WO2016154694A1

WO2016154694A1 - N-acylhydrazone compounds inhibiting histone desacetylase enzymes, pharmaceutical compositions containing same, and method for producing same

Info

Publication number: WO2016154694A1
Application number: PCT/BR2016/000034
Authority: WO
Inventors: Carlos Alberto Manssour Fraga; Daniel ALENCAR RODRIGUES
Original assignee: Universidade Federal Do Rio De Janeiro-Ufrj
Priority date: 2015-03-30
Filing date: 2016-03-30
Publication date: 2016-10-06
Also published as: BR102015007034A2; BR102015007034B1

Abstract

The present invention relates to N-acylhydrazone derivatives with histone deacetylase enzyme inhibiting activity, to anti-tumour pharmaceutical compositions that comprise said compounds, and to methods for producing the same. The present invention further provides a method for treating cell proliferative diseases by means of the histone deacetylase-inhibiting property. Formula (I)

Description

Patent Invention Descriptive Report

N-ACYLIDRAZONIC ENZYME INHIBITOR COMPOUNDS, PHARMACEUTICAL COMPOSITIONS CONTAINING THE

SAME, PROCESS FOR YOUR PRODUCTION

Field of the Invention

The present invention is related to Î²-acylhydrazonic derivatives which exhibit histone deacetylase enzyme inhibitory activity, anti-tumor pharmaceutical compositions comprising such compounds, and processes for their production. The present invention further provides a method of treating cell proliferative diseases due to the inhibitory property of histone deacetylases.

Background of the Invention

Epigenetics is concerned with the inheritance of information based on levels of gene expression, differing from genetics that encompasses the transmission of information based on information contained in the DNA sequence. The main epigenetic modifications found in mammals are DNA methylation and post-translational changes in histones (acetylation, deacetylation, methylation, phosphorylation, etc.) (Pachaiyappan, B. & Woster, PM, Bioorg. Med. Chem. Lett, 2014, 24, 21; Ropero, S. & Esteller, M, Mol. Oncol., 2007, 1,19).

The development of cancer is not restricted to genetic alterations, it is necessary to consider that epigenetic alterations may also be related to the process of tumorigenesis. One of the best studied modifications is DNA methylation and a particular case is the promoter hypermethylation of tumor suppressor genes, leading to non-expression of this gene and, consequently, to tumor development (Esteller, M. Oncogene, 2002, 21 , 5427; Ropero, S. & Esteller, M., Mol. Oncol., 2007, 1,19). However, it is necessary to recognize that when having a Inadequate epigenetic expression, genes can be suppressed, and when these genes relate to tumor suppressor genes, cell cycle inhibitors, differentiation factors, and apoptosis inducers, they lead to a loss of expression of their products and, consequently, advantages for tumor development (Glozak, MA & Seto, E. Oncogene, 2007, 26, 5420).

[004] In recent years, the study of the involvement of abnormal histone modification patterns and their relationship to cancer development has experienced a large growth, largely stimulated by the approval of Vorinostat (hydroxamic suberoylanilide acid (1) - SAHA ), in 2006, by the United States Food and Drug Administration (FDA) for the treatment of cutaneous T-cell lymphoma (Richon, VM Br. J. Cancer, 2006 95, S2 .; Witt, O. et al., Cancer Lett, 2009, 277, 8). SAHA is a histone deacetylase inhibitor and acts on modulation of gene expression, important in cell differentiation (Richon, V. Br. J. Cancer, 2006, 95, S2).

The nucleosome is a highly conserved multiprotein complex that occurs every 200 ± 40 base pairs in all eukaryotic genomes, with 146 base pairs coiling around the histone nucleus, which is formed from two copies of each of the histone proteins, H2A, H2B, H3 and H4. These proteins are arranged in two dimers of H2A and H2B and one tetramer of H3 and H4, which give rise to the octameric structure of the histone nucleus (Kornberg, RD Science, 1974, 184, 868 .; Luger, K. et al., Nature, 1997, 389, 251 (Kornberg, RD & Lorch, Y. Celi, 1999, 98, 285). The nucleosome is of utmost importance in DNA packaging in the nucleus, and this packaging generally inhibits interaction with DNA binding proteins, such as transcription factors (Luger, K. et al., Nature, 1997, 389, 251 ).

The histone nucleus is predominantly globular, except for the presence of tails / V-termini, rich in basic amino acid residues, which lack a definite structure, but these tails give the histones the possibility of a large number of modifications (Luger, K. et al., Nature, 1997, 389, 251; Kouzarides, T. Celi, 2007, 128, 693).

The best characterized and most abundant modifications are methylation and acetylation of histones. The histone acetylation pattern is regulated by two families of enzymes, in which histone acetyltransferases (HATs) catalyze the transfer of an acetyl group to the tail-lysine residues and the histone deacetylases (HDACs) remove the acetyl group from these. proteins (Kouzarides, T. Celi, 2007, 128, 693).

[008] The balance between histone acetylation and deacetylation may affect the structure of chromatin as it disrupts histone interactions with DNA. When acetylation of lysine residues at the ε-amino position occurs, the positive charge of this residue is neutralized and thus decreases the interaction with negatively charged DNA, favoring an open chromatin configuration, which allows access to specific transcription factors. , besides the transcription machinery. HDACs remove the acetyl group and consequently lead to a compact chromatin state, that is, gene expression is silenced (Glozak, MA & Seto, E. Oncogene, 2007, 26, 5420; Kouzarides, T. Celi, 2007, 128, 693). In addition, some HDACs are recognized for their important role in nonhistoric proteins by controlling the pattern of cytoplasmic protein acetylation and transcription factors (Witt, O. et al., Cancer Lett., 2009, 277, 8 ).

Eighteen HDACs have been identified in the human genome which can be divided into two broad groups: the zinc-dependent HDACs (classes I, Ha, llb and IV) and the known nicotinamide and adenine dinucleotide-dependent HDACs (NAD ⁺⁾ as sirtuins (class III). HDACs are further divided according to the phylogenetic sequence, in which in class I we have HDAC1, HDAC2, HDAC3 and HDAC8; in class IIa, HDAC4, HDAC5, HDAC7, HDAC9; in class llb, the HDAC6 and HDAC10 and the class IV to HDAC 1 1 as sole member. Sirtuins 1-7 form the class IH (Gregoretti, IV et al., J. Mol. Biol., 2004, 338, 17; Witt, O. et al., Cancer Lett., 2009, 277, 8).

[010] Classes I, II and IV are referred to as classic HDACs. Because they have zinc (Zn ⁺ ) dependent catalytic site, they can be inhibited by compounds that have the ability to chelate with this ion, such as hydroxamic acids. The term "histone deacetylase inhibitors" is commonly used for compounds targeting classic HDAC (class I, II and IV) (Gregoretti, IV et al., J. Mol. Biol., 2004, 338, 17; Witt, O. et al., Cancer Lett, 2009, 277, 8).

[01 1] Somatic mutations in HDAC genes are rare, but alterations in expression and problems in regulating these genes may be related to tumor development through altered gene transcription and nonhistoric proteins (New, M et al., Mol. Oncol., 2012, 6, 637).

[012] Imbalance between HAT and HDAC activities with consequent hypoacetylation may be a necessary step for human carcinogenesis, as an abnormal pattern of histone H4 modification, characterized by a loss of monoacetylation in lysine 16 and Lysine 20 trimethylation, present in repetitive DNA sequences, is seen only in cancer cells and is associated with tumorigenesis process. This modification in H4 is considered a cancer signature. In addition, HDAC overexpression can be observed in cancer cells of various organs such as stomach, colon and breast (Liu, T. et al., Cancer Treat. Rev., 2006, 32, 157).

[013] Chromosomal translocations may lead to the formation of abnormal chimeric proteins that recruit enzymes with HAT or HDAC activities and may lead to an unwanted effect on gene transcription. In leukemias promyelocytic, chromosomal translocation between the retinoic acid receptor α (RARa) and the promyelocytic leukemia protein (PL) leads to the formation of a PML-RARa fusion protein (t15; 17) that acts as a transcriptional repressor by high affinity interaction with corrpressors and consequent HDAC recruitment for the complexes (Epping, MT & Bernards, R. Int. J. Biochem. Celi. Biol., 2009, 41, 16 ;, Liu, T. et al., Cancer Treat Rev. 2006, 32, 157). RARa is a regulator of myeloid differentiation, is a member of the nuclear receptor superfamily, and acts as a transcription factor in the presence of its ligand; in its absence, RARa functions as a transcriptional repressor. When retinoic acid presents at physiological concentrations, it promotes conformational changes in its receptor and leads to the release of the repressor complex, followed by recruitment of co-activators that lead to transcription, however the PML-RARa fusion protein has the ability to bind to complexes containing HDAC and other chromatin modifying enzymes. Thus, PML-RARa is no longer sensitive to physiological concentrations of retinoic acid, leading to silencing of cell differentiation (Botrugno, OA et al., Cancer Lett., 2009, 280, 134; Epping, MT & Bernards, R. Int. J. Biochem. Celi. Bio., 2009, 41, 16).

PML-RARa fusion protein is not the only one that inhibits retinoic acid signaling, there are other translocation products that share features with PML-RARa, such as PLZF-RARa (Fingertip fusion protein). promyelocytic leukemia protein zinc with RARa), which is caused by t translocation (11; 17), this is a type of rare promyelocytic leukemia. Fusion proteins can be observed in acute myelocytic leukemias, such as the t (8,21) translocation that generates the AML1-ETO product (Botrugno, OA et al., Cancer Lett., 2009, 280, 134; Liu, T et al., Cancer Treat Rev. 2006, 32, 157).

[015] As noted, HDACs control a large number of processes that may be related to the tumorigenesis process. and also with tumor growth and advancement. Thus, the development of new HDAC inhibitor compounds may be of great interest in the fight against cancer.

[016] A large number of compounds have the ability to inhibit HDAC activity, mainly of class I and II, among which, with few exceptions they can be separated into structural classes such as hydroxamates, carboxylates, benzamides, electrophilic ketones. and macrocyclic peptides. Despite apparent structural diversity, both share a common pharmacophoric group, which concerns inhibitor-enzyme interaction elements (Miller, TA et al., J. Med. Chem., 2003, 46, 5097; Patel, V. et al., J. Med. Chem., 2009, 52, 2185).

[017] In general, HDAC inhibitors can be described by a metal interaction subunit that will interact with zinc at the enzyme's active site; a spacer, which will occupy the HDACs channel, so the compounds have some structural relationship with lysine, being possible to observe linear, cyclic, saturated or unsaturated spacers. And finally, a subunit for active site edge recognition consisting of hydrophobic groups, most often aromatic systems (Miller, T.A. et al., J. Med. Chem., 2003, 46, 5097).

[018] The preclinical efficacy of HDAC inhibitors is attributed to the gene activation promoted by these agents, which is related to the induction of histone N-terminal tails hyperacetylation, which will allow access to transcription factors in gene promoters. . However, due to the presence of a large number of non-histonic substrates it is not possible to know what are the key targets of HDAC inhibitor action, as simultaneous action on many substrates can have a synergistic effect to the final effect (Epping, MT & Bernards, R. Int. J. Biochem. Celi. Biol., 2009, 41, 16). HDAC inhibitors alter the transcription of a small portion of the expressed genes from 2 to 10% by histone acetylation and transcription factor acetylation. One gene that is commonly expressed is the p21 ^WAF1 cyclin-dependent kinase ^inhibitor , which is responsible for cell cycle arrest in transformed cells. Increased p21 expression leads to hypophosphorylation of the retinoblastoma protein (Rb) which leads to its cytoprotective growth suppressing state (Bolden, JE et al., Nat. Rev. Drug. Discov., 2006, 5, 769) .

[020] HDAC inhibitors promote the acetylation of a large number of transcription factors, including factors of great importance in the carcinogenesis process, such as p53, a tumor suppressor, which, when acetylated, increases its DNA binding that leads to transcription of the genes regulated by this factor. Acetylation confers not only the activation of this factor, but also increased stability, as the acetylated residues overlap those that would be ubiquitated, leading the protein to degradation, with the expression of target genes, leading to the induction of checkpoints. of cell cycle related to cell proliferation (Richon, VM Br. J. Cancer, 2006, 95, S2; Ropero, S. & Esteller, M, Mol. Oncol., 2007, 1, 19).

[021] There are two FDA-approved HDAC inhibitors to date for the treatment of cutaneous T-cell lymphoma, and SAHA (1) was initially approved in 2006, followed by the cyclic depsipeptide romidepsin (FK228 (3)). In 201 1, FK228 (3) was approved for the treatment of peripheral T-cell lymphoma. FK228 is a pentapeptide isolated from Chromobacterium violacium cultures, which contains a disulfide bond which is reduced in vivo to its active form (4) (Figure 1) (Thaler, F & Mercury, C. ChemMedChem, 2014, 9, 523).

[022] Several other HDAC inhibitors are in clinical phase (Phase I, II or III) for various types of cancers, solid or haematological. Although they have structural diversity, they all have similar structural requirements that confer the ability to interact with histone deacetylases, that is, they have in common the pharmacophoric edge-spacer-chelating element interaction model, as described earlier (Bradner, JE et al. (Ar. Chem. Biol., 2010, 6, 238).

[023] The patent literature contains several examples of compounds that act to inhibit HDAC, it is worth mentioning the large number of documents referring to the year 2014, they are US 2014/0142104, US 2014/0206645, US 2014/0371469, US 2014 / 0128391, WO 2014/014900, WO 2014/072714, WO 2014/1 16962, WO 2014/121062, WO 2014/131855, WO 2014/143666, WO 2014/147178, WO 2014/152444, WO 2014/159210, WO 2014/159218, WO 2014/160221, WO 2014/180984 and CN103880736A. Although these compounds protected by these documents have a great structural diversity, both have the same elements of interaction with the enzyme active site, which consists of the edge-spacer-chelating pharmacophore.

[024] CN103880841 A presents the structure of compounds / V-acylhydrazones which are used as histone deacetylase inhibitors, however in this document no substitution in function / V-acylidrazone is shown, for example by the use of methyl. amidic and iminic subunits, as shown in this document. In addition, the enzyme edge interaction group is very specific for the compounds shown in CN103880841 A.

