Compounds obtainable by the chemical modification of glycyrrhetinic acid, pharmaceutical preparations and uses thereof, and method for preparing same

Abstract

The present invention relates to compounds obtainable by the chemical modification of glycyrrhetinic acid, pharmaceutical preparations and uses thereof, and a method for preparing same. The method comprises chemically modifying glycyrrhetinic acid by transforming hydroxyl at position 3 into an N-arylsulphonylhydrazone and the subsequent reactions thereof. The method comprises obtaining arylated and heteroarylated glycyrrhetinic acid derivatives at position 3. The method further comprises obtaining glycyrrhetinic acid-derived spiropyrazoles. The method further comprises obtaining fused pyrazoles by expanding the A ring of the spiropyrazoles. The method further comprises obtaining tetracyclic glycyrrhetinic acid derivatives by opening the A ring of the spiropyrazoles. The obtainable compounds exhibit pharmacological activity against various diseases. The invention is suitable for use in the chemical and pharmaceutical industry, with an interest in the therapeutic activity of glycyrrhetinic acid and the derivatives thereof.

Description

[0001] COMPOUNDS OBTAINABLE BY CHEMICAL MODIFICATION OF GLYCYRRHETINIC ACID, PHARMACEUTICAL PREPARATIONS AND THEIR USES, AND METHOD FOR THEIR PREPARATION

[0002] TECHNICAL SECTOR

[0003] The invention presented herein describes novel chemical compounds derived from glycyrrhetinic acid modified by a functional change at the C3 position of its backbone. The chemical synthesis comprises the multi-step conversion of the hydroxyl group at position 3 into an Np-toluenesulfonylhydrazone and its subsequent transformation. The invention describes the synthesis of 3-aryl- and 3-heteroaryl-substituted glycyrrhetinic acid derivatives of formula (I) using palladium complexes and aryl and heteroaryl halides. The invention also comprises the synthesis of spiropyrazoles derived from glycyrrhetinic acid of formula (II) via 1,3-dipolar cycloaddition reactions with terminal acetylenes. The invention further describes the preparation of fused pyrazoles of formula (III) derived from glycyrrhetinic acid by ring expansion of the spiropyrazoles of formula (II).The invention also describes the ring-opening synthesis of tetracyclic pyrazoles of formula (IV) from spiropyrazoles of formula (II). The invention further describes that the prepared semi-synthetic derivatives of formulas (I), (II), (III), and (IV) exhibit antitumor activity superior to that of glycyrrhetinic acid.

[0004] The present invention is applicable in the field of the chemical industry and also the pharmaceutical industry, since both glycyrrhetinic acid and many of its derivatives have therapeutic activity against different diseases.

[0005] BACKGROUND OF THE INVENTION

[0006] Glycyrrhetinic acid is a naturally occurring pentacyclic triterpene. This compound is the aglycone of glycyrrhizic acid and is commonly obtained from the plant Glycyrrhizia glabra, commonly known as licorice. Glycyrrhetinic acid exhibits a very interesting biological activity profile (CS Graebin, H. Verli, JA Guimaraes, (2010) “Glycyrrhizin and glycyrrhetic acid: scaffolds to promising new pharmacologically active compounds” J. Braz. Chem. Soc. 21, 1595; CS Graebin “The pharmacological activities of Glycyrrhizinic acid (“Glycyrrhyzin”) and Glycyrrhetinic acid” in Sweeteners, Reference series in Phytochemistry, J.-M. Merillon, KG Ramawal, eds. P. 245-261, 2018), including anti-inflammatory, antiviral, anti-Alzheimer's, hepatoprotective, and antitumor activity. In particular, its anticancer properties have generated great interest, demonstrating cytotoxic activity against a wide variety of tumors.Its antitumor activity is associated with its ability to interfere with mitochondrial activity, and the enzyme serine hydroxymethyltransferase has been identified as a possible target (X. Jin, L. Li, Q. Peng, C. Gan, L. Gao, S. He, S. Tan, W. Pu, Y. Liu, Y. Gong, Y. Yao, G. Wang, X. Liu, M. Gong, P. Lei, H. Zhang, S. Qi, H. Xu, H. Hu, B. Dong, Y. Peng, D. Su, L. Dai, (2022) Glycyrrhetinic acid restricts mitochondrial energy metabolism by targeting SHMT2 Science 25 (5), 104349). However, the use of glycyrrhetinic acid as an antitumor agent has been limited by some adverse clinical effects that discourage its continued administration.

[0007] The chemical modification of glycyrrhetinic acid in the search for new derivatives with improved or novel biological activity has been the subject of numerous studies. This has led to the discovery of new molecules active against different therapeutic targets, such as new antiviral agents (MA Zígolo, M. Salinas, L. Alché, A. Baldessari, GG Liñares, (2018) Chemoenzymatic synthesis of new derivatives of glycyrrhetinic acid with antiviral activity. Molecular docking study, Bioorg. Chem. 78, 210; LA Baltina, H.-C. Lai, Y.-C. Liu, S.-H. Huang, M.-J. Hour, L.A. Baltina, TR Nugumanov, L.M. Khalilov, S.F. Petrova, C.-W. Lin, (2021) Glycyrrhetinic acid derivatives as Zika virus inhibitors: Synthesis and antiviral activity in vitro Bioorg. antiAlzheimer (FM Abdel Bar, DM Elimam, AS Mira, FF El- Senduny, FABadria, (2019) Derivatization, molecular docking and in vitro acetylcholinesterase inhibitory activity of glycyrrhizin as a selective anti-Alzheimer agent, Nat. Prod. Res. 33, 2591 ; S. Schwarz, S. D. Lucas, S. Sommerwerk, R. Csuk, (2014) Amino derivatives of glycyrrhetinic acid as potential inhibitors of cholinesterases. Bioorg. Med. Chem. 22, 3370), para el tratamiento de desórdenes metábolicos (I. Beseda, L. Czollner, P. S. Shah, R. Khunt, R. Gaware, P. Kosma, C. Stanetty, M. C. del Ruiz-Ruiz, H. Amer, K. Mereiter, T. Da Cunha, A. Odermatt, D. ClaBen-Houben, U. Jordis, (2010) Synthesis of glycyrrhetinic acid derivatives for the treatment of metabolic diseases Bioor. Med. Chem. 18, 433) y, muy especialmente, anticancerígenos. (Para una revisión ver B. Xu, G. R. Wu, X. Y. Zhang, M. M. Yan, R. Zhao, N. N. Xue, K. Fang, H. Wang, M. Chen, W. B. Guo, P.; L. Wang, H. M. Leí, (2017) An Overview of Structurally Modified Glycyrrhetinic Acid Derivatives as Antitumor Agents Molecules 22, 924).

[0008] In this description, the numbering shown in Figure 1 is used to refer to the different positions and rings of glycyrrhetinic acid.

[0009] The chemical modifications carried out on glycyrrhetinic acid have mainly focused on esterification and amidation reactions at the carboxylic acid at position 30, and on acylation reactions of the hydroxyl group at position 3. Functionalization reactions at position 4 of glycyrrhetinic acid derivatives have also been studied, following oxidation of the hydroxyl at position 3 to its corresponding carbonyl, and ring-opening reactions of A. A very recent review summarizes the structural variations that have been made in the preparation of glycyrrhetinic acid derivatives aimed at the search for new anticancer agents (H. Hussain, I. Ali, D. Wang, FL Hakkim, B. Westermann, I. Ahmed, AM Ashour, A. Khan, A. Hussain, IR Green, STA Shah, (2021) Glycyrrhetinic acid: a promising scaffold for the discovery of anticancer agents, Expert Opin. Drug Discov. 16, 1497).In addition, numerous patent documents describe chemically modified glycyrrhetinic acid derivatives with diverse therapeutic applications. For example, those contained in documents WO 2014 / 040052 A (“Glycyrrhetinic acid derivatives and methods of use thereof”), US 9,896,476 B (“Glycyrrhetic acid derivatives”), WO 2018 / 069086 A1 (“Hydroxamate triterpenoid derivatives”), WO 2019 / 060051 A1 (“Glycyrrhetinic acid derivatives for treating hyperkalemia”), or WO 2020 / 068689 A1 (“Terpinoid derivatives and uses thereof”).

[0010] / Vp-Toluenesulfonylhydrazones have been used as intermediates in organic synthesis in both Pd-catalyzed coupling reactions and 1,3-dipolar cycloaddition reactions. Palladium complex-catalyzed aryl halides coupling reactions lead to arylalkenes (J. Barluenga, P. Moriel, C. Valdés, F. Aznar, (2007), / V-tosylhydrazones as reagents for cross-coupling reactions: a route to polysubstituted olefins, Angew. Chem. Int. Ed. 46, 5587; J. Barluenga, M. Tomás- Gamasa, P. Moriel, F. Aznar, C. Valdés, (2008) Pd-Catalyzed Cross-Coupling Reactions with Carbonyls: Application in a Very Efficient Synthesis of 4-Aryltetrahydropyridines, Chem. Eur. J. 14, 4792). This reaction has been applied to / Vp-toluensulfonylhydrazones of diverse structures, including alpha-substituted cyclohexanone derivatives (J. Barluenga, M. Escribano, F. Aznar, C.Valdés, (2010) Arylation of a-chiral ketones by palladium-catalyzed cross-coupling reactions of tosylhydrazones with aryl halides, Angew. Chem. Int. Ed. 49, 6856). p-Toluenesulfonylhydrazones react with terminal alkynes via 1,3-dipolar cycloaddition reactions. Applying the reaction to linear ketones / Vp-toluenesulfonylhydrazones leads to 1H-pyrazoles in processes involving a 1,3-dipolar reaction followed by a 1,5-sigmatropic rearrangement (MC Pérez-Aguilar, C. Valdés, (2013) Regioselective one-step synthesis of pyrazoles from alkynes and N-tosylhydrazones: [3+2] dipolar cycloaddition / [1,5] sigmatropic rearrangement cascade, Angew. Chem. Int. Ed. 2013, 52, 7219).The reaction with / Vp-toluenesulfonylhydrazones derived from unsubstituted cyclic ketones yields spiropyrazoles, which can undergo rearrangement with ring expansion to produce fused NH-pyrazoles by sigmatropic 1,5 rearrangement of a substituent on carbon 5 to carbon 4 of the pyrazole (RR Merchant, DM Allwood, DC Blakemore, SV Ley, (2014) Regioselective preparation of saturated spirocyclic and ring-expanded fused pyrazoles, J. Org. Chem. 79, 8800-8811).

[0011] Despite the above, the current technique has limitations in providing new compounds derived from glycyrrhetinic acid that allow the development of new pharmaceutical preparations and applications.

[0012] EXPLANATION OF THE INVENTION

[0013] The present invention relates in one aspect to chemical compounds derived from glycyrrhetinic acid. It also relates to pharmaceutical preparations comprising these compounds and to the uses of these pharmaceutical preparations in preparing medicaments for various treatments. Furthermore, it also relates to a method for preparing glycyrrhetinic acid derivatives.

[0014] A first aspect of the present invention is, therefore, a compound obtainable by chemical modification of glycyrrhetinic acid, of formula (I), or formula (II), or formula (III), or formula (IV) where,

[0015] R 1 is selected from the group consisting of hydrogen, methyl, benzyl, branched or unbranched alkyl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, allyl, propargyl, substituted or unsubstituted heteroaryl;

[0016] Ar 1is selected from a group consisting of phenyl optionally substituted with one, two, three or four substituents selected from -F, Cl, -Br, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or a five-membered aromatic heterocycle containing one, two or three nitrogen atoms optionally substituted with one, two or three groups selected from -F, Cl, -Br, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2,

[0017] -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or a five-membered aromatic heterocycle containing an oxygen or sulfur atom, optionally containing a nitrogen atom and optionally substituted with one, two, or three groups selected from -F, Cl, -Br, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3,

[0018] -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or a six-membered nitrogen-containing aromatic heterocycle containing one, two, three, or four nitrogen atoms and optionally substituted with one, two, or three groups selected from -F, Cl, -Br, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or a naphthalene ring optionally substituted with one, two, three, or four substituents selected from -F, Cl, -Br, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or a quinoline ring optionally substituted with one, two, three or four substituents selected from -F, Cl, -Br, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl,branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or an isoquinoline ring optionally substituted with one, two, three or four substituents selected from -F, Cl, -Br, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or an indole ring optionally substituted with one, two, three or four substituents selected from -F, Cl, -Br, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or a condensed aromatic bicycle containing two, three, or four nitrogen atoms optionally substituted with one, two, three, or four substituents selected from -F, Cl, -Br, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl,

[0019] -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl; and

[0020] R 2is selected from the group consisting of phenyl optionally substituted with one, two, three or four substituents selected from -F, Cl, -Br, -I, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or a five-membered aromatic heterocycle containing one, two or three nitrogen atoms optionally substituted with one, two or three groups selected from -F, Cl, -Br, -I, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or an aromatic heterocycle of five members containing an oxygen or sulfur atom, optionally containing a nitrogen atom and optionally substituted with one, two or three groups selected from -F, Cl, -Br, -I, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2,-NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or a six-membered aromatic heterocycle containing one, two, three, or four nitrogen atoms and optionally substituted with one, two, or three groups selected from -F, Cl, -Br, -I, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or a naphthalene ring optionally substituted with one, two, three, or four substituents selected from -F, Cl, -Br, -I, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or a quinoline ring optionally substituted with one, two, three, or four substituents selected from -F, Cl, -Br, -I, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl,alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or an isoquinoline ring optionally substituted with one, two, three, or four substituents selected from -F, Cl, -Br, -I, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or an indole ring optionally substituted with one, two, three, or four substituents selected from -F, Cl, -Br, -I, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or a condensed aromatic bicycle containing two, three or four nitrogen atoms optionally substituted with one, two, three or four substituents selected from -F, Cl, -Br, -I, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R,CONH2, CONH-alkyl.,

[0021] In a preferred embodiment, R 1 is methyl. In another aspect, the present invention includes compounds possessing biological activities, such as inhibiting the growth of cells and microorganisms (including viruses), and thus being useful in the pharmaceutical field and in the treatment of diseases. The compounds of the invention may also be useful for research in biochemistry or cell biology. Therefore, another aspect is a pharmaceutical preparation comprising, among other components, a therapeutically effective amount of a compound according to any of formulas (I), (II), (III), or (IV), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, together with one or more pharmaceutically acceptable excipients or diluents.

[0022] In general, an “effective amount” of a compound is the amount necessary to achieve the desired result. The expression “pharmaceutically acceptable” or “pharmaceutically acceptable” refers to a biologically suitable material, meaning that the material can be administered to a subject without causing substantially harmful biological effects.

[0023] Any of the compounds of the invention may be used therapeutically as part of an acceptable pharmaceutical preparation or composition. Any person skilled in the art may create acceptable pharmaceutical compositions, which may consist of sterile solutions in water, saline solutions, or buffered solutions at physiological pH. Any of the compounds of the invention may be prepared in the form of a pharmaceutical composition. Pharmaceutical compositions may include various carriers, thickeners, diluents, buffers, preservatives, surfactants, and other agents, in addition to the compound of the invention. Pharmaceutical compositions may also include active ingredients such as antimicrobial, anti-inflammatory, or anesthetic agents.

[0024] The term "treatment," as used here, refers to combating the effects caused as a consequence of the disease or pathological condition of interest in a subject, including:

[0025] (i) inhibit the disease or pathological condition, for example, stop its development;

[0026] (i) alleviate the disease or pathological condition, for example, cause the regression of the disease or pathological condition or its symptoms;

[0027] (iii) to stabilize the disease or pathological condition. As used herein, a “subject” may include domesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cows, horses, pigs, sheep, goats, etc.), laboratory animals (e.g., mice, rabbits, guinea pigs, etc.), and birds. Preferably, the subject is a mammal such as a primate and, most preferably, a human being.

[0028] Another aspect of the invention relates to the pharmaceutical preparation of the invention for use in medicine for the treatment of various diseases.

[0029] In a preferred embodiment of the invention, the pharmaceutical preparation of the invention is used in the treatment of a disease selected from a list consisting of: erythromelalgia, peripheral arterial disease, renal artery stenosis, Buerger's disease, Raynaud's disease, disseminated intravascular coagulation, cerebrovascular disease, acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, hairy cell leukemia, T-cell prolymphocytic leukemia, juvenile myelomonocytic leukemia, systemic lupus erythematosus, scleroderma, hemolytic anemia, vasculitis, type 1 diabetes, Graves' disease, rheumatoid arthritis, osteoarthritis, psoriatic arthritis, Goodpasture syndrome, pernicious anemia, myopathy, Lyme disease, thrombophilia, coagulopathy, acute traumatic coagulopathy, sensory modulation disorder, atherosclerosis, inflammatory bowel disease, Alzheimer's disease,Ankylosing spondylitis, asthma, Crohn's disease, colitis, dermatitis, diverticulitis, fibromyalgia, hepatitis, nephritis, Parkinson's disease, skin disorders, and ulcerative colitis.

[0030] Another aspect is particularly the use of the above pharmaceutical preparation to prepare a drug with antitumor activity.

[0031] Another aspect is particularly the use of the above pharmaceutical preparation to prepare a drug for the treatment of Alzheimer's.

[0032] Another aspect is the use of the above pharmaceutical preparation to prepare a drug with antibacterial activity. Another aspect is the use of the above pharmaceutical preparation to prepare a drug with antiviral activity.

[0033] The compounds of the invention can be administered to the subject in several different ways, depending on whether the treatment is desired to be local or systemic, and depending on the area to be treated. Thus, for example, a compound of the present invention can be administered in the form of an ophthalmic solution, applied to the surface of the eye.In addition, a compound may be administered to a subject vaginally, rectally, intranasally, orally, by inhalation, or parenterally, whether by intradermal, subcutaneous, intramuscular, intraperitoneal, intrarectal, intra-arterial, intralymphatic, intravenous, intrathecal, and intratracheal routes, including intraperitoneal, intravenous, intradermal, intraspinal, intrastromal, intra-articular, and intrasynovial, intrathecal, intralesional, intra-arterial, intramuscular, intracranial, subcutaneous, intraorbital, intracapsular, topical, oral, by transdermal patches, percutaneous, nasal spray, surgical implant, internal surgical paint, or infusion pump.

[0034] The composition of the present invention may also take the form of a sustained-release drug formulation or any other conventional release system, such as nanoparticles, liposomes or nanospheres, polymeric material, biodegradable or non-biodegradable implant or biodegradable microparticles, such as biodegradable microspheres.

