCI ( 35 μΙ_ / ΐΎΊΐΎΐοΙ). Once the addition is complete, a solution of Ν2Η4Ή2Ο (4 eq.) Is slowly added thereto. The reaction mixture is stirred for the time indicated in each case. Subsequently, the reaction mixture is filtered over Celite® and the solvent is removed under reduced pressure. The crude is purified by chromatography on silica gel eluting with a hexane / AcOEt mixture (4: 1). Method B: To a solution of nitroarene (1 eq.) Dissolved in ethanol (0.44 mL / mmol) is added SnCl2-2H20 (5 eq.). The reaction mixture is heated at 70 ° C for the time indicated in each case. After that time, let it cool and add ice. Then, the reaction mixture is basified to pH = 7-8 with a solution of NaHC03 (5%) and extracted with AcOEt (3 x 0.68 mL / mmol). The organic extracts are combined and washed with a saturated solution of NaCl (3 x 0.68 mL / mmol), dried over anhydrous MgSO ₄ , filtered and concentrated to dryness. The residue obtained is purified by silica gel chromatography, as indicated in each compound.

Method C: A solution of nitroarene (1 eq.) And SnCl2-2H ₂ 0 (5 eq.) In ethanol (63 mL) is heated under reflux under an argon atmosphere for the time indicated in each case. It is then cooled and the pH thereof adjusted to 8 using a saturated solution of NaHC03. Filter on Celite®, wash with ethanol and concentrate to dryness. The crude is purified by chromatography on silica gel eluting with the solvent mixture indicated in each case.

Example 8. Preparation of 2- (pyrrol-1-yl) aniline (Compound 4a, Figure 1)

Method A. Using 1 - (2-nitrophenyl) pyrrole 2a (4.1 1 g; 21.8 mmol) and stirring the reaction mixture for 5.5 hours. Solid yellow. Rto .: 3.15 g; 91% Mp: 98-100 ° C {Lit.98 ° C). ¹ H-NMR (300 MHz, CD ₃ OD): δ 7.15 (td, 1 H, J = 7.9 Hz, J = 7.2 Hz, J = 1, 6 Hz); 7.08 (dd, 1 H, J = 7.9 Hz, J = 1.3 Hz); 6.89 (dd, 1 H, J = 7.9 Hz, J = 1.3 Hz); 6.83 (t, 2H, J = 2.1 Hz); 6.75 (td, 1 H, J = 7.9 Hz, J = 7.6 Hz, J = 1.3 Hz); 6.03 (t, 2H, J = 2.1 Hz) ppm. ¹³ C-NMR (75 MHz, CDCI3): δ 141.9; 128.5; 127.4; 127.1; 121.6 (2C); 118.4; 116.0; 109.3 (2C) ppm. HRMS (ESI ⁺ ) m / e: calculated for C10H11N2 [M + H] ⁺ : 159.0922; Found: 159.0920.

Example 9. Preparation of 5-methyl-2- (pyrrol-1-yl) aniline (Compound 4b, Figure 1)

Method B. Using 1- (4-methyl-2-nitrophenyl) pyrrole 2b (4.47 g; 22.1 mmol), heating the reaction mixture for 1 hour, purifying and eluting with hexane / AcOEt (9: 1) .

Solid brown. Rt .: 3.05 g; 80% Mp: 89 ° C (Lit. 89-90 ° C). ¹ H-NMR (300 MHz, CDCI3): δ 7.03 (d, 1H, J = 7.6 Hz); 6.81 (t, 2H, J = 2.0 Hz); 6.60 (m, 2 H); 6.33 (t, 2H, J = 2.0 Hz); 3.63 (Sancho, 2H); 2.31 (s, 3H) ppm. ¹³ C-NMR (75 MHz, CDCI ₃ ): δ 141.7; 138.5; 126.9; 125.1; 121.8 (2C); 119.1; 116.5; 109.1 (2C); 21.2 ppm HRMS (ESI ⁺ ) m / e: calculated for C11H13N2 [M + H] ⁺ : 173,1079; Found [M + H] ⁺ : 173,1074.

Example 10. Preparation of 4,5-dimethyl-2- (pyrrol-1-yl) aniline (Compound 4c, Figure 1)

Method B. Using 1- (4,5-dimethyl-2-nitrophenyl) pyrrole 2c (4.60 g; 21.3 mmol), heating the reaction mixture for 1.5 hours, purifying and eluting with a hexane / mixture. AcOEt (4: 1).

Solid yellow. Rt .: 2.87 g; 62% Mp: 84-85 ° C (Lit. 83-85 ° C). ¹ H-NMR (300 MHz, CDCI3): δ 6.92 (s, 1 H); 6.80 (t, 2H, J = 2.0 Hz); 6.62 (s, 1 H); 6.31 (t, 2H, J = 2.0 Hz); 3.51 (Sancho, 2H); 2.21 (s, 3 H); 2.16 (s, 3H) ppm. ¹³ C-NMR (75 MHz, CDCI3): δ 139.4; 136.9; 127.9; 126.5; 125.3; 121.7 (2C); 117.5; 109.0 (2C); 19.5; 18.6 ppm. HRMS (ESI ⁺ ) m / e: calculated for C12H1 ₅ N2 [M + H] ⁺ : 187.1235; Found: 187.1240. Example 11. Preparation of 5-methoxy-2- (pyrrol-1-yl) aniline (Compound 4d, Figure 1)

Method B. Using 1- (4-methoxy-2-nitrophenyl) pyrrole 2d (3.54 g; 16.2 mmol), purifying and eluting with a hexane / AcOEt mixture (4: 1).

Orange oil Rto .: 2.30 g; 75% ¹ H-NMR (300 MHz, CDCI ₃ ): δ 7.05 (d, 1H, J = 9.6 Hz); 6.76 (t, 2H, J = 2.0 Hz); 6.32 (m, 4H); 3.78 (s, 3 H); 3.66 (s _a ncho, 2H) ppm. ¹³ C-NMR (75 MHz, CDCI ₃ ): δ 159.8; 143.3; 128.1; 122.0 (2C); 121.2; 109.1 (2C); 103.6; 101.0; 55.4 ppm HRMS (ESI ⁺ ) m / e: calculated for CnHi ₃ N ₂ 0 [M + H] ⁺ : 189,1028; Found: 189.1035.

Example 12. Preparation of 5-trifluoromethyl-2- (pyrrol-1-yl) aniline (Compound 4e, Figure 1)

Method C. Using 1- (2-nitro-4-trifluoromethylphenyl) pyrrole 2e (2.92 g; 11.4 mmol), heating at reflux for 4.5 hours, purifying and eluting with hexane / AcOEt (4: 1) .

Solid orange. Rt .: 1.33 g; 52% Mp: 93-95 ° C (Lit. 92-94 ° C). ¹ H-NMR (300 MHz, CD ₃ OD): 57.23 (d, 1H, J = 8.2 Hz); 7.16 (d, 1H, J = 1.4 Hz); 6.98 (1H, dd, J = 8.2 Hz, J = 1.4 Hz); 6.90 (t, 2H, J = 2.0 Hz); 6.35 (t, 2H, J = 2.0 Hz) ppm. ¹³ C-NMR (50 MHz, CDCI3): δ 141.6; 129.4 (c, ² J _CF = 32.2 Hz); 129.3; 126.8; 123.3 (c, ¹ JCF = 272.4 Hz); 120.8 (2C); 114.9 (c, ³ J _CF = 3.8 Hz); 112.6 (c, ³ J _CF = 3.8 Hz); 110.0 (2C) ppm. HRMS (ESI ⁺ ) m / e: calculated for C11H9N2F3 [M + H] ⁺ : 227.0791; Found: 227.0796.

Example 13. Preparation of 4-chloro-2- (pyrrol-1-yl) aniline (Compound 4f, Figure 1)

Method C. Using 1- (5-chloro-2-nitrophenyl) pyrrole 2f (4.82 g; 21.7 mmol), heating the reaction mixture at reflux for 30 minutes, purification and eluting with hexane / AcOEt (4: one).

Solid orange. Rto .: 2.81 g; 67% Mp: 88-89 ° C {Lit. 87 ° C). ¹ H-NMR (300 MHz, CD3OD): δ 7.13 (dd, 1 H, J = 8.5 Hz, J = 2.3 Hz); 7.09 (d, 1 H, J = 2.3 Hz); 8.70 (d, 1 H, J = 8.5 Hz); 6.85 (t, 2H, J = 2.0 Hz); 6.32 (t, 2H, J = 2.0 Hz) ppm. ¹³ C-NMR (50 MHz, CDCI3): δ 140.6; 128.3; 127.9; 126.9; 122.5; 121.4 (2C); 116.8; 109.8 (2C) ppm. HRMS (ESI ⁺ ) m / e: calculated for Ci ₀ Hi ₀ N ₂ CI [M + H] ⁺ : 193.0533; Found: 193.0468.

Example 14. Preparation of 4,5-dichloro-2- (pyrrol-1-yl) aniline (Compound 4g, Figure 1)

Method C. Using 1 - (4,5-dichloro-2-nitrophenyl) pyrrole 2g (2.78 g; 10.8 mmol), heating at reflux for 30 minutes, purifying and eluting with a hexane / AcOEt mixture (1: 4).

Solid orange. Rto. 1.80 g; 74% Mp: 57-58 ° C {Lit. 58 ° C). ¹ H-NMR (300 MHz, CDCI ₃ ): 7.21 (s, 1 H); 6.87 (s, 1 H); 6.76 (t, 2H, J = 2.0 Hz); 6.32 (t, 2H, J = 2.0 Hz); 3.88 (Sancho, 2H) ppm. ¹³ C-NMR (75 MHz, CDCI _3): δ 141, 5; 131, 9; 128.3; 126.6; 121, 4 (2C); 120.5; 1 16.8; 1 10.1 (2C) ppm. HRMS (ESI ⁺ ) m / e: calculated for Ci ₀ H ₉ N ₂ CI ₂ [M + H] ⁺ : 227.0143; Found: 227.0133.

Synthesis of 2- (pyrrol-1-yl) acetanilides

A solution of the corresponding 2-pyrrole-1-alaniline (1 eq.) In a 1: 1 mixture of acetic acid and acetic anhydride (4 mL / mmol) is heated at 120 ° C for the time indicated in each case. The reaction mixture is then allowed to cool and concentrated to dryness. The reaction crude is dissolved in the minimum amount of AcOEt and washed with NaCl (sat) (3 x 3.5 mL / mmol), dried with anhydrous MgSO ₄ and the solvent is removed under reduced pressure. The residue is purified by chromatography on silica gel eluting with the solvent mixture indicated in each case.

Example 15. Preparation of 2- (pyrrol-1-yl) acetanilide (Compound 5a, Figure 1)

From 2- (pyrrol-1-yl) aniline 4a (2.28 g; 14.4 mmol), heating the reaction mixture for 20 minutes, purifying and eluting with hexane / AcOEt (2: 1). Solid orange. Rto .: 2.69 g; 93% Mp: 76-78 ° C (Lit. 73.5-74.5 ° C). ¹ H-NMR (300 MHz, CDCI3): δ 8.34 (d, 1 H, J = 8, 1 Hz); 7.36 (td, 1 H, J = 8, 1 Hz, J = 7.2 Hz, J = 1, 7 Hz); 7.25 (dd, 1 H, J = 7.6 Hz, J = 1, 7 Hz); 7, 13 (t _ap , 1 H, J = 7.6 Hz, J = 7.2 Hz); 6.96 (Sancho, 1 H); 6.77 (t, 2H, J = 2, 1 Hz); 6.38 (t, 2H, J = 2, 1 Hz); 2.03 (s, 3H) ppm. NMR C (75 MHz, CDCI ₃ ): δ 168.3; 133.6; 130.5; 128.7; 126.7; 124.1; 121.9 (2C); 121.4; 110.4 (2C); 24.7 ppm

Example 16. Preparation of N- [5-methyl-2- (pyrrol-1-yl)] acetanilide (Compound 5b, Figure 1)

From 5-methyl-2- (pyrrol-1-yl) aniline 4b (2.53 g; 14.7 mmol), heating for 30 minutes, purifying and eluting with hexane / AcOEt (2: 1).

Solid yellow. Rto: 2.43 g, 77%. Mp: 114-116 ° C. ¹ H-NMR (300 MHz, CDCI ₃ ): 58.16 (s, 1 H); 7.13 (d, 1H, J = 7.9 Hz); 6.94 (d, 1H, J = 7.9 Hz); 6.87 (Sancho, 1H); 6.74 (t, 2H, J = 2.0 Hz); 6.36 (t, 2H, J = 2.0 Hz); 2.38 (s, 3 H); 2.01 (s, 3H) ppm. ¹³ C-NMR (75 MHz, CDCI ₃ ): 5168.3; 138.9; 133.2; 128.1; 126.4; 124.8; 122.1 (2C); 121.9; 110.2 (2C); 24.7; 21.5 ppm IR (KBr): v _max 3312.7; 3138.0; 3104.6; 1663.7; 1589.1; 1533.3; 1496.5; 1416.5; 1328.8; 1289.9; 1252.3; 1102.9; 1074.9; 1066.2; 1012.8; 965.7; 950.7; 914.1; 879.2; 821.5; 731.6; 662.6; 630.7; 618.6; 588.9; 554.9 cm ^"1. HRMS (ESI ⁺ ) m / e: calculated for Ci ₃ H ₁₅ N ₂ 0 [M + H] ⁺ : 215.1184; found: 215.1190.