[025] It can then be seen that the compounds of the present invention are indeed novel, and considering the studies carried out, it can be stated that one skilled in the art would not be motivated to modify, without further difficulty, the existing structures of the present invention. of the art in order to reach the compounds of the present invention, which have differentiated HDAC inhibitory activity profile from the already described V-acylhydrazonic compounds, thus conferring inventive activity thereon. Summary of the Invention

[026] In a first aspect, the present invention relates to the identification of N-acylhydrazonic derivatives which exhibit histone deacetylase inhibitory activity (HDAC).

[027] Therefore, N-acylhydrazonic derivatives with structure according to

Where: Ar is phenyl, naphthyl, substituted phenyl and substituted naphthyl. Ar is heteroaryl and substituted heteroaryl chosen from: 1 H-pyrrol-2-yl, 1 H - pyrrol-3-yl, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophenyl; 3-yl, 1H-pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, 1H-imidazol-1-yl , 1 H -imidazol-2-yl, 1 H -imidazol-4-yl, 1 H -imidazol-5-yl, 1 HA, 2,3-triazoM-yl, 1 HA, 2,3-triazol-4-one yl, 1 HA, 2,3-triazazol-5-yl, 2H-1,2,3-triazazol-2-yl, 2HA, 2,3-triazol-4-yl, 2HA, 2,3-triazol-5 -1H-1,2,4-triazol-1-yl, 1 H -1,2,4-triazol-3-yl, 1 W -1,2,4-triazol-5-yl, 4HA, 2,4-triazol-4-yl, 4H-1,2,4-triazol-3-yl, 4H-1,2,4-triazol-5-yl, 1 H-tetrazol-1-yl 1 H-tetrazol -5-yl, 2H-tetrazol-2-yl, 2H-tetrazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl , isoxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, 1,2,4-oxadiazole -3-yl, 1,2,4-oxadiazol-5-yl, 1,2,5-oxadiazol-3-yl, 1,2,5-oxadiazol-4-yl, 1,2,4-thiadiazol-3 -1,2,4-thiadiazol-5-yl, 1,2,5-thiadiazol-3-yl, 1,2,5-thiadiazol-4-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl, pyridazin-1 3-yl, pyridazin-4-yl, pyridazin-5-yl, pyridazin-6-yl, pyrazin-2-yl, pyrazin-3-yl, pyrazin-5-yl, pyrazin-6-yl, 1, 3, 5-triazin-2-yl, 1,2,5-triazin-4-yl, 1,2,5-triazin-6-yl, 1,2,4-triazin-3-yl, 1,2,4- triazin-5-yl, 1,2,4-triazin-6-yl, 1H-indol-1-yl, 1H-indol-2-yl, 1H-indol-3-yl, 1H-indol-2-yl 5-yl, 1 H-indol-6-yl, 1 H-indol-7-yl, 1 H-indol-8-yl, 1 H-indazol-3-yl, 1 - / - indazol-5-yl, 1 H-indazol-6-yl, 1 H-indazol-7-yl, 1 H-indazol-8-yl, 1 H-benzo [d] imidazol-1-yl, 1 H-benzo [d] imidazol-2 -yl, 1 H-benzo [w /] imidazol-5-yl, 1 H-benzo [d] imidazol-6-yl, 1 H-benzo [d] imidazol-7-yl, 1 H-benzo [d] imidazol-8-yl, benzofuran-2-yl, benzofuran-3-yl, benzofuran-5-yl, benzofuran-6-yl, benzofuran-7-yl, benzofuran-8-yl, benzo [b] thiophen-2-yl, benzo [£> ] thiophen-3-yl, benzoflb] thiophen-5-yl, benzo [<b] thiophen-6-yl, benzo [?] thiophen-7-yl, benzo [£>] thiophen-8-yl, quinolin-2 -yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, isoquinolin-1-yl, isoquinolin-3-yl , isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl, isoquinolin-8-yl, quinazolin-2-yl, quinazolin-4-yl, quinazolin-5-yl, quinazolin -6-yl, quinazolin-7-yl, quinazolin-8-yl, quinoxalin-2-yl, quinoxalin-3-yl, quinoxalin-5-yl, quinoxalin-6-yl, quinoxalin-7-yl, quinoxalin-8 -il;

R ₂ and R ₃ independently correspond to H or CH ₃ .

B is selected from: matches;

(The)

Where W is O or S; Y is missing or is N, or CH ₂ .

(B)

Where W and Y are as defined above, R ₄ is selected from hydrogen, hydroxy, amino, halogen, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, dialkylaminosubstituted, substituted or unsubstituted alkylsulfonyl, CF3, CN, N ₃ , NO ₂ , sulfonyl, acyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycles.

(ç)

Where W and Y are as defined above, R 5 is selected from hydrogen and lower alkyl. Or pharmaceutically acceptable salts thereof. [032] A further object of the present invention is a process for producing the Î²-acylhydrazonic derivatives comprising the steps of:

a) esterification of a compound of formula (II):

The U

Ar ^ H

(«)

To produce a compound of formula (III):

The CH ₃

(III)

b) Hydrazinolysis of the compound obtained in the previous step generating a compound of formula (IV):

(IV)

c) Protection of the amine functional group with phthalic anhydride of the compound obtained in the previous step forming the compound of formula (V):

The

(V)

d) V-methylation of the compound obtained in the previous step forming the compound of general formula (VI):

(SAW)

e) Functional group deprotection of the compound obtained in the previous step generating the compound of formula (VII):

CH ₃

(VII)

f) Condensation with intermediates of formula (VIII) to give compounds of formula (I)

(VIII)

g) Compounds of general formula (VIII) are obtained by an acid chloride formation reaction and subsequent reaction with the appropriate nucleophiles.

Where: Ar is phenyl, naphthyl, substituted phenyl and substituted naphthyl. Ar is heteroaryl and substituted heteroaryl chosen from: 1 H-pyrrol-2-yl, 1 H-pyrrol-3-yl, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-one -1H-pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, 1H-imidazol-1-yl, 1H- imidazol-2-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl, 1H-1,2,3-triazol-1-yl, 1H-1,2,3-triazole 4-yl, 2,3-triazol-5-yl, 2H-1,2,3-triazol-2-yl, 2H-1,2,3-triazol-4-yl, 2H-1,2,3 -triazol-5-yl, 2,4-triazol-1-yl, 1H-1,2,4-triazol-3-yl, 2,4-triazol-5-yl, 4H-, 2,4 -triazol-4-yl, 4- [1,2-triazol-3-yl, 4H-1,2,4-triazol-5-yl, 1H-tetrazol-1-yl] -1H-tetrazol -5-yl, 2H-tetrazol-2-yl, 2H-tetrazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-β, isoxazol-4-yl , isoxazol-5-yl, thiazoi-2-ii, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, 1,2,4-oxadiazole -3-yl, 1,2,4-oxadiazol-5-yl, 1,2,5-oxadiazol-3-yl, 1,2,5-oxadiazol-4-yl, 1,2,4-thiadiazol-3 -1,2,4-thiadiazol-5-yl, 1,2,5-thiadiazol-3-yl, 1,2,5-thiadiazol-4-yl, pyridin-3-yl, pyridin-4-yl pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl, pyridazin-3-yl, pyridazin-4-yl, pyridazin-5-yl, pyridazin-6-yl, pyrazin -2-yl, pyrazin-3-yl, pyrazin-5-yl, pyrazin-6-yl, 1,2,5-triazin-2-yl, 1,2,5-triazin-4-yl, 1,3 , 5-triazin-6-yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl, 1,2,4-triazin-6-yl, 1H-indol-2-one 1-yl, 1H-indol-2-yl, 1H-indol-3-yl, 1W-indol-5-yl, 1H-indol-6-yl, 1H-indol-7-ii, 1W-indol -8-yl, 1 / - / - indazol-3-yl, 1H-indazol-5-yl, 1H-indazol-6-yl, 1H-indazol-7-yl, H-indazol-8-yl, 1 / - / - benzo [d] imidazol-1-yl, 1 H-benzo [d] imidazol-2-yl, 1 H-benzo [d] imidazol-5-yl, 1 - / - benzo [d] imidazole -6-yl, 1- [benzo [Gflimidazol-7-ii, 1H-benzo [d] iridazol-8-yl, b enzofuran-2-yl, benzofuran-3-yl, benzofuran-5-yl, benzofuran-6-yl, benzofuran-7-yl, benzofuran-8-yl, benzo [?] thiophen-2-yl, benzo [] thiophen -3-yl, benzo [?] Thiophen-5-yl, benzo [?] Thiophen-6-yl, benzo [? Thiophen-7-yl, benzo [6] thiophen-8-yl, quinolin-2-yl, quinolin -3-yl, quinolin-4-Π, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4 -yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl, isoquinolin-8-yl, quinazolin-2-yl, quinazolin-4-yl, quinazolin-5-yl, quinazolin-6-yl quinazolin-7-it, quinazolin-8-yl, quinoxalin-2-yl, quinoxalin-3-yl, quinoxalin-5-yl, quinoxalin-6-yl, quinoxalin-7-if, quinoxalin-8-yl;

R ₂ and R ₃ independently correspond to H or CH ₃ .

B is selected from: matches;

(The)

Where W is O or S; Y is missing or is N, or CH ₂ .

(B)

Where W and Y are as defined above, R ₄ is selected from hydrogen, hydroxy, amino, halogen, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, dialkylaminosubstituted, substituted or unsubstituted alkylsulfonyl, CF ₃ , CN, N ₃ , NO ₂ , sulfonyl, acyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycles.

(ç)

Where W and Y are as defined above, R ₅ is selected from hydrogen and lower alkyl.

In a second aspect, the present invention provides alternatives for the treatment of tumors by regulating epigenetic processes by regulating gene expression.

It is therefore a further object of the present invention a pharmaceutical composition comprising:

(a) an N-acylhydrazonic derivative having a structure according to general formula (I):

Where: Ar is phenyl, naphthyl, substituted phenyl and substituted naphthyl. Ar is heteroaryl and substituted heteroaryl chosen from: 1 H-pyrrol-2-yl, 1 H-pyrrol-3-yl, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-one β, 1 / - / - pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-ii, 1H-pyrazol-5-yl, 1H-imidazol-1-yl, 1H- imidazol-2-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl, 1H-1,2,3-triazol-1-yl, 1H-1,2,3-triazol-4 -1H-1,2,3-triazol-5-yl, 2H-1,2,3-triazol-2-yl, 2H-1,2,3-triazol-4-yl, 2H-1 2,3-triazol-5-yl, 1H-1,2,4-triazol-1-yl, 1H-1,2,4-triazol-3-yl, 1H-1,2,4-triazole -5-yl, 4H-1,2,4-triazol-4-yl, 4H-1,2,4-triazol-4-yl 3-yl, 4H-1,2,4-triazol-5-yl, 1 H-tetrazol-1-yl 1 H-tetrazol-5-yl, 2H-tetrazol-2-yl, 2H-tetrazol-5-yl oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazole -5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-ii, 1,2 , 5-oxadiazol-3-yl, 1,2,5-oxadiazol-4-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,2,5 -thiadiazol-3-yl, 1,2,5-thiadiazol-4-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidine -6-yl, pyridazin-3-yl, pyridazin-4-yl, pyridazin-5-yl, pyridazin-6-yl, pyrazin-2-yl, pyrazin-3-yl, pyrazin-5-yl, pyrazin-6 -1,2,3,5-triazin-2-yl, 1,2,5-triazin-4-yl, 1,2,5-triazin-6-yl, 1,2,4-triazin-3-yl 1,2,4-triazin-5-yl, 1,2,4-triazin-6-yl, 1H-indol-1-yl, 1H-indol-2-yl, 1H-indol-3-one 1 H-indol-5-yl, 1 H-indol-6-yl, 1 H-indol-7-yl, 1 H-indol-8-yl, 1 H-indazol-3-yl, 1 H- indazol-5-yl, 1H-indazol-6-yl, 1H-indazol-7-yl, 1H-indaz ol-8-yl, 1 H -benzo [d] imidazol-1-yl, 1 H-benzo [] imidazol-2-yl, 1 H - / - benzo [d] imidazol-5-yl, 1 H- benzo [cf] imidazol-6-yl, 1 H -benzo [c] imidazol-7-yl, 1H-benzo [d] imidazol-8-yl, benzofuran-2-yl, benzofuran-3-yl, benzofuran-5-yl, benzofuran-6-yl, benzofuran-7-yl, benzofuran-8-yl, benzo [?] thiophen-2-yl, benzo [jb] thiophen-3-yl, benzo [] thiophen-5 -yl, benzo [t>] thiophen-6-yl, benzo [b] thiophen-7-yl, benzo [i)] thiophen-8-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4 -yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, isoquinolin-isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6 -yl, isoquinolin-7-yl, isoquinolin-8-yl, quinazolin-2-yl, quinazol-4-yl, quinazolin-5-yl, quinazolin-6-yl, quinazolin-7-yl, quinazolin-8-yl yl, quinoxalin-2-yl, quinoxalin-3-yl, quinoxalin-5-yl, quinoxalin-6-yl, quinoxalin-7-yl, quinoxalin-8-yl.

R ₂ and R ₃ independently correspond to H or CH ₃ .

B is selected from: matches;

(The)

Where W is O or S; Y is missing or is N, or CH ₂ .

(B)

Where W and Y are as defined above, R ₄ is selected from hydrogen, hydroxy, amino, halogen, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, dialkylaminosubstituted, substituted or unsubstituted alkylsulfonyl, CF ₃₎ C, N ₃ , NO ₂ , sulfonyl, acyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycles.

(ç)

Where W and Y are as defined above, R ₅ is selected from hydrogen and lower alkyl. Or pharmaceutically acceptable salts thereof; and b) a pharmaceutically acceptable carrier.