[0035] Parenteral administration, if used, is generally by injection. Injectables can be prepared in various forms, such as liquid solutions or suspensions, solid forms suitable for dissolving or suspension before injection, or emulsions. Other forms of parenteral administration employ slow- or sustained-release systems to maintain a constant dose (see, for example, US Patent 3,710,795). Preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions, which may also contain buffers, diluents, and other additives. Examples of non-aqueous solvents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.Examples of aqueous solvents include water, aqueous-alcoholic solutions, emulsions, and suspensions, including saline and buffered solutions. Examples of parenteral vehicles include sodium chloride solution, Ringer's dextrose, sodium chloride and dextrose, etc. Preservatives and other additives, such as antimicrobial agents, antioxidants, chelating agents, and inert gases, may also be present. Topical formulations may include creams, lotions, gels, drops, suppositories, sprays, liquids, and powders. Certain conventional pharmaceutical carriers, aqueous, oily, or powder bases, thickeners, etc., may also be necessary or desirable. Oral compositions may include powders or granules, suspensions or solutions in water or non-aqueous media, capsules, or tablets. The inclusion of thickening agents, flavorings, diluents, emulsifiers, dispersants, etc., may be desirable.

[0036] Another aspect of the present invention is also a method for preparing glycyrrhetinic acid derivatives comprising the following steps: a) Mixing glycyrrhetinic acid of formula (0) with an alcohol or an alkyl halide with an effective amount of an acid or a base and an effective amount of a solvent to promote the following chemical esterification reaction to obtain the compound of formula (V) where,

[0037] R 1a) Select from the group consisting of hydrogen, methyl, benzyl, branched or unbranched alkyl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, allyl, propargyl, substituted or unsubstituted heteroaryl. b) Purify the mixture using purification means that remove the solvent and separation means that separate the compound of formula (V). c) Mix the separated compound of formula (V) with an effective amount of an oxidizing agent and an organic solvent to promote the following chemical reaction for the synthesis of the compound of formula (VI). where,

[0038] R 1It is selected from the group consisting of hydrogen, methyl, benzyl, branched or unbranched alkyl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, allyl, propargyl, substituted or unsubstituted heteroaryl. d) Purify the mixture using purification means that remove the solvent and separation means that separate the compound of formula (VI). e) Mix the separated compound of formula (VI) with an organic solvent and an arylsulfonylhydrazide of formula Ar 2 -SG>2NHNH2 and an acid, to promote the following chemical condensation reaction to obtain the N-arylsulfonylhydrazone compound of formula (Vil) where, R 1 is selected from the group consisting of hydrogen, methyl, benzyl, branched or unbranched alkyl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; and

[0039] Ar 2It is selected from the group consisting of phenyl, optionally substituted with one, two, three, four or five identical or different substituents, selected from methyl, linear alkyl, branched alkyl, O-alkyl, -CF3, -NO2, F, Cl, Br, CN, or phenyl. f) Purify the mixture using purification means that remove the solvent and separation means that separate the compound of formula (Vil).

[0040] In a preferred embodiment, in step e) the organic solvent is a mixture of dichloromethane and methanol, the acid is sulfuric acid, and the chemical reaction is promoted at a temperature between 40 and 70 e C for a period of time between 1 and 12 hours.

[0041] In another preferred embodiment, in step e) Ar 2 of the compound with formula (Vil) is the 4-tolyl group.

[0042] In another preferred embodiment, the method for preparing aryl or heteroarylated glycyrrhetinic acid derivatives of formula (I) further comprises the following steps: g.1) Mixing the / V-arylsulfonylhydrazone compound of formula (Vil) with an effective amount of an aromatic compound of formula Ar 1 -X in the presence of an effective amount of a base, a catalytically effective amount of a palladium catalyst, an effective amount of water, and an effective amount of an organic solvent at a temperature between 20 e C and 150 e C for a period of time between 3h and 24h to promote the following chemical reaction for the synthesis of the compound of formula (I) where,

[0043] R 1 is selected from the group consisting of hydrogen, methyl, benzyl, branched or unbranched alkyl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;

[0044] Ar 1is selected from a group consisting of phenyl optionally substituted with one, two, three or four substituents selected from -F, Cl, -Br, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or a five-membered aromatic heterocycle containing one, two or three nitrogen atoms optionally substituted with one, two or three groups selected from -F, Cl, -Br, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or a five-membered aromatic heterocycle containing a oxygen or sulfur atom, optionally containing a nitrogen atom and optionally substituted with one, two or three groups selected from -F, Cl, -Br, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl,N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or a six-membered nitrogen-containing aromatic heterocycle containing one, two, three, or four nitrogen atoms and optionally substituted with one, two, or three groups selected from -F, Cl, -Br, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or a naphthalene ring optionally substituted with one, two, three, or four substituents selected from -F, Cl, -Br, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or a quinoline ring optionally substituted with one, two, three, or four substituents selected from -F, Cl, -Br, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino,dialkylamino, CO2R, CONH2, CONH-alkyl, or an isoquinoline ring optionally substituted with one, two, three, or four substituents selected from -F, Cl, -Br, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or an indole ring optionally substituted with one, two, three, or four substituents selected from -F, Cl, -Br, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or an aromatic bicycle condensate containing two, three or four nitrogen atoms optionally substituted with one, two, three or four substituents selected from -F, Cl, -Br, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl;

[0045] X is selected from the group Cl, Br, I, triflate, mesylate, tosylate, nonaflate; and

[0046] Ar 2 It is selected from the group consisting of phenyl, optionally substituted with one, two, three, four or five identical or different substituents, methyl, linear alkyl, branched alkyl, O-alkyl, -CF3, -NO2, F, Cl, Br, CN, or phenyl. h.1) Purify the mixture using purification means that remove the solvent and separation means that separate the compound of formula (I).

[0047] In a more preferred embodiment, in step g.1) the mixture is heated to a temperature between 70 e C and 150 e C for a period of time between 3h and 24h.

[0048] In another more preferred embodiment, in step g.1) the mixture comprises 1 equivalent of N-arylsulfonylhydrazone compound of formula (Vil), from 1 to 5 equivalents of aromatic compound of formula Ar 1-X, from 0.05 to 0.3 equivalents of catalyst, from 1 to 10 equivalents of base and from 1 to 20 equivalents of water.

[0049] In another more preferred embodiment, in step g.1) the base is selected from the group containing alkoxides and phenoxides of alkali metals. In an even more preferred embodiment, the base is lithium tert-butoxide.

[0050] In another more preferred embodiment, in step g.1) the base is selected from the group containing alkali metal hydroxides.

[0051] In another more preferred embodiment, in step g.1) the base is selected from the group containing alkali metal carbonates. For the purposes of this invention and its description, these alkali metals refer to compounds where the metal is preferably lithium, sodium, potassium, cesium, or a combination thereof.

[0052] In another more preferred embodiment, in step g.1) the palladium catalyst is generated by adding a palladium compound and a ligand to the reaction medium. In an even more preferred embodiment, the palladium compound is [ts-di(benzylidene)acetone]dipalladium(O) and the ligand is 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (X-Phos).

[0053] In another more preferred embodiment, in stage g.1) Ar 2 of the compound with formula (Vil) is 4-tolyl.

[0054] In another specific embodiment of the method for preparing spiropyrazoles derived from glycyrrhetinic acid of formula (II), it further comprises the following steps: g.2) Mixing the N-arylsulfonylhydrazone compound of formula (Vil) with an effective amount of a terminal alkyne compound of formula R 2 -C=CH in the presence of an effective amount of a base and an effective amount of a solvent at a temperature between 20 e C and 150 eC for a period of time between 3h and 24h to promote the following chemical reaction for the synthesis of the compound of formula (II)

[0055] R 1 is selected from the group consisting of hydrogen, methyl, benzyl, branched or unbranched alkyl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; R 2is selected from the group consisting of phenyl optionally substituted with one, two, three or four substituents selected from -F, Cl, -Br, -I, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or a five-membered aromatic heterocycle containing one, two or three nitrogen atoms optionally substituted with one, two or three groups selected from -F, Cl, -Br, -I, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or an aromatic heterocycle of five members containing an oxygen or sulfur atom, optionally containing a nitrogen atom and optionally substituted with one, two or three groups selected from -F, Cl, -Br, -I, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2,-NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or a six-membered aromatic heterocycle containing one, two, three, or four nitrogen atoms and optionally substituted with one, two, or three groups selected from -F, Cl, -Br, -I, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or a naphthalene ring optionally substituted with one, two, three, or four substituents selected from -F, Cl, -Br, -I, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or a quinoline ring optionally substituted with one, two, three, or four substituents selected from -F, Cl, -Br, -I, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl,alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or an isoquinoline ring optionally substituted with one, two, three, or four substituents selected from -F, Cl, -Br, -I, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or an indole ring optionally substituted with one, two, three, or four substituents selected from -F, Cl, -Br, -I, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or a condensed aromatic bicycle containing two, three or four nitrogen atoms optionally substituted with one, two, three or four substituents selected from -F, Cl, -Br, -I, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R,CONH2, CONH-alkyl; and,

[0056] Ar 2 It is selected from the group consisting of phenyl, optionally substituted with one, two, three, four or five equal or different substituents selected from methyl, linear alkyl, branched alkyl, O-alkyl, -CF3, -NO2, F, Cl, Br, CN, phenyl. h.2) Purify the mixture by means of purification that remove the solvent and means of separation that separate the compound of formula (II).

[0057] In a more specific embodiment, in step g.2) the mixture is heated to a temperature between 70 and 150 e C for a period of time between 3h and 24h.

[0058] In another more specific embodiment, in step g.2) the base is selected from the group of alkali metal carbonates.

[0059] In another more specific embodiment, in stage g.2) Ar 2 of the compound with formula (Vil) is 4-tolyl.

[0060] In another more specific embodiment, the method for preparing derivatives of glycyrrhetinic acid of formula (III) and formula (IV) further comprises the following steps:

[0061] 2) Mix the compound of formula (II) with an effective amount of an acid and an effective amount of a solvent under an inert atmosphere at a temperature between 20 e C and 110 e C for a period of time between 1 and 24 h to promote the following chemical reaction of dissolution and synthesis of the compound of formula (III) and of the compound of formula (IV) where,

[0062] R 1 is selected from the group consisting of hydrogen, methyl, benzyl, branched or unbranched alkyl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;

[0063] R 2is selected from the group consisting of phenyl optionally substituted with one, two, three or four substituents selected from -F, Cl, -Br, -I, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or a five-membered aromatic heterocycle containing one, two or three nitrogen atoms optionally substituted with one, two or three groups selected from -F, Cl, -Br, -I, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or an aromatic heterocycle of five members containing an oxygen or sulfur atom, optionally containing a nitrogen atom and optionally substituted with one, two or three groups selected from -F, Cl, -Br, -I, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2,-NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or a six-membered aromatic heterocycle containing one, two, three, or four nitrogen atoms and optionally substituted with one, two, or three groups selected from -F, Cl, -Br, -I, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or a naphthalene ring optionally substituted with one, two, three, or four substituents selected from -F, Cl, -Br, -I, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or a quinoline ring optionally substituted with one, two, three, or four substituents selected from -F, Cl, -Br, -I, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl,alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or an isoquinoline ring optionally substituted with one, two, three, or four substituents selected from -F, Cl, -Br, -I, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or an indole ring optionally substituted with one, two, three, or four substituents selected from -F, Cl, -Br, -I, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or a condensed aromatic bicycle containing two, three or four nitrogen atoms optionally substituted with one, two, three or four substituents selected from -F, Cl, -Br, -I, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R,CONH2, CONH-alkyl. j.2) Purify the mixture using purification means that remove the solvent and separation means that separate the compounds of formula (III) and (IV).

[0064] In another, even more specific embodiment, in step 1.2) the mixture consisting of the compound of formula (II), the acid and the solvent, are kept at room temperature.

[0065] In another, even more specific embodiment, in step 1.2) the acid is boron trifluoride etherate (BF3-OEt2).

[0066] In a preferred embodiment of any of the methods, the purification means and the separation means of any of the steps comprise a liquid-liquid extraction process, solvent evaporation, and chromatography.

[0067] In another preferred embodiment of any of the methods, in step g.1), in step g.2) and in step g.2) the solvent is 1,4-dioxane.

[0068] One aspect of the invention provides a method for synthesizing compounds derived from glycyrrhetinic acid by structural modification at position 3. Glycyrrhetinic acid and many of its derivatives exhibit very interesting biological activity profiles. The glycyrrhetinic acid derivatives described in this invention are unknown, and no alternative method exists for their preparation.

[0069] Another aspect of the invention provides a method for introducing aryl and heteroaryl groups at position 3 of the glycyrrhetinic acid skeleton via C-C bond formation reactions through the preparation of N-arylsulfonylhydrazones and their subsequent coupling reaction with aryl or heteroaryl halides catalyzed by Pd. None of the methodologies described to date for the modification of glycyrrhetinic acid allow access to this class of derivatives. Likewise, although the C-C bond formation reaction between aryl halides and Np-toluenesulfonylhydrazones is known, there are no examples of its application to the modification of glycyrrhetinic acid or other triterpenes, nor to alpha,alpha-disubstituted N-arylsulfonylhydrazones.

[0070] Another aspect of the invention provides a method for synthesizing three families of compounds derived from glycyrrhetinic acid, featuring a pyrazole ring. The pyrazole ring is present in a large number of bioactive molecules, so its introduction into the structure of glycyrrhetinic acid can influence the modulation of its biological activity.

[0071] Another aspect of the invention provides a method for synthesizing glycyrrhetinic acid derivatives that have a spiropyrazole group at position 3. None of the previously described methodologies for modifying glycyrrhetinic acid provide access to this class of previously unknown spirocyclic derivatives. Furthermore, although the synthesis of spiropyrazoles from N-arylsulfonylhydrazones is known, there is no precedent for its application to modifying glycyrrhetinic acid or other triterpenes, nor to alpha,alpha-disubstituted N-arylsulfonylhydrazones.

[0072] Another aspect of the invention provides a method for synthesizing compounds derived from glycyrrhetinic acid from spiropyrazole derivatives by expanding ring A to access glycyrrhetinic acid derivatives having a seven-membered ring fused to a pyrazole.

[0073] Another aspect of the invention provides a method for preparing tetracyclic derivatives of glycyrrhetinic acid with opening of ring A and incorporation of a pyrazole ring.

[0074] Another aspect of the invention is that the chemical modifications made to glycyrrhetinic acid described herein have the capacity to generate compounds with improved therapeutic activity compared to the natural compound. This has been demonstrated through cytotoxicity studies performed on HeLa tumor cells. Several compounds of structure (I), structure (II), and structure (IV) with high, dose-dependent cytotoxic activity (IC50 in the range of 2-10 mM) have been identified, improving the activity of glycyrrhetinic acid against this cell line by an order of magnitude.

[0075] The present invention is applicable in the field of the chemical industry and also the pharmaceutical industry, since both glycyrrhetinic acid and many of its derivatives have therapeutic activity against different diseases.

[0076] BRIEF DESCRIPTION OF THE DRAWINGS

[0077] Figure 1 represents the prior art (PA) and shows the structure of glycyrrhetinic acid, formula (O). This figure also indicates the ring nomenclature, from A to D, the numbering of the positions, from 1 to 30, and their main chemical modifications, indicated by arrows. These chemical modifications include esterifications (E), amidations (A) of the carboxylic acid at position 30, reductions (R) of the carbonyl group at position 11, oxidations (O), esterifications (E), carbamoylations (C), aminations (M) of the hydroxyl group at position 3, and functionalization reactions (F) at position 2.

[0078] Fig. 2 represents the compounds of formulas (I), (II), (III) and (IV) derived from glycyrrhetinic acid, the subject of the invention.

[0079] Figure 3 schematically represents the synthesis of an AAp-toluenesulfonylhydrazone of formula (Vil) from glycyrrhetinic acid of formula (0) in a three-reaction process: the first is the esterification of the compound of formula (0) to promote the compound of formula (V), the second is the oxidation of the compound of formula (V) to promote the compound of formula (VI), and the third is the reaction of the compound of formula (VI) with p-toluen-A / -sulfonylhydrazide to promote the compound of formula (Vil). These three reactions correspond to those indicated in steps a), c), and e) of the method for the preparation of glycyrrhetinic acid derivatives. For the purposes of this invention and its description, the abbreviation Ts = 4-methylbenzenesulfonyl.

[0080] Fig. 4 corresponds to the synthesis of the compound of formula (I) (2S,4aS,6aS,6bR,8aR,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-10- (isoquinolin-4-yl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,12,12a,12b,13,14b-octadecahydropycene-2-methyl carboxylate from the Np-toluenesulfonylhydrazone of formula (VII) and the aromatic compound 4-bromoisoquinoline.

[0081] Fig. 5 corresponds to the synthesis of the compound of formula (I) (2S,4aS,6aS,6bR,8aR,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-10- (quinolin-8-yl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,12,12a,12b,13,14b-octadecahydropycene-2-methyl carboxylate from the Np-toluenesulfonylhydrazone of formula (VII) and the aromatic compound 8-bromoquinoline.

[0082] Fig. 6 corresponds to the synthesis of the compound of formula (I) (2S,4aS,6aS,6bR,8aR,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-10-(2-(methoxymethyl)phenyl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,12,12a,12b,13,14b-octadecahydropycene-2-methyl carboxylate from the Np-toluenesulfonylhydrazone of formula (VII) and the aromatic compound 1-bromo-2-(methoxymethyl)benzene.

[0083] Fig. 7 corresponds to the synthesis of the compound of formula (I) (2S,4aS,6aS,6bR,8aR,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-10-(6-bromopyridin-2-yl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,12,12a,12b,13,14b-octadecahydropycene-2-methyl carboxylate from the Np-toluenesulfonylhydrazone of formula (VII) and the aromatic compound 2,6-dibromopyridine.

[0084] Fig. 8 corresponds to the synthesis of the compound of formula (I) (2S,4aS,6aS,6bR,8aR,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-10-(3-methoxypyridin-2-yl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,12,12a,12b,13,14b-octadecahydropycene-2-methyl carboxylate from the Np-toluenesulfonylhydrazone of formula (VII) and the aromatic compound 2-bromo-3-methoxypyridine.