Example 17. Preparation of 4,5-dimethyl-2- (pyrrol-1-yl) acetanilide (Compound 5c, Figure 1)

From 4,5-dimethyl-2- (pyrrol-1-yl) aniline 4c (2.37 g; 12.7 mmol), heating for 15 minutes, purifying and eluting with a hexane / AcOEt mixture (4: 1 ). Yellow oil Rto: 2.65 g, 91%. Mp: 138-139 ° C. ¹ H-NMR (300 MHz, CDCI ₃ ): 5 8.05 (s, 1 H); 7.02 (s, 1 H); 6.84 (Sancho, 1 H); 6.74 (t, 2H, J = 2.0 Hz); 6.34 (t, 2H, J = 2.0 Hz); 2.28 (s, 3 H); 2.22 (s, 3 H); 2.00 (s, 3H) ppm. ¹³ C-NMR (75 MHz, CDCI ₃ ): 5168.3; 137.2; 132.9; 130.8; 128.5; 127.5; 122.8; 122.0 (2C); 110.1 (2C); 24.6; 19.7; 19.1 ppm IR (KBr): v _max 3251.4; 2917.1; 1667.0; 1592.4; 1530.2; 1451.4; 1407.9; 1368.1; 1338.5; 1320.0; 1290.5; 1266.0; 1090.0; 1070.1; 1021.9; 918.4; 870.2; 732.3; 629.7; 592.7 cm ^"1. HRMS (ESI ⁺ ) m / e: calculated for Ci ₄ Hi ₆ N ₂ 0 [M + H] ⁺ : 229.1335; found: 229.1411.

Example 18. Preparation 5-methoxy-2- (pyrrol-1-yl) acetanilide (Compound 5d, Figure 1) From 5-methoxy-2- (pyrrol-1-yl) aniline 4d (2.07 g; 1.0 mmol), heating for 10 minutes and eluting with a CH2CI2 / Acetone (9: 1) mixture.

Solid yellow. Challenge: 1.76 g; 70% Mp: 72-74 ° C (Lit. 73 ° C). ¹ H-NMR (300 MHz, CDCI3): δ 8.04 (d, 1 H, J = 2.0 Hz); 7.15 (d, 1 H, J = 8.6 Hz); 6.89 (Sancho, 1 H); 6.71 (t, 2H, J = 2.1 Hz); 6.65 (dd, 1 H, J = 8.6 Hz, J = 2.6 Hz); 6.36 (t, 2H, J = 2.1 Hz); 3.83 (s, 3 H); 2.00 (s, 3H) ppm. ¹³ C-NMR (75 MHz, CDCI ₃ ): δ 168.4; 159.6; 134.9; 127.5; 123.2; 122.3 (2C); 1 10.2 (2C); 109.8; 105.8; 55.6; 24.8 ppm HRMS (ESI ⁺ ) m / e: calculated for C13H1 ₅ N2O2 [M + H] ⁺ : 231, 1 128; Found: 231, 1 138.

Example 19. Preparation of 5-trifluoromethyl- (2-pyrrol-1-yl) acetanilide (Compound 5e, Figure 1)

From 5-trifluoromethyl-2- (pyrrol-1-yl) aniline 4e (1.19 g; 5.2 mmol), maintaining heating for 25 minutes, purifying and eluting with hexane / AcOEt (4: 1). Solid yellow. Rto .: 1, 08 g; 76% Mp: 1 15-1 17 ° C. ¹ H-NMR (300 MHz, CDCI3): δ 8.74 (s, 1 H); 7.38 (m, 2H); 7.12 (Sancho, 1 H); 6.79 (t, 2H, J = 2.0 Hz); 6.42 (t, 2H, J = 2.0 Hz); 2.06 (s, 3H) ppm. ¹³ C-NMR (75 MHz, CDCI ₃ ): δ 168.4; 133.9; 130.6 (c, ² J _CF = 32.8 Hz); 127.3 (c, ¹ J _CF = 272.5 Hz); 127.4; 127.0; 121.6 (2C); 120.9 (c, ³ J _CF = 3.7 Hz); 1 18.6 (c, ³ J _CF = 3.2 Hz); 1 1 1, 2 (2C); 24.7 ppm IR (KBr): v _max 3351, 9; 3139.0; 1639.9; 1619.8; 1590.6; 1533.2; 1481, 2; 1434.5; 1344.7; 1274.9; 1251, 6; 1225.4; 1,162.8; 1 1 16.8; 1059.9; 1010.8; 956.9; 924.2; 888.9; 835.2; 747.7; 651, 1; 618.7; 544.3 cm ^"1. HRMS (ESI ⁺ ) m / e: calculated for Ci3H ₁₂ F ₃ N ₂ 0 [M + H] ⁺ : 269.0896; found: 269.0924.

Example 20. Preparation of 4-chloro-2- (pyrrol-1-yl) acetanilide (Compound 5f, Figure 1)

From 4-chloro-2- (pyrrol-1-yl) aniline 4f (2.64 g; 13.7 mmol), maintaining heating for 20 minutes, purifying and eluting with a hexane / AcOEt mixture (4: 1) .

Solid yellow. Rto .: 2.66 g; 83% Mp: 127-129 ° C. ¹ H-NMR (200 MHz, CDCI3): δ 8.32 (d, 1 H, J = 8.5 Hz); 7.41 (dd, 1 H, J = 8.5 Hz, J = 2.1 Hz); 7.25 (d, 1 H, J = 2.1 Hz,); 6.96 _(br s cho, 1 H); 6.76 (t, 2H, J = 1, 7 Hz); 6.39 (t, 2H, J = 1.9 Hz); 2.03 (s, 3H) ppm. ¹³ C-NMR (75 MHz, CDCI ₃ ): δ 168.3; 132.2; 131, 3; 128.9; 128.6; 126.7; 122.5; 121.7 (2C); 1 10.9 (2C); 24.7 ppm IR (KBr): v _max 3244.2; 1664.1; 1602.8; 1496.5; 1415.3; 1372.0; 1299.7; 1252.3; 1 1 1 1, 2; 1097, 1; 1069, 1; 1013.8; 937.8; 865.9; 842.7; 813.3; 759.6; 739.3; 633.9; 598, 1; 580.3; 506.2 cm ^"1. HRMS (ESI ⁺ ) m / e: calculated for C12H12CIN2O [M + H] ⁺ : 235.0633; found: 235.0634.

Example 21. Preparation of 4,5-dichloro- (2-pyrrol-1-yl) acetanilide (Compound 5g, Figure 1)

From 4,5-dichloro-2- (pyrrol-1-yl) aniline 4g (2.82 g; 12.4 mmol), heating the reaction mixture for 10 minutes, purifying and eluting with hexane / AcOEt (2 :one ).

Solid yellow. Rto .: 2.69 g; 81% Mp: 143-144 ° C. ¹ H-NMR (300 MHz, CDCI ₃ ): δ 8.60 (s, 1 H); 7.35 (s, 1 H); 6.95 (Sancho, 1 H); 6.74 (t, 2H, J = 2.0 Hz); 6.40 (t, 2H, J = 2.0 Hz); 2.03 (s, 3H) ppm. ¹³ C-NMR (75 MHz, CDCI ₃ ): δ 168.2; 132.9; 132.6; 129.4; 128.0; 127.0; 122.4; 121.7 (2C); 1 1 1, 3 (2C); 24.7 ppm IR (KBr): v _max 3355.6; 3131, 8; 3029.2; 1691, 6; 1573.5; 1481, 2; 1385.9; 1328.8; 1306.9; 1279.0; 1238.7; 1,142.3; 1 1 14.8; 1066.6; 1023.5; 961, 7; 942.3; 902.3; 864.8; 748.2; 682.5; 648.6; 613.8; 554.5; 536.7 cm ^"1. HRMS (ESI ⁺ ) m / e: calculated for Ci ₂ Hn CI ₂ N ₂ 0 [M + H] ⁺ : 269.0243; found: 269.0259.

Synthesis of pyrrolo [1,2-a] quinoxalines

A mixture of the corresponding 2- (pyrrol-1-yl) acetanilide (1 eq.) And POCI3 (5 mL / mmol) is heated at reflux for the time indicated in each case. At the end of that time, the reaction mixture is cooled and concentrated to dryness. The obtained residue is poured onto a water / ice mixture (20 mL / mmol) and basified with a solution of NaHCÜ3 (5%) until pH = 7-8. It is extracted with CH ₂ CI ₂ (3 x 30 mL), the organic phases are dried with anhydrous MgSO ₄ , filtered and the solvent is removed to dryness. The residue obtained is purified by chromatography on silica gel eluting with a mixture CH ₂ CI ₂ / acetone (9: 1).

Example 22. Preparation of 4-methylpyrrolo [1,2-a] quinoxaline (Compound 6a, Figure 1)

From 2- (pyrrol-1-yl) acetanilide 5a (2.18 g; 10.9 mmol), maintaining heating for 1 hour and 15 minutes. Solid brown. Rto .: 1.77 g; 89% Mp: 138-140 ° C (Lit. 135.5-138 ° C). ¹ H-NMR (200 MHz, CDCI ₃ ): δ 7.89 (m, 2H); 7.82 (dd, 1H, J = 7.4 Hz, J = 2.3 Hz); 7.43 (m, 2H); 6.88 (dd, 1H, J = 4.2 Hz, J = 1.3 Hz); 6.83 (t, 1H, J = 3.2 Hz); 2.72 (s, 3H) ppm. IR (KBr): v _max 3439; 3099; 1611; 1529; 1481; 1416; 1380; 1361; 1323; 1258; 1212; 1042; 947; 859; 760; 732; 690; 650; 609; 534; 470 cm ^"1 .

Example 23. Preparation of 4,7-dimethylpyrrolo [1,2-a] quinoxaline (Compound 6b, Figure 1)

From 5-methyl-2- (pyrrol-1-yl) acetanilide 5b (0.65 g; 3.05 mmol), maintaining heating for 50 minutes.

Solid yellow. Rto .: 0.46 g; 77% Mp: 273 ° C. ¹ H-NMR (300 MHz, CDCI3): δ 8.38 (s, 1H); 8.21 (dd, 1H, J = 2.6 Hz, J = 1.6 Hz); 7.83 (d, 1H, J = 8.2 Hz); 7.47 (m, 2H); 7.13 (dd, 1H, J = 4.6 Hz, J = 2.6 Hz); 3.16 (s, 3 H); 2.52 (s, 3H) ppm. ¹³ C-NMR (75 MHz, CDCI3): δ 152.5; 136.7; 129.7; 125.6; 124.9; 124.4; 117.9; 115.6; 113.8; 113.8; 111.7; 21.1; 19.5 ppm IR (KBr): v _max 3423; 3095; 2624; 1885; 1624; 1598; 1550; 1507; 1405; 1377; 1285; 1260; 1111; 1046; 823; 753; 679; 601; 530 cm ^"1. HRMS (ESI ⁺ ) m / e: calculated for Ci ₃ H ₁₃ N ₂ [M + H] ⁺ : 197,1079; found: 197,1074.

Example 24. Preparation of 4,7,8-trimethylpyrrolo [1,2-a] quinoxaline (Compound 6c, Figure 1)

From 4,5-dimethyl-2- (pyrrol-1-yl) acetanilide 5c (2.89 g; 12.8 mmol), heating the reaction mixture for 1 hour.

Solid yellow. Rt .: 2.43 g; 91% Mp: 137-139 ° C. ¹ H-NMR (300 MHz, CDCI3): δ 7.77 (dd, 1 H, J = 2.6 Hz, J = 1, 2 Hz); 7.62 (s, 1 H); 7.51 (s, 1 H); 6.78 (m, 2H); 2.67 (s, 3 H); 2.38 (s, 3 H); 2.34 (s, 3 H) ppm. ¹³ C-NMR (75 MHz, CDCI ₃ ): δ 152.3; 136.1; 134.0; 133.7; 129.3; 126.1; 125.1; 113.9; 113.5; 112.9; 105.7; 21.9; 20.1; 19.6 ppm IR (KBr): v _max 3434.9; 3116.5; 2918.9; 1624.7; 1522.9; 1490.0; 1412.2; 1351.1; 1313.1; 1243.7; 1085.6; 1024.1; 887.8; 852.7; 747.9; 717.5; 603.4 cm ^"1. HRMS (ESI ⁺ ) m / e: calculated for Ci ₄ H ₁₅ N ₂ [M + H]: 211.1230; found: 211,1200. Example 25. Preparation of 7-methoxy-4-methylpyrrolo [1,2-a] quinoxaline (Compound 6d, Figure 1)

From 5-methoxy-2- (pyrrol-1-yl) acetanilide 5d (1.61 g; 7.0 mmol), heating for 35 minutes.

Solid brown. Rt .: 1.38 g; 93% Mp: 49-50 ° C {Lit. 50 ° C). ¹ H-NMR (300 MHz, CDCI ₃ ): δ 7.81 (dd, 1H, J = 2.3 Hz, J = 1.3 Hz); 7.71 (d, 1H, J = 8.9 Hz); 7.37 (d, 1 H, J = 2.6 Hz); 7.06 (dd, 1 H, J = 8.9 Hz, J = 2.6 Hz); 6.85 (dd, 1 H, J = 3.9 Hz, J = 1.3 Hz); 6.79 (dd, 1 H, J = 3.9 Hz, J = 2.6 Hz); 3.88 (s, 3 H); 2.71 (s, 3H) ppm. ¹³ C-NMR (75 MHz, CDCI ₃ ): δ 157.0; 153.9; 136.8; 125.9; 121.5; 115.9; 114.5; 113.9; 113.2; 110.5; 106.3; 55.6; 21.9 ppm IR (KBr): v _max 3085.5; 1616.1; 1593.5; 1523.6; 1490.7; 1350.0; 1299.8; 1258.9; 1245.9; 1198.3; 1160.8; 1048.5; 1029.8; 931.7; 876.9; 846.8; 770.5; 717.1; 621.2 cm ^"1. HRMS [ESI-TOF]: calculated for C13H13N2O [M + H] ⁺ : 213.1028; found: 213.1023.

Example 26. Preparation of 7-trifluoromethyl-4-methylpyrrolo [1,2-a] quinoxaline (Compound 6e, Figure 1)

From 5-trifluoromethyl-2- (pyrrol-1-yl) acetanilide 5e (0.96 g; 3.59 mmol), maintaining heating for 40 minutes.