It is a further object of the present invention a method of treating proliferative diseases comprising a step of administering to a patient an N-acylhydrazonic derivative of structure according to general formula (I):

Where: Ar is phenyl, naphthyl, substituted phenyl and substituted naphthyl. Ar is heteroaryl and substituted heteroaryl chosen from: 1 H -pyrrol-2-yl, 1H-pyrrol-3-yl, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, 1H-pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl -1H-pyrazol-5-yl, 1H-imidazol-1-yl, 1H-imidazol-2-yl, 1H-imidazoyl-4-yl, 1H-imidazol-5-yl, 1H-1 2,3-triazol-1-yl, 1H-1,2,3-triazol-4-yl, 1H-1,2,3-triazol-5-yl, 2H-1,2,3-triazole -2-yl, 2H-1,2,3-triazol-4-yl, 2H-1,2,3-triazol-5-yl, 1H-1,2,4-triazol-1 H -1 2,4-triazol-3-yl, 1H-1,2,4-triazol-5-yl, 4H-1,2,4-triazol-4-yl, 4H-1,2,4-triazol-2-one 3-yl, 4H-1,2,4-triazol-5-ii, 1 H-tetrazol-1-yl 1 H-tetrazol-5-yl, 2H-tetrazol-2-yl, 2H-tetrazol 5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazot-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-2-yl 5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2, 5-oxadiazol-3-yl, 1,2,5-oxadiazo-4-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,2,5 -thiadiazol-3-yl, 1,2,5-thiadiazol-4-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin n-5-yl, pyrimidin-6-yl, pyridazin-3-yl, pyridazin-4-yl, pyridazin-5-yl, pyridazin-6-yl, pyrazin-2-yl, pyrazin-3-yl, pyrazin-2-yl 5-yl, pyrazin-6-yl, 1,2,5-triazin-2-yl, 1,2,5-triazin-4-ii, 1,2,5-triazin-6-yl, 1,2, 4-triazin-3-yl, 1,2,4-triazin-5-yl, 1,2,4-triazin-6-yl, 1H-indol-1-yl, 1H-indol-2-yl, 1 H-indol-3-yl, 1 H-indol-5-yl, 1 H-indol-6-yl, 1 H-indol-7-yl, 1 H-indol-8-yl, 1 H-indazol-1 3-yl, 1H-indazol-5-yl, 1H-indazol-6-yl, 1H-indazol-7-yl, 1H-indazol-8-yl, 1H-benzo [d] imidazol-1 -1,1-H-benzo [c] imidazol-2-yl, 1 H-benzo [cfimidimid-5-ii, 1 H-benzophc / Jimidazol-Î³-yl, 1 / - / - benzo [c] imidazol-7 -1,1-H-benzo [d 3 imidazol-8-yl, benzofuran-2-yl, benzofuran-3-yl, benzofuran-5-yl, benzofuran-6-yl, benzofuran-7-yl, benzofuran-8-yl, benzo [b] thiophen-2-yl, benzo [b] thiophen-3-yl, benzo [/?] thiophen-5-yl, benzo [bjtiofen-6-yl, benzo [j] thiophen-7-yl, benzo [?>] Thiophen-8-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8- il, isoquinolin-1-i 1, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl, isoquinolin-8-yl, quinazolin-2-yl, quinazolin-4-yl, quinazolin-5-yl, quinazotin-6-yl, quinazolin-7-yl, quinazolin-8-yl, quinoxalin-2-yl, quinoxalin-3-yl, quinoxalin-5-yl, quinoxalin-6-yl, quinoxin-7-yl, quinoxalin-8-yl.

R ₂ and R ₃ independently correspond to H or CH ₃ .

B is selected from: matches;

(The)

[045] Where W is O or S; Y is missing or is N, or CH ₂

Where W and Y are as defined above, R ₄ is selected from hydrogen, hydroxy, amino, halogen, alkoxy, substituted alkoxy, alkylamino,. substituted alkylamino, dialkylamino, substituted dialkylaminos, substituted or unsubstituted alkylsulfonyl, CF ₃ , CN, N ₃ , NO ₂ , sulfonyl, acyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycles.

Where W and Y are as defined above, R ₅ is selected from hydrogen and lower alkyl. Or pharmaceutically acceptable salts thereof;

In a preferred embodiment, the derivatives are chosen from the group comprising:

(R) -3 - ((2- (4- (dimethylamino) benzoyl) -2-methylhydrazono) methyl) -A / - hydroxybenzamide (5g - LASSBio - 1908)

(E) -4 - ((2- (4- (dimethylamino) benzoyl) -2-methylhydrazono) methyl) - [N-hydroxybenzamide (5h - LASSBio - 1909)

(E) -3 - ((2- (4- (dimethylamino) benzoyl) hydrazono) methyl) - N -hydroxybenzamide (5i - LASSBio - 1910)

(E) -4 - ((2- (4- (dimethylamino) benzoyl) hydrazono) methyl) - N -hydroxybenzamide

(5j - LASSBio-1911) Description of the Figures

Figure 1: FDA approved HDAC inhibitors.

Figure 2: Genesis of new V-acylhydrazonic derivatives designed from trichostatin A (2).

Figure 3: Molecular anchoring of SAHA (1) (A), LASSBio-1909 (5h) (B), LASSBio-1910 (5i) (D) and LASSBio-191 (5j) (C) compounds. Rigid molecular mooring studies were performed using the GOLD 5.1 program (CCDC; License Number: G / 414/2006).

Figure 4: LASSBio-1909 rat liver HDAC IC50 determination (5h).

Figure 5: IC50 determination in LASSBio-1910 rat liver HDAC (5i)

Figure 6: Determination of IC ₅₀ in LASSBio-1911 rat liver HDAC (5j).

Detailed Description of the Invention

The following examples are for illustration purposes only, without limiting the scope of the present invention. Any variations that may be made by one of ordinary skill in the art should be considered to be within the scope of the present invention.

Derivatives / V-acylhydrazones

[050] The derivatives of the present invention are V-acylhydrazonic derivatives having structure according to the general formula (I):

Where: Ar is phenyl, naphthyl, substituted phenyl and substituted naphthyl. Ar is heteroaryl and substituted heteroaryl chosen from: 1 / - / - pyrrol-2-yl, 1H-pyrrol-3-yl, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophenyl; 3-yl, 1H-pyrazol-1-yl, 1H-pyrazol-3-yl, 1H- pyrazol-4-yl, 1H-pyrazol-5-yl, 1H-imidazol-1-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl , 1 H -1,2,3-triazol-1-yl, 1 H -1,2,3-triazol-4-yl, 1 H -1,2,3-triazol-5-yl, 2W-1, 2,3-triazol-2-yl, 2H-1,2,3-triazol-4-yl, 2H-1,2,3-triazol-5-yl, 1 H -1,2,4-triazo-yl -1 H -1,2,4-triazol-3-yl, 1 W -1,2,4-triazol-5-yl, 4H-1,2,4-triazol-4-yl, 4H-1,2 , 4-triazol-3-yl, 4H-1,2,4-triazol-5-yl, 1H-tetrazol-1-yl 1 H -tetrazol-5-yl, 2H-tetrazol-2-yl, 2H- tetrazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, thiazol-2-yl, thiazol-2-yl 4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-one yl, 1,2,5-oxadiazol-3-yl, 1,2,5-oxadiazol-4-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,2,5-thiadiazol-3-yl, 1,2,5-thiadiazol-4-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-2-one 5-yl, pyrimidin-6-yl, pyridazin-3-yl, pyridazin-4-yl, pyridazin-5-yl, pyridazin-6-yl, pyraz in-2-yl, pyrazin-3-yl, pyrazin-5-yl, pyrazin-6-yl, 1,2,5-triazin-2-yl, 1,2,5-triazin-4-yl, 1, 3,5-triazin-6-yl, 1,2,4-triazin-3-yl, 2,4-triazin-5-yl, 1,2,4-triazin-6-yl, 1 / - / - ^' indol-1-yl, 1H-indol-2-yl, 1H-indol-3-yl, 1H-indol-5-yl, 1H-indol-6-yl, 1H-indol-7- yl, 1 H-indol-8-yl, H-indazol-3-yl, 1 H-indazol-5-yl, 1 H-indazol-6-yl, 1 H-indazol-7-yl, 1 / - indazol-8-yl, 1 H-benzo [cf] imidazol-1-yl, 1 H-benzo [d] imidazol-2-yl, 1 H-benzo [d] imidazol-5-yl, 1 H-benzo [ c] imidazol-6-yl, 1H-benzo [c] imidazol-7-yl, 1H-benzo [d] imidazol-8-yl, benzofuran-2-yl, benzofuran-3-yl, benzofuran-5 -yl, benzofuran-6-yl, benzofuran-7-yl, benzofuran-8-yl, benzo [?] thiophen-2-yl, benzo [b] thiophen-3-yl, benzo [?] thiophen-5 yl, benzo [b] thiophen-6-yl, benzo [δ] thiophen-7-if, benzo [6] thiophen-8-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-5-yl 6-yl, isoquinolin-7-i 1, isoquinolin-8-yl, quinazolin-2-yl, quinazolin-4-yl, quinazolin-5-yl, quinazolin-6-yl, quinazolin-7-yl, quinazolin-8-yl, quinoxalin-2-yl, quinoxalin-3-yl, quinoxalin-5-yl, quinoxalin-6-yl, quinoxalin-7-yl, quinoxalin-8-yl.

R ₂ and R ₃ independently correspond to H or CH ₃ .

B is selected from: matches;

(The)

Where W is O or S; Y is missing or is N, or CH ₂

Where W and Y are as defined above, R ₄ is selected from hydrogen, hydroxy, amino, halogen, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted alkylamino, substituted or unsubstituted alkylsulfonyl, CF ₃ , CN, N ₃ , NO ₂ , sulfonyl, acyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycles.

(ç)

By way of example, this report describes the synthesis of the compounds:

(£) -3 - ((2- (4- (dimethylamino) benzoyl) hydrazono) methyl) benzoic acid (5a - LASSBio - 1902)

Methyl -3 - ((2- (4- (dimethylamino) benzoyl) hydrazono) methyl) benzoate (5b - LASSBio - 1903)

(E) -4 - ((2- (4- (dimethylamino) benzoyl) hydrazono) methyl) benzoic acid (5d - LASSBio - 1905)

(E) -4 - ((2- (4- (dimethylamino) benzoyl) hydrazono) methyl) methyl benzoate (5e - LASSBio - 1906)

(E) -3 - ((2- (4- (dimethylamino) benzoyl) -2-methylhydrazono) methyl) - N -hydroxybenzamide (5g - LASSBio - 1908)

(R) -4 - ((2- (4- (dimethylamino) benzoyl) -2-methylhydrazono) methyl) -A / - hydroxybenzamide (5h - LASSBio - 1909)

(R) -3 - ((2- (4- (dimethylamino) benzoyl) hydrazono) methyl) - N -hydroxyben

(5i-LASSBio-1910)

(E) -4 - ((2- (4- (dimethylamino) benzoyl) hydrazono) methyl) -Î ”-hydroxybenzam

(5j - LASSBio-1911)

(E) -3 - ((2- (4- (dimethylamino) benzoyl) -2-methylhydrazono) methyl) benzoic acid (5k - LASSBio -1912)

(E) -4 - ((2- (4- (dimethylamino) benzoyl) methylhydrazono) methyl) benzoic acid (5I - LASSBio -1913)

(E) -4- (1- (2- (4- (dimethylamino) benzo

(5m- LASSBio -1935)

(E) -4- (1- (2- (4- (dimethylamino) benzoyl) -2-methylhydrazono) ethyl) - N -hydroxybenzamide (5n - LASSBio - 1936)

Pharmaceutical Composition

[056] The present invention comprises the pharmaceutical composition for treating proliferative diseases with:

(a) V-acylhydrazonic derivatives having a structure according to general formula (I):

Where: Ar is phenyl, naphthyl, substituted phenyl and substituted naphthyl. Ar is heteroaryl and substituted heteroaryl chosen from: 1 / - / - pyrrol-2-yl, 1H-pyrrol-3-yl, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophenyl; 3-yl, 1H-pyrazol-1-yl, 1H-pyrazol-3-yl, λΗ-pyrazol-4-yl, 1H-pyrazol-5-yl, 1H-imidazoM-yl, 1H-Imidazol-2-yl -1 / - imidazol-4-yl, H-imidazol-5-yl, 1H-1,2,3-triazol-1-yl, 1H-1,2,3-triazol-4-yl, 1H-1 2,3-triazol-5-yl, 2H-1,2,3-triazol-2-yl, 2H-1,2,3-triazol-4-yl, 2H-1,2,3-triazol-5 -yl, 1H-1,2,4-triazole-1- yl, 1H-1,2,4-triazol-3-yl, 1H-1,2,4-triazol-5-yl, 4W-1,2,4-triazol-4-yl, 4H-1, 2,4-triazol-3-yl, 4H-1,2,4-triazol-5-yl, 1 H-tetrazol-1-yl 1 H-tetrazol-5-yl, 2 / - / - tetrazol-2-one yl, 2H-tetrazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, thiazol-2-yl yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4- oxadiazol-5-yl, 1,2,5-oxadiazol-3-yl, 1,2,5-oxadiazol-4-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazole 5-yl, 1,2,5-thiadiazol-3-yl, 1,2,5-thiadiazol-4-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4 yl, pyrimidin-5-yl, pyrimidin-6-yl, pyridazin-3-yl, pyridazin-4-yl, pyridazin-5-yl, pyridazin-6-yl, pyrazin-2-yl, pyrazin-3-yl, pyrazin-5-yl, pyrazin-6-yl, 1,2,5-triazin-2-yl, 1,2,5-triazin-4-yl, 1,2,5-triazin-6-yl, 1, 2,4-triazin-3-yl, 1,2,4-triazin-5-yl, 1,2,4-triazin-6-yl, 1H-indol-1-yl, 1H-indol-2-one 1 H-indol-3-yl, 1 H-indol-5-yl, 1 H-indol-6-yl, 1 H-indol-7-yl, 1 H-indol-8-yl, 1 H-indazol-3-yl, 1 H-indazol-5-yl, 1 H-indazol-6-yl, 1 H-indazol-7-yl, 1 H-indazol-8 -1yl, 1H-benzo [d] imidazol-1-yl, 1H-benzo [cijimidazol-2-yl, 1H-benzo [d] imidazol-5-yl, 1H-benzo [c] imidazol-6 -1H-benzo [d] imidazol-7-yl, 1 H-benzo [d] imidazol-8-yl, benzofuran-2-yl, benzofuran-3-yl, benzofuran-5-yl, benzofuran-6 -yl, benzofuran-7-yl, benzofuran-8-yl, benzo [6] thiophen-2-yl, benzo [jb] thiophen-3-yl, benzo [] thiophen-5-yl, benzo [j] thiophen -6-yl, benzo [6] thiophen-7-yl, benzo [6] thiophen-8-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin -6-yl, quinolin-7-yl, quinolin-8-yl, isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7 -yl, isoquinolin-8-yl, quinazolin-2-yl, quinazolin-4-yl, quinazolin-5-yl, quinazolin-6-yl, quinazolin-7-yl, quihazolin-8-yl, quinoxalin-2-yl quinoxalin-3-yl, quinoxalin-5-yl, quinoxalin-6-yl, quinoxalin-7-yl, quinoxalin-8-yl.