[0085] Fig. 9 corresponds to the synthesis of the compound of formula (I) (2S,4aS,6aS,6bR,8aR,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-10-(2-aminopyridin-3-yl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,12,12a,12b,13,14b-octadecahydropycene-2-methyl carboxylate from the Np-toluenesulfonylhydrazone of formula (VII) and the aromatic compound 2-amino-3-bromopyridine.

[0086] Figure 10 corresponds to the synthesis of the compound with formula (I)

[0087] (2S,4aS,6aS,6bR,8aR,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-10-(3-cyanopyridin-2-yl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,12,12a,12b,13,14b-octadecahydropycene-2-methyl carboxylate from the Np-toluenesulfonylhydrazone of formula (VII) and the aromatic compound 2-bromo-3-cyanopyridine.

[0088] Figure 11 corresponds to the synthesis of the compound with formula (II)

[0089] (3S,4aR,6aR,6bS,8aS, 11 S, 12aR, 14aR, 14bS)-5'-(3-bromophenyl)-4,4,6a,6b,8a, 1 1, 14b- heptamethyl-14-oxo- 1,4, 4a, 5, 6, 6a, 6b, 7, 8, 8a, 9, 10, 11, 12, 12a, 14, 14a, 14b-octadecahydro-2H- spiro[picene-3,3'-pyrazole]-11-carboxylate from Np-toluenesulfonylhydrazone of formula (VII) and the terminal alkyne 3-bromophenylacetylene.

[0090] Figure 12 corresponds to the synthesis of the compound of formula (II)

[0091] (3S,4aR,6aR,6bS,8aS,11 S,12aR,14aR,14bS)-5'-(2-fluorophenyl)-4,4,6a,6b,8a,11 ,14b- heptamethyl-14-oxo-1 ,4,4a,5,6,6a,6b,7,8,8a,9,10,11 ,12,12a,14,14a,14b-octadecahydro-2H- spiro[picene-3,3'-pyrazole]-11 -methyl carboxylate from the Np-toluenesulfonylhydrazone of formula (VII) and the terminal alkyne 2-fluorophenylacetylene.

[0092] Figure 13 corresponds to the synthesis of the compound with formula (II)

[0093] (3S,4aR,6aR,6bS,8aS,11 S,12aR,14aR,14bS)-5'-(4-fluorophenyl)-4,4,6a,6b,8a,11 ,14b- heptamethyl-14-oxo-1 ,4,4a,5,6,6a,6b,7,8,8a,9,10,11 ,12,12a,14,14a,14b-octadecahydro-2H- spiro[picene-3,3'-pyrazole]-11 -methyl carboxylate from the Np-toluenesulfonylhydrazone of formula (VII) and the terminal alkyne 4-fluorophenylacetylene.

[0094] Figure 14 corresponds to the synthesis of the compound of formula (II)

[0095] (3S,4aR,6aR,6bS,8aS,11 S,12aR,14aR,14bS)-5'-(3,4-difluorophenyl)-4,4,6a,6b,8a,1 1 ,14b- heptamethyl-14-oxo-1 ,4,4a,5,6,6a,6b,7,8,8a,9,10,11 ,12,12a,14,14a,14b-octadecahydro-2H- spiro[picene-3,3'-pyrazole]-11 -methyl carboxylate from the Np-toluenesulfonylhydrazone of formula (VII) and the terminal alkyne 3,4-difluorophenylacetylene.

[0096] Figure 15 corresponds to the synthesis of the compound with formula (II)

[0097] (3S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-5'-(2-thiophenyl)-4,4,6a,6b,8a,11,14b-heptamethyl-14-oxo-1,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-octadecahydro-2H-spiro[picene-3,3'-pyrazole]-11-methyl carboxylate from the Np-toluenesulfonylhydrazone of formula (VII) and the terminal alkyne 2-thiophenylacetylene. Fig. 16 corresponds to the synthesis of the compound of formula (II)

[0098] (3S,4aR,6aR,6bS,8aS, 11S, 12aR, 14aR, 14bS)-5'-(4-cyanophenyl)-4,4,6a,6b,8a, 11,14b- heptamethyl-14-oxo-1,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-octadecahydro-2H- spiro[picene-3,3'-pyrazol]-11-methyl carboxylate from the Np-toluenesulfonylhydrazone of formula (V1) and the terminal alkyne 4-cyanophenylacetylene.

[0099] Fig. 17 corresponds to the synthesis of the compound of formula (II) (3S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-5'-(4-methoxycarbonylphenyl)-4,4,6a,6b,8a,11,14b-heptamethyl-14-oxo-1,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-octadecahydro-2H-spiro[picene-3,3'-pyrazole]-11-methyl carboxylate from the Np-toluenesulfonylhydrazone of formula (VII) and the terminal alkyne 4-

[0100] (methoxycarbonyl)phenylacetylene.

[0101] Fig.18 corresponds to the synthesis of the compound of formula (II) (3S,4aR,6aR,6bS,8aS,11 S,12aR,14aR,14bS)-5'-(pyridin-2-1l)-4,4,6a,6b,8a,11 ,14b- heptamethyl-14-oxo- 1 ,4, 4a, 5, 6, 6a, 6b, 7, 8, 8a, 9, 10, 11 , 12, 12a, 14, 14a, 14b-octadecahydro-2H- spiro[picene-3,3'-pyrazole]-11 -methyl carboxylate from the Np-toluenesulfonylhydrazone of formula (VII) and the terminal alkyne 2-pyridynylacetylene.

[0102] Fig. 19 corresponds to the synthesis of the compound of formula (II) (3S,4aR,6aR,6bS,8aS,11 S,12aR,14aR,14bS)-5'-(4-(trifluoromethyl)phenyl)- 4,4,6a,6b,8a,11 ,14b-heptamethyl-14-oxo-1 ,4,4a,5,6,6a,6b,7,8,8a,9,10,11 ,12,12a,14,14a, 14b-octadecahydro-2H-spiro[picene-3,3'-pyrazol]-1 1 -methyl carboxylate from the Np-toluenesulfonylhydrazone of formula (VII) and the terminal alkyne 4-(trifluoromethyl)phenylacetylene.

[0103] La Fig.20 corresponde a la síntesis de los compuestos de fórmula (III) (2bR,4S,6aS,8aS,8bR,10aR,17aS,17bR)-14-(3-bromofenil)-4,6a,8a,8b,11 ,11 ,17a- heptametil-1 -oxo-2b,3,4,5,6,6a,7,8,8a,8b,9,10,10a,1 1 ,16,17,17a, 17b-octadecahidro-1 H- criseno[1 ,2-e]pirazolo[1 ,5-a]azep¡n-4-carbox¡lato de metilo y de fórmula (IV) (3S,4aR,6aR,7S,8S,10aR,10bS,12aS)-7-(2-(3-(3-bromophenyl)-1 H-pirazol-5-yl)ethyl)-3,7, 10a, 10b,12a-pentametil-6-oxo-8-(prop-1 -en-2-yl)-1 ,2,3,4,4a,6,6a,7,8,9,10,10a,10b,1 1 ,12,12a- hexadecahidrocriseno-3-carboxylato de metilo a partir del correspondiente compuesto de fórmula (II). La Fig.21 corresponde a la síntesis de los compuestos de fórmula (III) (2bR,4S,6aS,8aS,8bR,10aR,17aS,17bR)-14-(4-cianofenil)-4,6a,8a,8b,11 ,11 ,17a- heptametil-1 -oxo-2b,3,4,5,6,6a,7,8,8a,8b,9,10,10a,1 1 ,16,17,17a, 17b-octadecahidro-1 H- criseno[1 ,2-e]pirazolo[1 ,5-a]azep¡n-4-carbox¡lato de metilo y de fórmula (IV) (3S,4aR,6aR,7S,8S,10aR,10bS,12aS)-7-(2-(3-(4-cyanophenyl)-1 H-pirazol-5-yl)ethyl)- 3,7, 10a, 10b, 12a-pentamethyl-6-oxo-8-(prop-1 -en-2-yl)- 1 ,2,3,4,4a,6,6a,7,8,9,10,10a,10b,1 1 ,12,12a-hexadecahidrochseno-3-carboxylato de metilo a partir del correspondiente compuesto de fórmula (II).

[0104] Fig.22 corresponds to the summary of the formula (III) (2bR,4S,6aS,8aS,8bR,10aR,17aS,17bR)-14-(thiophen-2-yl)-4,6a,8a,8b,11,11,17a-heptamet¡l- 1 -oxo-2b,3,4,5,6,6a,7,8,8a,8b,9,10,10a,11,16,17,17a,17b-octadecahidro-1 H-criseno[1,2-e]pyrazolo[1,5-a]azepin-4-carboxylate of methyl starting from the corresponding formula (II).

[0105] Fig.23 corresponds to the synthesis of the compound of formula (III) (2bR,4S,6aS,8aS,8bR,10aR,17aS,17bR)-14-(3-aminophenyl)-4,6a,8a,8b,11,11,17a-heptamethyl-1 -oxo-2b,3,4,5,6,6a,7,8,8a,8b,9,10,10a,1 1,16,17,17a, 17b-octadecahydro-1 H-chrysene[1,2-e]pyrazolo[1,5-a]azepine-4-carboxylate methyl from the corresponding compound of formula (II).

[0106] Fig. 24 corresponds to the synthesis of the compound of formula (IV) (3S,4aR,6aR,7S,8S,10aR,10bS,12aS)-3,7,10a,10b,12a-pentamethyl-6-oxo-8-(prop-1 -en-2-yl)-7-(2-(3-(pyridin-2-yl)-1 H-pyrazol-5-yl)ethyl)-1 ,2,3,4,4a,6,6a,7,8,9,10,10a,10b,11 ,12,12a-methyl hexadecahydrochrysene-3-carboxylate from the corresponding compound of formula (II).

[0107] La Fig.25 corresponde a la síntesis de los compuestos de fórmula (III) (2bR,4S,6aS,8aS,8bR,10aR,17aS,17bR)-14-(4-metoxicarbonil)fen¡l-4,6a,8a,8b,11 ,11 ,17a- heptametil-1 -oxo-2b,3,4,5,6,6a,7,8,8a,8b,9,10,10a,1 1 ,16,17,17a, 17b-octadecahidro-1 H- criseno[1 ,2-e]pirazolo[1 ,5-a]azep¡n-4-carbox¡lato de metilo de y de fórmula (IV) (3S,4aR,6aR,7S,8S,10aR,10bS,12aS)-7-(2-(3-(4-(metoxicarbonyl)fen¡l)-1 H-pirazol-5- ¡l)ethil)-3,7,10a,10b,12a-pentametil-6-oxo-8-(prop-1 -en-2-¡l)-1 ,2,3,4,4a,6,6a,7,8,9,10,10a, 10b, 11 ,12,12a-hexadecahidrocriseno-3-carboxylato de metilo a partir del correspondiente compuesto de fórmula (II). TI

[0108] Fig. 26 corresponds to the synthesis of the compound of formula (IV) (3S,4aR,6aR,7S,8S,10aR,10bS,12aS)-3,7,10a,10b,12a-pentamethyl-6-oxo-8-(prop-1 -en-2-yl)-7-(4-trifluoromethylphenyl)-1 H-pyrazol-5-yl)ethyl)-1 ,2, 3, 4, 4a, 6, 6a, 7, 8, 9, 10,10a,10b,11 ,12,12a- methyl hexadecahydrochrysene-3-carboxylate from the corresponding compound of formula (II).

[0109] Fig. 27 corresponds to the IC50 values ​​obtained in the antitumor activity assays of the compounds of formula (I) against a HeLa cell line.

[0110] Fig. 28 corresponds to the IC50 values ​​obtained in the antitumor activity assays of the compounds of formula (II) against a HeLa cell line.

[0111] Fig.29 corresponds to the IC50 values ​​obtained in the antitumor activity assays of the compounds of formula (IV) against a HeLa cell line.

[0112] Figure 30 corresponds to the structure determined by X-ray diffraction for the compound of formula (II) (3S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-5'-(4-cyanophenyl)-4,4,6a,6b,8a,11,14b-heptamethyl-14-oxo-

[0113] 1,4, 4a, 5, 6, 6a, 6b, 7, 8, 8a, 9, 10,11,12,12a,14,14a,14b-octadecahydro-2H-spiro[picene-3,3'-pyrazole]-11-methyl carboxylate from which the stereochemistry of the spironic carbon of the compound of formula (II) is determined. Fig. 30A shows the structure of the compound of formula (II). Fig. 30B and Fig. 30C correspond to the result of the X-ray diffraction analysis of the compound of interest.

[0114] PREFERRED EMBODIMENT OF THE INVENTION

[0115] For a better understanding of the present invention, the following examples of preferred embodiments are set out, described in detail, which should be understood without limiting the scope of the invention.

[0116] ANTITUMOR ACTIVITY ASSAYS To analyze the therapeutic effects of the glycyrrhetinic acid derivatives of the present invention, the cytotoxicity of the synthesized compounds was evaluated in HeLa cells through cell viability assays. For this purpose, MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfonatophenyl)-2H-tetrazolium) assays were performed, a technique commonly used to evaluate the antitumor activity of chemical compounds. Ninety-six-well plates were used in which the cells were cultured at a density of 1500 cells per well for 24 hours at 37°C. eC and with 5% CO2. The plates were then treated with glycyrrhetinic acid derivatives of formulas (I), (II), (III), and (IV) dissolved in DMSO at concentrations of 1, 2, 5, 10, 20, 50, 70, 90, and 100 mM for 72 hours. Triplicates were made for each concentration and for the controls, in which an amount of DMSO equivalent to that used in the cells to which the compounds were added was added. After 72 hours of incubation, the culture medium was replaced with 100 j L PBS, and 20 j L of MTS was added to each well. After 1 hour of incubation at 37 e C, absorbance was measured at 490 nm. IC50 values ​​were calculated from the data obtained using the GraphPad Prism program (8.2.1). In the following examples, the IC50 values ​​are given for the compounds obtained as described in each one and which showed significant activity.

[0117] EXAMPLE 1

[0118] This example describes the synthesis of the compound of formula (Vil) from the compound glycyrrhetinic acid of formula (O) where R 1 It is the methyl group and the arylsulfonylhydrazide of formula Ar 2 -SO2NHNH2 where Ar 2is 4-tolyl. The main reactions of this method are represented in Figure 3. The method comprised the following steps: a) Glycyrrhetinic acid of formula (0) (6.4 mmol, 3 g) was dissolved in 60 mL of acetone and 3.5 grams of potassium carbonate (25.6 mmol, 4 eq) and 3.6 g of methyl iodide (25.6 mmol, 4 eq) were added. The resulting suspension was stirred for 24 hours at room temperature. In this first stage, the reaction shown in Figure 3 was promoted, where the compound with formula (V) (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-hydroxy-2,4a,6a,6b,9,9,12a-heptamethyl-13-OXO-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropycene-2-methyl carboxylate was obtained. b) The solvent was removed by vacuum distillation and chloroform (50 mL) and H2O (50 mL) were added. The phases were separated and the organic layer was washed with H2O (50 mL) and dried on Na2SÜ4.The solution was filtered through filter paper and concentrated by vacuum distillation, yielding the compound of formula (V) (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-hydroxy-2,4a,6a,6b,9,9,12a-heptamethyl- 13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropycene-2-methyl carboxylate, which was used in the next stage without any further purification. c) The compound of formula (V) obtained in step b) (3.05g) was dissolved in anhydrous dichloromethane (60 mL) and 2.8 g of PCC (9.4 mmol) were added. The mixture was stirred at room temperature for two hours. In this stage, the reaction represented in Figure 3 was promoted, where the compound with formula (VI) (2S,4aS,6aS,6bR,8aR, 12aS, 12bR, 14bR)-2,4a,6a,6b,9,9, 12a-heptamethyl-10, 13-dioxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,1,12,12a,12b,13,14b-icosahydropicene-2-carboxylate of methyl was obtained. d) The mixture from stage c) was poured onto 50 mL of H2O.40 mL of dichloromethane were added and the phases were separated. The aqueous phase was extracted twice with 30 mL of dichloromethane. The organic phases were combined and washed successively with 40 mL of H₂O, 40 mL of aqueous solution saturated with sodium bicarbonate, and 40 mL of H₂O. The organic layer was dried over Na₂S₄. The solution was filtered through filter paper and concentrated by vacuum distillation, yielding the compound with formula (VI) (2S,4aS,6aS,6bR,8aR, 12aS, 12bR, 14bR)-2,4a,6a,6b,9,9, 12a-heptamethyl-10, 13-dioxo-1,2,3.

[0119] 4, 4a, 5, 6, 6a, 6b, 7, 8, 8a, 9, 10, 11, 12, 12a, 12b, 13, 14b-icosahydropicene-2-carboxylate methyl was used in the next step without any further purification. e) The compound of formula (VI) (2 g, 4.1 mmol) was dissolved in the minimum volume of dichloromethane and p-toluenesulfonylhydrazide (818 mg, 1.1 eq), MeOH (10 mL) and four drops of concentrated H2SC4 were added under a nitrogen atmosphere. The resulting mixture was stirred under reflux for 14 hours and allowed to reach room temperature.

[0120] In this stage, the reaction shown in Figure 3 was promoted, yielding the compound with the formula (Vil) (2S,4aS,6aS,6bR,8aR,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyll-13-oxo-10-(2-tosylhydrazinoylidene)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-methylicosahydropycene-2-carboxylate. f) The solvent was removed by vacuum distillation, and 10 mL of water and 10 mL of dichloromethane were added. The layers were separated, and the aqueous phase was extracted three times with dichloromethane. The combined organic phases were dried over Na2SC>4. The solution was filtered through filter paper and concentrated by vacuum distillation. The resulting residue was purified by silica gel column chromatography using a mixture of hexane and ethyl acetate in a 3:1 ratio as eluent, yielding

[0121] 2.3 g (90 %) del compuesto (2S,4aS,6aS,6bR,8aR,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a- heptametill-13-oxo-10-(2-tosilhidrazinoilideno)-1 ,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11 ,12,12a, 12b,13,14b-icosahidrop¡ceno-2-carbox¡lato de metilo (Vil).