Solid brown. Rt .: 0.88 g; 98% Mp: 128-130 ° C. ¹ H-NMR (300 MHz, CDCI3): δ 8.17 (s, 1H); 7.92 (d, 1H, J = 2.6 Hz); 7.88 (d, 1H, J = 8.6 Hz); 7.67 (d, 1H, J = 8.6 Hz); 6.94 (d, 1H, J = 3.6 Hz); 6.89 (t, 1H, J = 3.2 Hz); 2.73 (s, 3H) ppm. ¹³ C-NMR (75 MHz, CDCI3): δ 155.0; 135.3; 129.1; 127.0 (c, ² J _CF = 32.8 Hz); 126.5 (c, ³ J _CF = 3.7 Hz); 126.1; 123.9 (c, ¹ J _CF = 271.7 Hz); 123.1 (c, ³ J _CF = 3.7 Hz); 114.8; 114.4; 114.1; 107.5; 21.8 ppm IR (KBr): v _max 3104.4; 1628.4; 1530.4; 1503.7; 1458.6; 1419.8; 1333.8; 1299.1; 1208.5; 1164.0; 1141.8; 1107.6; 1089.5; 1032.8; 899.4; 828.4; 766.2; 737.2; 695.8; 652.7; 606.3; 525.9 cm ^"1. HRMS (ESI ⁺ ) m / e: calculated for C13H9F3N2 [M + H] ⁺ : 251.0791; found: 251.0752.

Example 27. Preparation of 8-chloro-4-methylpyrrolo [1,2-a] quinoxaline (Compound 6f, Figure 1)

From 4-chloro- (2-pyrrol-1-yl) acetanilide 5f (2.52 g; 10.7 mmol), heating the reaction mixture for 40 minutes. Solid yellow. Rto .: 2.03 g; 87% Mp: 143-144 ° C. ¹ H-NMR (300 MHz, CDCI ₃ ): δ 7.79 (m, 3H); 7.34 (dd, 1 H, J = 8.6 Hz, J = 2.3 Hz); 6.88 (dd, 1 H, J = 3.9 Hz, J = 1.3 Hz); 6.84 (c, 1 H, J = 2.8 Hz); 2.69 (s, 3 H) ppm. ¹³ C-NMR (75 MHz, CDCI ₃ ): δ 153.8; 134.4; 132.2; 130.3; 127.8; 126, 1; 125.4; 1 14.4; 1 14.0; 1 13.8; 107.0; 21.9 ppm. IR (KBr): v _max 3098.8; 1609.7; 1529.8; 1476.4; 1458.4; 1417.9; 1380.9; 1350.9; 1312.4; 1253.3; 1210.3; 1 129.5; 1 1 18.5; 1085, 1; 1036.3; 862.5; 845.6; 814.0; 793.2; 740.1; 676.8; 613.7; 570.4; 514.3; 463.5 cm ^"1. HRMS (ESI ⁺ ) m / e: calculated for Ci ₂ H ₉ CIN ₂ [M + H] ⁺ : 217.0527; found: 217.0551.

Example 28. Preparation of 7,8-dichloro-4-methylpyrrolo [1,2-a] quinoxaline (Compound 6g, Figure 1)

From 4,5-dichloro- (2-pyrrol-1-yl) acetanilide 5g (2.69 g; 10.0 mmol), heating the reaction mixture for 45 minutes.

Solid brown. Rto .: 2.49 g; 99% Mp: 197-199 ° C. ¹ H-NMR (500 MHz, CDCI ₃ ): δ 7.93 (s, 1 H); 7.81 (s, 1 H); 7.75 (dd, 1 H, J = 2.7 Hz, J = 1.3 Hz); 6.90 (dd, 1 H, J = 4.0 Hz, J = 1.3 Hz); 6.84 (dd, 1 H, J = 4.0 Hz, J = 2.7 Hz); 2.68 (s, 3 H) ppm. ¹³ C-NMR (75 MHz, CDCI ₃ ): δ 154.9; 134.7; 130.5; 129.8; 128.7; 126.2; 125.8; 1 15.2; 1 15, 1; 1 14.5; 108.1; 21.7 ppm. IR (KBr): v _max 3448.4; 3093.2; 2925.4; 2361, 7; 1718.3; 1606.3; 1478.0; 1409.2; 1298.0; 1216.5; 1 130.4; 1047.8; 879.4; 851, 8; 745, 1; 638.7; 603.7; 547.8 cm ^"1. HRMS (ESI ⁺ ) m / e: calculated for Ci ₂ H ₉ CI ₂ N ₂ [M + H] ⁺ : 251, 0137; found: 251, 0158.

Pyrrolo bromination [1,2-a] quinoxalines

To a solution of the corresponding pyrrolo [1,2-a] quinoxaline (1 eq.) Dissolved in DMF (7.2 mL / mmol) cooled to -10 ° C, a solution of NBS (1 eq. ) dissolved in DMF (5.6 mL / mmol) at an addition rate of 0.17 mL / min. Once the addition is complete, the reaction mixture is allowed to reach room temperature and a saturated NaCl solution (15 mL / mmol) is added. It is extracted with CH ₂ CI ₂ (5 x 15 mL / mmol) and the organic phases are dried with anhydrous MgSO ₄ , filtered and concentrated to dryness. The reaction crude obtained is purified by chromatography on silica gel eluting with a hexane / AcOEt mixture (9: 1). Example 29. Preparation of 1-bromine-4,7,8-trimethylpyrrolo [1,2-a] quinoxaline (Compound 7hi, Figure 2)

From 4,7,8-trimethylpyrrolo [1,2-a] quinoxaline 6c (0.40 g; 1.94 mmol).

Solid cream. Rto .: 0.29 g; 52% Mp: 139-140 ° C. ¹ H-NMR (200 MHz, CDCI ₃ ): δ 8.98 (s, 1 H); 7.63 (s, 1 H); 6.79 (c _ap , 2H, J = 3.8 Hz); 2.64 (s, 3 H); 2.40 (s, 3 H); 2.35 (s, 3H) ppm. ¹³ C-NMR (75 MHz, CDCI ₃ ): δ 152.3; 136.6; 134.4; 133.6; 129.3; 125.0; 122.7; 1 16.8; 1 13.4; 1 13.3; 93.8; 24.3; 20.2; 19.5 ppm IR (KBr): v _max 3435.4; 2970.1; 2914.9; 1681, 8; 1624.7; 1578.9; 1530.5; 1477.7; 1410.6; 1379.9; 1352.2; 1218.1; 1 153.7; 1041, 6; 91 1, 9; 882.8; 857.2; 764.4; 734.9; 684.0; 674.3 cm ^"1. HRMS [ESI-TOF]: calculated for Ci ₄ H ₁₄ N ₂ Br [M + H] ⁺ : 289.0340; found: 289.0338.

Example 30. Preparation of 1-bromo-8-chloro-4-methylpyrrolo [1,2-a] quinoxaline (Compound 7¡i, Figure 2)

From 8-chloro-4-methylpyrrolo [1,2-a] quinoxaline 6f (0.51 g; 2.37 mmol).

Solid yellow. Rto .: 0.47 g; 69% Mp: 193-194 ° C. ¹ H-NMR (500 MHz, CDCI ₃ ): δ 9.22 (d, 1 H, J = 2.2 Hz); 7.79 (d, 1 H, J = 8.6 Hz); 7.40 (dd, 1 H, J = 8.6 Hz, J = 2.0 Hz); 6.87 (d, 1 H, J = 4.2 Hz); 6.83 (d, 1 H, J = 4.2 Hz); 2.65 (s, 3 H) ppm. ¹³ C-NMR (75 MHz, CDCI ₃ ): δ 152.9; 135.5; 131, 1; 130.3; 128.9; 127.9; 125.9; 1 19.0; 1 15.2; 107.6; 99.4; 21.5 ppm. IR (KBr): v _max 3127.5; 2919.2; 1606.8; 1532.1; 1467.6; 1417.6; 1375.2; 1095.0; 1048.8; 848.6; 819.4; 763.4; 754.7; 677.8; 576.9; 459.8 cm ^"1. HRMS (ESI ⁺ ) m / e: calculated for Ci ₂ H ₉ BrCIN ₂ [M + H] ⁺ : 294.9632; found: 294.9648.

Example 31. Preparation of 3-bromo-4,7,8-trimethylpyrrolo [1,2-a] quinoxaline (Compound 7ji, Figure 2)

From 4,7,8-trimethylpyrrolo [1,2-a] quinoxaline 6c (0.40 g; 1.94 mmol).

Solid yellow. Rt .: 0.21 g; 39% Mp: 190-192 ° C. ¹ H-NMR (200 MHz, CDCI3): δ 7.70 (d, 1 H, J = 2.5 Hz); 7.57 (s, 1 H); 7.45 (s, 1 H); 6.78 (d, 1 H, J = 2.5 Hz); 2.93 (s, 3 H); 2.37 (s, 3 H); 2.33 (s, 3H) ppm. ¹³ C-NMR (75 MHz, CDCI3): δ 151.6; 135.1; 134.4; 129.4; 128.0; 126.5; 1 18.2; 1 15.6; 1 15.5; 106.7; 98.4; 21, 5; 20.5; 19.4 ppm IR (KBr): v _max 3434.3; 3107.6; 2966.2; 2917.7; 1708.5; 1621, 4; 1575.7; 1512.1; 1485.5; 1408.4; 1375.7; 1342.0; 1218.1; 1 137.3; 1098.2; 1006.9; 975.2; 916.7; 882.3; 853.2; 758.5; 735.5; 691, 1; 673.3; 605 cm ^"1. HRMS [ESI-TOF]: calculated for Ci ₄ Hi ₄ N ₂ Br [M + H] ⁺ : 289.0340; found: 289.0345.

Example 32. Preparation of 1,2-dibromo-4,7,8-trimethylpyrrolo [1,2- a] quinoxaline (Compound 7ki, Figure 2)

From 4,7,8-trimethylpyrrolo [1,2-a] quinoxaline 6c (0.40 g; 1.94 mmol).

Solid brown. Rto .: 0.10 g; 8% Mp: 177-178 ° C. ¹ H-NMR (300 MHz, CDCI ₃ ): δ 8.93 (s, 1 H); 7.62 (s, 1 H); 6.84 (s, 1 H); 2.93 (s, 3 H); 2.39 (s, 3 H); 2.34 (s, 3 H) ppm. ¹³ C-NMR (75 MHz, CDCI ₃ ): δ 151.6; 135.6; 135.1; 129.3; 126.5; 125.1; 121.8; 1 17.6; 1 15.8; 1 15.5 (2C); 24.6; 20.5; 19.4 ppm IR (KBr): v _max 3434.2; 3120.9; 2914.5; 1574.4; 1486.1; 1475.2; 1435.8; 1402.9; 1341, 3; 1 192.2; 1,159.8; 1013.2; 881, 3; 854.7; 801, 7; 675.7; 564.1 cm ^"1. HRMS [ESI-TOF]: calculated for Ci ₄ Hi ₃ BrN ₂ [M + H] ⁺ : 368.9420; found: 368.9429.

Example 33. Preparation of 2-bromo-8-chloro-4-methylpyrrolo [1,2-a] quinoxaline (Compound 7li, Figure 2)

From 8-chloro-4-methylpyrrolo [1,2-a] quinoxaline 6f (0.51 g; 2.37 mmol).

Solid yellow. Rto .: 84.5 mg; 12% Mp: 180-182 ° C. ¹ H-NMR (300 MHz, CDCI ₃ ): δ 7.74 (d, 1 H, J = 8.6 Hz); 7.70 (m, 2 H); 7.33 (dd, 1 H, J = 8.6 Hz, J = 2.3 Hz); 6.85 (d, 1 H, J = 2.9 Hz); 2.94 (s, 3H) ppm. ¹³ C-NMR (75 MHz, CDCI ₃ ): δ 153.7; 132.6; 130.4; 130.3; 126.4; 125.9; 122.5; 1 17.8; 1 14.1; 1 13.2; 95.3; 24.4 ppm IR (KBr): vmax 3436.0; 3099.2; 2359.3; 1604.1; 1482.5; 1409.5; 1343.9; 1 1 1 1, 8; 1086.9; 1009.6; 986.8; 855.9; 819.1; 760.7; 729.2; 686.0; 568.2 cm ^"1. HRMS (ESI ⁺ ) m / e: calculated for Ci ₂ H ₉ BrCIN ₂ [M + H] ⁺ : 294.9632; found: 294.9625.

Synthesis of N-aminopyrrolo [1,2-a] quinoxalinium mesitylenesulfonates

To a solution of the corresponding pyrrolo derivative [1,2-a] quinoxaline (1 eq.) Dissolved in the indicated volume of CH ₂ CI ₂ cooled to 0 ° C is added, dropwise, a solution of MSH (1 , 5 eq.) In the indicated volume of CH ₂ CI ₂ . Once the addition is complete, the reaction mixture is kept under stirring at room temperature for 2 hours, diethyl ether is added and kept stirring for 30 minutes. The precipitate formed is filtered and purified by recrystallization in an EtOH / AcOEt mixture. Example 34. Preparation of 5-amino-1-bromo-4,7,8-trimethylpyrrolo [1,2-a] quinoxal-5-inium mesitylenesulfonate (Compound 8h _; Figure 2)

From 1-bromo-4,7,8-trimethylpyrrolo [1,2-a] quinoxaline 7rH (0.25 g; 0.86 mmol) dissolved in CH ₂ CI ₂ (4 mL) and MSH (0.39 g, 1.29 mmol) dissolved in CH ₂ CI ₂ (4 mL). Solid yellow. Rto .: 0.29 g; 69% Mp: 232-233 ° C. ¹ H-NMR (500 MHz, DMSO-d ₆ ): 59.11 (s, 1 H); 8.28 (s, 1 H); 8.04 (d, 1 H, J = 4.6 Hz); 7.46 (d, 1 H, J = 4.6 Hz); 6.92 (Sancho, 2H); 6.66 (s, 2H); 3.04 (s, 3 H); 2.48 (s, 3 H); 2.46 (s, 3 H); 2.43 (s, 6H); 2.13 (s, 3H) ppm. ¹³ C-NMR (75 MHz, DMSO-d ₆ ): δ 153.0; 142.1; 138.0; 136.3; 135.5; 135.2; 129.2 (2C); 126.8; 125.4; 125.2; 122.9; 119.6; 119.3; 115.6; 108.8; 101.5; 22.1 (2C); 19.7; 19.5; 19.0; 16.2 ppm IR (KBr): v _max 3257.9; 3135.1; 2916.0; 1601.7; 1545.5; 1483.1; 1421.8; 1379.9; 1216.6; 1178.7; 1082.9; 1014.7; 891.4; 845.3; 778.0; 676.9; 579.4; 547.4; 474.9 cm ^"1. HRMS (ESI ⁺ ) m / e: calculated for Ci ₄ H ₁₅ BrN ₃ [M] ⁺ : 304.0444; found: 304.0438.