R 2 and R 3 independently correspond to H or CH ₃ .

B is selected from: matches;

(The)

W

^ Υ ^Λ Ν- ° ^Η

H

Where W is O or S; Y is missing or is N, or CH ₂ .

(B)

Where W and Y are as defined above, R ₄ is selected from hydrogen, hydroxy, amino, halogen, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, dialkylaminosubstituted, substituted or unsubstituted alkylsulfonyl, CF ₃ , CN, N ₃ , NO ₂ , sulfonyl, acyl, aliphatic, substituted aliphatic, aryan, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycles.

(ç)

W

Where W and Y are as defined above, R 5 is selected from hydrogen and lower alkyl. Or pharmaceutically acceptable salts thereof and

b) a pharmaceutically acceptable carrier.

The pharmaceutical composition described herein preferably comprises an active ingredient selected from LASSBio-1909 (5h), LASSBio-1911 (5j), LASSBio-1910 (5i), LASSBio-1908 (5g), and their counterparts (5a-n) , agents designed as HDAC inhibitors designed from Trichostatin A (2) (Figure 2).

Pharmaceutical compositions containing the compounds of the invention are usually prepared following conventional methods and may be administered in a variety of dosage forms, for example orally in the form of tablets, capsules, sugar or film-coated tablets, liquid solutions. or suspensions; rectal route in the form of suppositories; parenterally, ie intramuscularly, or by intravenous and / or intrathecal and / or intraspinal infusion or injection.

[063] For example, solid oral forms may contain, along with the active compound, diluents, ie lactose, dextrose, sucrose, cellulose, cornstarch or potato starch; lubricants, ie silica, talc, stearic acid, magnesium or calcium stearate, and / or polyethylene glycols; binding agents, for example starches, gum arabic, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disintegrating agents, for example a starch, alginic acid, alginates or sodium starch glycolate; effervescent mixture; dyes; sugars; wetting agents such as lectin, polysorbates, lauryl sulfates; and, generally, pharmacologically inactive and non-toxic substances used in pharmaceutical formulations. Said pharmaceutical preparations may be manufactured in known manner, for example by means of mixing, granulating, tableting, sugar coating, or film coating processes.

Liquid dispersions for oral administration may be, for example, syrups, emulsions and suspensions. Syrups may contain as a carrier, for example, sucrose or sucrose with glycerine and / or manita and / or sorbitol. Suspensions and emulsions may contain as a carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.

Suspensions or solutions for intramuscular injection may contain, together with the active compound, a pharmaceutically acceptable carrier, ie sterile water, olive oil, ethyl oleate, glycols, ie propylene glycol, and, if desired, appropriate amount of lidocaine hydrochloride. Solutions for intravenous injections or infusions may contain as a carrier, for example sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline or they may contain as a propylene glycol carrier.

Suppositories may contain together with the active compound a pharmaceutically acceptable carrier, for example cocoa butter, polyethylene glycol, sorbitan polyoxyethylene, fatty acid ester surfactant or lecithin.

Production Process of N-Acylhydrazonic Derivatives

[067] The compounds of the present invention were designed through convergent syntheses, obtained in good to excellent chemical yields, using synthetic methodology described here (Schemes 1, 2 using classical reactions such as:

• Converting Functional Groups

^■ Functional Group Protection and Unprotection

^■ Acid Condensation Reaction

This is 1

Reactors and conditions: a) KOH, ₁₂ , Methanol, 0 ° C, 10h, 57%; b) N ₂ H ₄ .H ₂ O, Ethanol, 80 ° C, 18h, 95%; c) phthalic anhydride, without solvent, 180 ° C, 2h, 76%; d) CH ₃ I, K ₂ CO ₃ , Acetone, 50 ° C, 18h, 92%; e) N ₂ K .H ₂ 0 Ethanol 80 ° C, 2h, 79%.

Scheme 2

13a-d

Reactors and conditions: f) (1) oxalyl chloride, CH ₂ CI ₂ , cat. DF, 0 ° C, 2 h (2) NH 2 H (50% aqueous solution), TEA, THF, 0 ° C, 20 ', 64-70%;

Scheme 3:

Reagents and conditions: g) _aq HCl 37% cat., Ethanol, rt, 64-98%; h) AcOH cat., Ethanol, microwave, 80 ° C, 30min, 45%; i) AcOH cat., Ethanol, microwave, 135 ° C, 120min, 38%;

[068] The process of producing derivatives of formula (I) then comprises the steps of:

a) esterification of a compound of formula (II):

THE

Ar- ^ H

THE")

To produce a compound of formula (III):

THE

A CH ₂

"The

(III)

THE

Ar "N ²

H

(IV)

(V)

(V!)

H ₃

(VII)

f) Condensation with the intermediates of formula generates! (VIII) to give compounds of general formula (I)

(VIII)

Where: Ar is phenyl, naphthyl, substituted phenyl and substituted naphthyl. Ar is heteroaryl and substituted heteroaryl chosen from:

1 H-pyrrol-2-yl, 1 H-pyrrol-3-yl, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, 1 H-pyrazol-2-yl

1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, 1H-imidazol-1-yl, 1H-imidazol-1-yl

2-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl, 2,3-triazol-1-yl, 1H-1,2,3-triazol-4-yl, 1H -1,2,3-triazol-5-yl, 2H-1,2,3-triazol-2-yl, 2H-, 2,3-triazol-4-yl, 2H-1,2,3-triazole 5-yl, 1-1,4,4-triazol-1-yl, 1H-1,2,4-triazol-3-yl, 1 W -1,2,4-triazol-5-yl, 4H-1,2,4-triazol-4-yl, 4 / - / - 1,2,4-triazol-3-yl, 4H-1,2,4-ίπ3ΖθΙ-5-ίΙ, 1 H-tetrazol-2 1-yl 1 W-tetrazol-

5-yl, 2H-tetrazol-2-yl, 2H-tetrazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-2-yl

3-yl, isoxazol-4-yl, isoxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5- yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,5-oxadiazol-3-yl, 1,2,5-oxadiazol-4-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,2,5-thiadiazol-3-yl, 1,2,5-thiadiazol-4-yl, pyridin-2-one 3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl, pyridazin-3-yl, pyridazin-4-yl, pyridazin-5 il, pyridazin-

6-yl, pyrazin-2-yl, pyrazin-3-yl, pyrazin-5-yl, pyrazin-6-yl, 1,2,5-triazin-2-yl, 1,2,5-triazin-4-one yl, 1,2,5-triazin-6-yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl, 1,2,4-triazin-6-yl, 1 H-indol-1-yl, 1 H-indol-2-yl, 1 H-indol-3-yl, 1 H-indol-5-yl, 1 H-indol-6-yl, 1 H-indol-2-yl 7-yl, 1H-indol-8-yl, 1H-indazol-3-yl, 1H-indazol-5-yl, 1H-indazol-6-yl, 1H-indazol-7-yl, 1 H-indazol-8-yl, 1 H-benzo [d] imidazol-1-yl, 1 H-benzo [d] imidazol-2-yl, 1 H-benzo [cf] imidazol-5-yl, 1- -benzo [c] imidazol-6-yl, 1 H -benzo [d] imidazol-7-yl, 1H-benzo [cf] imidazol-8-yl, benzofuran-2-yl, benzofuran-3-yl, benzofuran-5-yl, benzofuran-6-yl, benzofuran-7-yl, benzofuran-8-yl, benzo [b] thiophen-2-yl, benzo [b] thiophen-3-yl, benzo [b] thiophen-5-yl, benzo [b] thiophen-6-yl, benzo [?] thiophen-7-yl, benzo [i)] thiophen-8-yl , quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, isoquinolin-1-yl, isoquinolin -3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl, isoquinolin-8-yl, quinazolin-2-yl, quinazolin-4-yl, quinazolin-5 -yl, quinazolin-6-yl, quinazolin-7-yl, quinazolin-8-yl, quinoxalin-2-yl, quinoxalin-3-yl, quinoxalin-5-yl, quinoxalin-6-yl, quinoxalin-7-yl quinoxalin-8-yl.

R ₂ and R ₃ independently correspond to H or CH 3.

B is selected from: matches;

(The)

Where W is O or S; Y is missing or is N, or CH ₂ .

(

Where W and Y are as defined above, R ₄ is selected from hydrogen, hydroxy, amino, halogen, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylaminp, dialkylaminosubstituted, substituted or unsubstituted alkylsulfonyl, CF _{3 |} CN, N3, N0 _2, sulfonyl, acyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic.

(ç)

Where W and Y are as defined above, R ₅ is selected from hydrogen and lower alkyl. More specifically, the compounds (5a-5n) of the present invention may be prepared by a key condensation step comprising the reaction between hydrazide intermediates (8 and 11) and ketone carbonyl or aldehyde functionalized intermediates. formula VIII (Scheme 3).

Even more particularly, (E) -3 - ((2- (4- (dimethylamino) benzoyl) hydrazono) methyl) benzoic acid (5a - LASSBio - 1902), (E) -3- ((2- ( Methyl 4- (dimethylamino) benzoyl) hydrazono) methyl) benzoate (5b - LASSBio

- 1903), (R) -3 - ((2- (4- (dimethylamino) benzoyl) -2-methylhydrazono) methyl) methyl (5c - LASSBio - 1904), (R) -4 - ((2 - (4- (dimethylamino) benzoyl) hydrazono) methyl) benzoic (5d - LASSBio - 1905), (E) -4- ((2- (4- (dimethylamino) benzoyl) hydrazono) methyl) benzoate (5e - LASSBio

- 1906), (E) -4 - ((2- (4- (dimethylamino) benzoyl) -2-methylhydrazono) methyl) methyl (5f - LASSBio - 1907), (£) -3 - ((2- (4- (dimethylamino) benzoyl) -2-methylhydrazono) methyl) - N -hydroxybenzamide (5g - LASSBio - 1908), (E) -4 - ((2- (4- (dimethylamino) benzoyl) -2-methylhydrazono ) methyl) - / V-hydroxybenzamide (5h LASSBio - 1909), (.Er) -3 - ((2- (4- (dimethylamino) benzoyl) hydrazono) methyl) - / V-hydroxybenzamide (5i - LASSBio - 1910) , (E) -4 - ((2- (4- (dimethylamino) benzoyl) hydrazono) methyl) - N -hydroxybenzamide (5j - LASSBio-1911), (E) -3 - ((2- (4- (dimethylamino) benzoyl) -2-methylhydrazono) methyl) benzoic acid (5k - LASSBio - 1912), (£) -4 - ((2- (4- (dimethylamino) benzoyl) methylhydrazono) methyl) benzoic acid (51 - LASSBio - 1913), (E) -4- (1- (2- (4- (dimethylamino) benzoyl) hydrazono) ethyl) - N -hydroxybenzamide (5m - LASSBio - 1935), (E) -4- (1- ( 2- (4- (dimethylamino) benzoyl) -2-methylhydrazono) ethyl) - / V-hydroxybenzamide (5n - LASSBio - 1936) and its isomers and regioisomers were designed from structural modifications Trichostatin A (Figure 2); and rationally designed as histone deacetylase inhibitors, planning was confirmed using rigidly anchored molecular modeling (Figures 3 and 4).

[075] A detailed description of the synthetic methods of this invention. for some of the claimed compounds is reported in the following examples.

Example 1- Methyl 4-dimethylamino benzoate (7)

In a 50 ml reaction flask, 500 mg (3.35 mmol) of 4-dimethylamino benzaldehyde (6) was added and solubilized with 5 ml of methanol, the reaction mixture was stirred under bath. of ice (0 ° C). Then, in two Erlenmeyers, 1.105 g of molecular iodine ( ₁₂ ) (4.35 mmol) and 487.76 mg of potassium hydroxide (KOH) (8.71 mmol) were weighed separately. The contents of each vial were solubilized with 10 mL of methanol with the aid of an ultrasound device. The methanol KOH solution was placed in an ice bath to reach a temperature of 0 ° C. The methanol KOH solution and the methanol iodine solution were added separately to the aldehyde-containing solution, the order is not important, however, the iodine and KOH cannot be mixed before being added. After addition of all the contents, the reaction mixture was stirred at 0 ° C for 10h, whereby by CCD monitoring (Rf: 0.62; eluent: hexane: ethyl acetate 20%; developer: UV in 254 nm), it was observed that the reaction did not happen completely. 50 ml of sodium bisulfite solution were added to the reaction medium and the contents were stirred for 30 minutes at 0 ° C, observing the formation of a white precipitate which was filtered, resulting in 339.7 mg of a white solid. (Methyl 4-dimethylamino benzoate) melting point of 97 - 99 ° C, in 57% yield.

[077] ¹ H NMR (400 MHz, CDCl ₃₎ δ (ppm): 7.91 (2H, d, J = 8.0 Hz, H-2 and

H-6); 6.66 (2H, d, J = 8.0 Hz, H3 and H5); 3.85 (3H, s, -OCH ₃ ); 3.03 (6H, s, -N (CH ₃ ) ₂ ).

¹³ C NMR (100 MHz, CDCl ₃ ) δ (ppm): 167.57 (C = 0); 153.25 (C-4); 131.35 (C-2 and C-6); 117.25 (C-1); 1 10.94 (C-3 and C-5); 51, 58 (-0Ç_H _3); 40.29 (-N (CH ₃ ) ₂ ). [079] IR ^(cm-1): 1697.82 (00 _a.); 1278.09 (C-0).

Mass Spectrometry (M ⁺ , positive polarity): 179.97 (M + H)

Example 2- 4-dimethylamino-benzoidrazide (8)

To a 50 mL flask was added 2.93 g of methyl 4-dimethylamino benzoate (7) (16.35 mmol), 20 mL of methanol and 8.0 mL of hydrazine hydrate (163, 51 mmol). The reaction mixture was kept under stirring at reflux temperature, around 70 ° C for 18h. After this time, by analyzing the reaction CCD plate, it was possible to observe the termination of the reaction (Rf: 0.36; eluent: dichloromethane: 5% methanol; developer: UV at 254 nm). Methanol was concentrated under reduced pressure, causing a white solid to precipitate which was filtered off and washed with 50 mL hexane and 50 mL ethyl ether. 2.77g of this white solid was obtained, mp 170-172 ° C.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 9.39 (1H, sl, NH amide); 7.69 (2H, d, J = 8.0 Hz, H-2 and H-6); 6.65 (2H, d, J = 8.0 Hz, H3 and H5); 4.33 (2H, sl, -NJtb); 2.95 (6H, s, -N (CH ₃ ) ₂ ).