[0122] Datos espectroscopios:

[0123] 1 H NMR (300 MHz, CDCI3) 5 = 7.84 (d, J=8.2, 2H), 7.28 (d, J=8.1 , 2H), 5.71 (s, 1 H), 3.69 (s, 3H), 2.83 - 2.66 (m, 1 H), 2.41 (s, 3H), 2.24 - 2.13 (m, 1 H), 2.11 - 1.74 (m, 7H), 1.70 - 1.51 (m, 3H), 1.48 - 1.26 (m, 10H), 1.18 - 1.03 (m, 15H), 0.93 (s, 3H), 0.80 (s, 3H).

[0124] 13 C NMR (75 MHz, CDCI3) 5 199.9 (C=O), 177.0 (C=O), 170.0 (C=N), 143.7 (C), 135.6 (C),

[0125] 129.3 (2 CH), 128.5 (C), 128.3 (3 CH), 61.0 (CH), 55.0 (CH3), 51.9 (CH), 48.5 (CH), 45.3 (C), 44.1 (C), 43.4 (C), 41.9 (C), 41.2 (CH2), 38.5 (CH2), 37.8 (C), 36.7 (CH2), 32.3 (CH2), 31 .9 (C), 31 .2 (CH2), 28.6 (CH3), 28.4 (CH3), 28.2 (CH2), 26.6 (CH2), 26.5 (CH2), 23.8 (CH3), 21.7 (CH3), 20.2 (CH3), 18.7 (CH2), 18.6 (CH3), 15.5 (CH3), 14.3 (CH3).

[0126] HRMS (ESI): caled, for M+H [C 38 H 55 N2O5S]: 651.3826, found: 651.3826.

[0127] EXAMPLE 2

[0128] This example describes the synthesis of the compound of formula (I) from the compound of formula (Vil) where R 1 is the methyl group and where Ar 2 It is 4-tolyl and an aromatic compound Ar 1 X where Ar 1-X is 4-bromoisoquinoline. The method comprised the following steps: g.1) In a reaction tube, the compound β-alsulfonylhydrazone (Vil) (74 mg, 0.15 mmol), the aromatic compound 4-bromoisoquinoline (62 mg, 0.3 mmol), lithium tert-butoxide (64 mg, 0.8 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos) (28 mg, 0.06 mmol), tris(dibenzylideneacetone)dipalladium (O) (6.8 mg, 0.05 mmol), H2O (10 L), and 1,4-dioxane (1.2 mL) were mixed in a nitrogen atmosphere. The mixture was shaken at 110 eThe mixture was heated to C for 14 hours and allowed to reach room temperature. In this first stage, the reaction shown in Figure 4 was promoted, yielding the compound (2S,4aS,6aS,6bR,8aR,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-10-(isoquinolin-4-yl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,12,12a,12b,13,14b-octadecahydropycene-2-methyl carboxylate of formula (I). h.1) The mixture was filtered through a thin layer of celite. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography, using a mixture of hexane and ethyl acetate, in proportions (2:1 ), as eluent, obtaining 60 mg (yield 67%) of the compound (2S,4aS,6aS,6bR, 8aR,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-10-(isoquinolin-4-yl)-1 ,2,3,4, 4a,5,6,6a,6b,7,8,8a,9,12,12a,12b,13,14b-octadecahydropycene-2-carboxylate methyl of formula (I).

[0129] Rf (SiO2, Hexane: Ethyl acetate, 2:1) = 0.3.

[0130] Datos espectroscópicos:

[0131] 1 H NMR (300 MHz, CDCI3) 5 = 7.97 (dd, =20.5, 8.2, 2H), 7.71 - 7.50 (m, 2H), 7.41 (m, 1 H), 6.97 (s, 1 H), 5.74 (s, 1 H), 5.50 (m, 1 H), 3.70 (s, 3H), 3.32 (dt, J=17.9, 6.7, 1 H), 2.20 - 1.81 (m, 7H), 1.80 - 1.57 (m, 7H), 1.31 - 1.20 (m, 13H), 1.18- 1.10 (m, 6H), 0.99- 0.73 (m, 6H).

[0132] 13 C NMR (75 MHz, CDCI3) 5 200.1 (C=O), 177.1 (C=O), 169.9 (C), 147.8 (C), 145.8 (C),

[0133] 136.9 (C), 136.6 (C), 136.1 (C), 129.9 (CH), 129.8 (CH), 128.8 (CH), 128.4 (CH), 127.7 (CH), 126.8 (CH), 126.2 (CH), 120.3 (CH), 51.9 (CH3), 48.5 (CH), 45.3 (C) 44.2 (C), 43.4 (C), 42.3 (CH2), 41 .3 (CH2), 37.9 (CH2), 37.3 (CH), 36.3 (C), 34.2 (CH), 32.0 (C), 31 .3 (CH2),

[0134] 30.9 (CH3), 28.7 (CH3), 26.6 (CH2), 26.2 (CH2), 26.1 (CH2), 25.9 (CH3), 24.2 (CH3), 22.9 (CH3), 19.2 (CH2), 18.3 (CH3), 16.7 (CH3).

[0135] HRMS (ESI): caled, for M+H [C4oH 52N03]: 594.3942, found: 594.3947.

[0136] IC50 vs. HeLa cells: 3.3 pJ.

[0137] EXAMPLE S

[0138] This example describes the synthesis of the compound of formula (I) from the compound of formula (Vil) where R 1 is the methyl group and where Ar 2 It is 4-tolyl and an aromatic compound Ar 1 X where Ar 1 -X is 8-bromoquinoline. The method comprised the following steps: g.1) In a reaction tube, the compound / V-arylsulfonylhydrazone (Vil) (74 mg, 0.15 mmol), the aromatic compound 8-bromoquinoline (62 mg, 0.3 mmol), lithium tert-butoxide (64 mg, 0.8 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (XPhos) (28 mg, 0.06 mmol), tris(dibenzylideneacetone)dipalladium (O) (6.8 mg, 0.05 mmol), H2O (10 L) and 1,4-dioxane (1.2 mL) were mixed in a nitrogen atmosphere. The mixture was shaken at 110 eThe mixture was heated to C for 14 hours and allowed to reach room temperature. In this first stage, the reaction shown in Figure 5 was promoted, where the compound (2S,4aS,6aS,6bR,8aR,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-10-(quinolin-8-yl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,12,12a,12b,13,14b-octadecahydropycene-2-methyl carboxylate of formula (I) was obtained. h.1) The mixture was filtered through a thin layer of celite. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography, using a mixture of hexane and ethyl acetate, in proportions (4:1 ), as eluent, obtaining 44 mg (49% yield) of the compound (2S,4aS,6aS, 6bR,8aR,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-10-(quinolin-8-1l)-1 ,2,3, 4, 4a, 5, 6, 6a, 6b, 7, 8, 8a, 9, 12, 12a, 12b, 13, 14b-octadecahydropycene-2-carboxylate of formula (I).

[0139] Rf (SiOs, Hexane: Ethyl acetate, 4: 1 ) = 0.2.

[0140] Datos espectroscópicos:

[0141] 1 H NMR (300 MHz, CDCI3) 5 = 8.93 (dd, J=4.2, 1 .8, 1 H), 8.09 (dd, J=8.3, 1 .9, 1 H), 7.79 - 7.63 (m, 1 H), 7.53 - 7.41 (m, 2H), 7.31 (dd, =8.2, 4.1 , 1 H), 5.72 (s, 1 H), 5.40 (dd, =6.4, 1 .9, 1 H), 3.69 (s, 3H), 3.25 (dd, =17.7, 6.4, 1 H), 2.57 (s, 1 H), 2.18 - 1 .72 (m, 8H), 1 .70 - 1 .52 (m, 4H), 1 .45 (m, 4H), 1 .38 (m, 5H), 1 .25 (m, 2H), 1 .21 (m, 3H), 1 .15 (s, 3H), 0.96 (m, 6H), 0.83 (s, 3H).

[0142] 13C NMR (75 MHz, CDCI3) 5 200.3 (C=O), 177.1 (C=O), 169.5 (C), 149.8 (CH), 148.3 (C), 142.5 (C), 142.2 (C), 136.0 (CH), 131.7 (CH), 128.9 (CH), 128.5 (C), 126.8 (CH), 125.3 (CH), 125.1 (CH), 120.5 (CH), 60.8 (CH), 52.4 (CH), 51.9 (CH3), 48.5 (CH), 45.26 (C), 44.2 (C), 43.4 (C) 42.2 (CH2), 41.3 (CH2), 38.3 (C), 37.9 (CH2), 36.5 (C), 32.2 (C), 32.0 (CH2), 31.3 (CH2), 29.9 (CH3), 28.7 (CH3), 28.5 (CH3), 26.6 (2 CH2), 23.4 (CH3), 22.12 (CH3), 19.3 (CH2), 18.4 (CH3), 16.5 (CH3). HRMS (ESI): caled, for M+H [C40H52NO3]: 594.3942, found: 594.3948.

[0143] IC50 against HeLa cells: 4.9 |iM.

[0144] EXAMPLE 4

[0145] This example describes the synthesis of the compound of formula (I) from the compound of formula (Vil) where R 1 is the methyl group and where Ar 2 It is 4-tolyl and an aromatic compound Ar 1 X where Ar 1-X is 1-bromo-2-(methoxymethyl)benzene. The method comprised the following steps: g.1) In a reaction tube, the compound / V-arylsulfonylhydrazone (Vil) (74 mg, 0.15 mmol), the aromatic compound 1-bromo-2-(methoxymethyl)benzene (60 mg, 0.3 mmol), lithium tert-butoxide (64 mg, 0.8 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos) (28 mg, 0.06 mmol), tris(dibenzylideneacetone)dipalladium (O) (6.8 mg, 0.05 mmol), H2O (10 pL), and 1,4-dioxane (1.2 mL) were mixed in a nitrogen atmosphere. The mixture was shaken at 110 eThe mixture was heated to C for 14 hours and allowed to reach room temperature. In this first stage, the reaction shown in Figure 6 was promoted, where the compound (2S,4aS,6aS,6bR,8aR,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-10-(2-(methoxymethyl)phenyl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,12,12a,12b,13,14b-methyl octadecahydropycene-2-carboxylate of formula (I) was obtained. h.1) The mixture was filtered through a thin layer of celite. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography, using a mixture of hexane and ethyl acetate, in proportions (5:1), as eluent, obtaining 57 mg (65% yield) of the compound

[0146] (2S,4aS,6aS,6bR,8aR,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-10-(2- (methoxymethyl)phenyl)-1 Methyl 2,3,4,4a,5,6,6a,6b,7,8,8a,9,12,12a,12b,13,14b-octadecahydropicene-2-carboxylate of formula (I).

[0147] Rf (SiOs, Hexano: Acetato de etilo, 5:1 ) = 0,3.

[0148] Datos espectroscopios:

[0149] 1 H NMR (300 MHz, CDCI3) 5 = 7.47 (dd, J=7.7 , 1.4, 1 H), 7.30 - 7.21 (m, 1 H), 7.17 (td, J=7.4, 1.5, 1 H), 7.08 (dd, =7.6, 1.6, 1 H), 5.72 (s, 1 H), 5.31 (d, J=6.2, 1 H), 4.46 (s, 2H), 3.69 (s, 3H), 3.36 (s, 3H), 3.30 - 3.12 (m, 1 H), 2.48 (s, 1 H), 2.17 - 1.48 (m, 1 1 H), 1.44 - 1.23 (m, 11 H), 1.17 (m, 7H), 1 .10 - 0.96 (m, 4H), 0.82 (s, 6H).

[0150] 13 C NMR (75 MHz, CDCI3) 5 200.1 (C=O), 177.0 (C=O), 169.7 (C), 142.7 (C), 141.0 (C), 137.6 (C), 131.3 (CH), 128.8 (CH), 127.9 (CH), 126.7 (CH), 125.9 (CH), 72.6 (CH2), 60.8 (CH3), 58.4 (CH), 52.63 (CH3), 51 .90 (CH), 48.5 (CH), 45.2 (C), 44.2 (C), 43.4 (C), 32.2 (C),

[0151] 41 .3 (CH2), 37.9 (2XCH2), 36.2 (C), 32.2 (C), 32.0 (CH2), 31 .2 (CH2), 30.1 (CH), 28.7 (CH3),

[0152] 28.4 (CH3), 26.6 (2xCH2), 23.4 (CH3), 22.1 (CH3), 20.8 (CH3), 19.1 (CH2), 18.4 (CH3), 16.6 (CH3).

[0153] HRMS (ESI): caled, for M+H [C 39 H 55 NO4]: 587.4095, found: 587.4082.

[0154] IC50 vs. HeLa cells: 41.4 pJ.

[0155] EXAMPLE 5

[0156] This example describes the synthesis of the compound of formula (I) from the compound of formula (Vil) where R 1 is the methyl group and where Ar 2 It is 4-tolyl and an aromatic compound Ar 1 X where Ar 1-X is 2,6-dibromopyridine. The method comprised the following steps: g.1) In a reaction tube, the compound / V-arylsulfonylhydrazone (Vil) (74 mg, 0.15 mmol), the aromatic compound 2,6-dibromopyridine (71 mg, 0.3 mmol), lithium tert-butoxide (64 mg, 0.8 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (XPhos) (28 mg, 0.06 mmol), tris(dibenzylideneacetone)dipalladium (O) (6.8 mg, 0.05 mmol), H2O (10 L) and 1,4-dioxane (1.2 mL) were mixed in a nitrogen atmosphere. The mixture was shaken at 110 eThe mixture was heated to C for 14 hours and allowed to reach room temperature. In this first stage, the reaction shown in Figure 7 was promoted, where the compound (2S,4aS,6aS,6bR,8aR,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-10-(6-bromopyridin-2-yl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,12,12a,12b,13,14b-methyl octadecahydropycene-2-carboxylate of formula (I) was obtained. h.1) The mixture was filtered through a thin layer of celite. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography, using a mixture of hexane and ethyl acetate, in proportions (5:1), as eluent, obtaining 39 mg (42% yield) of the compound (2S,4aS,6aS,6bR,8aR,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-10-(6-bromopyridin-2-yl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,12,12a,12b,13,14b-octadecahydropycene-

[0157] methyl 2-carboxylate of formula (I).

[0158] Rf (SiO2, Hexano: Acetato de etilo, 5:1 ) = 0,2.

[0159] Datos espectroscopios:

[0160] 1 H NMR (300 MHz, CDCI3) 5 = 7.44 (td, J=7.7 , 7.3, 3.6, 1 H), 7.30 (d, J=7.9, 1 H), 7.15 (d, J=7.5, 1 H), 5.77 - 5.59 (m, 2H), 3.69 (s, 3H), 3.26 (dd, J=18.1 , 6.4, 1 H), 2.44 (s, 1 H), 2.17 - 1 .93 (m, 4H), 1 .93 - 1 .78 (m, 2H), 1.74 - 1 .42 (m, 4H), 1.41 - 1 .02 (m, 25H), 0.82 (s, 3H). 13 C NMR (75 MHz, CDCI3) 5 200.0 (C=O), 177.1 (C=O), 169.8 (C), 163.6 (C), 144.3 (C), 140.2 (C), 138.2 (CH), 128.8 (CH), 128.0 (CH), 125.5 (CH), 123.1 (CH), 60.9 (CH), 53.17 (CH), 51.9 (CH3), 48.5 (CH), 45.2 (C), 44.2 (C), 43.4 (C), 42.6 (CH2), 41. F4 (CH2), 37.9 (CH2), 37.3 (C), 36.1 (C), 32.1 (C), 32.0 (CH2), 31.3 (CH2), 29.6 (CH3), 28.7 (CH3), 28.5 (CH3), 26.6 (2 CH2), 23.4 (CH3), 21 .6 (CH3), 18.9 (CH2), 18.3 (CH3), 16.7 (CH3).

[0161] HRMS (ESI): caled, for M+H [C36H48BrNO3]: 622.2890, found: 622.2899.

[0162] IC50 vs. HeLa cells: 2.3 pJ.

[0163] EXAMPLE 6

[0164] This example describes the synthesis of the compound of formula (I) from the compound of formula (Vil) where R 1 is the methyl group and where Ar 2 It is 4-tolyl and an aromatic compound Ar 1 X where Ar 1 -X is 2-bromo-3-methoxypyridine. The method comprised the following steps: g.1) In a reaction tube, the compound β-arylsulfonylhydrazone (V1l) (74 mg, 0.15 mmol), the aromatic compound 2-bromo-3-methoxypyridine (56 mg, 0.3 mmol), lithium tert-butoxide (64 mg, 0.8 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (XPhos) (28 mg, 0.06 mmol), tris(dibenzylideneacetone)dipalladium (O) (6.8 mg, 0.05 mmol), H2O (10 mL), and 1,4-dioxane (1.2 mL) were mixed in a nitrogen atmosphere. The mixture was shaken at 1 10 eThe mixture was heated to C for 14 hours and allowed to reach room temperature. In this first stage, the reaction shown in Figure 8 was promoted, yielding the compound (2S,4aS,6aS,6bR,8aR,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-10-(3-methoxypyridin-2-yl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,12,12a,12b,13,14b-methyl octadecahydropycene-2-carboxylate of formula (I). h.1) The mixture was filtered through a thin layer of celite. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography, using a mixture of hexane and ethyl acetate, in proportions (5:1), as eluent, obtaining 43 mg (50% yield) of the compound

[0165] (2S,4aS,6aS,6bR,8aR,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-10-(3-methoxypyridin-2-yl)-1 Methyl 2,3,4,4a,5,6,6a,6b,7,8,8a,9,12,12a,12b,13,14b-octadecahydropicene-2-carboxylate of formula (I).

[0166] Rf (S¡02, Hexano: Acetato de etilo, 1 : 1 ) = 0,4.

[0167] Spectroscopic data:

[0168] 1 H NMR (300 MHz, CDCI3) 5 = 8.17 (dd, =4.1 , 2.0, 1 H), 7.22 - 7.06 (m, 2H), 5.71 (s, 1 H), 5.39 (dd, J=6.5, 1 .9, 1 H), 3.75 (s, 3H), 3.71 (s, 3H). 3.21 (dd, J=17.6, 6.5, 1 H), 2.48 (s, 1 H), 2.16 - 1.77 (m, 6H), 1.77 - 1.42 (m, 5H), 1.41 - 1.23 (m, 10H), 1.19 (s, 3H), 1.14 (s, 3H), 1 .02 (s, 4H), 0.95 (s, 3H), 0.83 (s, 4H).