Example 35. Preparation of 5-amino-1-bromo-8-chloro-4-methylpyrrolo [1,2-a] quinoxal-5-inium mesitylenesulfonate (Compound 8¡i, Figure 1)

From 1-bromo-8-chloro-4-methylpyrrolo [1,2-a] quinoxaline 7 (0.40 g; 1.36 mmol) dissolved in CH ₂ CI ₂ (40 mL) and MSH (0.63 g; 2.05 mmol) dissolved in CH ₂ CI ₂ (40 mL).

Solid brown. Rto .: 0.39 g; 56% Mp: 232-234 ° C. ¹ H-NMR (500 MHz, CD ₃ OD): δ 9.49 (d, 1 H, J = 2.2 Hz); 8.54 (d, 1 H, J = 9.2 Hz); 8.02 (d, 1 H, J = 4.8 Hz); 7.83 (dd, 1 H, J = 9.2 Hz, J = 2.2 Hz); 7.45 (d, 1 H, J = 4.8 Hz); 6.79 (s, 2H); 3.15 (s, 3 H); 2.53 (s, 6H); 2.24 (s, 3H) ppm. ¹³ C-NMR (75 MHz, DMSO-d ₆ ): 5154.8; 142.1; 135.6; 135.2 (2C); 132.3; 129.2 (2C); 128.0; 127.9; 126.9; 125.8; 123.6; 121.7; 120.5; 115.2; 110.8; 22.2 (2C); 19.8; 16.5 ppm IR (KBr): v _max 3330.7; 3121.5; 2926.6; 1604.1; 1550.4; 1480.5; 1423.1; 1403.4; 1190.1; 1131.8; 1086.5; 1018.6; 902.8; 843.9; 804.5; 678.3; 582.7; 547.9; 453.9 cm ^"1. HRMS (ESI ⁺ ) m / e: calculated for Ci ₂ Hi ₀ BrCIN ₃ [M] ⁺ : 311, 9719; found: 311, 9720.

Example 36. Preparation of 5-amino-4-methylpyrrolo [1,2- a] quinoxal-5-inium mesitylenesulfonate (Compound 10a, Figure 2) Using 4-methylpyrrolo [1,2-a] quinoxaline 6a (0.61 g; 3.34 mmol) dissolved in CH ₂ CI ₂ (13 ml_) and MSH (1.54 g; 5.02 mmol) dissolved in CH ₂ CI ₂ (13 ml_).

Solid yellow. Rto .: 1, 14 g; 86% Mp: 225-227 ° C (Lit. 224-226 ° C). ¹ H-NMR (500 MHz, DMSO-de): δ 9.04 (dd, 1 H, J = 2.6 Hz, J = 1, 2 Hz); 8.54 (d, 1 H, J = 8.4 Hz); 8.42 (d, 1 H, J = 8.4 Hz); 8.00 (d, 1 H, J = 4.4 Hz); 7.85 (t, 1 H, J = 7.8 Hz); 7.75 (t, 1 H, J = 7.8 Hz); 7.33 (m, 1 H); 6.92 (s _a ncho, 2H); 6.63 (s, 2H); 3.09 (s, 3 H); 2.42 (s, 6H); 2, 1 1 (s, 3H) ppm. ¹³ C-NMR (75 MHz, DMSO-d ₆ ): δ 155.4; 135.6; 135.2 (2C); 129.6; 129.2 (2C); 128, 1; 126.7; 125.9; 123.9; 123.3; 1 19.6; 1 19.2; 1 17.8; 1 15.6; 101.5; 22.2 (2C); 19.7; 16.8 ppm. HRMS (ESI ⁺ ) m / e: calculated for C12H12N3 [M] ⁺ : 198, 1031; Found: 198, 1 108.

Example 37. Preparation of 5-amino-4,7-dimethylpyrrolo [1,2-a] quinoxal-5-inium mesitylenesulfonate (Compound 10b, Figure 2)

From 4,7-dimethylpyrrolo [1,2-a] quinoxaline 6b (0.33 g; 1.71 mmol) dissolved in CH2CI2 (7 ml_) and MSH (0.78 g; 2.56 mmol) dissolved in CH ₂ CI ₂ (7 ml_).

Solid yellow. Rt .: 0.53 g; 77% Mp: 284-285 ° C. ¹ H-NMR (300 MHz, DMSO-d ₆ ): δ 8.99 (s, 1 H); 8.44 (d, 1 H, J = 8.6 Hz); 8.25 (s, 1 H); 7.97 (d, 1 H, J = 4.3 Hz); 7.70 (d, 1 H, J = 8.2 Hz); 7.31 (dd, 1 H, J = 4.6 Hz, J = 2.6 Hz); 6.86 (s, 2H); 6.69 (s, 2 H); 3.08 (s, 3 H); 2.54 (s, 3 H); 2.45 (s, 6H); 2.13 (s, 3H) ppm. ¹³ C-NMR (125 MHz, DMSO-de): 5 155, 1; 142.3; 136.8; 135.6; 135.3 (2C); 130.6; 129.3 (2C); 127.9; 123.9; 123.6; 123.2; 1 19.1; 1 18.9; 1 17.7; 1 15.6; 22.2 (2C); 20.5; 19.7; 16.8 ppm. IR (KBr): v _max 3237.6; 3104.6; 161 1, 5; 1546.8; 1485.8; 1460, 1; 1418.7; 1379.3; 1304.0; 1,171.7; 1082.6; 1014.2; 841, 0; 823.0; 763.4; 680.3; 579.0 cm ^"1. HRMS (ESI ⁺ ) m / e: calculated for C13H14N3 [M] ⁺ : 212, 1 182; found: 212, 1 178.

Example 38. Preparation of 5-amino-4,7,8-trimethylpyrrolo [1,2-a] quinoxal-5-inium mesitylenesulfonate (Compound 10c, Figure 2)

From 4,7,8-trimethylpyrrolo [1,2-a] quinoxaline 6c (0.78 g; 3.73 mmol) dissolved in CH2CI2 (10 ml_) and MSH (1.72 g; 5.60 mmol) dissolved in CH ₂ CI ₂ (10 ml_).

Solid yellow. Challenge: 1, 02 g; 65% Mp: 253-254 ° C. ¹ H-NMR (200 MHz, DMSO-d ₆ ): 8.36 (m, 1 H); 7.80 (s, 1 H); 7.62 (s, 1 H); 7.36 (d, 1 H, J = 4.2 Hz); 6.73 (t, 1 H, J = 3.2 Hz); 6.31 ( _{broad s0.2H} ); 6, 10 (s, 2H); 1, 91 (s, 3 H); 1, 87 (s, 12H); 1.59 (s, 3H) ppm. ¹³ C-NMR (75 MHz, DMSO-d ₆ ): 5 153.9; 142.2; 139.6; 135.9; 135.6; 135.3 (2 C); 129.2 (2C); 125.9; 123.9; 123.2; 123.0; 119.3; 118.4; 117.6; 115.8; 22.2 (2C); 19.7; 19.1; 19.0; 16.6 ppm. IR (KBr): v _max 3240.6; 3107.1; 2971.0; 1603.5; 1547.2; 1457.5; 1415.7; 1381.4; 1211.2; 1173.9; 1082.8; 1013.7; 883.6; 843.3; 758.3; 677.9; 579.8 cm ^"1. HRMS (ESI ⁺ ) m / e: calculated for Ci ₄ Hi ₆ N ₃ [M] ⁺ : 226, 1339; found: 226.1342.

Example 39. Preparation of 5-amino-4-methyl-7- methoxypyrrolo [1,2-a] quinoxal-5-inium mesitylenesulfonate (Compound 10d, Figure 2)

From 4-methyl-7-methoxypyrrolo [1,2-a] quinoxaline 6d (0.42 g; 2.01 mmol) dissolved in CH ₂ CI ₂ (8 mL) and MSH (0.92 g; 3, 01 mmol) dissolved in CH ₂ CI ₂ (8 mL). Solid yellow. Rto .: 0.68 g; 80% Mp: 285 ° C. ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 8.96 (d, 1 H, J = 1.3 Hz); 8.48 (d, 1 H, J = 9.2 Hz); 7.93 (dd, 1 H, J = 4.4 Hz, J = 1.3 Hz); 7.86 (d, 1H, J = 2.4 Hz); 7.47 (dd, 1H, J = 9.2 Hz, J = 2.4 Hz); 7.29 (dd, 1H, J = 4.4 Hz, J = 2.4 Hz); 6.85 (s, 2H); 6.63 (s, 2H); 3.95 (s, 3 H); 3.07 (s, 3 H); 2.42 (s, 6H); 2.11 (s, 3H) ppm. ¹³ C-NMR (75 MHz, DMSO-d ₆ ): δ 157.5; 155.3; 142.1; 135.6; 135.2 (2C); 129.4; 129.2 (2C); 123.5; 123.0; 120.0; 118.6; 117.7; 117.2; 117.1; 102.6; 55.7; 22.2 (2C); 19.8; 16.9 ppm. IR (KBr): v _max 3218.9; 3107.0; 1613.6; 1553.9; 1525.8; 1492.2; 1406.5; 1376.3; 1316.1; 1270.2; 1219.8; 1165.4; 1086.5; 1070.4; 1031.1; 1014.2; 851.6; 828.5; 779.3; 683.9; 582.7; 528.0 cm ^"1. HRMS (ESI ⁺ ) m / e: calculated for Ci ₃ Hi ₄ N ₃ 0 [M] ⁺ : 228.1131; found: 228.1148.

Example 40. Preparation of 5-amino-7-trifluoromethyl-4- methylpyrrolo [1,2-a] quinoxal-5-inium mesitylenesulfonate (Compound 10e, Figure 2)

From 7-trifluoromethyl-4-methylpyrrolo [1,2-a] quinoxaline 6e (0.28 g; 1.12 mmol) dissolved in CH ₂ CI ₂ (5 mL) and MSH (0.512 g; 1.68 mmol ) dissolved in CH ₂ CI ₂ (5 mL). Solid yellow. Rt .: 0.32 g; 62% Mp: 299 ° C. ¹ H-NMR (200 MHz, CD ₃ OD): 58.96 (m, 1H); 8.84 (s, 1 H); 8.62 (d, 1H, J = 8.5 Hz); 8.15 (d, 1H, J = 8.5 Hz); 8.06 (d, 1 H, J = 4.2 Hz); 7.40 (t, 1 H, J = 2.3 Hz); 6.81 (s, 2H); 3.23 (s, 3 H); 2.58 (s, 6H); 2.24 (s, 3H) ppm. ¹³ C-NMR (75 MHz, DMSO-d ₆ ): δ 157.5; 142.0; 135.8; 135.3 (2C); 129.3 (2C); 128.6; 126.7; 126.6 (c, ¹ J _CF = 269 Hz); 126.5 (c, ² J _CF = 32.8 Hz); 126.0; 125.4; 123.9; 122.3; 121.0 (c, ² J _CF = 32.8 Hz); 118.7; 117.4; 22.2 (2C); 19.8; 17.0 ppm. IR (KBr): v _max 3245.7; 3107.0; 1601.9; 1553.2; 1462.1; 1418.9; 1383.3; 1336.2; 1302.6; 1242.3; 1175.9; 1132.6; 1084.0; 1015.6; 912.3; 848.2; 831.9; 762.4; 681.2; 580.9 cm ^"1. HRMS (ESI ⁺ ) m / e: calculated for C13H11F3N3 [M] ⁺ : 266.0900; found: 266.0911.

Example 41. Preparation of 5-amino-8-chloro-4-methylpyrrolo [1,2-a] quinoxal-5-inium mesitylenesulfonate (Compound 10f, Figure 2)

From 8-chloro-4-methylpyrrolo [1,2-a] quinoxaline 6f (0.40 g; 1.88 mmol) dissolved in CH2CI2 (9 mL) and MSH (0.91 g; 2.96 mmol) dissolved in CH ₂ CI ₂ (9 mL).

Solid yellow. Rto .: 0.66 g; 81% Mp: 277-278 ° C. ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 9.07 (dd, 1 H, J = 2.7 Hz, J = 1, 1 Hz); 8.78 (d, 1 H, J = 2.2 Hz); 8.41 (d, 1 H, J = 8.9 Hz); 8.04 (dd, 1 H, J = 4.4 Hz, J = 1, 1 Hz); 7.83 (dd, 1 H, J = 9.2 Hz, J = 2.2 Hz); 7.36 (c, 1H, J = 2.7 Hz); 6.94 (s, 2H); 6.67 (s, 2H); 3.09 (s, 3 H); 2.13 (s, 6H); 2.07 (s, 3H) ppm. ¹³ C-NMR (75 MHz, DMSO-d ₆ ): 5155.7; 142.2; 135.6; 135.2 (2C); 134.0; 129.2 (2C); 127.1; 126.8; 126.6; 124.6; 123.6; 121.6; 119.8; 118.2; 115.6; 22.2 (2C); 19.7; 16.8 ppm. IR (KBr): v _max 3251.6; 3107.5; 1602.8; 1550.1; 1483.8; 1416.9; 1381.7; 1327.1; 1217.8; 1172.9; 1083.5; 1014.1; 879.8; 835.9; 818.1; 762.2; 681.0; 580.6; 547.8; 470.0 cm ^"1. HRMS (ESI ⁺ ) m / e: calculated for C12H11CIN3 [M] ⁺ : 232.0636; found: 232.0635.