¹³ C NMR (50 MHz, DMSO-cfe) δ (ppm): 166.28 (C = 0); 152.03 (C-4); 128.22 (C-2 and C-6); 1 19.55 (C-1); 11.85 (C-3 and C-5); 39.69 (-N (CH ₃ ) ₂ ).

[083] IR (cm ^"1): 3295.96 and 3179.97 (u -NH _2, asymmetric and symmetric stretching _i ^ T32 6.1, ₁ ^ 5 (NH amide), 1596.98 (C = 0 amide).

Mass Spectrometry (M ⁺ , positive polarity): 179.96 (M + H)

Example 3- 4- (dimethylamino) -A- (1'-dioxoisoindolin-1-benzamide (9)

[084] In a ^"50 - mL flask was added 500 mg of 4-dimethylamino benzoidrazida (8) · (2.847 mmol) and allowed to stir the flask contents temperature of 180 ° C to be appreciated the After melting the contents, thereafter added 843.47 mg (5.695 mmol) of phthalic anhydride. addition of phthalic anhydride, a yellow solid was observed to form in the middle of the reaction mixture, with the addition of both solids previously white in color. The reaction was kept under stirring at 180 ° C for 2h, when CCD was observed, the absence of the hydrazide stain and the appearance of a yellowish spot (Rf: 0.45; eluent: dichloromethane: 10% methanol; developer: UV at 254 nm). When the reaction flask was removed from the heating, it was attempted to solubilize the contents with organic solvent, however the product formed had low solubility in hexane and dichloromethane, so the solid was triturated with a gral and pistil, then washed with 100 g. mL of hexane and 100 mL of dichloromethane to remove excess phthalic anhydride. Finally, the solid was washed with 100 mL of saturated sodium carbonate solution. 668 mg (76% yield) of a yellow solid with melting point greater than 250 ° C was obtained.

[085] RN ¹ H (200 MHz, DMSO-d _<6) δ (ppm): 10.86 (1H, brs, NH amide); 8.06 - 7.88 (4H, m, H-2, H-3 ', H-4' and H-5 '); 7.82 (2H, d, J = 8.0 Hz, H-2 and H-6); 6.77 (2H, d, J = 8.0 Hz, H-3 and H-5); 3.01 (6H, s, -N (CH ₃ ) ₂ ).

¹³ C NMR (50 MHz, DMSO-Î ± ^* ₆ ) δ (ppm): 165.87 (C = 0 imide); 165.26 (C = 0 amide); 153.10 (C-4); 135.44 (C-3 'and C-4'); 129.64 (CV and C-6 '); 129.43 (C-2 and C-6); 123.85 (C-2 'and C-5'); 1.82 (C-1); 1.86 (C-3 and C-5); 39.70 (- C (Ç_H ₃₎ _2).

IR (cm- ¹ ): 3275.30 (Î´ amide NH); 1732.67 and 1654.60 (α C = 0 imide, asymmetric and symmetrical stretching); 1599.04 (α C = 0 amide).

[088] Mass spectrometry (M ⁺ , positive polarity): 310.08

(M + H)

4- (dimethylamino) -Î ”- (1,3-dioxoisoindolin-2-yl) - N-methylbenzamide To a 50 ml flask was added 2.3 g (7.44 mmol) of 4- (dimethylamino) - / V- (1,3-dioxoisoindolin-2-yl) benzamide (9) 20 ml acetone and 3.085 g (22.32 mmol) of potassium carbonate (K ₂ CO ₃ ). The reaction mixture was kept under stirring at 50 ° C, then 1.07 ml (14.88 mmol) of methyl iodide (CH ₃ I) was added and a reflux system was coupled and the mixture was maintained. under 50 ° C under reflux for 18h. After this, a more nonpolar product was observed (Rf: 0.75; eluent: dichloromethane: 10% methanol; developer: UV at 254 nm). 15 mL of distilled water was added and the remaining acetone was concentrated under reduced pressure, the yellow solid which was vacuum filtered. 2.2 g (92% yield) of a yellow solid with melting point greater than 250 ° C were obtained.

¹ H NMR (300 Hz, DMSO-d ₆ ) δ (ppm): 8.01 - 7.83 (4H, m, δ-2 ', H-3', H-4 'and H-5 '); 7.32 - 7.14 (2H, m, H-2 and H-6); 6.63 - 6.41 (2H, m, H-3 and H-5); 3.25 (3H, s, -NCH ₃ ); 2.85 (6H, s, -N (CH ₃ ) ₂ ).

¹³ C NMR (75 MHz, DMSO-d ₆ ) δ (ppm): 165.59 (C = 0 imide and C = 0 amide); 151.85 (C-4); 135.30 (C-3 'and C-4'); 129.27 (C-1 'and C-6'); 128.41 (C-2 and C-6); 123.84 (C-2 'and C-5'); 11.95 (C-1); 110.63 (C-3 and C-5); 39.46 (-N (CH ₃ ) ₂ ). The -NH ₃ H signal probably has a chemical shift similar to the DMSO-Gf ₆ equivalent, and is impossible to visualize.

IR (cm ^-1 ): 1728.18 and 1656.52 (o C = 0 imide, asymmetric and symmetrical stretching); 1608.91 (o C = 0 amide).

[093] Mass spectrometry (M ⁺ , positive polarity): 324.08

(+ H)

Example 5 - 4- (dimethylamino) - [N-methylbenzoidrazide (11)

To a 50 ml flask was added 1-55 g of 4- (dimethylamino) - / V- (1,3-dioxoisoindolin-2-yl) - / V-methylbenzamide () (4.64 mmol) , 10 mL methanol and 0.25 mL hydrazine hydrate (5.11 mmol). The reaction mixture was kept under stirring at reflux temperature, around 70 ° C for 2h. After this time by CCD plate analysis it was observed that the reaction was terminated due to absence of 4- (dimethylamino) - / V- (1,3-dioxoisoindo | in-2-yl) - / V stain methylbenzamide and the appearance of a more polar product (Rf: 0.52; eluent: dichloromethane: 10% methanol; developer: UV at 254 nm). The reaction mixture was poured into 20 ml of saturated sodium carbonate solution and extracted with aliquots of ethyl acetate (5 x 10 ml). The organic phase was dried with anhydrous sodium sulfate and concentrated under reduced pressure. 711 mg of a yellowish solid (79% yield), m.p. 123-127 ° C, were obtained.

¹ H NMR (200 MHz, DMSO-d ₆ ) δ (ppm): 7.48 (2H, d, J = 8.0 Hz, H-2 and H-6); 6.65 (2H, d, J = 8.0 Hz, H3 and H5); 4.86 (2H, sl, -NJ); 3.13 (3H, s, -NCH ₃ ); 2.95 (6H, s, -N (CH ₃ ) ₂ ).

¹³ C NMR (50 MHz, DMSO-d ₆ ) δ (ppm): 169.43 (C = 0); 151.06 (C-4); 130.16 (C-2 and C-6); 122.35 (C-1); 1.41 (C-3 and C-5); 39.79 (N (Ç_H ₃₎ _2). The -NÇH ₃ signal probably has a similar chemical shift as the DMSO-cfe equivalent, and is impossible to visualize.

IR (cm ^-1 ): 3292.99 and 3195.15 (o -NH ₂ , asymmetric and symmetrical stretching); 2909.29 and 2819.96 (o -CH ₃ , asymmetrical and symmetrical stretching); 1590, 52 (α C = 0 amide).

[098] Mass spectrometry (M ⁺ , positive polarity): 193.99

(M + H)

Example 6 - 4-Acetyl- / N-hydroxybenzamide (13d)

In a 50 ml flask was added 100mg of 4-acetylbenzoic acid () (0.6093 mmol), 1 drop of dimethylformamide (DMF) as catalyst, 20mL of dichloromethane and 105μΙ- of oxalyl chloride (1, 2186 mmol). The reaction mixture was kept under stirring at room temperature. for 2h until total consumption of 4-acetylbenzoic acid was monitored by CCD. In another 100 ml reaction flask, 20mL of tetrahydrofuran (THF), 56μl of 50% aqueous hydroxylamine solution (0.6093mmol) and 250μl of triethylamine (TEA) (1.828mmol) were added. This solution was cooled to 0 ° C with an ice bath. Then the solution containing the 4-acetylbenzoic acid chloride was dripped for 10 minutes into the solution containing the hydroxylamine. After addition, the reaction mixture was stirred at 0 ° C for 30 min. At the end of the reaction, the flask contents were poured into a 10% sodium hydroxide solution and extracted with aliquots of dichloromethane (4x1 OmL). The aqueous phase was then acidified with a 10% hydrochloric acid solution to pH 2 and extracted with aliquots of ethyl acetate (4x1 OmL). The organic phase was poured into a 5% sodium bicarbonate solution and further extracted (4x1 OmL). The organic phase was dried with anhydrous sodium sulfate and concentrated under reduced pressure. 70 mg of a white solid (Rf: 0.54; eluent: dichloromethane: 10% methanol; developer: UV at 254 nm) with melting point of 198 ° C (yield 64%) were obtained.

[100] ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 11 1.39 (1H, sl, NH hydroxamic acid); 9.19 (1H, sl, -OH hydroxamic acid); 8.01 (2H, d, J = 8.4Hz, H-2 and H-6); 7.87 (2H, d, J = 8.4 Hz, H-3 and H-5); 2.61 (3H, s, -CH ₃ imine).

[101] ¹³ C NMR (75 MHz, DMSO-d ₆ ) δ (ppm): 198.06 (C = 0 ketone); 163.61 (C = 0 hydroxamic acid); 138.81 (C-4); 136.79 (C-1); 128.45 (C-3 and C-5); 127.42 (C-2 and C-6); 27.10 (-Ç_H _3).

[102] IR (cm ^-1 ): 3293.21 (NH hydroxamic acid); 2742.17 (OH hydroxamic acid); 1680.20.31 (C = 0 ketone); 1268.35 (the CN).

[103] Mass spectrometry (M ^" , negative polarity): 178.18 (M-

H)

Example 7 - General methodology for the synthesis of N-acylhydrazones (5a-5n) [104] To a 50 ml flask was added 1.676 mmol of (4- (dimethylamino) benzoidrazide (8) or 4- (dimethylamino) -N-methylbenzoidrazide (11)) hydrazide, 1.676 mmol of the respective aldehydes (3-formylbenzoic acid (12a) and 4-formyl benzoic acid (12b); methyl 3-formyl benzoate (14a) and methyl 4-formyl benzoate (14b); 3-formyl - V-hydroxybenzamide (13a) and 4-formyl-A (hydroxybenzamide (13b)). Then 10 mL of ethanol and 1 drop of 37% hydrochloric acid were added. The reaction mixture was allowed to stir at room temperature for two hours. Solid precipitation was observed in the reaction medium which was vacuum filtered.

Example 8 - (R) -3 - ((2- (4- (dimethylamino) benzoyl) hydrazono) methyl) benzoic acid (5a-LASSBio - 1902)

[105] 482.6 mg of a yellow solid were obtained (Rf: 0.35; eluent: dichloromethane: 10% methano; developer: UV at 254 nm), mp 283.63 ° C (93% yield )

[106] ¹ H NMR (500 Hz, DMSO-cfe) δ (ppm): 11.66 (1H, si, NH amide); 8.49 (1H, sl, CH imine); 8.31 (1H, s, H-2 '); 7.98 (1H, d, J = 7.7Hz, H-4 '); 7.92 (1H, d, J = 7.7Hz, H-6 '); 7.84 (2H, d, J = 8.6Hz, H-2 and H-6); 7.59 (1H, dd, J = 7.7Hz and 7.7Hz, H-5 '); 6.77 (2H, d, J = 8.6Hz, H-3 and H-5); 3.01 (6H, s, -N (CH ₃ ) ₂ ).

[107] ¹³ C NMR (50 MHz, DMSO-d ₆ ) δ (ppm): 167.38 (C = 0 carboxylic acid); 163.42 (C = 0 amide); 152.93 (C-4); 145.45 (C-imine); 135.55 (C-1 '); 131.68 (C-6 '); 131, 14 ^(C-1 3); 130.59 (C-4 '); 129.65 (C-2 and C-6); 129.57 (C-5 '); 127.55 (C-2 '); 1 19.67 (C-1); 1111.23 (C-3 and C-5); 40.07 (N (Ç_H ₃₎ _2).

[108] IR (cm ^"1): 3333.71 (u NH amide), 2909.29 (O - _CH3), 1700.35 (C = 0 of amide acid), 1592.04 (C = u Amide) 1521.32 (o C = N).

[109] Mass spectrometry (M ⁺ , positive polarity): 312.17

(M + H) Example 9 - methyl (E) -3 - ((2- (4- (dimethylamino) benzoyl) hydrazono) methyl) benzoate (5b - LASSBio - 1903),

[110] 506.5 mg of a yellow solid were obtained (Rf: 0.17; effluent: hexane.ethyl acetate 30%; developer: UV at 254 nm), mp 193 ° C (89% yield ).

[11] RN ¹ H (400 MHz, D 3 SO ₆ ) δ (ppm): 11 1.68 (1H, sl, NH amide); 8.49 (1H, sl, CH imine); 8.34 (1H, s, H-2 '); 7.98 (1H, d, J = 7.8Hz, H-4 '); 7.94 (1H, d, J = 7.8Hz, H-6 '); 7.84 (2H, d, J = 8.6Hz, H-2 and H-6); 7.61 (1H, dd, J = 7.8 Hz and 7.8 Hz, H-5 '); 6.77 (2H, d, J = 8.6Hz, H-3 and H-5); 3.91 (3H, s, -OCH ₃ ); 3.01 (6H, s, -N (CH ₃ ) ₂ ).