[0169] 13 C NMR (75 MHz, CDCl3) 5 200.2 (C=O), 177.1 (C=O), 169.6 (C), 154.5 (C), 152.1 (C), 141.0 (C), 140.0 (CH), 128.9 (CH), 125.5 (CH), 122.3 (CH), 117.9 (CH). 60.7 (CH3), 55.5 (CH3), 52.9 (CH), 51 .9 (CH), 48.6 (CH), 45.3 (C), 44.2 (C), 43.4 (2C), 42.1 (CH2), 41 .4 (CH2), 37.9 (CH2), 36.4 (C), 32.2 (C), 32.0 (CH2), 31.3 (CH2), 29.6 (CH3), 28.7 (CH3), 28.5 (CH3), 26.6 (2CH2), 23.5 (CH3), 21.5 (CH3), 18.9 (CH2), 18.4 (CH3), 16.2 (CH3).

[0170] HRMS (ESI): cald., for M+H [C37H52 NO4]: 574.3898, found: 574.3891.

[0171] IC50 vs. HeLa cells: 10.3 pJ.

[0172] EXAMPLE 7

[0173] This example describes the synthesis of the compound of formula (If) from the compound of formula (Vil) where R 1 is the methyl group and where Ar 2 It is 4-tolyl and an aromatic compound Ar 1 X where Ar 1 -X is 2-amino-3-bromopyridine. The method comprised the following steps: g.1) In a reaction tube, the compound β-arylsulfonylhydrazone (V1l) (74 mg, 0.15 mmol), the aromatic compound 2-amino-3-bromopyridine (51 mg, 0.3 mmol), lithium tert-butoxide (64 mg, 0.8 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (XPhos) (28 mg, 0.06 mmol), tris(dibenzylideneacetone)dipalladium (O) (6.8 mg, 0.05 mmol), H2O (10 L), and 1,4-dioxane (1.2 mL) were mixed in a nitrogen atmosphere. The mixture was shaken at 31

[0174] 110 eThe mixture was heated to C for 14 hours and allowed to reach room temperature. In this first stage, the reaction shown in Figure 9 was promoted, where the compound (2S,4aS,6aS,6bR,8aR,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-10-(2-aminopyridin-3-yl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,12,12a,12b,13,14b-octadecahydropycene-2-methyl carboxylate of formula (I) was obtained. h.1) The mixture was filtered through a thin layer of celite. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography, using a gradient mixture of pure dichloromethane to dichloromethane:methanol (98:2) as the eluent, yielding 42 mg (50% yield) of the compound (2S,4aS,6aS,6bR,8aR,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-10-(2-aminopyridin-3-yl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,12,12a,12b,13,14b-octadecahydropycene-2-methyl carboxylate of formula (I).

[0175] Rf (S¡02, diclorometano: metanol, 98: 2) = 0,2.

[0176] Datos espectroscopios:

[0177] 1 H NMR (300 MHz, CDCI3) 5 = 7.92 (d, J=5.0, 1 H), 7.16 (dd, =7.3, 1.7, 1 H), 6.59 (dd, J=7.3, 5.0, 1 H), 5.71 (s, 1 H), 5.48 (d, J=6.1 , 1 H), 4.74 (bs, 2H), 3.69 (s, 4H), 3.23 (dd, J=17.9, 6.4, 1 H), 2.46 (s, 1 H), 2.17 - 1.50 (m, 8H), 1.45 - 1.11 (m, 18H), 1.09 - 0.90 (m, 7H), 0.82 (s, 4H).

[0178] 13 C NMR (75 MHz, CDCI3) 5 199.9 (C=O), 177.0 (C=O), 169.8 (C), 128.7 (C), 141.1 (C), 128.7 (2CH), 127.1 (2CH), 122.3 (C), 1 13.0 (CH), 60.8 (CH), 51 .9 (CH3), 48.5 (2CH), 45.2 (C), 44.2 (C), 43.4 (C), 42.3 (CH2),41.4 (CH2), 38.5 (C), 37.9 (CH2), 36.1 (C), 32.1 (CH2), 32.0 (C), 31.3 (CH2), 29.4 (CH3), 28.7 (CH3), 28.4 (CH3), 26.6 (2CH2), 23.4 (CH3), 21.5 (CH3), 19.1 (CH2), 18.3 (CH3), 16.8 (CH3).

[0179] HRMS (ESI): caled, for M+H [C36H5IN2O3]: 559.3894, found: 559.3902.

[0180] IC50 vs. HeLa cells: 12.0 pJ.

[0181] EXAMPLE S

[0182] This example describes the synthesis of the compound of formula (I) from the compound of formula (Vil) where R 1 is the methyl group and where Ar 2 It is 4-tolyl and an aromatic compound Ar 1 X where Ar 1 -X is 2-bromo-3-cyanopyridine. The method comprised the following steps: g.1 ) In a reaction tube, the compound / V-arylsulfonylhydrazone (Vil) (74 mg, 0.15 mmol), the aromatic compound 2-bromo-3-cyanopyridine (54 mg, 0.3 mmol), lithium tert-butoxide (64 mg, 0.8 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (XPhos) were mixed

[0183] (28 mg, 0.06 mmol), tris(dibenzylideneacetone)dipalladium (0) (6.8 mg, 0.05 mmol), H2O (10 mL) and 1,4-dioxane (1.2 mL) in a nitrogen atmosphere. The mixture was stirred at 110 eThe mixture was heated to C for 14 hours and allowed to reach room temperature. In this first stage, the reaction shown in Figure 10 was promoted, where the compound (2S,4aS,6aS,6bR,8aR,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-10-(3-cyanopyridin-2-yl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,12,12a,12b,13,14b-octadecahydropycene-2-carboxylate of formula (I) was obtained. h.1) The mixture was filtered through a thin layer of celite. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography, using a mixture of hexane and ethyl acetate in proportions (3:1) as eluent, obtaining 39 mg (46% yield) of the compound (2S,4aS,6aS,6bR,8aR,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-10-(3-cyanopyridin-2-yl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,12,12a,12b,13,14b-octadecahydropycene-2-carboxylate of formula (I).

[0184] Rf (SiOs, hexane: ethyl acetate, 3: 1 ) = 0.1.

[0185] Datos espectroscópicos:

[0186] 1 H NMR (300 MHz, CDCI3) 5 = 8.73 (dd, J=4.9, 1 .8, 1 H), 7.96 (dd, J=7.9, 1 .9, 1 H), 7.75 - 7.56 (m, 1 H), 5.83 - 5.55 (m, 2H), 3.69 (s, 3H), 3.34 (dd, J=18.2, 6.3, 1 H), 2.48 (s, 1 H), 2.19 - 1.76 (m, 7H), 1.79 - 1.52 (m, 14H), 1.45 - 1.08 (m, 11 H), 0.93 (s, 3H), 0.83 (s, 3H). 13 C NMR (75 MHz, CDCI3) 5 199.9 (C=O), 177.1 (C=O), 169.8 (C), 165.3 (C), 151.0 (CH), 145.9 (C), 130.1 (C), 128. 8(CH), 1 17.9 (C), 11 1.1 (C), 60.7 (CH), 52.5 (CH3), 51.9 (CH), 48.5 (CH), 45.2 (C), 44.2 (C), 43.4 (C), 42.2 (CH2), 41.3 (CH2), 38.2 (C), 37.9 (CH), 37.9 (CH2), 37.3 (CH), 36.2 (C), 34.2 (CH), 32.0 (C), 32.0 (CH2), 32.0 (2CH2), 29.4 (CH3), 28.7 (CH3), 28.5 (CH3), 23.5 (CH3), 21 .6 (CH3), 18.8 (CH2), 18.3 (CH3), 16.7 (CH3).

[0187] HRMS (ESI): caled, for M+H [C37H49N2O3]: 569.3738, found: 569.3744. IC50 frente a células HeLa: 14.7 .M.

[0188] EJEMPLO 9

[0189] This example describes the synthesis of the compound of formula (II) from the compound of formula (Vil) where R 1 is the methyl group and where Ar 2 It is 4-tolyl and a terminal alkyne of formula R 2 -C=CH where R 2 is the 3-bromophenyl group. The method comprised the following steps: g.2) In a reaction tube, the compound β-al-sulfonylhydrazone (V1) (148 mg, 0.3 mmol), the terminal alkyne 3-bromophenylacetylene (161 mg, 0.9 mmol), CS2CO3 (211 mg, 0.60 mmol), and 1,4-dioxane (2.4 mL) were mixed in a nitrogen atmosphere. The mixture was shaken at 1 10 eC for 14 hours and allowed to reach room temperature. In this first stage, the reaction represented in Figure 1 was promoted, where the compound (3S,4aR,6aR,6bS,8aS, 11S, 12aR, 14aR, 14bS)-5'-(3-bromophenyl)-4,4,6a,6b,8a, 11, 14b-heptamethyl-14-oxo-1,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-octadecahydro-2H-spiro[picene-3,3'-pyrazole]-11-methyl carboxylate of formula (II) was obtained. h.2) The mixture was neutralized with 5 mL of an aqueous solution saturated with ammonium chloride (NH4Cl). 5 mL of dichloromethane were added and the phases were separated. The aqueous phase was extracted twice more with 5 mL of dichloromethane. The organic layers were combined and dried with sodium sulfate. The solution was filtered through filter paper and concentrated by vacuum distillation.The resulting residue was purified by silica gel chromatography, using a mixture of hexane, ethyl acetate and dichloromethane in proportions (5:1:0.5) as eluent, obtaining 104 mg (51% yield) of the compound (3S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-5'-(3-bromophenyl)-4,4,6a,6b,8a,11,14b-heptamethyl-14-oxo-1,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12.

[0190] 12a, 14,14a, 14b-octadecahydro-2H-spiro[p¡cene-3,3'-pyrazol]-1 1 -methyl carboxylate of formula (II).

[0191] Rf (SÍO2, Hexane: Ethyl acetate: dichloromethane, 5: 1: 0.5) = 0.3.

[0192] Spectroscopic data:

[0193] 1H NMR (300 MHz, CD2CI2) 5 = 8.21 (s, 1 H), 7.99 (d, J=8.0, 1 H), 7.53 (d, J=7.4, 1 H), 7.36 (t, J=7.9, 1 H), 7.08 (s, 1 H), 5.64 (s, 1 H), 3.68 (s, 3H), 2.91- 1 .54 (m, 1 H), 2.76 (s, 1 H), 2.51 - 2.37 (m, 1 H), 2.25 - 1 .76 (m, 7H), 1 .75 - 1 .54 (m, 2H), 1 .47 (s, 3H), 1.51 - 1 .40 (m, 1 H), 1 .44 - 1 .33 (m, 1 H), 1 .33 (s, 4H), 1 .32 - 1 .03 (m, 11 H), 1 .08 - 0.97 (m, 1 H), 1 .02 - 0.85 (m, 1 H), 0.83 (s, 4H), 0.89 - 0.74 (m, 1 H), 0.42 (s, 3H).

[0194] 13 C NMR (75 MHz, CD2CI2) 5 200.5 (C=O), 177.4 (C=O), 170.1 (C), 153.7 (C), 139.1 (CH), 133.9 (C), 132.2 (CH), 131.0 (CH), 130.4 (CH), 128.9 (CH), 126.1 (CH), 123.3 (C), 106.5 (C), 62.1 (CH), 52.7 (CH), 52.1 (CH3), 48.9 (CH), 45.9 (C), 44.5 (C), 43.9 (C), 41.6 (CH2), 41 .0 (CH2), 39.1 (C), 38.32 (2CH2), 33.0 (CH2), 32.4 (CH3), 31 .6 (C), 28.9 (CH3), 28.7 (CH3), 27.4 (CH3), 27.0 (2CH2), 26.9 (CH2), 24.5 (CH3), 24.0 (CH3), 19.1 (CH3), 18.2 (CH2), 16.8 (CH3).

[0195] HRMS (ESI): caled, for M+H [C 39 H 52 BrN2O3]: 675.3156, found: 675.3159.

[0196] IC50 vs. HeLa cells: 46.8 pJ.

[0197] EXAMPLE 10

[0198] This example describes the synthesis of the compound of formula (II) from the compound of formula (Vil) where R 1 is the methyl group and where Ar 2 It is 4-tolyl and a terminal alkyne of formula R 2 -C=CH where R 2 is the 2-fluorophenyl group. The method comprised the following steps: g.2) In a reaction tube, the compound / V-arylsulfonylhydrazone (Vil) (148 mg, 0.3 mmol), the terminal alkyne 2-fluorophenylacetylene (108 mg, 0.9 mmol), Cs2CO3 (211 mg, 0.60 mmol) and 1,4-dioxane (2.4 mL) were mixed in a nitrogen atmosphere. The mixture was shaken at 1 10 eThe mixture was heated to C for 14 hours and allowed to reach room temperature. In this first stage, the reaction shown in Figure 12 was promoted, where the compound (3S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-5'-(2-fluorophenyl)-4,4,6a,6b,8a,11,14b-heptamethyl-14-oxo-1,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-octadecahydro-2H-spiro[picene-3,3'-pyrazole]-11-methyl carboxylate of formula (II) was obtained. h.2) The mixture was neutralized with 5 mL of an aqueous solution saturated with ammonium chloride (NH4Cl). 5 mL of dichloromethane were added and the phases were separated. The aqueous phase was extracted twice more with 5 mL of dichloromethane. The organic layers were combined and dried with sodium sulfate. The solution was filtered through filter paper and concentrated by vacuum distillation.The resulting residue was purified by chromatography using a mixture of hexane, ethyl acetate and dichloromethane in proportions (5:1:0.5) as eluent, yielding 101 mg (55% yield) of the compound (3S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-5'-(2-fluorophenyl)-4,4,6a,6b,8a,11,14b-heptamethyl-14-oxo-1,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-octadecahydro-2H-spiro[picene-3,3'-pyrazol]-11 -methyl carboxylate of formula (II).

[0199] Rf (S¡02, Hexane: Ethyl acetate: dichloromethane, 5: 1: 1) = 0.4.

[0200] Spectroscopic data:

[0201] 1 H NMR (300 MHz, CD2CI2) 5 = 8.55 (td, J=7.6, 2.0, 1 H), 7.44 - 7.25 (m, 2H), 7.26 - 7.14 (m, 2H), 5.64 (s, 1 H), 3.67 (s, 3H), 2.96 - 2.69 (m, 2H), 2.54 - 2.38 (m, 1 H), 2.24 - 1 .76 (m, 7H), 1 .75 - 1 .54 (m, 3H), 1 .51 - 0.96 (m, 22H), 0.90 - 0.74 (m, 4H), 0.42 (s, 3H).

[0202] 13C NMR (75 MHz, CD2CI2) 5 200.5 (C=O), 177.4 (C=O), 170.1 (C), 161.5 (C, d, J=250.6), 148.6 (C, d, J=4.1 ), 142.5 (CH, d, =11 .5), 130.5 (CH, d, J=8.7), 129.9 (CH, d, J=3.1 ), 128.9 (CH), 125.0 (CH, d, J=3.5), 120.1 (CH, d, =12.6), 116.6 (CH), 1 16.4 (d, J=21.8), 107.0 (C), 62.1 (CH),53.3 (CH), 52.1 (CH3), 48.9 (CH3), 45.9 (C), 44.5 (C), 43.9 (C), 41.6 (CH2), 40.9 (C), 39.2 (CH2), 38.4 (C), 38.3 (CH2), 33.0 (CH2), 32.4 (CH2), 31.6 (C), 28.9 (CH2), 28.7 (CH3), 27.4 (CH3), 27.0 (CH2), 26.9 (CH2), 24.5 (2CH3), 24.0 (CH3), 19.1 (CH3), 18.2 (CH2), 16.9 (CH3).

[0203] HRMS (ESI): caled, for M+H [C 39 H 52 FN2O3]: 615.3956, found: 615.3963.

[0204] IC50 against HeLa cells: 25.7 .M.

[0205] EXAMPLE 1 1

[0206] This example describes the synthesis of the compound of formula (II) from the compound of formula (Vil) where R 1 is the methyl group and where Ar 2It is 4-tolyl and a terminal alkyne of formula R 2 -C=CH where R 2 is the 4-fluorophenyl group. The method comprised the following steps: g.2) In a reaction tube, the compound / V-arylsulfonylhydrazone (Vil) (148 mg, 0.3 mmol), the terminal alkyne 4-fluorophenylacetylene (108 mg, 0.9 mmol), Cs2CO3 (211 mg, 0.60 mmol) and 1,4-dioxane (2.4 mL) were mixed in a nitrogen atmosphere. The mixture was shaken at 1 10 eThe mixture was heated to C for 14 hours and allowed to reach room temperature. In this first stage, the reaction shown in Figure 13 was promoted, where the compound (3S,4aR,6aR,6bS,8aS, 11S, 12aR, 14aR, 14bS)-5'-(4-fluorophenyl)-4,4,6a,6b,8a, 11, 14b-heptamethyl-14-oxo-1,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-octadecahydro-2H-spiro[picene-3,3'-pyrazole]-11-methyl carboxylate of formula (II) was obtained. h.2) The mixture was neutralized with 5 mL of an aqueous solution saturated with ammonium chloride (NH4Cl). 5 mL of dichloromethane were added and the phases were separated. The aqueous phase was extracted twice more with 5 mL of dichloromethane. The organic layers were combined and dried with sodium sulfate. The solution was filtered through filter paper and concentrated by vacuum distillation.The resulting residue was purified by chromatography using a mixture of hexane, ethyl acetate and dichloromethane in proportions (5:1:0.5) as eluent, yielding 83 mg (45% yield) of the compound (3S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-5'-(4-fluorophenyl)-4,4,6a,6b,8a,11,14b-heptamethyl-14-oxo-1,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-octadecahydro-2H-spiro[picene-3,3'-pyrazol]-11-carboxylate methyl of formula (II).

[0207] Rf (S¡02, Hexane: Ethyl acetate: dichloromethane, 5: 1: 0.5) = 0.2.

[0208] Spectroscopic data:

[0209] 1 H NMR (300 MHz, CD2CI2) 5 = 8.13 - 7.96 (m, 2H), 7.25 - 7.09 (m, 2H), 6.98 (s, 1 H), 5.64 (s, 1 H), 3.68 (s, 3H), 2.90 - 2.69 (m, 2H), 2.52- 2.35 (td, J=14, 1 H), 2.24 - 1 .77 (m, 8H), 1.75 - 1 .55 (m, 3H), 1 .53 - 1 .1 1 (m, 20H), 1.10 - 0.92 (m, 2H), 0.92 - 0.74 (m, 6H).