Example 42. Preparation of 5-amino-7,8-dichloro-4-methylpyrrolo [1,2-a] quinoxal-5-inium mesitylenesulfonate (Compound 10g, Figure 2)

From 7,8-dichloro-4-methylpyrrolo [1,2-a] quinoxaline 6g (0.15 g; 0.57 mmol) dissolved in CH ₂ CI ₂ (8 mL) and MSH (0.26 g; 0.85 mmol) dissolved in CH ₂ CI ₂ (3 mL). Solid brown. Rt .: 0.21 g; 80% Mp: 282-284 ° C. ¹ H-NMR (500 MHz, CD ₃ OD): δ 8.91 (dd, 1 H, J = 2.6 Hz, J = 1, 2 Hz); 8.79 (s, 1 H); 8.70 (s, 1 H); 8.02 (dd, 1 H, J = 4.5 Hz, J = 1.2 Hz); 7.37 (dd, 1H, J = 4.5 Hz, J = 2.6 Hz); 6.87 (s, 2H); 2.63 (s, 9H); 2.26 (s, 3H) ppm. ¹³ C-NMR (50 MHz, DMSO-d ₆ ): δ 156.8; 135.5; 135.2 (2C); 131.9; 129.2 (2C); 128.8; 127.9; 125.5; 125.2; 123.7; 121.1; 120.5; 118.5; 117.7; 109.3; 22.2 (2C); 19.8; 16.9 ppm. IR (KBr): v _max 3411.6; 3128.7; 2970.9; 2841.8; 1694.7; 1594.3; 1537.9; 1466.6; 1434.1; 1362.9; 1307.2; 1250.2; 1165.9; 1076.5; 1038.8; 864.9; 809.4; 732.1; 611.0; 566.1 cm ^"1. HRMS (ESI ⁺ ) m / e: calculated for Ci2H ₁₀ CI ₂ N3 [M] ⁺ : 266.0246; found: 266.0241. Synthesis of pyridazino [2,3-a] pyrrolo [2,1-c] quinoxalin-9-inium salts

Method A: To a solution of the corresponding 5- aminopyrrolo [1,2-a] quinoxal-5-inium mesylenesulfonate (1 eq.) In ethanol (0.1 mL / mmol), is added

2.3-butanedione (1 eq.) Followed by triethylamine (1 eq.). The reaction mixture is stirred at room temperature for the time indicated in each case. The solvent is removed under reduced pressure and the residue obtained is triturated in diethyl ether, obtaining a precipitate that is finally filtered. The solid obtained is recrystallized from an EtOH / AcOEt mixture.

Method B: To a solution of the corresponding 5- aminopyrrolo mesylenesulfonate [1,2-a] quinoxal-5-inium (1 eq.) In ethanol (0.1 mL / mmol), is added

1,4-dioxan-2,3-diol (1, 1 eq.), Followed by triethylamine (1, 1 eq), and is heated to reflux for the time indicated in each case. Then, the reaction mixture is concentrated to dryness and triturated in diethyl ether, obtaining a precipitate that is filtered and recrystallized using an EtOH / AcOEt mixture.

Method C: To a solution of the corresponding 5- aminopyrrolo [1,2-a] quinoxal-5-inium mesylethenesulfonate (1 eq.) In acetone (0.1 mL / mmol), acenaphthoquinone (1.1 eq) is added .) and finally, NaOAc (1, 1 eq.). The reaction mixture is heated at reflux for 4 hours. After this time, the solvent is removed under reduced pressure and the residue obtained is triturated in diethyl ether, obtaining a precipitate that is filtered. The solid obtained is recrystallized from an EtOH / AcOEt mixture.

Method D: To a solution of the corresponding mesinylenesulfonate of 5- aminopyrrolo [1,2-a] quinoxal-5-inium (1 eq.) In methanol (0.42 mL / mmol), 3,4-hexanedione is added ( 1, 1 eq.), Followed by triethylamine (1, 1 eq.). The reaction mixture is stirred at room temperature for 3 hours and then concentrated to dryness. The reaction crude is triturated in diethyl ether, obtaining a precipitate that is filtered and recrystallized from a MeOH / diethyl ether mixture.

Method E: To a solution of the corresponding 5- aminopyrrolo [1,2-a] quinoxal-5-inium mesylenesulfonate (1 eq.) In methanol (29.8 mL / mmol), 3,4-hexanedione is added ( 2 eq.) Followed by triethylamine (1 eq.). The reaction mixture is stirred at room temperature for the time indicated in each case. After this time, the precipitate formed is filtered and triturated in MeOH. Example 43. Preparation of 7-bromo-2, 3,10,11-tetramethylpyridazino [2,3-a] pyrrolo [2,1-c] quinoxal-13-inium mesitylenesulfonate (Compound 9hi, Figure 2)

Method A. Using 5-amino-1-bromo-4,7,8-trimethylpyrrolo [1,2-a] quinoxal-5-inium 8hi mesylethenesulfonate (96.4 mg; 0.19 mmol) and maintaining stirring for 10 minutes

Greenish solid. Rto .: 96.1 mg; 90% Mp: 21 1 -213 ° C. ¹ H-NMR (300 MHz, CD ₃ OD): 5.30 (s, 1 H); 8.83 (s, 1 H) ;, 8.82 (s, 1 H); 8.02 (d, 1 H, J = 4.7 Hz); 7.30 (d, 1 H, J = 4.4 Hz); 6.81 (s, 2H); 2.86 (s, 3 H); 2.71 (s, 3 H); 2.59 (s, 3 H); 2.58 (s, 9H); 2.21 (s, 3H) ppm. ¹³ C-NMR (75 MHz, CD ₃ OD): δ 161.5; 147.4; 142.8; 139.9; 139.2; 138.1; 138.0; 131.6 (2C); 128.5 (2C); 128.1; 126.9; 124.0; 123.7; 121, 4; 1 18.3; 1 16.6; 108.3; 101, 4; 23.2 (2C); 20.8; 20.6; 20.5; 19.9; 19.4 ppm IR (KBr): v _max 3413.9; 3072.9; 2918.5; 2360.0; 2314.6; 1626.0; 1594.8; 1552.7; 1478.3; 1393.4; 1262.3; 1,187.6; 1083.4; 1013.0; 912.8; 884.5; 848.9; 802.1; 676 cm ^"1. HRMS [ESI-TOF]: calculated for Ci ₈ Hi ₇ BrN ₃ [M] ⁺ : 354.0600; found: 354.0603.

Example 44. Preparation of 7-bromo-10-chloro-2,3-diethylpyridazino [2,3-a] pyrrolo [2,1-c] quinoxal-13-inium bromide (Compound 9¡i, Figure 2)

Method E. From 5-amino-1-bromo-8-chloro-4-methylpyrrolo [1,2-a] quinoxal-5-inium 8¡i mesylenesulfonate (0.23 g; 0.45 mmol) and maintaining stirring for 3 hours, a yellow solid (0.14 g) is obtained which is suspended in CH ₂ CI ₂ (32 ml_), cooled to 0 ° C, HBr (40 μΙ_; 1, 12 mmol) is added and kept stirring at said temperature for 10 minutes. After that time, the reaction mixture is stirred at room temperature for 6.5 hours and then concentrated to dryness. The residue obtained is triturated using ethyl ether.

Solid yellow. Rt .: 0.17 g; 79% Mp: 200-202 ° C. ¹ H-NMR (300 MHz, CD ₃ OD): δ 9.61 (d, 1 H, J = 2.0 Hz); 9.1 1 (d, 1 H, J = 9.4 Hz); 8.82 (s, 1 H), 8.26 (d, 1 H, J = 4.7 Hz); 7.92 (dd, 1 H, J = 9.4 Hz, J = 2.0 Hz); 7.41 (d, 1 H, J = 4.7 Hz); 3.27 (c, 2H, J = 7.3 Hz); 3.09 (c, 2H, J = 7.3 Hz); 1.60 (t, 3H, J = 7.3 Hz); 1.53 (t, 3H, J = 7.3 Hz) ppm. ¹³ C-NMR (75 MHz, CD ₃ OD): 5 164.3; 153.0; 138.9; 137.9; 130.9; 129.2; 128.3; 126.7; 124.7; 124.3; 123.3; 1 18.0; 1 17.8; 109.5; 27.4; 26.0; 12.3; 10.9 ppm IR (KBr): v _max 3422.5; 3022.7; 2930.5; 2363.5; 1623.8; 1599.8; 1552.0; 1471, 8; 1397.3; 1373.0; 1253.4; 1 100.3; 1053.0; 975.8; 932, 1; 849.6; 840.5; 799.8; 780.4; 652.4 cm ^"1. HRMS [ESI-TOF]: calculated for Ci ₈ Hi ₆ BrCIN ₃ [M] ⁺ : 390.0189; found: 390.0185.

Example 45. Preparation of 7-bromo-10,11-dimethylpyridazino [2,3-a] pyrrolo [2,1-c] quinoxal-13-inium mesitylenesulfonate (Compound 9ji, Figure 2)

Method B. Using 5-amino-1-bromo-4,7,8-trimethylpyrrolo [1,2-a] quinoxal-5-inium 8hi (94.7 mg; 18.8 mmol) mesylenesulfonate and heating the mixture of reaction for 10 minutes.

Solid green. Rto .: 59.4 mg; 60% Mp: 205-206 ° C. ¹ H-NMR (300 MHz, CD ₃ OD): δ 9.36 (s, 1 H); 9.23 (dd, 1 H, J = 4.4 Hz, J = 1.2 Hz); 9.09 (dd, J = 9, 1 Hz, J = 1, 2 Hz); 8.85 (s, 1 H); 8.22 (c, 1 H, J = 4.4 Hz); 8, 15 (d, 1 H, J = 4.4 Hz); 7.39 (d, 1 H, J = 4.7 Hz); 6.84 (s, 2H); 2.62 (s, 3 H); 2.59 (s, 6H); 2.58 (s, 3 H); 2.23 (s, 3H) ppm. ¹³ C-NMR (75 MHz, CD ₃ OD): 5 150.3; 143.7; 140.0; 139.6; 139.4; 138.8; 138.1; 132.8; 131.6 (2C); 131, 3; 128.4 (2C); 127.3; 124.5; 124.3; 121.6; 1 18.4; 1 17.6; 109.6; 23.2 (2C); 20.8; 20.6; 19.9 ppm. IR (KBr): v _max 3423.8; 3061, 2; 2971, 5; 2927.5; 1621, 6; 1536.9; 1477.57; 1417.62; 1388.71; 1255.8; 1220.6; 1,183.6; 1084.6; 1013.7; 902.8; 876.9; 848.3; 792.9; 677.6 cm ^"1. HRMS [ESI-TOF]: calculated for Ci ₆ Hi ₃ BrN ₃ [M] ⁺ : 326.0287; found: 326.0289.

Example 46. Preparation of 10-chloro-2,3-diethylpyridazino [2,3- a] pyrrolo [2,1-c] quinoxal-13-inium bromide (Compound 9ni, Figure 2)

Method E. Using 5-amino-8-chloro-4-methylpyrrolo [1, 2- a] quinoxal-5-inio 8fi mesylenesulfonate (0.36 g; 0.84 mmol) and stirring for 4 hours gives a solid ocher (0.16 g) which is suspended in water (1 1 mL), cooled to 0 ° C, concentrated HBr (58 μΙ_; 0.52 mmol) is added and kept stirring at that temperature for 10 minutes. After that time, the reaction mixture is stirred at room temperature for 3 hours and 45 minutes and the precipitate formed is filtered. The filtrate waters are lyophilized, obtaining the product. Solid orange. Rt .: 89.4 mg; 27% Mp: 251-252 ° C. ¹ H-NMR (200 MHz, CD ₃ OD) δ 9.00 (d, 1 H, J = 9.3 Hz); 8.81 (s, 1 H), 8.78 (d, 1 H, J = 2.5 Hz); 8.65 (d, 1 H, J = 2.1 Hz); 8.17 (d, 1H, J = 4.2 Hz); 7.83 (dd, 1H, J = 9.3 Hz, J = 1.7 Hz); 7.30 (t _ap , 1 H, J = 3.4 Hz); 3.25 (c, 2H, J = 7.2 Hz); 3.09 (c, 2H, J = 7.6 Hz); 1, 61 (t, 3H, J =

7.2 Hz); 1.53 (t, 3H, J = 7.6 Hz) ppm. ¹³ C-NMR (75 MHz, CD ₃ OD): δ 144.4; 140.8; 139.9; 138.7; 138.1; 131.6; 128.9; 126.8; 126.1; 122.8; 121.1; 118.1; 117.6; 115.8; 20.8; 20.5; 20.2; 20.0 ppm IR (KBr): v _max 3415.1; 3025.2; 2970.4; 2932.4; 1619.7; 1601.5; 1551.3; 1473.8; 1428.5; 1375.7; 1246.7; 1160.7; 1101.8; 1051.1; 911.9; 886.6; 777.9; 698.3; 650.7 cm ^"1. HRMS [ESI-TOF]: calculated for Ci ₈ H ₁₇ CIN ₃ [M] ⁺ : 310,1106; found: 310,1093.

Example 47. Preparation of 2,3-dimethylpyridazino [2,3- a] pyrrolo [2,1-c] quinoxal-13-inium mesitylenesulfonate (Compound 11a, Figure 2)

Method A. Using 5-amino-4-methylpyrrolo [1,2-a] quinoxal-5-inium 10a (145 mg; 36.6 mmol) and maintaining stirring for 20 minutes.