[11] ¹³ C-NMR (50 MHz, DMSO-cfe) δ (ppm): 166.25 (C = 0 ester); 163.34 (C = 0 amide); 152.87 (C-4); 145.17 (C-imine); 135.66 (CV); 132.17 (C-6 '); 130.40 (C-3 '); 129.76 (C-2 and C-6); 129.74 (C-5 '); 129.55 (C-4 '); 127.04 (C-2 '); 1 19.51 (C-1); 11.15 (C-3 and C-5); 52.62 (-OCH ₃ ); 39.97 (N (Ç_H ₃₎ _2).

[113] IR (em- ¹ ): 3351.45 (an amide NH); 2904.65 (o -CH ₃ ); 1714.55 (C = O of ester); 1603.52 (o C = 0 amide); 1525.26 (o C = N).

[114] Mass spectrometry (M \ positive polarity): 326.21

(M + H)

Example 10 - (R) -4 - ((2- (4- (dimethylamino) benzoyl) hydrazono) methyl) benzoic acid (5d - LASSBio - 1905)

[115] 325.3 mg of a yellow solid were obtained (Rf: 0.36; eluent: dichloromethane: 10% methanol; developer: UV at 254 nm) with melting point greater than 300 ° C (62% yield)

[116] ¹ H NMR (400 MHz, DMSO-c ₆ ) δ (ppm): 11 1.80 (1 H, sl, NH amide); 8.54 (1H, sl, CH imine); 8.00 (2H, d, J = 8.2 Hz, H-3 'and H-5'); 7.86 (2H, d, J = 8.7Hz, H-2 and H-6); 7.81 (2H, d, J = 8.2 Hz, H-2 'and H-6'); 6.76 (2H, d, J = 8.7Hz, H-3 and H-5); 3.01 (6H, s, -N (CH ₃ ) ₂ ).

[117] ³ C-NMR (50 MHz, DMSO-o * ₆ ) δ (ppm): 167.36 (C = 0 carboxylic acid); 163.48 (C = 0 amide); 152.83 (C-4); 145.30 (C-imine); 139.60 (C-1 '); 131.72 (C-4 '); 130.11 (C-3 'and C-5'); 129.43 (C-2 and C-6); 127.27 (C-2 'and C-6'); 1 19.59 (C-1); 1131 (C-3 and C-5); 40.18 (-N (CH ₃ ) ₂ ).

[118] IR (cm ^-1 ): 3224.56 (amide NH); 1698.87 (C = O of carboxylic acid); 1672.17 (α C = 0 amide); 1536.92 (o C = N).

[119] Mass spectrometry (R / T, positive polarity): 312.17

(M + H)

Example 11 - Methyl (E) -4 - ((2- (4- (dimethylamino) benzoyl) hydrazono) methyl) benzoate (5e - LASSBío - 1906)

[120] 484.6 mg of a yellow solid were obtained (Rf: 0.23; eluent: hexane: 30% ethyl acetate; developer: UV at 254 nm), mp 255.88 ° C (yield: 89%).

[121] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 11 1.84 (1H, sl, NH amide); 8.52 (1H, sl, CH imine); 8.03 (2H, d, J = 8.4 Hz, H-3 'and H-5'); 7.87 (2H, d, J = 8.9 Hz, H-2 and H-6); 7.84 (2H, d, J = 8.4 Hz, H-2 'and H-6'); 6.83 (2H, d, J = 8.9 Hz, H-3 and H-5); 3.88 (3H, s, -OCH ₃ ); 3.02 (6H, s, -N (CH ₃ ) ₂ ).

[122] ¹³ G NMR (50 MHz, DMSO-d ₆ ) δ (ppm): 166.24 (C = 0 ester); 163.34 (C = 0 amide); 152.44 (C-4); 145.12 (C-imine); 139.50 (C-1 '); 130.27 (C-4 '); 130.02 (C-3 'and C-5'); 129.73 (C-2 and C-6); 127.33 (C-2 'and C-6'); 120.24 (C-1); 1111.78 (C-3 and C-5); 52.55 (-OCH ₃ ); 40.32 (-N (CH ₃ ) ₂ ).

[123] IR (cm ^-1 ): 3307.21 (amide NH); 1692.03 (C = O of ester); 1660.43 (α C = 0 amide); 599.29 (υ C = N). [124] Mass spectrometry (M ⁺ , positive polarity): 326.20

(M + H)

Example 12 - (R) -3 - ((2- (4- (dimethylamino) benzoyl) -2-methylhydrazono) methyl) -Î ”- hydroxybenzamide (5g - LASSBio - 1908),

[125] 472.7mg of a white solid were obtained (Rf: 0.52; eluent: dichloromethane: methanol 10%; developer: UV at 254 nm), mp 197.52 ° C (83% yield )

[126] ¹ H NMR (400 MHz, DMSO-o ^* ₆ ) δ (ppm): 8.05 (1 H, s, CH imine); 8.00 (1H, sl, H-2 '); 7.73 - 7.69 (4H, m,, H-2 and H6, H-4 'and H-6'); 7.47 (1H, dd, J = 7.8Hz and 7.7Hz, H-5 '); 6.98 (2H, d, J = 7.8Hz, H-3 and H-5); 3.49 (3H, s, -NCH ₃ ); 3.05 (6H, s, -N (CH ₃ ) ₂ ).

[127] ¹³ C-NMR (50 MHz, DMSO-d ₆ ) δ (ppm): 169.51 (C = 0 amide); 164.35 (C = 0 hydroxamic acid); 150.42 (C-4); 139.30 (C-imine); 135.69 (C-1 '); 133.78 (C-3 '); 132.26 (C-2 and C-6); 129.25 (C-6 '); 129.20 (C-5 '); 127.59 (C-4 '); 126.45 (C-2 '); 124.51 (C-1); 11.54 (C-3 and C-5); 41, 22 (-N (Ç_H ₃₎ _2); 29.36 (- No. ₃ ).

[128] IR (cm ^-1 ): 3170 (Î´ NH hydroxamic acid); 1650.67 (Î ± C = hydroxamic acid); 1635.28 (o C = 0 amide); 1589.06 (o C = N ); 1047.66 (o CH).

[129] Mass spectrometry (M ⁺ , positive polarity): 341, 20

(M + H)

Example 13 - (E) -4 - ((2- (4- (dimethylamino) benzoyl) -2-methylhydrazono) methyl) -A / - hydroxybenzamide (5h - LASSBio - 1909)

[130] 432mg of a white solid were obtained (Rf: 0.52; eluent: dichloromethane: methanol 10%; developer: UV at 254 nm), mp 2.15 ° C (75% yield) [131] ¹ H NMR (400 Hz, DMSO-d ₆ ) δ (ppm): 8.05 (1 H, s, CH imine); 7.79 (2H, d, J = 8.2 Hz, H-3 'and H-5'); 7.72 (2H, d, J = 8.7Hz, H-2 and H-6); 7.63 (2H, δ, J = 8.2 Hz, H-2 'and H-6'); 7.12 (2H, d, J = 8.7Hz, H-3 and H-5); 3.49 (3H, s, -NCH ₃ ); 3.07 (6H, s, -N (CH ₃ ) ₂ ).

[132] ¹³ C NMR (50 Hz, DMSO-d ₆ ) δ (ppm): 169.49 (C = O amide); 163.94 (CO hydroxamic acid); 149.49 (C-4); 139.36 (C-imine); 137.86 (C-1 '); 133.28 (C-4 '); 132.09 (C-2 and C-6); 127.47 (C-3 'and C-5'); 127.00 (C-2 'and C-6'); 126.44 (C-1); 11.93 (C-3 and C-5); 41.93 (-N (CH ₃ ) ₂ ); 29.39 (-NHC ₃ ).

[133] IR (cm ^-1 ): 2963,47 and 2809,27 (o -CH ₃ ); 1631.01 (C = 0 hydroxamic acid and C = 0 amide); 1591.49 (o C = N); 1047.73 (the CN).

[134] Mass spectrometry ( ⁺ , positive polarity): 341, 20

(M + H)

Example 14 - (E) - ⁱ 3 - ((2- (4- (dimethylamino) benzoyl) hydrazono) methyl) - / V-hydroxybenzamide (5i - LASSBio - 1910)

[135] 450mg of a yellow solid were obtained (Rf: 0.30; eluent: dichloromethane: 10% methanol; developer UV at 254 nm), m.p. 216.45 ° C (82% yield)

[136] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 11.17 (1 H, sl, NH amide); 8.50 (1H, sl, CH imine); 8.11 (1H, s, H-2 '); 7.87 (2H, d, J = 8.7Hz, H-2 and H6); 7.84 (H, d, J = 7.9 Hz, H-6 '); 7.78 (1H, d, J = 7.9Hz, H-4 '); 7.54 (1H, dd, J = 7.9Hz and 7.9Hz, H-5 '); 6.81 (2H, d, J = 8.7Hz, H-3 and H-5); 3.01 (6H, s, -N (CH ₃ ) ₂ ).

[137] ¹³ C NMR (50 MHz, DMSO-d ₆ ) δ (ppm): 164.14 (C = 0 hydroxamic acid); 163.32 (C = 0 amide); 152.63 (C-4); 145.77 (C-imine); 135.26 (C-1 '); 133.74 (C-3 '); 129.73 (C-2 and C-6); 129.45 (C-5 ^* ); 129.40 (C-6 '); 128.22 (C- '); 125.69 (C-2 '); 120.09 C-1); 1111.54 (C-3 and C-5); 40.21 (-N (CH ₃ ) ₂ ). [138] IR (cm ^-1 ): 3183.89 (Î´ NH hydroxamic acid); 1656.48 (Î »C = 0 of hydroxamic acid); 1600.26 (Î» C = 0 amide); 1520.26 (Î »C = N) 1286.62 (CN).

[139] Mass spectrometry ( ⁺ , positive polarity): 327.20

(M + H)

Example 15 - (E) -4 - ((2- (4- (dimethylamino) benzoyl) hydrazono) methyl) -A / - hydroxybenzamide (5j - LASSBio-1911)

[140] 460mg of a yellow solid were obtained (Rf: 0.27; eluent: dichloromethane: 10% methanol; developer: UV at 254 nm), mp 260.52 ° C (84% yield)

[141] NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 11.67 (1H, si, NH amide); 11 1.32 (1H, sl, NH hydroxamic acid); 8.47 (1H, sl, CH imine); 7.84 (2H, d, J = 8.5 Hz, H-2 and H-6); 7.83 (2H, d, J = 7.7Hz, H-3 'and H-5'); 7.78 (2H, d, J = 7.7Hz, H-2 'and H-6'); 6.77 (2H, d, J = 8.5 Hz, H-3 and H-5); 3.00 (6H, s, -N (CH ₃ ) ₂ ).

[142] ¹³ C-NMR (50 MHz, DMSO-d ₆ ) δ (ppm): 164.14 (C = 0 hydroxamic acid); 163.41 (C = 0 amide); 152.90 (C-4); 145.52 (C-imine); 137.78 (C-1 '); 134.02 (C-4 '); 129.67 (C-2 and C-6); 127.70 (C-3 'and C-5'); 127.17 (C-2 'and C-6'); 1 19.66 (C-1); 1111.25 (C-3 and C-5); 40.09 (N (Ç_H ₃₎ _2).

[143] IR (cm ^-1 ): 3234.41 (NH hydroxamic acid); 1643.31 (C = 0 hydroxamic acid); 1599.99 (α C = 0 amide); 1520.54 (α C = N); 1287.95 (CN).

[144] Mass spectrometry (M ⁺ , positive polarity): 327.20

(M + H)

Example 16 - (R) -3 - ((2- (4- (dimethylamino) benzoyl) -2-methylhydrazono) methyl) benzoic acid (5k - LASSBio - 1912) [145] 408.8 mg of a white solid (Rf: 0.56; eluent: dichloromethane: 10% methanol; developer: UV at 254 nm) were obtained, mp 236.37 ° C (75% yield )

[146] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.23 (1 H, s, H-2 '); 8.07 (1H, sl, CH imine); 7.92 (1H, d, J = 7.8Hz, H-4 '); 7.81 (1H, d, J = 7.8Hz, H-6 '); 7.70 (2H, d, J = 8.9 Hz, H-2 and H-6); 7.54 (1H, dd, J = 7.8Hz and 7.8Hz, H-5 '); 6.87 (2H, d, J = 8.9Hz, H-3 and H-5), 3.48 (3H, s, -NCH ₃ ); 3.03 (6H, s, -N (CH ₃ ) ₂ ).

[147] ¹³ C NMR (50 MHz, DMSO-d ₆ ) δ (ppm): 169.61 (C = 0 amide); 167.34 (C = 0 carboxylic acid); 151.04 (C-4); 138.93 (C-imine); 135.92 (CT); 132.32 (C-2 and C-6); 131.56 (C-3 '); 131.08 (C-6 '); 130.10 (C-4 '); 129.51 (C-5 '); 128.16 (C-2 '); 123.09 (C-1); 1111.64 (C-3 and C-5); 40.72 (N (Ç_H ₃₎ _2); 29.33 (- No. ₃ ).

[148] IR (cm ^-1 ): 2551, 28 (o-OH carboxylic acid dimer); 1687.04 (o C = 0 of carboxylic acid); 1644.87 (o C = 0 amide); 16 (α C = N).

[149] Mass spectrometry (M ⁺ , positive polarity): 326.19

(M + H)

Example 17 - (£) -4 - ((2- (4-

(dimethylamino) benzoyl) methylhydrazono) methyl) benzoic (51 - LASSBio - 1913)

[150] 472.7mg of a yellowish white solid (Rf: 0.50; eluent: dichloromethane: 10% methanol; developer: UV at 254 nm) with melting point greater than 300 ° C (86% yield) were obtained. )

[151] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.03 (1 H, sl, CH imine); 7.97 (2H, d, J 8.3 Hz, H-3 'and H-5'); 7.71 (2H, d, J = 8.3 Hz, H-2 'and H-6'); 7.67 (2H, d, J = 8.9 Hz, H-2 and H-6); 6.74 (2H, d, J = 8.9 Hz, H-3 and H-5); 3.48 (3H, s, -NCH ₃ ); 3.01 (6H, s, -N (CH ₃ ) ₂ ). [152] ¹³ C NMR (50 MHz, DMSO-d ₆ ) δ (ppm): 169.67 (C = 0 amide); 167.29 (C = 0 carboxylic acid); 152.08 (C-4); 139.63 (C-1 '); 138.50 (C-imine); 132.56 (C-2 and C-6); 131.16 (C-4 '); 129.60 (C-3 'and C-5'); 127.11 (C-2 'and C-6'); 120.88 (C-1); 1 10.38 (C-3 and C-5); 39.93 (N (Ç_H ₃₎ _2); 29.52 (-NHC ₃ ).