[0210] 13C NMR (75 MHz, CD2CI2) 5 200.5 (C=O), 177.3 (C=O), 170.1 (C), 165.2 (C), 163.5 (C, d, J=248.1 ), 154.1 (C), 137.2 (CH), 129.4 (2CH, d, J=8.2), 128.9 (CH, d, J=6.8), 116.26 (2 CH, d, J=21.7), 106.3 (C), 62.1 (CH), 53.2 (CH), 52.1 (CH3), 48.9 (CH), 45.9 (C), 44.5 (C), 43.9 (C), 41.6 (CH2), 40.9 (C), 39.2 (CH2), 38.3 (CH2), 33.0 (CH2), 32.3 (2C), 31.6 (CH2), 28.9 (CH3), 28.65 (CH3), 27.5 (CH2), 27.0 (2 CH2), 24.5 (2CH3), 24.0 (CH3), 19.0 (CH3), 18.2 (CH2), 16.8 (CH3).

[0211] HRMS (ESI): caled, for M+H [C39H 52 FN2O3]: 615.3956, found: 615.3959.

[0212] IC50 vs. HeLa cells: 21.4 pJ

[0213] EXAMPLE 12

[0214] This example describes the synthesis of the compound of formula (II) from the compound of formula (Vil) where R 1 is the methyl group and where Ar 2 It is 4-tolyl and a terminal alkyne of formula R 2 -C=CH where R 2is the 3,4-difluorophenyl group. The method comprised the following steps: g.2) In a reaction tube, the compound / V-al-sulfonylhydrazone (Vil) (148 mg, 0.3 mmol), the terminal alkyne 3,4-difluorophenylacetylene (124 mg, 0.9 mmol), Cs2CO3 (211 mg, 0.60 mmol) and 1,4-dioxane (2.4 mL) were mixed in a nitrogen atmosphere. The mixture was shaken at 110 e The mixture was heated to C for 14 hours and allowed to reach room temperature. In this first stage, the reaction shown in Figure 14 was promoted, yielding the compound (3S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-5'-(3,4-difluorophenyl)-

[0215] 4,4,6a,6b,8a,11,14b-heptamethyl-14-oxo-1,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-octadecahydro-2H-spiro[picene-3,3'-pyrazol]-1,1-methyl carboxylate of formula (II). h.2) The mixture was neutralized with 5 mL of an aqueous solution saturated in ammonium chloride (NH4Cl). 5 mL of dichloromethane were added and the phases were separated. The aqueous phase was extracted twice more with 5 mL of dichloromethane. The organic layers were combined and dried with sodium sulfate. The solution was filtered through filter paper and concentrated by vacuum distillation.The resulting residue was purified by chromatography using a mixture of hexane and ethyl acetate in proportions (8:1) as eluent, yielding 99 mg (52% yield) of the compound (3S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-5'-(3,4-difluorophenyl)-4,4,6a,6b,8a,11,14b-heptamethyl-14-oxo-1,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-octadecahydro-2H-spiro[picene-3,3'-pyrazole]-11-methylcarboxylate of formula (II).

[0216] Rf (SiO2, Hexane: Ethyl acetate, 5:1) = 0.4.

[0217] Spectroscopic data:

[0218] 1 H NMR (300 MHz, CD2CI2) 5 = 7.90 (m, 1 H), 7.85 - 7.74 (m, 1 H), 7.28 (dt, =10.1, 8.4, 1 H), 7.03 (s, 1 H), 5.64 (s, 1 H), 3.68 (s, 3H), 2.92 - 2.68 (m, 2H), 2.44 (td, J=14.2, 3.7, 1 H), 2.26 - 1 .75 (m, 9H), 1 .74 - 1 .55 (m, 2H), 1.53 - 1 .04 (m, 20H), 0.95 - 0.72 (m, 7H).

[0219] 13C NMR (75 MHz, CD2CI2) 5 200.4 (C=O), 177.4 (C=O), 170.1 (C), 153.1 (C), 152.8 (C), 149.5 (C), 138.5 (CH), 128.9 (CH), 124.0 (CH), 118.3 (CH, d, J=16.4), 1 16.5 (CH, d, J=17.7), 106.7 (C), 62.1 (CH), 53.3 (CH), 52.1 (CH3), 48.9 (CH), 45.9 (C), 44.5 (2C), 43.9 (C), 41.7 (CH2), 41.0 (C), 39.1 (CH2), 38.3 (CH2), 33.0 (CH2), 32.4 (2C), 31.6 (CH2), 28.9 (CH3), 28.7 (CH3), 27.5 (CH2), 26.9 (2CH2), 24.5 (2CH3), 24.0 (CH3), 19.1 (CH3), 18.2 (CH2), 16.8 (CH3).

[0220] HRMS (ESI): caled, for M+H [C 39 H5oF2N203]: 633.3862, found: 633.3840.

[0221] IC50 vs. HeLa cells: 14.4 pJ.

[0222] EXAMPLE 13

[0223] This example describes the synthesis of the compound of formula (II) from the compound of formula (Vil) where R 1 is the methyl group and where Ar 2 It is 4-tolyl and a terminal alkyne of formula R 2 -C=CH where R 2is the 2-thiophenyl group. The method comprised the following steps: g.2) In a reaction tube, the compound / V-al-sulfonylhydrazone (Vil) (148 mg, 0.3 mmol), the terminal alkyne 2-thiophenylacetylene (97 mg, 0.9 mmol), CS2CO3 (211 mg, 0.60 mmol) and 1,4-dioxane (2.4 mL) were mixed in a nitrogen atmosphere. The mixture was shaken at 110 eC for 14 hours and allowed to reach room temperature. In this first stage, the reaction represented in Figure 15 was promoted, where the compound (3S,4aR,6aR,6bS,8aS,11 S,12aR,14aR,14bS)-5'-(2-thiophenyl)-4,4,6a,6b,8a,11 ,14b- heptamethyl-14-oxo- 1 ,4, 4a, 5, 6, 6a, 6b, 7, 8, 8a, 9, 10, 11 , 12, 12a, 14, 14a, 14b-octadecahydro-2H- spiro[picene-3,3'-pyrazole]-11 -methyl carboxylate of formula (II) was obtained. h.2) The mixture was neutralized with 5 mL of an aqueous solution saturated with ammonium chloride (NH4Cl). 5 mL of dichloromethane were added and the phases were separated. The aqueous phase was extracted twice more with 5 mL of dichloromethane. The organic layers were combined and dried with sodium sulfate. The solution was filtered through filter paper and concentrated by vacuum distillation. The resulting residue was purified by chromatography using a mixture of hexane, ethyl acetate, and dichloromethane in proportions (5:1:0).5) as an eluent, obtaining 108 mg (60 %) yield of the compound (3S,4aR,6aR,6bS,8aS,11 S,12aR,14aR,14bS)-5'-(2-thiophophenyl)-4,4,6a,6b,8a,11 ,11 . 14b-heptamethyl-14-oxo- 1 ,4, 4a, 5, 6, 6a, 6b, 7, 8, 8a, 9, 10, 11 , 12, 12a, 14, 14a, 14b-octadecahydro- 2H-spiro[pyceno-3,3'-pyrazole]-11 -methyl carboxylate of formula (II).

[0224] Rf (ZO2, Hexane: Ethyl acetate: dichloromethane, 5:1 : 0.5) = 0.3.

[0225] Spectroscopic data:

[0226] 1 H NMR (300 MHz, CD2CI2) 5 = 7.68 (dd, J=3.6, 1.2, 1 H), 7.40 (dd, J=5.0, 1.2, 1 H), 7.14 (dd, =5.1 , 3.6, 1 H), 6.83 (s, 1 H), 5.64 (s, 1 H), 3.67 (s, 3H), 2.84 (dt, J=13.4, 3.4, 1H), 2.75 (s, 1H), 2.42 (td, J=14.2, 3.8, 1H), 2.23 - 1.74 (m, 9H), 1.76 - 1.53 (m, 3H), 1.52 - .39 (m, 4H), 1.39 - 1.28 (m, 6H), 1.20 (s, 3H), 1.14 (d, =3.0, 6H), 1.09 - 0.96 (m, 1H), 0.83 (s, 4H), 0.43 (s, 3H).

[0227] 13C NMR (75 MHz, CD2CI2) 5 200.5 (C=O), 177.4 (C=O), 170.1 (C), 149.8 (C), 135.0 (CH), 134.8 (C), 128.9 (CH), 128.4 (CH), 126.9 (CH), 126.9 (CH), 106.7 (C), 62.1 (CH3), 53.3 (CH), 52.1 (CH), 48.9 (CH), 45.9 (CH), 44.5 (C), 43.9 (2C), 41.6 (C), 41.0 (CH2), 39.1 (C), 38.3 (2CH2), 33.0 (CH2), 32.3 (C), 31.6 (CH2), 28.9 (CH3), 28.7 (CH3), 27.6 (CH2), 27.0 (CH2), 26.9 (CH2), 24.5 (CH3), 24.4 (CH3), 24.0 (CH3), 19.1 (CH3), 18.2 (CH2), 16.8 (CH3). HRMS (ESI): caled, for M+H [C37H51N2O3S]: 603.3615, found: 603.3618.

[0228] EXAMPLE 14

[0229] This example describes the synthesis of the compound of formula (II) from the compound of formula (Vil) where R 1 is the methyl group and where Ar 2 It is 4-tolyl and a terminal alkyne of formula R 2 -C=CH where R 2is the 4-cyanophenyl group. The method comprised the following steps: g.2) This step is similar to that described in example 9. In this example, (114 mg, 0.9 mmol) of the terminal alkyne 4-cyanophenylacetylene was used. In this first stage, the reaction represented in Figure 16 was promoted, where the compound (3S,4aR,6aR,6bS,8aS, 11 S, 12aR, 14aR, 14bS)-5'-(4-cyanophenyl)-4,4,6a,6b,8a, 11, 14b- heptamethyl-14-oxo- 1,4, 4a, 5, 6, 6a, 6b, 7, 8, 8a, 9, 10, 11, 12, 12a, 14, 14a, 14b-octadecahydro-2H- spiro[picene-3,3'-pyrazole]-11-methyl carboxylate of formula (II) was obtained. h.2) This step is similar to that described in example 9. The chromatographic purification was carried out using a mixture of hexane, ethyl acetate, dichloromethane in proportions (5:1:0.5) as eluent, obtaining 83 mg (45% yield) of the compound (3S,4aR,6aR,6bS,8aS, 11 S, 12aR, 14aR, 14bS)-5'-(4-cyanophenyl)-4,4,6a,6b,8a, 11, 14b- heptamethyl-14-oxo- 1,4, 4a, 5, 6, 6a, 6b, 7, 8, 8a, 9, 10, 11, 12, 12a, 14, 14a, 14b-octadecahydro-2H- spiro[picene-3,3'-pyrazole]-11-methyl carboxylate of formula (II).

[0230] Rf (S¡02, Hexane: Ethyl acetate: dichloromethane 5: 1: 1) = 0.2.

[0231] Spectroscopic data:

[0232] 1 H NMR (300 MHz, CD2CI2) 5 = 8.27 - 8.07 (m, 2H), 7.84 - 7.72 (m, 2H), 7.22 (s, 1 H), 5.64 (s, 1 H), 3.67 (s, 3H), 2.86 (dt, J=13.4, 3.5, 1 H), 2.75 (s, 1 H), 2.54 - 2.37 (m, 1 H), 2.25 - 1 .76 (m, 7H), 1.74 - 1 .09 (m, 22H), 1 .08 - 0.97 (m, 1 H), 0.90 - 0.75 (m, 6H), 0.42 (s, 3H). 13C NMR (75 MHz, CD2CI2) 5200.41 (C=O), 177.3 (C=O), 170.2 (C), 153.4 (C), 141.2 (CH), 136.0 (C), 133.2 (2CH), 128.9 (CH), 128.0 (2CH), 119.2 (C), 1 12.7 (C), 107.0 (C), 62.1 (CH3), 53.2 (CH), 52.1 (CH), 48.9 (CH), 45.9 (C), 44.5 (2C), 43.9 (C), 41.6 (CH2), 41.2 (C), 39.1 (CH2), 38.3 (2CH2), 33.0 (CH2), 32.3 (C), 31.6 (CH2), 28.9 (CH3), 28.6 (CH3), 27.4 (CH2), 27.0 (CH2), 26.9 (CH2), 24.6 (CH3), 24.5 (CH3), 24.0 (CH3), 19.1 (CH3), 18.1 (CH2), 16.8 (CH3).

[0233] HRMS (ESI): caled, for M+H [C4oH 52 N303]: 642.4003, found: 642.4010. The three-dimensional structure of this compound of formula (II) was solved by xy-ray diffraction and is shown in Figure 30.

[0234] EXAMPLE 15

[0235] This example describes the synthesis of the compound of formula (II) from the compound of formula (Vil) where R 1 is the methyl group and where Ar 2 It is 4-tolyl and a terminal alkyne of formula R 2-C=CH where R 2 is the 4-(methoxycarbonyl)phenyl group. The method comprised the following steps: g.2) This step is similar to that described in example 9. In this example, (144 mg, 0.9 mmol) of the terminal alkyne 4-(methoxycarbonyl)phenylacetylene was used. In this first step, the reaction shown in Figure 17 was promoted, where the compound (3S,4aR,6aR,6bS,8aS,11 S,12aR,14aR,14bS)-5'-(4-methoxycarbonylphenyl)-4,4,6a,6b,8a,11 was obtained.

[0236] 14b-heptamethyl-14-oxo- 1,4, 4a, 5, 6, 6a, 6b, 7, 8, 8a, 9, 10, 11, 12, 12a, 14, 14a, 14b-octadecahydro- 2H-spiro[picene-3,3'-pyrazole]-11-carboxylate methyl of formula (II). h.2) This step is similar to that described in example 9. The chromatographic purification was carried out using a mixture of hexane, ethyl acetate, dichloromethane in proportions (5:0.5:1) as eluent, obtaining 78 mg (40% yield) of the compound (3S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-5'-(4-methoxycarbonylphenyl)-4,4,6a,6b,8a,11,

[0237] 14b-heptamethyl-14-oxo- 1,4, 4a, 5, 6, 6a, 6b, 7, 8, 8a, 9, 10, 11, 12, 12a, 14, 14a, 14b-octadecahydro- 2H-spiro[picene-3,3'-pyrazole]-11-carboxylate methyl of formula (II).

[0238] Rf (SÍO2, Hexane: Ethyl acetate: dichloromethane 5: 0.5: 1 ) = 0.1.

[0239] Spectroscopic data:

[0240] 1H NMR (300 MHz, CD2CI2) 5 = 8.12 (s, 4H), 7.18 (s, 1 H), 5.64 (s, 1 H), 3.91 (s, 3H), 3.67 (s, 3H), 2.86 (dt, J=13.3, 3.4, 1 H), 2.76 (s, 1 H), 2.52 - 2.36 (m, 1 H), 2.25 - 1 .76 (m, 8H), 1.74 - 1 .50 (m, 3H), 1 .47 (s, 4H), 1 .40 - 1 .31 (m, 5H), 1 .24 - 1 .14 (m, 9H), 1 .09 - 0.92 (m, 1 H), 0.89 - 0.80 (m, 6H), 0.43 (s, 3H).

[0241] 13 C NMR (75 MHz, CD2CI2) 5200.4 (C=O), 177.3 (C=O), 170.1 (C), 167.0 (C=O), 154.2 (C),

[0242] 140.1 (CH), 136.0 (C), 130.8 (C), 130.5 (2CH), 128.9 (C), 127.4 (2CH), 106.6 (C), 62.1 (CH3), 53.3 (CH), 52.6 (CH), 52.1 (CH), 48.9 (CH), 45.9 (C), 44.5 (C), 43.9 (C), 41.6 (CH2),

[0243] 41 .1 (C), 39.1 (CH2), 38.3 (2CH2), 33.0 (CH2), 32.4 (C), 31 .6 (CH2), 28.9 (CH3), 28.7 (CH3), 27.4 (CH3), 27.0 (CH2), 27.0 (CH2), 24.5 (CH3), 24.5 (CH3), 24.0 (CH3), 19.1 (CH3), 18.2 (CH2), 16.8 (CH3).

[0244] HRMS (ESI): cald., for M+H [C4IH 55 N2O5]: 655.4105, found: 655.4113.

[0245] EXAMPLE 16

[0246] This example describes the synthesis of the compound of formula (II) from the compound of formula (Vil) where R 1 is the methyl group and where Ar 2 It is 4-tolyl and a terminal alkyne of formula R 2 -C=CH where R 2is the 2-pyridinyl group. The method comprised the following steps: g.2) This step is similar to that described in example 9. In this example, (93 mg, 0.9 mmol) of the terminal alkyne 2-pyridynylacetylene was used. In this first stage, the reaction shown in Figure 18 was promoted, where the compound (3S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-5'-(pyridine-2-1l)-4,4,6a,6b,8a,11,14b-heptamethyl-14-oxo-1,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-octadecahydro-2H-spiro[picene-3,3'-pyrazole]-11-methyl carboxylate of formula (II) was obtained. h.2) This stage is similar to that described in example 9.Chromatographic purification was carried out using a mixture of hexane, ethyl acetate, and dichloromethane in proportions (3:1:2) as eluent, yielding 112 mg (63% yield) of the compound (3S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-5'-(pyridine-2-11)-4,4,6a,6b,8a,11,14b-heptamethyl-14-oxo-1,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-octadecahydro- Methyl 2H-spiro[picene-3,3'-pyrazole]-11-carboxylate of formula (II).

[0247] Rf (S¡02, Hexane: Ethyl acetate: dichloromethane 3: 1: 2) = 0.2.

[0248] Spectroscopic data:

[0249] 1H NMR (300 MHz, CD2CI2) 5 = 8.69 - 8.56 (m, 1 H), 8.44 - 8.34 (m, 1 H), 7.84 (td, J=7.7 , 1.8, 1 H), 7.51 (s, 1 H), 7.35 - 7.19 (m, 1 H), 5.64 (s, 1 H), 3.66 (s, 3H), 2.85 (dt, J=13.3, 3.4, 1 H), 2.75 (s, 1 H), 2.46 (td, J=14.1 , 3.6, 1 H), 2.29 - 1 .78 (m, 7H), 1.74 - 1 .53 (m, 3H), 1 .53 - 1.29 (m, 10H), 1.28 - 1.08 (m, 12H), 0.81 (d, J=2.0, 4H), 0.43 (s, 3H).