Greenish solid. Rto .: 0.10 g; 65% Mp: 215-216 ° C. ¹ H-NMR (300 MHz, CD ₃ OD): δ 8.90 (dd, 1 H, J = 8.5 Hz, J = 1, 2 Hz); 8.79 (s, 1 H); 8.65 (dd, 1 H, J = 2.6 Hz, J = 1.2 Hz); 8.36 (d, 1H, J = 8.5 Hz); 7.92 (m, 2H); 7.75 (td, 1H, J = 8.5 Hz, J = 1.2 Hz); 7.21 (dd, 1H, J = 4.4 Hz, J = 2.6 Hz); 6.69 (s, 2 H); 2.84 (s, 3 H); 2.70 (s, 3 H); 2.53 (s, 6H); 2.12 (s, 3H) ppm. ¹³ C-NMR (75 MHz, CD ₃ OD): δ 161.4; 147.9; 140.8; 139.8; 139.4; 138.0; 133.4; 131.5 (2C); 128.9 (2C); 128.8; 128.5; 128.1; 123.4; 121.5; 121.4; 118.3; 117.5; 116.6; 23.3 (2C); 20.8; 20.6; 19.5 ppm IR (KBr): v _max 3448.1; 3080.7; 1732.7; 1629.4; 1606.0; 1555.7; 1499.0; 1483.4; 1395.9; 1335.5; 1250.6; 1190.8; 1083.5; 1014.1; 918.7; 876.7; 848.7; 764.9; 676.1; 640.2; 579.8; 547.8; 527.5; 482.2 cm ^"1. HRMS (ESI ⁺ ) m / e: calculated for Ci ₆ Hi ₄ N ₃ [M] ⁺ : 248.1188; found: 248.1163.

Example 48. Preparation of 2,3,10,11-tetramethylpyridazino [2,3-a] pyrrolo [2,1-c] quinoxal-13-inium mesitylenesulfonate (Compound 11b, Figure 2)

Method A. Using 5-amino-4,7,8-trimethylpyrrolo mesylenesulfonate [1, 2- a] quinoxal-5-inium 10b (96.1 mg; 0.22 mmol) and stirring for 30 minutes.

Greenish solid. Rto .: 59 mg; 56% Mp: 242-243 ° C. ¹ H-NMR (300 MHz, CD ₃ OD): δ 8.83 (s, 1H); 8.72 (s, 1 H); 8.65 (m, 1 H); 8.23 (s, 1 H); 7.96 (d, 1H, J = 3.2 Hz); 7.23 (m, 1 H); 6.82 (s, 2H); 2.86 (s, 3 H); 2.71 (s, 3 H); 2.60 (s, 9H); 2.56 (s, 3 H); 2.21 (s, 3H) ppm. ¹³ C-NMR (75 MHz, CD ₃ OD): δ 161, 1; 147.0; 144.4; 140.8; 139.9; 138.8; 138.7; 138.1; 131.6 (2C); 128.9 (2C); 126.8; 126.1; 122.8; 121.5; 121, 1; 1 18.1; 1 17.6; 1 15.8; 23.2 (2C); 20.8; 20.5; 20.2; 20.0; 19.4 ppm IR (KBr): vmax 3430.8; 3080.8; 2927.6; 1626.7; 1603.2; 1553.6; 1500.1; 1474.0; 1457.2; 1394.1; 1256.5; 1 173.6; 1084.4; 1012.2; 878.7; 854.3; 767.2; 678.1; 580.4; 549.4; 527.6 cm ^"1. HRMS [ESI-TOF]: calculated for Ci ₈ Hi ₈ N ₃ [M] ⁺ : 276.1495; found: 276.1494.

Example 49. Preparation of 2,3,11-trimethylpyridazino [2,3-a] pyrrolo [2,1-c] quinoxal-13-inium mesitylenesulfonate (Compound 11c, Figure 2)

Method A. Using 5-amino-4,7-dimethylpyrrolo [1, 2- a] quinoxal-5-inio 10c mesylenesulfonate (124.0 mg; 0.30 mmol) and stirring for 20 minutes.

Greenish solid. Rto .: 68.0 mg; 49% Mp: 146-147 ° C. ¹ H-NMR (300 MHz, CD ₃ OD): δ 8.79 (s, 1 H); 8.72 (s, 1 H); 8.62 (s, 1 H); 8.25 (d, 1 H, J = 8.6 Hz); 7.94 (d, 1 H, J = 4.3 Hz); 7.75 (d, 1 H, J = 8.6 Hz); 7.21 (t, 1 H, J = 2.9 Hz); 6.73 (s, 2H); 2.85 (s, 3 H); 2.71 (s, 3 H); 2.63 (s, 3 H); 2.55 (s, 6H); 2.15 (s, 3H) ppm. ¹³ C-NMR (75 MHz, CD3OD): δ 161, 2; 147.6; 140.8; 139.9; 139.5; 139.3; 138.1; 134.4; 131.5 (2C); 128.9 (2C); 127.9; 126.7; 123.1; 121, 4; 120.9; 1 18.2; 1 17.3; 1 16.2; 23.3 (2C); 21, 4; 20.8; 20.5; 19.5 ppm IR (KBr): v _max 3432.4; 2918.0; 1735.9; 1629.9; 1603.5; 1553.6; 1509.0; 1459.1; 1393.4; 1317.7; 1 188.4; 1083.8; 1014.1; 676.2; 581.2 cm ^"1. HRMS (ESI ⁺ ) m / e: calculated for Ci ₇ Hi ₆ N ₃ [M] ⁺ : 262.1339; found: 262.1339.

Example 50. Preparation of 2,3-dimethyl-11-methoxypyridazino [2,3-a] pyrrolo [2,1-c] quinoxal-13-inium mesitylenesulfonate (Compound 11d, Figure 2)

Method A. Using 5-amino-4-methyl-7-methoxypyrrolo [1, 2- a] quinoxal-5-inio 10d mesylenesulfonate (1 17.2 mg; 0.27 mmol) and maintaining stirring for 30 minutes.

Solid dark green. Rt .: 49.9 mg; 38% Mp: 273-274 ° C. ¹ H-NMR (200 MHz, CD3OD): δ 8.87 (s, 1 H); 8.66 (m, 1 H); 8.43 (d, 1 H, J = 2.5 Hz); 8.38 (d, 1 H, J = 9.3 Hz); 7.98 (d, 1 H, J = 4.2 Hz); 7.58 (dd, 1 H, J = 9.3 Hz, J = 2.5 Hz); 7.25 (t _ap , 1 H, J = 3.4 Hz); 6.85 (s, 2H); 4.06 (s, 3 H); 2.87 (s, 3 H); 2.73 (s, 3 H); 2.62 (s, 6H); 2.23 (s, 3H) ppm. ¹³ C-NMR (75 MHz, CD ₃ OD): δ 161, 1; 160.2; 147.5; 140.8; 139.9; 139.5; 138.1; 131.6 (2C); 129.2; 128.9 (2C); 123.0; 122.9; 121, 4; 121, 3; 1 18.9; 1 18.1; 1 15.7; 103.9; 56.8; 23.3 (2C); 20.8; 20.5; 19.5 ppm IR (KBr): v _max 3468.5; 2930.4; 1623.4; 1555.6; 1535.5; 1508.8; 1458.7; 1396.6; 1318.0; 1257.0; 1085.9; 1016.1; 853.0; 842.7; 750.6; 677.1; 609.5; 579.6; 548.1 cm ^"1. HRMS (ESI ⁺ ) m / e: calculated for Ci ₇ H ₁₆ N ₃ 0 [M] ⁺ : 278,1288; found: 278,1291.

Example 51. Preparation of 2,3-dimethyl-11-trifluoromethylpyridazino [2,3-a] pyrrolo [2,1-c] quinoxal-13-inium mesitylenesulfonate (Compound 11e, Figure 2)

Method B. Using 5-amino-7-trifluoromethyl-4-methylpyrrolo [1,2-a] quinoxal-5-inium 10e (103.1 mg; 0.22 mmol) mesylenesulfonate and heating the reaction mixture for 10 minutes .

Solid black. Rto .: 54.4 mg; 48% Mp: 288-290 ° C. ¹ H-NMR (300 MHz, CD ₃ OD): δ 9.23 (s, 1 H); 8.93 (s, 1 H); 8.80 (dd, 1 H, J = 2.6 Hz, J = 1, 3 Hz); 8.63 (d, 1 H, J = 8.8 Hz); 8.24 (d, 1 H, J = 8.8 Hz); 8.09 (dd, 1 H, J = 4.1 Hz, J = 1.3 Hz); 7.32 (dd, 1 H, J = 4.1 Hz; J = 2.9 Hz); 6.77 (s, 2H); 2.89 (s, 3 H); 2.75 (s, 3 H); 2.55 (s, 6H); 2.19 (s, 3H) ppm. IR (KBr): v _max 3448.2; 3105.8; 2360.9; 1629.5; 1458.0; 1335.0; 1317.7; 1 126.4; 1074.8; 1014.9; 832.3; 807.2; 677.3; 578.8; 549.0 cm ^"1. HRMS (ESI ⁺ ) m / e: calculated for C1 ₇ H13F3N3 [M] ⁺ : 316,1056; found: 316,1051.

Example 52. Preparation of 10-chloro-2,3-dimethylpyridazino [2,3-a] pyrrolo [2,1-c] quinoxal-13-inium mesitylenesulfonate (Compound 11 f, Figure 2)

Method A. Using 5-amino-8-chloro-4-methylpyrrolo [1,1- a] quinoxal-5-inium 10f mesyletnesulfonate (1 16.9 mg; 0.27 mmol) and maintaining stirring for 30 minutes.

Solid black. Rto .: 54.5 mg; 43% Mp: 231-232 ° C. ¹ H-NMR (300 MHz, CD ₃ OD): δ 8.90 (d, 1 H, J = 9.2 Hz); 8.83 (s, 1 H), 8.68 (dd, 1 H, J = 2.6 Hz, J = 1, 3 Hz); 8.53 (s, 1 H), 7.99 (d, 1 H, J = 4.3 Hz); 7.75 (dd, 1 H, J = 9.2 Hz, J = 1, 6 Hz); 7.24 (t _ap , 1 H, J = 3.4 Hz); 6.72 (s, 2H); 2.87 (s, 3H), 2.73 (s, 3H), 2.62 (s, 6H,), 2.24 (s, 3H) ppm. ¹³ C-NMR (75 MHz, CD ₃ OD): δ 161.6; 148.2; 1408; 139.8; 139.5; 139.3; 138.1; 131.5 (2C); 129.7; 129.1; 128.7 (2C); 127.0; 123.9; 123.2; 121.9; 118.6; 117.6; 117.0; 23.3 (2C); 20.8; 20.5; 19.5 ppm IR (KBr): v _max 3422.4; 3076.1; 1735.1; 1602.8; 1556.7; 1472.4; 1432.1; 1248.6; 1178.3; 1084.2; 1013.0; 843.4; 827.1; 769.1; 676.8; 606.9; 578.9 cm ^"1. HRMS (ESI ⁺ ) m / e: calculated for Ci ₆ Hi ₃ CIN ₃ [M] ⁺ : 282.0793; found: 282.0795.

Example 53. Preparation of 10,11-dichloro-2,3-dimethylpyridazino [2,3-a] pyrrolo [2,1-c] quinoxal-13-inium mesitylenesulfonate (Compound 11g, Figure 2)

Method A. Using 5-amino-7,8-dichloro-4-methylpyrrolo [1,2- a] quinoxal-5-inium 10g mesylenesulfonate (132.2 mg; 0.28 mmol) and maintaining stirring for 20 minutes.

Solid black. Rto .: 51.6 mg; 35% Mp: 289-290 ° C. ¹ H-NMR (200 MHz, CD ₃ OD): δ 9.13 (s, 1H), 8.92 (s, 1H), 8.82 (s, 1H), 8.76 (d, 1H, J = 2.5 Hz); 8.06 (d, 1H, J = 4.2 Hz); 7.29 (t _ap , 1H, J = 3.6 Hz); 6.82 (s, 2H), 2.88 (s, 3H), 2.74 (s, 3H), 2.61 (s, 6H), 2.25 (s, 3H) ppm. ¹³ C-NMR (75 MHz, CD ₃ OD); δ 149.3; 1743.7; 140.7; 140.1; 140.0; 138.1; 137.9, 137.5; 136.2; 132.3; 131.6 (2C); 129.0; 128.3 (2C); 124.4; 123.0; 119.6; 118.9; 117.4; 23.2 (2C); 20.8; 20.4; 19.5 ppm IR (KBr): v _max 3422.3; 3080.6; 1603.1; 1499.3; 1372.1; 1288.6; 1188.2; 1084.7; 1015.4; 885.7; 848.6; 762.8; 677.7; 581.7 cm ^"1. HRMS (ESI ⁺ ) m / e: calculated for Ci ₆ Hi ₂ CI ₂ N ₃ [M] ⁺ : 316.0403; found: 316.0401.

Example 54. Preparation of acenaphth mesylethenesulfonate [1 ', 2': 3,4] pyridazino [2,3-a] pyrrolo [2,1-c] quinoxal-9-inium (Compound 11k, Figure 2)

Method C. 5-Amino-4-methylpyrrolo [1,2-a] quinoxal-5-inio 10a (73.6 mg; 0.18 mmol) mesylenesulfonate is used.

Solid orange. Rto .: 0.10 g; 99% Mp: 327-328 ° C. ¹ H-NMR (300 MHz, CD ₃ OD): δ 9.49 (s, 1 H); 9.02 (d, 1 H, J = 8.9 Hz); 8.72 (m, 1 H); 8.56 (d, 1 H, J = 6.9 Hz); 8.52 (d, 1 H, J = 7.2 Hz); 8.38 (d, 1 H, J = 7.9 Hz); 8.26 (t, 2H, J = 7.4 Hz); 8.12 (d, 1 H, J = 3.9 Hz); 7.94 (m, 3 H); 7.79 (t, 1 H, J = 7.9 Hz); 7.31 (c, 1 H, J = 3.4 Hz); 6.85 (s, 2H); 2.62 (s, 6H); 2.24 (s, 3H); 1.92 (s, 3H) ppm. ¹³ C-NMR (75 MHz, CD ₃ OD): δ 157.8; 140.8; 140.1; 138.5; 138.2 (2C); 133.7; 133.4; 133.0; 131.6 (2C); 131.4; 130.8; 130.6; 130.1; 129.5; 128.9 (2C); 128.7; 128.5; 127.9; 125.4; 123.9; 123.0; 121.4; 120.4; 118.9; 117.6; 117.2; 23.3 (2C); 20.8 ppm IR (KBr): v _max 3424.3; 3090.9; 1631.0; 1605.4; 1543.7; 1482.2; 1445.6; 1419.3; 1212.0; 1196.2; 1085.4; 1017.0; 951.9; 852.2; 833.8; 781.2; 768.5; 675.8; 585.2; 550.3 cm ^"1. HRMS [ESI-TOF]: calculated for C24H14N3 [M] ⁺ : 344.1182; found: 344.1197.