[153] IR (cm ^-1 ): 3075.65 (α-OH carboxylic acid dimer); 1705.61 (C = 0 of carboxylic acid); 1610.02 (o C = 0 amide); 1590.04 (o C = N).

[154] Mass spectrometry (WT, positive polarity): 326.20

(M + H)

Example 18 - (R) -4- (1- (2- (4- (dimethylamino) benzoyl) hydrazono) ethyl) - N -hydroxybenzamide (5m - LASSBio - 1935),

[155] In a G30-type microwave tube (Monowave 300), 200mg of 4-dimethylaminobenzoidrazide (8) (1,116 mmol), 200mg of 4-acetyl-V-hydroxybenzamide (13d) (1 0.16 mmol), 10 mL Ethanol and 1 drop acetic acid as catalyst. The microwave was set to reach 80 ° C in 2 minutes and the reaction contents were allowed to remain under microwave irradiation for 30 minutes. After this time a white solid precipitated and was vacuum filtered. 171 mg of a white solid were obtained, 45% yield.

[156] ¹ H NMR (400 MHz, DMSO-c / ₆ ) δ (ppm): 11 1.32 (1H, sl, NH hydroxamic acid); 10.45 (1H, sl, NH amide); 9.09 (1H, sl, -OH hydroxamic acid); 7.89 (2H, d, J = 8.4 Hz, H-3 'and H-5'); 7.81 (2H, d, J = 8.9 Hz, H-2 and H-6); 7.81 (2H, d, J = 8.4 Hz, H-2 'and H-6'); 6.75 (2H, d, J = 8.9 Hz, H-3 and H-5); 3.00 (6H, s, -N (CH ₃ ) ₂ ); 2.38 (3H, s, -CH ₃ imine).

[157] ¹³ C NMR (50 MHz, DMSO-cfe) δ (ppm): 164.51 (C = 0 amide), 164.06 (C = 0 hydroxamic acid); 152.76 (C-4); 151.92 (C-imine); 141.16 (C-1 ^! ); 133.24 (C-4 '); 130.10 (C-2 and C-6); 127.07 (C-2 'and C-6'); 126.49 (C-3 'and C-5'); 120.72 (C-1); 1151 (C-3 and C-5); 40.09 (-N (C ₃ H ₃ ) ₂ ); 14.35 _(CH3 imine).

[158] Mass spectrometry (M ⁺ , positive polarity): 341, 21

(M + H)

Example 19 - (E) -4- (1- (2- (4- (dimethylamino) benzoyl) -2-methylhydrazono) ethyl) - V-hydroxybenzamide (5n - LASSBio - 1936)

[159] In a G30-type microwave tube (Monowave 300), 215mg of 4- (dimethylamino) - / V-methylbenzoidrazide (11) (1,116 mmol), 200mg of 4-acetyl-N were added. -hydroxybenzamide (13d) (1,116 mmol), 10mL Ethanol and 1 drop acetic acid as catalyst. The microwave was set to reach 125 ° C in 2 minutes and the reaction contents were allowed to remain under microwave irradiation for 4 hours. After this time, it was observed that there was no change from the reaction mixture components by visualization on the thin chromatography plate, so the reaction mixture was concentrated, leading to the formation of a yellowish solid which was washed with ethyl acetate (40mL). and recrystallized from hot ethanol. A yellowish solid precipitated and was vacuum filtered. 152mg of a white solid were obtained, yield 38%.

[160] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 11 1.32 (1H, sl, NH hydroxamic acid); 9.13 (1H, sl, -OH hydroxamic acid); 7.87 (2H, d, J = 8.5 Hz, H-3 'and H-5'); 7.80 (2H, d, J = 8.5 Hz, H-2 'and H-6'); 7.41 (2H, d, J = 8.9 Hz, H-2 and H-6); 6.64 (2H, d, J = 8.9 Hz, H-3 and H-5); 3.27 (3H, s, -NCH ₃ ); 2.94 (6H, s, -N (CH ₃ ) ₂ ); 2.31 (3H, s, -CH ₃ imine).

[161] ¹³ C NMR (50 MHz, DMSO-d ₆ ) δ (ppm): 169.17 (C = 0 amide); 167.22 (C-imine); 163.88 (C = 0 hydroxamic acid); 151.90 (C-4); 139.84 (C-1 '); 134.50 (C-4 '); 130.72 (C-2 'and C-6'); 127.27 (C-2 'and C-6'); 127.20 (C-3 'and C-5'); 121.77 (C-1); 1.78 (C-3 and C-5); 40.08 (-NCH ₃ ); 39.94 (N (Ç_H ₃₎ _2); 17.25 (-CH ₃ imine). [162] Mass spectrometry (M \ positive polarity): 353.23

(M + H)

Example 20 - Biochemical Assessment

[163] N-acylhydrazonic derivatives designed as HDAC inhibitors as candidates for antitumor drugs have been evaluated for their ability to inhibit histone deacetylase enzymatic activity, i.e., their ability to inhibit enzyme substrate deacetylation.

[164] The spectroscopically synthesized and synthesized N-acylhydrazonic analogs showed inhibitory capacity of the enzyme histone deacetylase, and when performing the enzyme inhibition assay using the concentration of 1 μΜ the compounds 5g, 5h, 5i and 5j showed 33 , 4%, 90.4%, 66%, and 90.4% inhibition percentage, respectively, as shown in table 1:

[165] Table 1 - Determination of percent inhibition of rat liver HDAC activity (Hoffman, K. et al. Nuclei Acids Res, 1998, 27,

2057).

Percentage of

Inhibition compounds at 1.0μ

„OH

90.4%

H ₃ C. CH ₃ H

N

CH ₃ LASSBio-1909 - 5h

[166] The 50% inhibitory concentration (IC50) of examples 5h, 5i and 5j were 18, 1200 and 21 namomolar, respectively, as shown in table 2. The inhibition curves for IC50 determination of 5h, 5i and 5j are 4, 5 and 6 respectively.

[167] Table 2 - Determination of percent inhibition of rat liver HDAC activity (Hoffman, K. et al. Nuclei Acids Res, 1998, 27, 2057).

Cl ₅₀ in liver HDAC Rat compounds (nM)

[168] The assay used to determine percent inhibition and consequent determination of Cl ₅₀ was performed as described by Hoffman and colleagues (Hoffman, K. et al. Nuclei Acids Res, 1998, 27, 2057). [169] Subsequently, the selectivity profile for the most active derivatives in the rat liver HDAC inhibition model was evaluated for inhibition profile against human class I and llb enzymes. Table 3 shows the Cl ₅₀ values obtained for the / V-acylhydrazonic derivatives against HDAC1, H DAC2, H DAC6 and H DAC8.

[170] Table3. Inhibitory profile of N-acylhydrazonic derivatives and trichostatin A against human HDAC, HDAC1, 2, 6 and 8.

Inhibition of human HDAC isoforms, IC50 (uM) ^at

HDAC 1 Composite HDAC 2 HDAC6 HDAC8

aThe values are the average of three experiments and are presented as IC50 values in μΜ. The compounds were examined by a seven-point enzymatic assay with a three-fold serial dilution from 10 μΜ of 5i and 5g and 3 μΜ to 5j, 5h, 5m and 5n.

[171] The assay used for IC50 determination was performed as described by Strahl and Allis (Strahl, B. D. and Allis, C. D. Nature 2000, 403, 41).

[172] The compounds described herein are compounds that act as dual inhibitors of HDAC6 and HDAC8.

Claims

1 . N-acylhydrazonic compounds characterized by being inhibitors of the enzyme histone deacetyls general mule (I):

Where:

Ar is phenyl, naphthyl, substituted phenyl and substituted naphthyl. Ar is heteroaryl and substituted heteroaryl chosen from:

1 H-pyrrol-2-yl, 1 H-pyrrol-3-yl, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, 1 H-pyrazol-1-yl -1 / - / - pyrazol-3-yl, 1H-pyrazol-4-yl, 1 / - / - pyrazol-5-yl, 1H-imidazol-1-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl, 1H-1,2,3-triazol-1-yl, 1H-1,2,3-triazol-4-yl, 1H-1 2,3-triazol-5-yl, 2H-1,2,3-triazol-2-yl, 2H-1,2,3-triazol-4-yl, 2H-1,2,3-triazol-5 -1H-1,2,4-triazol-1-yl, 1H-1,2,4-triazol-3-yl, 1H-1,2,4-triazol-5-yl, 4H- 1,2,4-triazol-4-yl, 4H-1,2,4-triazol-3-yl, 4H-1,2,4-triazol-5-yl, 1H-tetrazol-1-yl 1 H -tetrazol-5-yl, 2H-tetrazol-2-yl, 2H-tetrazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-2-yl

5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-one yl, isothiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,5-oxadiazol-3-yl, 1,2,5- oxadia2ol-4-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,2,5-thiadiazol-3-yl, 1,2,5-thiadiazole 4-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl, pyridazin-3-yl, pyridazin-4- yl, pyridazin-5-yl, pyridazin-6-yl, pyrazin-2-yl, pyrazin-3-yl, pyrazin-5-yl, pyrazin-6-yl, 1,2,5-triazin-2-yl, 1,2,5-triazin-4-yl, 1,2,5-triazin-6-yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl, 1, 2,4-triazine

6-yl, 1H-indol-1-yl, 1-indol-2-yl, 1H-indol-3-yl, 1H-indol-5-yl, 1H-indol-6-yl, 1H - indol-7-yl, 1H-indol-8-yl, 1H-indazol-3-yl, 1H-indazol-5-yl, 1H-indazol-6-yl, 1H-indazol-7- yl, 1 H-indazol-8-yl, 1 H-benzo [d] imidazol-1-yl, 1 / - / - benzo [d] imidazol-2-yl, 1 H-benzo [c] imidazol-5 -1H-benzo [c] imidazol-6-yl, 1 H-benzo [d] imidazol-7-yl, 1 H-benzo [d] imidazol-8-yl, benzofuran-2-yl, benzofuran 3-yl, benzofuran-5-yl, benzofuran-6-yl, benzofuran-7-yl, benzofuran-8-yl, benzo [6] thiophen-2-yl, benzo [?] thiophen-3-yl, benzo [Î ± thiophen-5-yl, benzo [Î³thiophen-6-yl, benzo [b] thiophen-7-yl, benzo [ò] thiophen-8-yl, quinolin-2 -yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, isoquinolin-1-if, isoquinolin-3-yl , isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-ii, isoquinolin-7-yl, isoquinolin-8-yl, quinazolin-2-yl, quinazolin-4-yl, quinazolin-5-it, quinazolin -6-yl, quinazolin-7-yl, quinazolin-8-yl, quinoxalin-2-yl, quinoxalin-3-yl, quinoxalin-5-yl, quinoxalin-6-yl, quinoxalin-7-yl, quinoxalin-8 -l.

R ₂ and R 3 independently correspond to H or CH 3.

B is selected from: matches;

Where W and Y are as defined above, R ₄ is selected from hydrogen, hydroxy, amino, halogen, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, diacylamino, substituted or unsubstituted alkylsulfonyl, CF ₃ , CN, N ₃ , NO ₂ , sulfonyl, acyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycles.

(ç)

or pharmaceutically acceptable salts thereof.

Compounds according to claim 1, characterized by the history deacetylases 1 -1 1.

Compounds according to claim 1, characterized in that they are selected from the group comprising:

(E) -3 - ((2- (4- (dimethylamino) benzoyl) hydrazono) methyl) benzoic acid (hereinafter called LASSBio - 1902);

(£) -3 - ((2- (4- (dimethylamino) benzoyl) hydrazono) methyl) methyl benzoate (5b - hereinafter called LASSBio - 1903);

(E) -3 - ((2- (4- (dimethylamino) benzoyl) -2-methylhydrazono) methyl) methyl benzoate (5c - hereafter called LASSBio - 1904);

(E) -4 - ((2- (4- (dimethylamino) benzoyl) hydrazono) methyl) benzoic acid (hereinafter called LASSBio - 1905);

(E) -4 - ((2- (4- (dimethylamino) benzoyl) hydrazono) methyl) methyl benzoate (5e - hereinafter called LASSBio - 1906);

(E) methyl 4 - ((2- (4- (dimethylamino) benzoyl) -2-methylhydrazono) methyl) benzoate (5f - hereinafter called LASSBio - 1907);

(E) -3 - ((2- (4- (dimethylamino) benzoyl) -2-methylhydrazono) methyl) -Î ”-hydroxybenzamide (5g - hereinafter called LASSBio - 1908);

(E) -4 - ((2- (4- (dimethamino) benzoyl) -2-methylhydrazono) methyl) -N-hydroxybenzamide (5h - hereinafter called LASSBio - 1909);

(R) -3 - ((2- (4- (dimethylamino) benzoyl) hydrazono) methyl) -Î ”-htdroxybenzamide (hereinafter called LASSBio - 1910);

(E) -4 - ((2- (4- (dimethylamino) benzoyl) hydrazono) methyl) -Î ”-hydroxybenzamide (5j - hereinafter called LASSBio-1911);

(E) -3 - ((2- (4- (dimethylamino) benzoyl) -2-methylhydrazono) methyl) benzoic acid (5k - hereinafter called LASSBio - 912);

(E) -4 - ((2- (4- (dimethylamino) benzoyl) methylhydrazono) methyl) benzoic acid (hereinafter called LASSBio - 1913);

(E) -4- (1- (2- (4- (dimethylamino) benzoyl) hydrazono) ethyl) -Î ± -hydroxybenzamide (5m - hereinafter called LASSBio - 1935);

(E) -4- (1- (2- (4- (dimethylamino) benzoyl) -2-methylhydrazono) ethyl) -Î ”-hydroxybenzamide (5n - hereafter called LASSBio - 1936);

(R) -4 - ((2-benzoylhydrazono) methyl) -N-hydroxybenzamide (6a);

(E) -4 - ((2-benzoyl-2-methylhydrazono) methyl) -Î ± -hydroxybenzarrtide (6b);

(E) -4 - ((2 - ([1,1'-biphenyl] -4-carbonyl) hydrazono) methyl) -Î ± -hydroxybenzamide (6c); (E} -4 - ((2 - ([1, 1 - biphenyl] -4-carbonyl) -2-methyl-hydrazono) methyl) - / V-hidroxtbenzamida (6d);

(E) -4 - ((2- (4 - ((dimethylamino) methyl) benzoyl) hydrazo

(6e);

(E) -4 - ((2- (4 - ((dimethylamino) methyl) benzoyl) -2-methylhydrazono) methyl) -4-

hydroxybenzamide (6f);

(R) -A / - (2-aminophenyl) -4 - ((2- (4- (dimethylamino) benzoyl) hydrazono) methyl) ben

(6g)

(E) -N - (2-Aminophenyl) -4 - ((2- (4- (dimethylamino) benzoyl) -2-methylhydrazono) methyl) benzamide (6h)

(E) - / V- (2-amino-4-fluorophenyl) -4 - ((2- (4- (dimethylamino) benzoyl) hydrazono) methyl) benzamide (6i)

(R) - V- (2-amino-4-fluorophenyl) -4 - ((2- (4- (dimethylamino) benzoyl) -2-methyl-hydrazono) methyl) benzamide (6j)

(E) - [N- (2-amino-4- (thiophen-2-yl) phenyl) -4 - ((2- (4- (dimethylamino) benzoyl) hydrazono) methyl) benzamide (6k)

(E) - [N- (2-amino-4- (thiophen-2-yl) phenyl) -4 - ((2- (4- (dimethylamino) benzoyl) -2- (hydrazono) methyl) benzamide (61)

(R) -3 - ((2- (4- (dimethylamino) benzoyl) -2-methylhydrazono) methyl) -Î²-hydroxybenzothioamide (6m);

(E) -4 - ((2- (4- (dimethylamino) benzoyl) -2-methylhydrazono) methyl) - N-hydroxybenzothioamide (6n);

(R) -3 - ((2- (4- (dimethylamino) benzoyl) hydrazono) methyl) -Î ± -hydroxybenzothioamide (6Â °);

(E) -4 - ((2- (4- (dimethylamino) benzoyl) hydrazono) methit) -A / - hydroxybenzothioamide (6p)

and combinations thereof.