[0250] 13 C NMR (75 MHz, CD2CI2) 5 200.3 (C=O), 177.3 (C=O), 170.0 (C), 155.8 (C), 150.7 (CH), 142.3 (CH), 137.3 (CH), 128.9 (CH), 124.0 (CH), 122.3 (CH), 106.0 (C), 62.1 (CH), 53.2 (CH), 53.2 (C), 52.1 (CH3), 48.9 (CH), 45.9 (C), 44.5 (2C), 43.9 (C), 41.6 (C), 41.0 (CH2), 39.2 (CH2), 38.3 (2CH2), 33.0 (CH2), 32.3 (C), 31.6 (CH2), 28.9 (CH3), 28.7 (CH3), 27.4 (CH2), 27.0 (CH2), 24.6 (CH3), 24.5 (CH3), 24.0 (CH3), 19.1 (CH3), 18.2 (CH2), 16.8 (CH3).

[0251] EJEMPLO 17

[0252] This example describes the synthesis of the compound of formula (II) from the compound of formula (Vil) where R 1 is the methyl group and where Ar 2 It is 4-tolyl and a terminal alkyne of formula R 2 -C=CH where R 2 is the 4-(trifluoromethyl)phenyl group. The method comprised the following steps: g.2) This step is similar to that described in Example 9. In this example, (153 mg, 0.9 mmol) of the terminal alkyne 4-(trifluoromethyl)phenylacetylene was used. In this first step, the reaction shown in Figure 19 was promoted, where the compound (3S,4aR,6aR,6bS,8aS,11 S,12aR,14aR,14bS)-5'-(4-(trifluoromethyl)phenyl)-4,4,6a,6b,8a,11 , was obtained

[0253] 14b-heptamethyl-14-oxo- 1,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-octadecahydro-2H-spiro[picene-3,3'-pyrazole]-11-methyl carboxylate of formula (II). h.2) This step is similar to that described in example 9. The chromatographic purification was carried out using a mixture of hexane, ethyl acetate, dichloromethane in proportions (8:1:1) as eluent, obtaining 107 mg (55% yield) of the compound (3S,4aR,6aR,

[0254] 6bS,8aS, 1 1 S, 12aR, 14aR, 14bS)-5'-(trif lu oromethi l)ph enyl) -4,4, 6a,6b,8a, 11,14b-heptamethyl- 14- oxo- 1,4, 4a, 5, 6, 6a, 6b, 7, 8, 8a, 9, 10, 11, 12, 12a, 14, 14a, 14b-octadecahydro-2H-spiro[picene- 3, S'-pyrazole]- 11-methyl carboxylate of formula (II).

[0255] Rf (S¡02, Hexane: Ethyl acetate: dichloromethane 8: 1: 1) = 0.2.

[0256] Spectroscopic data:

[0257] 1H NMR (300 MHz, CD2CI2) 5 = 8.18 (d, =8.1 , 2H), 7.73 (d, J=8.2, 2H), 7.18 (s, 1 H), 5.64 (s, 1 H), 3.67 (s, 3H), 2.86 (dt, J=13.4, 3.4, 1 H), 2.76 (s, 1 H), 2.46 (p, =14.2, 3.8, 1 H), 2.26 - 2.04 (m, 3H), 2.07 - 1 .76 (m, 4H), 1 .76 - 1 .49 (m, 4H), 1 .47 (s, 3H), 1.41 - 1 .26 (m, 6H), 1.27 - 1.07 (m, 10H), 1.09 - 0.95 (m, 1H), 0.89 - 0.76 (m, 5H), 0.43 (s, 3H).

[0258] 13 C NMR (75 MHz, CD2CI2) 5 200.5 (C=O), 177.4 (C=O), 170.2 (C), 153.8 (C), 140.1 (CH), 135.3 (C), 130.6 (CF3), 128.9 (CH), 127.8 (CH), 126.3 (2CH), 126.2 (CH), 106.1 (C), 62.1 (CH), 53.3 (C), 53.3 (CH), 52.1 (CH3), 48.9 (CH), 45.9 (C), 44.5 (C), 43.9 (C), 41.6 (CH2), 41.1 (C), 39.1 (CH2), 38.3 (CH2), 33.0 (CH2), 32.4 (C), 31.6 (CH2), 28.9 (CH3), 28.7 (CH3), 27.4 (CH2), 27.0 (CH2), 26.9 (CH2), 24.5 (CH3), 24.5 (CH3), 24.0 (CH3), 19.1 (CH3), 18.2 (CH2), 16.9 (CH3).

[0259] HRMS (ESI): calcd, for M+H [C 40 H 52 N2O3]: 665.3925, found: 665.3933.

[0260] EXAMPLE 18

[0261] This example describes the synthesis of compounds of formula (III) and (IV) from the compound of formula (II) where R 1 is the methyl group and where R 2 It is the 3-bromophenyl group. The method comprised the following steps:

[0262] 2) In a reaction tube, the compound of formula (II) (101 mg, 0.15 mmol) was dissolved in 1,4-dioxane to obtain a 0.05 M solution under a nitrogen atmosphere. One equivalent of boron fluoride etherate (BF3-Et2O) (1 eq) was added to the solution. The reaction tube was sealed and the reaction was stirred at 20 eC for 14h. In this first stage, the reaction represented in Figure 20 was promoted, where the compounds (2bR,4S,6aS,8aS,8bR,10aR,17aS,17bR)-14-(3-bromophenyl)-4,6a,8a,8b,1 1 ,11 , 17a-heptamethyl-1 -oxo-2b,3,4,5,6,6a,7,8,8a,8b,9,10,10a,11 ,16,17,17a,17b-octadecahydro- 1 H-chrysene[1 ,2-e]pyrazolo[1 ,5-a]azepin-4-carboxylate methyl of formula (III) and the compound (3S,4aR,6aR,7S,8S,10aR,10bS,12aS)-7-(2-(3-(3-bromophenyl)-1 H-pyrazol-5-yl)ethyl)-3,7, 10a,10b, 12a-pentamethyl-6-oxo-8-(prop-1 -en-2-yl)-1 ,2, 3, 4, 4a, 6, 6a, 7, 8, 9, 10, 10a, 10b, 11 ,12,12a-methyl hexadecadecahydrochrysene-3-carboxylate of formula (IV). j.2) The mixture was neutralized with 5 mL of an aqueous solution saturated in sodium bicarbonate (NaHCO3). 5 mL of dichloromethane were added and the phases were separated. The aqueous phase was extracted twice more with 5 mL of dichloromethane. The organic layers were combined and dried with sodium sulfate.The solution was filtered through filter paper and concentrated by vacuum distillation. The resulting residue was found to be a mixture of compounds (III) and (IV). Compounds (III) and (IV) were separated by flash silica gel chromatography, using as eluent a mixture of hexane, ethyl acetate and dichloromethane in a gradient of (5:1:0.5 to 2:1:1), obtaining 40 mg (40% yield) of the compound (2bR,4S,6aS,8aS,8bR,10aR,17aS,17bR)-14-(3-bromophenyl)-4,6a,8a,8b,11,11,17a-heptamethyl-1-oxo-2b,3,4,5,6,6a,7,8,8a,8b,9,10,10a,11,16,17,17a,17b-octadehydro-1H-csene[1 methyl ,2-e]pyrazolo[1,5-a]azepín-4-carboxylate of formula (III) and 29 mg (yield 29%) of the compound (3S,4aR,6aR,7S,8S,10aR,10bS,12aS)-7- (2-(3-(3-bromophenyl)-1 H-pyrazole-5-(l)ethyl)-3,7,10a,10b,12a-pentamethyl-6-oxo-8-(prop-1-en-2-yl)-1,2,3,4,4a,6,6a,7,8,9,10,10a,10b,11,12,12a-hexadecahydrochrysene-3-carboxylate methyl of formula (IV).

[0263] Datos físicos del compuesto (III):

[0264] Rf (S¡02, Hexano: Acetato de etilo: diclorometano, 5: 1 : 0,5) = 0,5.

[0265] 1 H NMR (300 MHz, CDCI3) 5 = 7.95 (s, 1 H), 7.67 (d, J=7.7 , 1 H), 7.35 (d, =8.8, 1 H), 7.21 (t, J=7.8, 1 H), 6.20 (s, 1 H), 5.70 (s, 1 H), 3.69 (s, 3H), 2.91 - 2.68 (m, 3H), 2.32 (m, 1 H), 2.16 - 1.56 (m, 15H), 1.52 - 1.10 (m, 18H), 1.09 - 0.96 (m, 1 H), 0.94 - 0.73 (m, 4H).

[0266] 13 C NMR (75 MHz, CDCI3) 5 199.5 (C=O), 177.0 (C=O), 189.0 (C), 147.0 (C), 146.1 (C), 136.5 (C), 130.1 (CH), 129.9 (CH), 129.0 (CH), 128.4 (CH), 124.0 (CH), 122.8 (C), 101.9 (CH), 67.4 (C), 59.9 (CH3), 52.4 (CH), 52.0 (CH), 48.5 (CH), 45.5 (CH3), 44.2 (C), 43.7 (C),

[0267] 42.7 (C), 41.2 (CH2), 41.1 (CH2), 37.8 (CH2), 32.8 (CH2), 32.6 (CH3), 32.1 (C), 31.2 (CH2),

[0268] 28.7 (CH2), 28.5 (CH2), 26.5 (CH3), 25.9 (CH3), 23.2 (CH3), 22.2 (CH2), 21.3 (CH2), 19.7 (CH3), 18.5 (CH3).

[0269] HRMS (ESI): caled, for M+H [C39H 52 BrN2O3]: 675.3156, found: 675.3162.

[0270] Datos físicos del compuesto (IV):

[0271] Rf (S¡O2, Hexano: Acetato de etilo: diclorometano, 5: 1 : 0,5) = 0,1 .

[0272] 1 H NMR (300 MHz, CDCI3) 5 = 7.91 (s, 1 H), 7.68 (d, J=7.8, 1 H), 7.40 (d, =7.8, 2H), 7.22 (d, J=7.9, 1 H), 7.22 (d, J=7.9, 1 H), 6.30 (s, 1 H), 5.70 (s, 1 H), 4.91 (s, 1 H), 4.75 (s, 1 H), 3.67 (s, 3H), 2.82 - 2.69 (m, 3H), 2.55 - 2.43 (m, 1 H), 2.19 - 1 .94 (m, 4H), 1 .82 (d, =33.3, 7H), 1 .45 - 1 .21 (m, 14H), 1.21 - 1 .08 (m, 6H), 0.92 - 0.74 (m, 5H).

[0273] 13C NMR (75 MHz, CDCI3) 5 200.6 (C=O), 177.1 (C=O), 170.4 (C), 147.1 (C), 146.5 (C), 135.5 (C), 130.5 (2CH), 128.7 (CH), 128.6 (2CH), 124.2 (CH), 122.9 (C), 114.3 (CH2), 59.6 (CH3), 53.2 (CH), 52.0 (CH), 48.4 (CH), 45.3 (C), 44.2 (C), 43.8 (C), 43.7 (C), 43.1 (C), 41.3 (CH2), 38.8 (CH2), 37.9 (CH2), 31 .9 (C), 31 .5 (CH2), 31.2 (CH2), 28.4 (CH3), 26.5 (CH2), 25.2 (CH3), 23.8 (CH2), 23.3 (CH3), 20.8 (CH2), 20.0 (CH3), 18.9 (CH3), 18.4 (CH3), 17.8 (CH2), 16.0 (CH3).

[0274] HRMS (ESI): caled, for M+H [C 39 H 52 BrN2O3]: 675.3156, found: 675.3163.

[0275] IC50 of compound (IV) against HeLa cells: 10.4 .M.

[0276] EXAMPLE 19 This example describes the synthesis of compounds of formula (III) and (IV) from the compound of formula (II) where R 1 is the methyl group and where R 2is the 4-cyanophenyl group. The method comprised the following steps: i.2) In a reaction tube, the compound of formula (II) (93 mg, 0.15 mmol) was dissolved in 1,4-dioxane to obtain a 0.05 M solution under a nitrogen atmosphere. One equivalent of boron fluoride etherate (BFs-EtsO) (1 eq) was added to the solution. The reaction tube was sealed and the reaction was shaken at 20 eC for 14h. In this first stage, the reaction represented in Figure 21 was promoted, where the compound (2bR,4S,6aS,8aS,8bR,10aR,17aS,17bR)-14-(4-cyanophenyl)-4,6a,8a,8b,1 1 ,1 1 , 17a-heptamethyl-1 -oxo-2b,3,4,5,6,6a,7,8,8a,8b,9,10,10a,11 ,16,17,17a,17b-octadecahydro- 1 H-chrysene[1 ,2-e]pyrazolo[1 ,5-a]azepin-4-carboxylate of methyl formula (III) and the compound (3S,4aR,6aR,7S,8S,10aR,10bS,12aS)-7-(2-(3-(4-cyanophenyl)-1 H-pyrazol-5-yl)ethyl)-3,7, 10a,10b, 12a-pentamethyl-6-oxo-8-(prop-1 -en-2-yl)-1 ,2, 3, 4, 4a, 6, 6a, 7, 8, 9, 10, 10a, 10b, 11 ,12,12a-methyl hexadecadecahydrochrysene-3-carboxylate of formula (IV). j.2) The mixture was neutralized with 5 mL of an aqueous solution saturated in sodium bicarbonate (NaHCO3). 5 mL of dichloromethane were added and the phases were separated. The aqueous phase was extracted twice more with 5 mL of dichloromethane. The organic layers were combined and dried with sodium sulfate.The solution was filtered through filter paper and concentrated by vacuum distillation. The resulting residue was found to be a mixture of compounds (III) and (IV). Compounds (III) and (IV) were separated by chromatography using a mixture of hexane, ethyl acetate, and dichloromethane in proportions (3:1:1) as eluent, yielding 33 mg (35% yield) of the compound (2bR,4S,6aS,8aS,8bR,10aR,17aS,17bR)-14-(4-cyanophenyl)-4,6a,8a,8b,11,11,17a-heptamethyl-1-oxo-2b,3,4,5,6,6a,7,8,8a,8b,9,10,10a,11,16,17,17a,17b-octadecahydro-1H-csene[1,2-e]pyrazolo[1 methyl 5-a]azepin-4-carboxylate of formula (III) and 23 mg (25% yield) of the compound (3S,4aR,6aR,7S,8S,10aR,10bS,12aS)-7-(2-(3-(4-cyanophenyl)-1 H-pyrazol-5-yl)ethyl)-3,7,10a, Methyl 10b,12a-pentamethyl-6-oxo-8-(prop-1-en-2-yl)-1,2,3,4,4a,6,6a,7,8,9,10,10a,10b,11,12,12a-hexadecahydrocñsene-3-carboxylate of formula (IV).

[0277] Datos físicos del compuesto (III):

[0278] Rf (SÍO2, Hexano: Acetato de etilo: diclorometano, 3: 1 : 1 ) = 0,4. 1 H NMR (300 MHz, CDCI3) 5 = 7.93 - 7.79 (m, 2H), 7.68 - 7.53 (m, 2H), 6.26 (s, 1 H), 5.70 (s, 1 H), 3.68 (s, 3H), 2.91 - 2.63 (m, 3H), 2.40- 2.25 (m, 1 H), 2.17 - 1.62 (m, 17H), 1.54 - 0.92 (m, 17H), 0.89 - 0.74 (m, 4H).

[0279] 13 C NMR (75 MHz, CDCI3) 5 199.4 (C=O), 177.0 (C=O), 169.0 (CN), 146.5 (C), 138.7 (C),

[0280] 132.4 (2 CH), 128.9 (CH), 125.7 (2 CH), 119.5 (CH), 110.1 (C), 102.5 (CH), 67.7 (C), 60.5 (C), 59.9 (CH3), 52.3 (CH), 51.9 (CH), 48.4 (CH), 45.4 (C), 44.1 (C), 43.6 (C), 42.7 (CH2), 41.1 (C), 41.1 (CH2), 37.8 (CH2), 32.7 (C), 32.6 (CH2), 32.0 (CH3), 31.2 (CH2), 28.7 (CH3),

[0281] 28.4 (CH3), 26.5 (2 CH2), 25.9 (CH3), 23.1 (CH3), 22.2 (CH2), 21.3 (CH2), 19.7 (CH3), 18.4 (CH3).

[0282] HRMS (ESI): caled, for M+H [C4oH 52N303]: 622.4003, found: 622.401 1.

[0283] Datos físicos del compuesto (IV):

[0284] Rf (S¡O2, Hexano: Acetato de etilo: diclorometano, 3: 1 : 1 ) = 0,25

[0285] 1 H NMR (300 MHz, CDCI3) 5 = 7.87 (d, =8.2, 2H), 7.65 (d, J=8.4, 2H), 6.39 (s, 1 H), 5.70 (s, 1 H), 4.89 (s, 1 H), 4.75 (s, 1 H), 3.67 (s, 3H), 2.88 - 2.66 (m, 2H), 2.63 - 2.38 (m, 1 H), 2.19 - 1 .95 (m, 4H), 1 .93 - 1 .64 (m, 6H), 1 .46 - 1 .07 (m, 21 H), 0.88 - 0.72 (m, 6H).

[0286] 13 C NMR (75 MHz, CDCI3) 5200.6 (C=O), 177.0 (C=O), 170.7 (C), 147.1 (C), 132.6 (2 CH),

[0287] 128.5 (CH), 126.0 (2 CH), 1 19.3 (C), 1 14.3 (CH2), 11 1.0 (C), 101.6 (CH), 59.7 (CH3), 53.3 (CH), 52.0 (CH), 48.6 (CH), 45.3 (C), 44.1 (C), 43.8 (2C), 43.1 (C), 41.3 (CH2), 39.3 (C), 38.8 (CH2), 37.9 (CH2), 32.0 (C), 31 .5 (CH2), 31 .2 (CH2), 29.8 (C), 28.38 (CH3), 26.7 (CH2),

[0288] 26.5 (CH2), 23.5 (CH3), 20.7 (CH2), 19.9 (CH3), 19.0 (CH3), 18.4 (CH3), 17.8 (CH2), 16.0 (CH3).

[0289] HRMS (ESI): caled, for M+H [C 40 H 52 N3O3]: 622.4003, found: 622.401 1.