Example 55. Preparation of 10,11-dimethylpyridazino [2,3-a] pyrrolo [2,1-c] quinoxal-13-inium mesitylenesulfonate (Compound 111, Figure 2)

Method B. Using 5-amino-4,7,8-trimethylpyrrolo [1, 2- a] quinoxal-5-inio 10c mesitethylene sulphonate (130.0 mg; 0.30 mmol) and heating the reaction mixture for 20 minutes .

Solid black. Rt .: 78.9 mg; 56% Mp: 279-280 ° C. ¹ H-NMR (300 MHz, CD ₃ OD): δ 9.22 (s, 1 H); 9.11 (d, 1 H, J = 8.8 Hz); 8.77 (m, 2 H); 8.31 (s, 1 H); 8.21 (dd, 1 H, J = 8.8 Hz, J = 3.6 Hz); 8.09 (d, 1H, J = 4.1 Hz); 7.32 (m, 1 H); 6.87 (s, 2H); 2.64 (s, 6H); 2.63 (s, 3 H); 2.58 (s, 3 H); 2.25 (s, 3H) ppm. ¹³ C-NMR (75 MHz, CD ₃ OD): δ 150.1; 145.2; 140.8; 140.2; 140.0; 139.1; 138.2; 132.4; 131.7; 131.6 (2C); 127.2 (2C); 126.5; 123.7; 122.1; 121.3; 118.7; 117.8; 116.9; 23.3 (2C); 20.8; 20.3; 20.0 ppm IR (KBr): v _max 3393.8; 3114.7; 3044.0; 1620.4; 1553.6; 1528.6; 1500.3; 1476.8; 1448.5; 1389.1; 1346.1; 1288.5; 1246.3; 1211.3; 1166.2; 1084.7; 1012.3; 911.5; 859.3; 844.6; 830.7; 754.3; 677.1; 583.5 cm ^"1. HRMS [ESI-TOF]: calculated for Ci ₆ Hi ₄ N ₃ [M] ⁺ : 248.1182; found: 248.1179.

Example 56. Preparation of 10-chloropyridazino [2,3- a] pyrrolo [2,1-c] quinoxal-13-inium mesitylenesulfonate (Compound 11m, Figure 2)

Method B. Using 5-amino-8-chloro-4-methylpyrrolo [1,2- a] quinoxal-5-inium 10f mesylethenesulfonate (122.0 mg; 0.28 mmol) and heating at reflux for 20 minutes.

Solid dark green. Rt .: 60.3 mg; 47% Mp: 275-276 ° C. ¹ H-NMR (300 MHz, CD3OD): δ 9.26 (dd, 1H, J = 4.2 Hz, J = 1.3 Hz); 9.15 (dd, 1H, J = 8.9 Hz, J = 1.3 Hz); 8.97 (d, 1H, J = 9.4 Hz); 8.85 (d, 1H, J = 2.5 Hz); 8.66 (d, 1H, J = 2.1 Hz); 8.27 (dd, 1H, J = 8.9 Hz, J = 4.7 Hz); 8.16 (d, 1H, J = 4.2 Hz); 7.84 (dd, 1H, J = 9.4 Hz, J = 2.1 Hz); 7.35 (t _ap , 1H, J = 3.6 Hz); 6.85 (s, 2H), 2.61 (s, 6H); 2.24 (s, 3H) ppm. ¹³ C-NMR (75 MHz, CD ₃ OD): δ 150.5; 141.1; 140.8; 140.1; 140.0; 138.2; 133.4; 131.8; 131.6 (2C); 130.1; 129.1 (2C); 127.6; 124.9; 123.5; 122.5; 119.2; 118.1; 117.9; 23.3 (2C); 20.8 ppm IR (KBr): v _max 3422.3; 3091.1; 1623.3; 1605.6; 1557.7; 1535.0; 1497.0; 1472.9; 1431.8; 1189.2; 1086.1; 1016.0; 848.7; 810.3; 752.4; 678.8; 851.4 cm ^"1. HRMS (ESI ⁺ ) m / e: calculated for C14H9CIN3 [M] ⁺ : 254.0480; found: 254.0479.

Example 57. Preparation of 2,3-diethyl-10,11-dimethylpyridazino [2,3-a] pyrrolo [2,1-c] quinoxal-13-inium mesitylenesulfonate (Compound 11n, Figure 2)

Method D. Using 5-amino-4,7,8-trimethylpyrrolo mesylenesulfonate [1, 2- a] quinoxal-5-inium 10c (101.6 mg; 0.23 mmol).

Solid orange. Rt .: 78.7 mg; 65% Mp: 224-226 ° C. ¹ H-NMR (300 MHz, CD ₃ OD): δ 8.71 (s, 1H); 8.70 (s, 1 H); 8.67 (m, 1 H); 8.24 (s, 1 H); 8.06 (d, 1H, J = 4.1 Hz); 7.24 (dd, 1 H, J = 4.1 Hz, J = 2.6 Hz); 6.80 (s, 2 H); 3.28 (c, 2H, J = 7.3 Hz); 3.06 (c, 2H, J = 7.3 Hz); 2.60 (s, 3 H); 2.58 (s, 6H); 2.57 (s, 3 H); 2.20 (s, 3 H); 1.59 (t, 3H, J = 7.3 Hz); 1.52 (t, 3H, J = 7.3 Hz) ppm. ¹³ C-NMR (75 MHz, CD ₃ OD): δ 151.4; 144.4; 139.9; 138.9; 138.6; 138.2; 131.6 (2C); 127.1 (2C); 126.9; 126.4; 122.8; 121.4; 121.1; 119.1; 118.1; 117.8; 117.7; 116.0; 27.4; 25.8; 23.3 (2C); 20.8; 20.3; 20.1; 12.3; 11.1 ppm IR (KBr): v _max 3435.9; 3090.6; 2970.2; 2918.8; 2358.9; 2341.6; 1624.4; 1552.1; 1455.0; 1386.7; 1190.1; 1084.3; 1016.4; 879.8; 849.5; 765.7; 675.7 cm ^"1. HRMS [ESI-TOF]: calculated for C ₂₀ H ₂ 2N ₃ [M] ⁺ : 304.1808; found: 304.1820.

Example 58. Growth inhibitory capacity of amastigotes in the logarithmic phase of growth by compounds 9 and 11 (Figure 3)

The treatment of amastigotes of Leishmania infantum with the compounds was carried out during the logarithmic growth phase at a concentration of 1x10 ⁶ parasites / mL at 37 ° C for 24 hours. A volume of 1 μΙ_ of dimethylsulfoxide (DMSO) was added to the positive growth controls. Each of compounds 9 and 11 was added to the cultures in a volume of 1 μΙ_ of different concentrations of compound in DMSO to generate a final concentration range between 0.04 μΜ and 25 μΜ. The percentage of Live cells were evaluated by flow cytometry by the method of exclusion of propidium iodide, according to which live and dead cells can be differentiated by the emission of fluorescence by dead cells as a result of the entry into the cell interior of the propidium iodide and its intercalation in cellular DNA.

The concentration that causes a 50% reduction in parasite growth (IC ₅ o) was determined by the formula: y = 100% / (1 + (x / IC ₅ o) ^s ) where y represents the percentage of growth of the parasites with respect to the control without compound, x the concentration of compound in μΜ and s is the slope factor. The results were adjusted to this formula by means of a non-linear adjustment using the Graphit6 (Erithacus) program.

The results obtained are detailed in Figure 4 and show that the compounds have a strong inhibitory capacity for parasite growth.

Example 59. Comparison of the cytotoxic effect of compounds 9 and 11 on human cells (THP-1) and amastigotes of Leishmania infantum (Figure 4)

Drug treatment of THP-1 cells was carried out during the logarithmic growth phase at a concentration of 4x10 ⁵ cells / mL at 37 ° C and 5% CO ₂ for 24 hours. A volume of 1 μί of dimethylsulfoxide (DMSO) was added to the positive growth controls. Each of compounds 9 and 11 was added to the cultures in a volume of 1 μί of different concentrations of compound in DMSO to generate a range of final concentrations comprised between 0.25 μΜ and 4 μΜ. The percentage of living cells was evaluated by flow cytometry by the method of exclusion of propidium iodide described in the previous example.

The concentration that causes a 50% reduction in cell growth (IC50) was determined by the formula: y = 100% / (1 + (x / IC ₅ o) ^s ) where y represents the percentage growth of the cells. cells with respect to the control without compound, x the concentration of compound in μΜ and s is the slope factor. The results were adjusted to this formula by means of a non-linear adjustment using the Graphit6 (Erithacus) program.

The parameter called the selectivity index (IS), which corresponds to the ratio between the IC ₅ 0 observed for amastigotes of Leishmania infantum and for THP-1 human cell line has been used to compare the cytotoxicity of the compounds against both types of cells. The higher this index, the greater the selectivity of the compound against the parasites.

Example 60. Comparison of the cytotoxic effect of compounds 9 and 11 with miltefosine in amastigotes of Leishmania infantum and THP-1 cells (Figure 4)

All the compounds of series 9 and series 1 1 show greater activity against amastigotes of Leishmania infantum than the miltefosine drug, one of the most recent drugs used in the treatment of visceral leishmaniasis, as it appears from their children. IC ₅ values.

All the compounds of series 9 and 1 1 have better selectivity indices than those obtained by the miltefosine drug.

Example 61. Determination of the percentage of inhibition of PTP1 B by compounds 9 and 11

To evaluate the activity of the different PTP1 B inhibitors, a colorimetric kit (BML-AK822 Enzo, Life Sciences) was used that measures the phosphatase activity of PTP1 B. The assay is based on reacting PTP1 B in vitro with a specific substrate, IR5, which contains sequences from the β subunit of the insulin receptor, and using suramin as a specific inhibition control. The assay is carried out in a 96-well plate, successively adding the assay buffer, the inhibitors to a final concentration of 1 μΜ, the recombinant enzyme and the substrate. After incubation for 10 minutes at room temperature, absorbance at 620 nm is measured. After this time, the detection reagent is added and the absorbance at 620 nm is measured after 30 minutes. To calculate the activity, the following formula is applied:

[test sample (30 min) (nmol P0 ₄ ^{2 ~} ) - "zero time" (nmol P0 ₄ ^{2 "} )]

% Activity = x100%

[Control (30 min) (nmol P0 ₄ ^{2 "} ) -" zero time "(nmol P0 ₄ ^2" )]

The percentage of activity inhibition is expressed as follows:

% Inhibition = 100 -% Activity Example 63. Determination of IC ₅ or PTP1 B of compounds 9 and 11

The same method as in the previous example was used to determine the IC50 of the inhibitors, making a dose-response curve for them at concentrations 0.25 μΜ, 0.5 μΜ, 1 μΜ, 2 μΜ and 4 μΜ. The activity was calculated with the same formula as in the previous example and with the activity results and concentrations the value of IC50 was calculated using a computer program.

Claims

CLAIMS Formula Compound

where Ri, R2 and R3 can be any of the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, carbocycle or heterocycle, aromatic or heteroaromatic; chlorine, bromine or iodine; where R ₅ , R ₆ , R 7 and Rs may be any of the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, carbocycle or heterocycle, aromatic or heteroaromatic; fluorine, chlorine, bromine or iodine; nitro; thiol; thioether (RS-) where the substituent R may be equal to any of the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, carbocycle or heterocycle, aromatic or heteroaromatic; ether (RO-) where the substituent R has been defined above; primary, secondary (RNH-) or tertiary (R'R "N-) amino where the substituents R 'and R" in the nitrogen may be the same or different, and may be hydrogen or any of the group indicated for R; primary (RCONH-), secondary (RCONR'-) or tertiary (RCONR'R "-) acylamino where the radical R of the acyl group can be hydrogen or any of the group indicated for R and the substituents R 'and R" have been defined previously; hydroxy; acyloxy (RCOO-) where the radical R of the acyl group can be hydrogen or any of the group indicated for R; (RCO-) acyl where the radical R acyl group can be hydrogen or any of the group indicated for R; primary, secondary (R'NHCO-) or tertiary (R "R'NCO-) carboxamide where the substituents R 'and R" in the nitrogen may be any of the group indicated for R; alkoxycarbonyl (ROCO-) where the substituent R in the oxygen may be equal to any of the group indicated for R; carboxy; where Rg and R ₁ 0 may be the same or different and any one to choose between hydrogen, alkyl, aryl or heteroaryl;

and where Rg and _R1 0 can also form part of a saturated, carboaromatic or heteroaromatic carbocyclic ring; Y

2. Compound according to claim 1, wherein Ri is selected from bromine, chlorine, iodine and hydrogen.

3. Compound according to any of claims 1 or 2, wherein R ₂ , R3, R5 or Rs are hydrogen, preferably R ₂ , R3, R5 and Rs are hydrogen

4. Compound according to any of claims 1 to 3, wherein R6 is selected from hydrogen, chlorine, bromine, iodine, fluorine, (C ₁ -C4) alkyl optionally substituted by at least one halo group, preferably substituted by three fluorine groups forming the group -CF ₃ ; and RO-, where R is preferably (C1-C4) alkyl;

5. Compound according to reivindiacaciones 1 to 4, where Rg and R ₁ 0 are the same and are selected from _(C1 - C4), hydrogen or form part of a same carboaromatic ring.