4. Pharmaceutical composition comprising:

(a) N-acylhydrazonic compounds characterized by being inhibitors of the enzyme histone deacetylase (HDAC) and having general formula (I):

Where:

1 H-pyrrol-2-yl, 1 H-pyrrol-3-yl, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, 1 H-pyrazol-1-yl -1 / - / - pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, 1H-imidazol-1-yl, 1 / - / - imidazol-2-yl, N-imidazol-4-yl, 1 H - imidazol-5-yl, 1 H -1,2,3-triazol-1-yl, 1H-1,2,3-triazol-4-yl, 1H -1,2,3-triazol-5-yl, 2H-1,2,3-triazol-2-yl, 2H-1,2,3-triazol-4-yl, 2H-1,2,3-triazole -5-yl, 1H-1,2,4-triazol-1-yl, 1H-1,2,4-triazol-3-yl, 1H-1,2,4-triazol-5-yl, 4H-1,2,4-triazol-4-yl, 4H-1,2,4-triazol-3-yl, 4H-1,2,4-triazol-5-yl, 1H-tetrazol-1-yl 1 / - / - Tetrazol-5-yl, 2H-tetrazol-2-yl, 2H-tetrazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-2-yl

5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-one yl, isothiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,5-oxadiazol-3-yl, 1,2,5- oxadiazol-4-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,2,5-thiadiazol-3-yl, 1,2,5-thiadiazole 4-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl, pyridazin-3-yl, pyridazin-4 yl, pyridazin-5-yl, pyridazin-6-yl, pyrazin-2-yl, pyrazin-3-yl, pyrazin-5-yl, pyrazin-6-yl, 1,2,5-triazin-2-yl, 1,2,5-triazin-4-yl, 1,2,5-triazin-6-yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl, 1, 2,4-triazine

6-yl, 1H-indol-1-yl, 1H-indol-2-yl, 1 H-indol-3-yl, 1H-indol-5-yl, 1H-indol-6-yl, 1 H-indol-7-yl, 1 H-indol-8-yl, 1 H-indazoyl-3-yl, 1-indazol-5-yl, 1 H-indazol-6-yl, β-indazol-7 -yl, 1 / - / - indazol-8-yl, 1 H-benzo [d] imidazol-1-yl, 1 / - / - benzo [d] imidazol-2-yl, 1 H-benzo [c /] imidazol-5-yl, 1 / - / - benzo [d] imidazol-6-yl, 1 / - / - benzo [d] imidazol-7-yl, 1 H-benzo [d] imidazol-8-yl, benzofuran -2-yl, benzofuran-3-yl, benzofuran-5-yl, benzofuran-6-yl, benzofuran-7-yl, benzofuran-8-yl, benzo [] thiophen-2-yl, benzo [b] thiophen 3-yl, benzo [b] thiophen-5-yl, benzo [fc]] thiophen-6-yl, benzo [b] thiophen-7-yl, benzo [?] thiophen-8-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl yl, isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl, isoquinolin-8-yl, quinazolin-2-yl, quinazolin-4-yl, quinazolin-5-yl, quinazolin-6-yl, quinazolin-7-yl, quinazolin-8-yl, quinoxalin-2-yl, quinoxalin-3-yl, quinoxalin-5-yl, quinoxalin-2-yl 6-yl, quinoxalin-7-yl, quinoxalin-8-yl.

R2 and R3 independently correspond to H or CH3.

B is selected from: matches;

(The)

Where W is O or S; Y is missing or is N, or CH ₂ .

(B)

Where W and Y are as defined above, R ₄ is selected from hydrogen, hydroxy, amino, halogen, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylaminos, substituted or unsubstituted alkylsulfonyl, CF ₃ , CN, N ₃ , NO ₂ , sulfonyl, acyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycles.

(ç)

or pharmaceutically acceptable salts thereof and

b) a pharmaceutically acceptable carrier.

Composition according to Claim 4, characterized by HDAC 1 -1 1.

Composition according to Claim 5, characterized in that the compounds are selected from the group comprising:

(R) -3 - ((2- (4- (dimethylamino) benzoyl) -2-methylhydrazono) methyl) methyl benzoate (5c - hereafter called LASSBio - 1904);

(E) -4 - ((2- (4- (dimethylamino) benzoyl) hydrazono) methyl) benzoic acid (5d hereafter called LASSBio - 905);

(£) methyl 4 - ((2- (4- (dimethylamino) benzoyl) -2-methylhydrazono) methyl) benzoate (5f - hereinafter called LASSBio - 1907);

(E) -3 - ((2- (4- (dimethylamino) benzoyl) -2-methylhydrazono) methyl) - / V-hydroxybenzamide (5g - hereinafter called LASSBio - 1908);

(R) -4 - ((2- (4- (dimethylamino) benzoyl) -2-methylhydrazono) methyl) - V-hydroxybenzamide (5h - hereinafter called LASSBio - 1909);

(E) -3 - ((2- (4- (dimethylamino) benzoyl) hydrazono) methyl) - [N-hydroxybenzamide (hereinafter called LASSBio - 1910);

(E) -4 - ((2- (4- (dimethylamino) benzoyl) hydrazono) methyl) -W-hydroxybenzamide (5j - hereinafter called LASSBio-1911);

(E) -3 - ((2- (4- (dimethylamino) benzoyl) -2-methylhydrazono) methyl) benzoic acid (5k - hereinafter called LASSBio - 1912);

(E) -4 - ((2- (4- (dimethylamino) benzoyl) methylhydrazono) methyl) benzoic acid (51 - hereinafter called LASSBio - 1913);

(E) -4- (1- (2- (4- (dimethylamino) benzoyl) hydrazono) ethyl) -Î ”-hydroxybenzamide (5m - hereinafter called LASSBio - 1935);

(R) -4- (1- (2- (4- (dimethylamino) benzoyl) -2-methylhydrazono) ethyl) -N-hydroxybenzamide (5n - hereafter called LASSBio - 1936);

(E) -4 - ((2-benzoylhydrazono) methyl) -Î ± -hydroxybenzamide (6a);

(E) -4 - ((2-benzoyl-2-methylhydrazono) methyl) - N -hydroxybenzamide (6b);

(E) -4 - ((2 - ([1'-biphenyl] -4-carbonyl) hydrazono) methyl) - N -hydroxybenzam (6c); (E) -4 - ((2 - ([1'-Biphenyl] -4-carbonyl) -2-methylhydrazono) methyl) -A-hydroxybenza

(6d);

(R) -4 - ((2- (4 - ((dimethylamino) methyl) benzoyl) h)

(6e);

(E) -4 - ((2- (4 - ((dimethylamino) methyl) benzoyl) -2-m

hydroxybenzamide (6f);

(E) - / V- (2-aminophenyl) -4 - ((2- (4- (dimethylamino) benzoyl) hydrazono) m

(6g)

(R) - / V- (2-aminophenyl) -4 - ((2- (4- (dimethylamino) benzoyl) -2-methyl)

hydrazono) methyl) benzamide (6h)

(E) -A / - (2-amino-4-fluprofenyl) -4 - ((2- (4- (dimethylamino) benzoyl) -2-methylhydrazono) methyl) benzamide (6j)

(E) - / V- (2-amino-4- (thiophen-2-yl) phenyl) -4 - ((2- (4- (dimethylamino) benzoyl) hydrazono) methyl) benzamide (6k)

(E) -A / - (2-amino-4- (thiophen-2-yl) phenyl) -4 - ((2- (4- (dimethylamino) ben)

hydrazono) methyl) benzamide (61)

(R) -3 - ((2- (4- (dimethylamino) benzoyl) -2-methylhydrazono) methyl) -1H-hydroxybenzothioamide (6m);

(E) -4 - ((2- (4- (dimethylamino) benzoyl) -2-methylhydrazono) methyl) - N -hydroxybenzothioamide (6n);

(E) -3 - ((2- (4- (dimethylamino) benzoyl) hydrazono) methyl) -Î ± -hydroxybenzothioamide (6Â °);

(E) -4 - ((2- (4- (dimethylamino) benzoyl) hydrazono) methyl) - N -hydroxybenzothioamide (6p);

and combinations thereof.

7. The process of producing derivatives of formula (I)

(I)

which comprises the steps of:

a) esterification of a compound of formula (II):

The U

Ar- ^ H

(II)

To produce a compound of formula (III):

(III)

(IV)

(SAW)

CH ₃

(VII)

(VIII)

g) Compounds of general formula (VIII) are obtained by an acid chloride formation reaction and subsequent reaction with the appropriate nucleophiles. Where:

1H-pyrrol-2-yl, 1H-pyrrol-3-yl, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, 1H-pyrazol-1-yl, 1 H-pyrazol-3-yl, 1 H-pyrazol-4-yl, 1 H-pyrazol-5-yl, 1 H-imidazol-1-yl, 1 H-imidazol-2-yl, 1 H-imidazol-1-yl 4-yl, 1H-imidazol-5-yl, 1H-1,2,3-triazol-1-yl, 1H-1,2,3-triazol-4-yl, 1H-1,2, 3-triazol-5-yl, 2H-1,2,3-triazol-2-yl, 2W-1,2,3-triazol-4-yl, 2H-1,2,3-triazol-5-yl, 2,4-triazol-1-yl, 1 H-, 2,4-triaz: ol-3-yl, 2,4-triazol-5-yl, 4H-1,2,4-triazol-4-one yl, 4H-1,2,4-triazol-3-yl, 4H-1,2,4-triazol-5-yl, 1H-tetrazol-1-yl 1 H-Tetrazol-5-yl, 2H-Tetrazol-2-yl, 2H-Tetrazol-5-yl, Oxazol-2-yl, Oxazol-4-yl, Oxazol-2-yl

5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-one yl, isothiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazof-5-yl, 1,2,5-oxadiazol-3-yl, 1,2,5- oxadiazol-4-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,2,5-thiadiazol-3-yl, 1,2,5-thiadiazol-2-one 4-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl, pyridazin-3-yl, pyridazin-4 yl, pyridazin-5-yl, pyridazin-6-yl, pyrazin-2-yl, pyrazin-3-yl, pyrazin-5-yl, pyrazin-6-yl, 1,2,5-triazin-2-yl, 1,2,5-triazin-4-yl, 1,2,5-triazin-6-yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl, 1, 2,4-triazine

6-yl, 1 H-indol-1-yl, 1 H-indol-2-yl, 1 H-indol-3-ii, 1 H-indol-5-yl, 1H-indol-6-yl, 1H- indol-7-yl, 1H-indol-8-yl, 1H-indazol-3-yl, 1H-indazol-5-yl, 1H-indazol-6-yl, 1H-indazol-7-yl, 1 H-indazol-8-yl, 1H-benzo [d] imidazol-1-yl, 1 H-benzo [d] imidazol-2-yl, 1 H-benzo [d] imidazol-5-yl, 1 H-benzo [d] imidazol-6-yl, 1H-benzo [d] imidazol-7-yl, 1 / - / - benzo [d] imidazol-8-yl, benzofuran-2-yl, benzofuran-3-yl, benzofuran-5 -yl, benzofuran-6-yl, benzofuran-7-yl, benzofuran-8-yl, benzo [b] thiophen-2-yl, benzo [δ] thiophen-3-yl, benzo [o] thiophen-5-yl , benzo [t]] thiophen-6-yl, benzo [6] thiophen-7-yl, benzo [f] thiophen-8-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl, isoquinolin-8-yl, quinazolin-2-yl, quinazolin-4-yl, quinazolin-5-yl, quinazolin-6-yl, quinazolin-7-yl, quinazolin-2-one 8-yl, quinoxalin-2-yl, quinoxalin-3-yl, quinoxalin-5-yl, quinoxal in-6-yl, quinoxalin-7-yl, quinoxalin-8-yl.

R ₂ and R 3 independently correspond to H or CH ₃ .

B is selected from: matches;

(The)

W

Λ A .OH

> γ

H

Where W is O or S; Y is missing or is N, or CH ₂ .

(B)

Where W and Y are as defined above, R ₄ is selected from hydrogen, hydroxy, amino, halogen, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, dialquilaminosubstituído, substituted or unsubstituted alquilsulfonila, CF3, CN, N3, _NO2 , sulfonyl, acyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycles.

(ç)

A process according to claim 7 further comprising steps of interconversion of functional groups and / or protection and deprotection of functional groups.