6. Compound according to claim 1, wherein said compounds are selected from:

a) 7-Bromo-2,3,10,1 1-tetramethylpyrididazino [2,3- a] pyrrolo [2,1-c] quinoxal-13-inium mesylethenesulfonate (Compound 9hi)

b) 7-Bromo-10-chloro-2,3-diethylpyridazino [2,3-a] pyrrolo [2,1-c] quinoxal-13-inium bromide (Compound 9¡i)

c) 7-Bromo-10,1 1-dimethylpyrididazino [2,3-a] pyrrolo [2,1-c] quinoxal-13-inium mesylethenesulfonate (Compound 9ji)

d) 10-Chloro-2,3-diethylpyridazino [2,3-a] pyrrolo [2,1-c] quinoxal-13-inium bromide (Compound 9ni,)

e) 2,3-Dimethylpyridazino [2,3-a] pyrrolo [2,1-c] quinoxal-13-inium mesitylenesulfonate (Compound 1 1 a)

f) 2,3,10,1 1 -tetramethylpyrididazino [2,3-a] pyrrolo [2,1-c] quinoxal-13-inium mesitylenesulfonate (Compound 1 1 b)

g) 2,3,1 1 -trimethylpyridazino [2,3-a] pyrrolo [2,1-c] quinoxal-13-inium mesitylenesulfonate (Compound 1 1 c) h) 2,3-dimethyl-1 1 -methoxypyridazino [2,3-a] pyrrolo [2,1-c] quinoxal-13-inium mesylethenesulfonate (Compound 1 1 d)

i) 2,3-Dimethyl-1 1 -trifluoromethylpyridazino [2,3- a] pyrrolo [2,1-c] quinoxal-13-inium mesitylenesulfonate (Compound 1 1 e)

j) 10-Chloro-2,3-dimethylpyridazino [2,3-a] pyrrolo [2,1-c] quinoxal-13-inium mesitylenesulfonate (Compound 1 1f)

k) 10,1 1-Dichloro-2,3-dimethylpyridazino [2,3- a] pyrrolo [2,1-c] quinoxal-13-inium mesylethenesulfonate (Compound 1 1 g)

I) Acenaphth mesitylenesulfonate [1 ', 2': 3,4] pyridazino [2,3-a] pyrrolo [2,1-c] quinoxal-9-inium (Compound 1 1 k)

m) 10,1 1 -dimethylpyridazino [2,3-a] pyrrolo [2,1-c] quinoxal- mesitylenesulfonate

13-inio (Compound 1 11)

n) 10-Chloropyridazino [2,3-a] pyrrolo [2,1-c] quinoxal-13-inium mesitylenesulfonate (Compound 1 m); Y

o) 2,3-Diethyl-10,1 1-dimethylpyridazino [2,3-a] pyrrolo [2,1-c] quinoxal-13-inium mesitylenesulfonate (Compound 1 1 n)

7. A Leishmania parasite growth inhibitor consisting of a compound according to any one of claims 1 to 6.

8. Use of a compound according to any of claims 1 to 6 as a growth inhibitor of the Leishmania parasite.

9. A PTP1 B inhibitor consisting of a compound according to any one of claims 1 to 6.

10. Use of a compound according to any of claims 1 to 6 as a PTP1 B inhibitor.

eleven . A synthesis process for preparing a compound according to claims 1 to 6 comprising:

a) transform pyrroloquinoxalines 6

where Ri, R2 and R3 can be any of the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, carbocycle or heterocycle, aryl or heteroaryl;

where R ₅ , R ₆ , R 7 and Rs may be any of the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, carbocycle or heterocycle, aryl or heteroaryl; fluorine, chlorine, bromine or iodine; nitro; thiol; thioether (RS-) where the substituent R may be equal to any of the group indicated for R ₄ except hydrogen; ether (RO-) where the substituent R may be equal to any of the group indicated for R ₄ except hydrogen; primary, secondary (RNH-) or tertiary (RR'N-) amino where the substituents R and R 'in the nitrogen may be equal to any of the group indicated for R ₄ except hydrogen; primary (RCONH-), secondary (RCONR'-) or tertiary (RCONR'R "-) acylamino where the radical R of the acyl group may be equal to any of the group indicated for R ₄ and the substituents R 'and R" in the nitrogen may be equal to any of the group indicated for R ₄ except hydrogen; hydroxy; acyloxy (RCOO-) where the radical R of the acyl group may be equal to any of the group indicated for R ₄ ; (RCO-) acyl where the radical R acyl group may be equal to any of the group indicated for R4; primary, secondary (RNHCO-) or tertiary (RR'NCO-) carboxamide where the substituents R and R 'in the nitrogen may be equal to any of the group indicated for R ₄ except hydrogen; alkoxycarbonyl (ROCO-) where the substituent R in the oxygen may be equal to any of the group indicated for R ₄ except hydrogen; or carboxy,

in halopirroloquinoxalines 7i

where X is any to choose between chlorine, bromine or iodine;

where R ₂ and R 3 can be any of the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, carbocycle or heterocycle, aryl or heteroaryl;

and where R ₄ , R5, R6, R7 and Rs have been defined above,

by reaction with an N-halosuccinimide.

and / or in halopyrrinoquinoxalines 72

where X is any to choose between chlorine, bromine or iodine;

wherein R1 and _R3 may be any of the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, carbocyclic or heterocyclic, aryl or heteroaryl;

and where R ₄ , R5, R6, R7 and Rs have been defined above,

by reaction with an N-halosuccinimide;

and / or in 7z halopyrroloquinoxalines

where X is any to choose between chlorine, bromine or iodine;

where R1 and _R2 may be any of the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, carbocyclic or heterocyclic, aryl or heteroaryl;

and wherein _R4, R5, R6, R7 and Rs are defined above;

by reaction with an N-halosuccinimide;

transform halopyrrinoquinoxalines 7i

where X, R2, R3, R4, R5, R6, R7 and Rs have been defined above;

in aminoquinoxalinium salts 81

MSTS- where X, R2, R3, R4, R5, R6, R7 and Rs have been defined above;

by reaction with hydroxylamine O-mesitylenesulfonate (MSH);

or hydroxylamino-O-sulfonic acid (HOSA);

or 0- (2,4-dinitrophenyl) hydroxylamine.

transform halopyrroloquinoxalines 7 ₂

where X, R1, R3, R ₄ , R ₅ , R6, R7 and Rs have been defined above;

in aminoquinoxalinium salts 82

MSTS- where X, R1, R3, R ₄ , R5, R6, R7 and Rs have been defined above; and where Y can be any one to choose between mesitylenesulfonate or any pharmaceutically acceptable anion;

by reaction with hydroxylamine O-mesitylenesulfonate (MSH);

or hydroxylamino-O-sulfonic acid (HOSA);

or 0- (2,4-dinitrophenyl) hydroxylamine.

d) transform 7z halopyrrinoquinoxalines

where X, Ri, R2, R ₄ , R5, R6, R7 and Rs have been defined above;

in aminoquinoxalinium salts 83

where X, R1, R2, R ₄ , R5, R6, R7 and Rs have been defined above;

by reaction with hydroxylamine O-mesitylenesulfonate (MSH);

or hydroxylamino-O-sulfonic acid (HOSA);

or 0- (2,4-dinitrophenyl) hydroxylamine.

e) transform aminoquinoxalinium salts 81

STS- where X, Y, R2, R3, R4, R5, R6, R7 and Rs have been defined above;

in the pyrimidopyrroloquinoxalinium salts 9i

MSTS- where Rg and R10 can be any one of choice between hydrogen, alkyl, aryl or heteroaryl;

by reaction with a 1,2-diketone of general formula

where Rg and R10 have been defined above,

in the presence of a base to choose between triethylamine and sodium acetate, transform the amino uinoxalinium salts 82

STS- where X, Y, R1, R3, R ₄ , R5, R6, R7 and Rs have been defined above;

in pyrimidopyrroloquinoxalinium salts 92

MSTS- where X, Y, R1, R3, _R4, R5, R6, R7, Rs, R9 and R10 defined above;

by reaction with a 1,2-diketone of general formula where Rg and R10 have been defined above,

in the presence of a base to choose between triethylamine and sodium acetate, g) transform the aminoquinoxalinium salts 83

where X, Y, R1, R2, _R4, R5, R6, R7 and Rs are defined above;

in pyrimidopyrroloquinoxalinium salts 93

where X, Y, R1, R ₂ , R ₄ , R5, R6, R7, Rs, R9 and R10 have been defined above;

by reaction with a 1,2-diketone of general formula,

where Rg and R10 have been defined above,

in the presence of a base to choose between triethylamine and sodium acetate, h) transform the pyrroloquinoxalines 6

where R1, _R2 and R3 may be any of the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, carbocyclic or heterocyclic, aryl or heteroaryl; and where R ₄ , R5, F R7 and Rs have been defined above;

in the aminoquinoxalinium salts 10

MSTS- where Y, R1, R2, R ₄ , R5, R6, R7 and Rs have been defined above;

by reaction with hydroxylamine O-mesitylenesulfonate (MSH);

or hydroxylamino-O-sulfonic acid (HOSA);

or 0- (2,4-dinitrophenyl) hydroxylamine.

transform aminoquinoxalinium salts 10

MSTS- where Y, R1, R ₂ , R3, R ₄ , R5, R6, R7 and Rs have been defined above; in pyrimidopyrroloquinoxalinium salts 11

MSTS- where Y, R1, R ₂ , R3, R ₄ , R5, R6, R7, Rs R9 and R10 have been defined above;

in the presence of a base to choose between triethylamine and sodium acetate.

12. Use of an intermediate selected from the compounds of formula 6, 7, 7 ₂ , 7 ₃ , 81, 82, 83 or 10 described in claim 1, to prepare a compound of formula (I) according to any of the claims 1 to 6

13. Compound of formula 6

wherein R1 to Rs are described in any of claims 1 to 4 and 1 1, except the compounds when:

R1 R2, R3, R5, R6, R7 and Rs are hydrogen and R ₄ is methyl; Y

R1 R2, R3, R5, R7 and Rs are hydrogen, R ₄ is methyl and Re is methoxy.

14. Compound according to the preceding claim selected from: 4,7-dimethylpyrrolo [1,2-a] quinoxaline; 4,7,8-trimethylpyrrolo [1,2-a] quinoxaline; 7- trifluoromethyl-4-methylpyrrolo [1,2-a] quinoxaline; 8-chloro-4-methylpyrrolo [1, 2- a] quinoxaline; and 7,8-dichloro-4-methylpyrrolo [1,2-a] quinoxaline.

15. Compound of formula 7 ₅ 7 ₂ or 7 ₃

7i 7 ₂ 7 ₃

wherein R1 to Rs and X are described in any of claims 1 to 4 and 1 1.

16. Compound according to the preceding claim selected from: 1-bromine-4,7,8-trimethylpyrrolo [1,2-a] quinoxaline; 1-Bromo-8-chloro-4-methylpyrrolo [1, 2- a] quinoxaline; 3-Bromo-4,7,8-trimethylpyrrolo [1,2-a] quinoxaline; 1,2-dibromo-4,7,8-trimethylpyrrolo [1,2-a] quinoxaline; and 2-bromo-8-chloro-4-methylpyrrolo [1, 2- a] quinoxaline.

17. Compound of formula 81, 82 or 83

MSTS- MSTS- MSTS-

wherein R1 to Rs and X are described in any of claims 1 to 4 and 1 1.

18. Compound according to the preceding claim selected from: 5-amino-1-bromo-4,7,8-trimethylpyrrolo [1,2-a] quinoxal-5- inium mesylenesulfonate or 5-amino-1-bromo- mesylenesulfonate 8-Chloro-4-methylpyrrolo [1, 2- a] quinoxal-5-inium.

19. Compound of formula 10

MSTS-

10

wherein R1 to Rs are described in any one of claims 1 to 4 and 1 1, and except the compounds when R1 R2, R3, R5, R6, R7 and Rs are hydrogen and R ₄ is methyl.

20. Compound according to the preceding claim wherein the compound is selected from: 5-amino-4,7-dimethylpyrrolo [1,2-a] quinoxal-5-inium mesitylenesulfonate; 5-amino-4,7,8-trimethylpyrrolo [1,2-a] quinoxal-5-inium mesitylenesulfonate; 5-amino-4-methyl-7-methoxypyrrolo [1,2-a] quinoxal-5-inium mesitylenesulfonate; 5-amino-7-trifluoromethyl-4-methylpyrrolo [1,2-a] quinoxal-5- inium mesitylenesulfonate; 5-amino-8-chloro-4-methylpyrrolo [1,2-a] quinoxal-5-inium mesitylenesulfonate; and 5-amino-7,8-dichloro-4-methylpyrrolo [1,2-a] quinoxal-5-inium mesitylenesulfonate.

twenty-one . Pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 6 together with a pharmaceutically acceptable carrier.

22. Use of a compound of formula (I) according to any of claims 1 to 6 for the preparation of a medicament for the treatment or prevention of infections caused by the Leishmania parasite.

23. Use of a compound of formula (I) according to any of claims 1 to 6 for the preparation of a medicament for the treatment or prevention of diseases in which PTP1 B is involved in its pathogenesis.

24. Use according to the preceding claim, wherein the diseases in which PTP1 B is involved can be selected from the list comprising: insulin resistance, glucose intolerance, obesity, diabetes mellitus, hypertension and ischemic diseases of blood vessels large and small, conditions that accompany type 2 diabetes including dyslipidemia, for example, hyperlipidemia and hypertriglyceridemia, atherosclerosis, vascular restenosis, irritable bowel syndrome, pancreatitis, fat cell cancer and carcinomas, osteoporosis, neurodegenerative and infectious diseases, and diseases involved with inflammation and immune system, renal insufficiency (diabetic and non-diabetic), diabetic nephropathy, glomerulonephritis, glomerular sclerosis, proteinuria of primary renal disease, diabetic retinopathy, all types of heart failure including acute and chronic congestive heart failure, dysfunction of the ventricle left and hypertrophic cardiomyopathy, diabetic cardiac myopathy, ventricular and supraventricular arrhythmias, atrial fibrillation and atrial palpitation, angina pectoris (both unstable and stable), myocardial infarction and its sequelae, ischemia / reperfusion injury, harmful vascular restoration including vascular restenosis, treatment of other vascular disorders such as migraines, peripheral vascular disease and Raynaud's disease, multiple sclerosis, cerebral infarction, spinal cord injury, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and polyglutamine diseases such as Huntington and spinocerebellar ataxia, Infectious diseases including leishmaniasis, diseases involved in inflammation and the immune system and diseases involved in muscle degeneration.