[0290] EXAMPLE 20

[0291] This example describes the synthesis of the compound of formula (III) from the compound of formula (II) where R 1 is the methyl group and where R 2 It is the thiophen-2-yl group. The method comprised the following steps:

[0292] 2) In a reaction tube, the compound of formula (II) (90 mg, 0.15 mmol) was dissolved in 1,4-dioxane to obtain a 0.05 M solution under a nitrogen atmosphere. One equivalent of boron fluoride etherate (BF3-Et2O) (1 eq) was added to the solution. The reaction tube was sealed and the reaction was shaken at 20 eC for 14h. In this first stage, the reaction shown in Figure 22 was promoted, where the compound (2bR,4S,6aS,8aS,8bR,10aR,17aS,17bR)-14-(thiophen-2-yl)-4,6a,8a,8b,11,11,17a-heptamethyl-

[0293] 1-oxo-2b,3,4,5,6,6a,7,8,8a,8b,9,10,10a,11,16,17,17a,17b-octadecahydro-1H-chrysene[1,2-e]pyrazolo[1,5-a]azepin-4-carboxylate methyl of formula (III). j.2) The mixture was neutralized with 5 mL of an aqueous solution saturated in sodium bicarbonate (NaHCO3). 5 mL of dichloromethane were added and the phases were separated. The aqueous phase was extracted twice more with 5 mL of dichloromethane. The organic layers were combined and dried with sodium sulfate. The solution was filtered through filter paper and concentrated by vacuum distillation.Compound (III) was purified by silica gel chromatography, using a mixture of dichloromethane and methanol, in proportions (99:1) as eluent, obtaining 47 mg (52% yield) of the compound (2bR,4S,6aS,8aS,8bR,10aR,17aS,17bR)-14-(thiophen-2-yl)-4,6a,8a,8b,11,11,17a-heptamethyl-1-oxo-2b,3,4,5,6,6a,7,8,8a,8b,9,10,10a,11,16,17,17a,17b-octadecahydro-1H-chrysene[1,2-e]pyrazolo[1,5-a]azepin-4-carboxylate methyl of formula (III).

[0294] Physical data:

[0295] Rf (S¡02, dichloromethane: methanol, 99: 1) = 0.7.

[0296] 1 H NMR (300 MHz, CDCI3) 5 = 7.22 (dd, J=3.5, 1.2, 1 H), 7.15 (dd, =5.1, 1.2, 1 H), 6.99 (dd, J=5.0, 3.5, 1 H), 6.11 (s, 1 H), 5.69 (s, 1 H), 3.68 (s, 3H), 2.88 - 2.63 (m, 3H), 2.39 - 2.24 2.32 (m, 1 H), 2.13 - 1.93 (m, 6H), 1.93 - 1.63 (m, 11 H), 1.42 - 1.31 (m, 8H), 1.30 - 1.20 (m, 3H), 1.1 1 - 1.19 (m, 6H), 1.07 - 0.94 (m, 1H), 0.81 (s, 3H).

[0297] 13C NMR (75 MHz, CDCI3) 5 199.5 (C=O), 177.0 (C=O), 171.3 (C), 168.9 (C), 145.9 (C), 143.9 (C), 137.9 (C), 128.9 (CH), 127.3 (CH), 123.7 (CH), 122.9 (CH), 101.9 (CH), 67.2 (C),

[0298] 60.5 (CH2), 59.9 (CH3), 52.4 (CH), 51.9 (CH), 48.4 (CH), 45.44 (C), 44.12 (C), 43.6 (C),

[0299] 42.5 (CH2), 41.1 (2CH2), 37.8 (CH2), 32.8 (CH2), 32.0 (C), 31.2 (CH2), 28.7 (CH3), 28.4 (CH3), 26.5 (CH2), 25.8 (CH3), 23.1 (CH3), 22.1 (CH2), 21.2 (CH2), 19.7 (CH3), 18.5 (CH3), 14.3 (CH3).

[0300] HRMS (ESI): caled, for M+H [C37H5IN2O3S]: 603.3615, found: 603.3628.

[0301] EXAMPLE 21

[0302] This example describes the synthesis of the compound of formula (III) from the compound of formula (II) where R 1 is the methyl group and where R 2 is the 3-aminophenyl group. The method comprised the following steps: 1.2) In a reaction tube, the compound of formula (II) (91 mg, 0.15 mmol) was dissolved in

[0303] I,4-dioxane was diluted to a 0.05 M solution under a nitrogen atmosphere. One equivalent of boron fluoride etherate (BF3-Et2O) (1 eq) was added to the solution. The reaction tube was sealed and the reaction was stirred at 20 e C for 14h. In this first stage, the reaction represented in Figure 23 was promoted, where the compounds (2bR,4S,6aS,8aS,8bR,10aR,17aS,17bR)-14-(3-aminophenyl)-4,6a,8a,8b,11,11,17a-heptamethyl-1-oxo-2b,3,4,5,6,6a,7,8,8a,8b,9,10,10a,11,16,17,17a,17b-octadecahydro-

[0304] 1 H-chrysene[1,2-e]pyrazolo[1,5-a]azepin-4-methyl carboxylate of formula (III). j.2) The mixture was neutralized with 5 mL of an aqueous solution saturated in sodium bicarbonate (NaHCO3). 5 mL of dichloromethane were added and the phases were separated. The aqueous phase was extracted twice more with 5 mL of dichloromethane. The organic layers were combined and dried with sodium sulfate. The solution was filtered through filter paper and concentrated by vacuum distillation. Compound (III) was purified by silica gel chromatography, using as eluent a mixture of hexane, ethyl acetate and dichloromethane in proportions (3: 1 : 1 ), obtaining 23 mg (25% yield) of the compound (2bR,4S,6aS,8aS,8bR,10aR,17aS,17bR)-14-(3-aminophenyl)-4,6a,8a,8b,

[0305] II. methyl of formula (III).

[0306] Physical data:

[0307] Rf (SiO2, Hexane: Ethyl acetate: Dichloromethane, 3: 1: 1) = 0.3.

[0308] 1 H NMR (300 MHz, CDCl3) δ = 7.23 - 7.03 (m, 3H), 6.65 - 6.52 (m, 1 H), 6.17 (s, 1 H), 5.70 (s, 1 H), 3.69 (s, 3H), 2.93 - 2.53 (m, 3H), 2.38 - 2.24 (m, 1 H), 2.15 - 1 .54 (m, 15H), 1.51 - 1.08 (m, 19H), 1.09 - 0.92 (m, 1 H), 0.91 - 0.73 (m, 5H).

[0309] 13 C NMR (75 MHz, CDCl3) δ 199.6 (C=O), 177.4 (C=O), 168.9 (C), 148.5 (C), 145.7 (C),

[0310] 135.3 (C), 129.4 (CH), 128.9 (CH), 116.3 (CH), 1 14.2 (CH), 112.2 (CH), 67.1 (C), 59.83 (CH3), 52.4 (CH), 51.9 (CH), 48.4 (CH), 45.4 (C), 44.1 (C), 43.6 (C), 42.7 (CH2), 41.1 (2CH2), 37.8 (CH2), 32.8 (CH2), 32.5 (CH), 32.0 (C), 31.2 (CH2), 29.8 (C), 29.5 (C), 28.7 (CH3), 28.43 (CH3), 26.5 (CH2), 25.9 (CH3), 23.1 (CH3), 22.2 (CH2), 21.2 (CH2), 19.7 (CH3), 18.5 (CH3),

[0311] 14.3 (CH3).

[0312] HRMS (ESI): caled, for M+H [C39H54N3O3]: 612.4160, found: 612.4166.

[0313] EXAMPLE 22 This example describes the synthesis of the compound of formula (IV) from the compound of formula (II) where R 1 is the methyl group and where R 2 It is the pyridine-2-yl group. The method comprised the following steps:

[0314] 2) In a reaction tube, the compound of formula (II) (90 mg, 0.15 mmol) was dissolved in 1,4-dioxane to obtain a 0.05 M solution under a nitrogen atmosphere. One equivalent of boron fluoride etherate (BF3-Et2O) (1 eq) was added to the solution. The reaction tube was sealed and the reaction was shaken at 20 eC for 14h. In this first stage, the reaction represented in Figure 24 was promoted, where the compound (3S,4aR,6aR,7S,8S,10aR,10bS,12aS)-3,7,10a,10b,12a-pentamethyl-6-oxo-8-(prop-1-en-2-yl)-7-(2-(3-(pyridin-2-yl)-1H-pyrazol-5-yl)ethyl)-1,2,3,4,4a,6,6a,7,8,9,10,10a,10b,11,12,12a-methyl hexadecahydrochrysene-3-carboxylate of formula (IV) was obtained. j.2) The mixture was neutralized with 5 mL of an aqueous solution saturated in sodium bicarbonate (NaHCO3). Five milliliters of dichloromethane were added and the phases were separated. The aqueous phase was extracted twice more with 5 milliliters of dichloromethane. The organic layers were combined and dried with sodium sulfate. The solution was filtered through filter paper and concentrated by vacuum distillation.Compound (IV) was purified by silica gel chromatography, using as eluent a mixture of hexane, ethyl acetate and dichloromethane in proportions (1 : 1 : 1 ), obtaining 42 mg (yield 47%) (3S,4aR,6aR,7S,8S,10aR,10bS,12aS)-3,7,10a,10b,12a-pentamethyl-6-oxo-8-(prop-1 -en-2-yl)-7-(2-(3-(pyridin-2-yl)-1 H-pyrazol-5-yl)ethyl)-1 ,2,3,4,4a,6,6a,7,8,9,10,10a,10b,11 ,12,12a- methyl hexadecahydrocosene-3-carboxylate of formula (IV).

[0315] Physical data:

[0316] Rf (S¡02, Hexane: Ethyl acetate: dichloromethane, 3: 1: 1) = 0.4.

[0317] 1 H NMR (300 MHz, CDCI3) 5 = 8.57 (d, J=4.8, 1 H), 7.78 - 7.62 (m, 2H), 7.21 - 7.11 (m, 1 H), 6.43 (s, 1 H), 5.67 (s, 1 H), 4.87 (s, 1 H), 4.75 (s, 1 H), 3.64 (s, 3H), 2.83 - 2.65 (m, 3H), 2.60 - 2.42 (m, 1 H), 2.20 - 1 .92 (m, 4H), 1.91 - 1 .65 (m, 5H), 1.63 - 1 .05 (m, 20H), 0.99 (d, J=13.3, 1H), 0.90 - 0.72 (m, 6H).

[0318] 13C NMR (75 MHz, CDCI3) 5 200.3 (C=O), 177.0 (C=O), 169.8 (C), 169.6 (C), 149.3 (CH), 147.0 (2C), 136.9 (CH), 128.6 (CH), 122.5 (CH), 120.1 (CH), 114.2 (CH2), 102.0 (CH), 59.90 (CH3), 53.0 (CH), 51.9 (CH), 50.8 (CH), 48.4 (CH3), 45.2 (C), 44.1 (C), 43.8 (C), 41.2 (CH2), 39.3 (C), 38.9 (CH2), 37.8 (CH2), 31 .9 (C), 31 .9 (C), 31 .5 (CH2), 31 .2 (CH2), 28.7 (CH3), 28.4 (CH3), 26.6 (CH2), 26.5 (CH2), 23.9 (CH3), 23.7 (CH3), 23.5 (CH2), 20.0 (CH2), 18.8 (CH3). HRMS (ESI): caled, for M+H [C38H52N3O3]: 598.4012, found: 598.4003.

[0319] IC50 against HeLa cells: 10.0 |iM.

[0320] EXAMPLE 23

[0321] This example describes the synthesis of compounds of formula (III) and (IV) from the compound of formula (II) where R 1 is the methyl group and where R 2 It is the group (4-methoxycarbonylphenyl). The method comprised the following steps:

[0322] 2) In a reaction tube, the compound of formula (II) (90 mg, 0.15 mmol) was dissolved in 1,4-dioxane to obtain a 0.05 M solution under a nitrogen atmosphere. One equivalent of boron fluoride etherate (BF3-Et2O) (1 eq) was added to the solution. The reaction tube was sealed and the reaction was shaken at 20 eC for 14h. In this first stage, the reaction represented in Figure 25 was promoted, where the compound (2bR,4S,6aS,8aS,8bR,10aR,17aS,17bR)-14-(4-methoxycarbonyl)phenyl-4,6a,8a,8b,11,11,17a-heptamethyl-1-oxo-2b,3,4,5,6,6a,7,8,8a,8b,9,10,10a,11,16,17,17a,17b-octadehydro-1H-csene[1,2-e]pyrazolo[1,5-a]azepin-4-carboxylate of methyl formula (III) was obtained and (3S,4aR,6aR,7S,8S,10aR,10bS,12aS)-7-(2-(3-(4-(methoxycarbonyl)phenyl)-1H-pyrazol-5-1l)ethyl)-3,7,10a,10b,12a-pentamethyl-6-oxo-8-(prop-1-en-2-1l)-1,2,3,4,4a,6,6a,7,8,9,10,10a,10b,11,12,12a-methyl hexadecadecahydrocosene-3-carboxylate of formula (IV). j.2) The mixture was neutralized with 5 mL of an aqueous solution saturated in sodium bicarbonate (NaHCO3). 5 mL of dichloromethane were added and the phases were separated. The aqueous phase was extracted twice more with 5 mL of dichloromethane. The organic layers were combined and dried with sodium sulfate.The solution was filtered through filter paper and concentrated by vacuum distillation. Compound (III) was purified by silica gel chromatography, using a mixture of hexane, ethyl acetate and dichloromethane in proportions (2:1:1), yielding 49 mg (50% yield) of the compound (2bR,4S,6aS,8aS,8bR,10aR,17aS,17bR)-14-(4-methoxycarbonyl)phenyl-4,6a,8a,8b,11,11,17a-heptamethyl-1-oxo-2b,3,4,5,6,6a,7,8,8a,8b,9,10,10a,11,16,17,17a,17b-octadecahydro-1H-csene[1,2-e]pyrazolo[1 methyl ,5-a]azepín-4-carboxylate of formula (III) and 34 mg (35% yield) of the compound (3S,4aR,6aR,7S,8S, 10aR,10bS,12aS)-7-(2-(3-(4-(methoxycarbonyl)phenyl)-1 H-pyrazol-5-yl)ethyl)-3,7,10a,10b,12a- pentamethyl-6-oxo-8-(prop-1 -en-2-yl)-1,2,3,4,4a,6,6a,7,8,9,10,10a,.

[0323] 10b, 11, 12, 12a-methyl hexadecahrysene-3-carboxylate of formula (IV).

[0324] Physical data of the compound (III):

[0325] Rf (SiO2, Hexano: Acetato de etilo: diclorometano, 2: 1 : 1 ) = 0,5.

[0326] 1 H NMR (300 MHz, CDCI3) 5 = 8.08 - 7.94 (m, 2H), 7.91 - 7.77 (m, 2H), 6.28 (s, 1 H), 5.69 (s, 1 H), 3.90 (s, 4H), 3.68 (s, 4H), 2.88 - 2.61 (m, 3H), 2.47 - 2.22 (m, 1 H), 2.16 - 1 .63 (m, 14H), 1.43 - 1.09 (m, 19H), 0.80 (s, 3H).

[0327] 13 C NMR (75 MHz, CDCI3) 5 199.5 (C=O), 177.0 (C=O), 169.0 (C), 167.3 (C), 147.2 (C), 146.2 (C), 138.8 (C), 130.0 (2CH), 128.9 (CH), 128.4 (C), 125.2 (2CH), 102.4 (CH), 67.5 (2C), 59.9 (CH), 52.4 (CH3), 52.1 (CH3), 51.9 (CH), 48.4 (CH), 45.4 (C), 44.1 (C), 43.6 (C), 42.6 (CH2), 41.1 (2CH2), 37.8 (CH2), 32.7 (CH2), 32.6 (CH3), 32.0 (C), 31.2 (CH2), 28.7 (CH3), 28.4 (CH3), 26.5 (CH2), 25.9 (CH3), 23.1 (CH3), 22.2 (CH2), 21.3 (CH2), 19.7 (CH3),

[0328] 18.5 (CH3).

[0329] HRMS (ESI): caled, for M+H [C4IH 55 N2O5]: 655.4105, found: 655.4114.

[0330] Datos físicos del compuesto (IV):

[0331] Rf (SiO2, Hexano: Acetato de etilo: diclorometano, 2: 1 : 1 ) = 0,2.

[0332] 1 H NMR (300 MHz, CDCI3) 5 = 8.1 1 - 7.95 (m, 2H), 7.89 - 7.75 (m, 2H), 6.40 (s, 1 H), 5.69 (s, 1 H), 4.89 (s, 1 H), 4.75 (s, 1 H), 3.91 (s, 3H), 3.66 (s, 3H), 2.66 - 2.84 (s, 2H), 2.65 - 2.31 (m, 1 H), 2.21 - 1.61 (m, 10H), 1.61 - 0.88 (m, 21 H), 0.73 - 0.89 (m, 6H).

[0333] 13 C NMR (75 MHz, CDCI3) 5 200.6 (C=O), 177.0 (C=O), 170.4 (2C), 167.1 (C), 147.1 (C)

[0334] 146.5 (CH), 137.7 (C), 130.1 (CH), 129.0 (C), 128.4 (CH), 125.5 (CH), 1 14.2 (CH2), 101.6 (CH), 59.7 (CH3), 53.2 (CH), 52.2 (CH), 51.6 (CH), 48.6 (CH), 45.3 (C), 44.1 (C), 43.8 (C), 43.1 (C), 41 .2 (CH2), 39.3 (C), 38.8 (CH2), 37.9 (CH2), 31 .9 (C), 31 .5 (CH2), 31 .2 (CH2), 28.7 (CH3), 26.5 (CH2), 25.2 (CH3), 23.8 (CH2), 23.5 (CH3), 20.8 (CH2), 20.0 (CH3), 18.9 (CH3), 18.4 (CH3), 17.8 (CH2), 15.9 (CH3).

[0335] HRMS (ESI): caled, for M+H [C4IH 55 N2O5]: 655.4105, found: 655.4114.

[0336] EXAMPLE 24

[0337] This example describes the synthesis of the compound of formula (IV) from the compound of formula (II) where R 1 is the methyl group and where R 2 is the 4-trifluoromethylphenyl group. The method comprised the following steps: 1.2) In a reaction tube, the compound of formula (II) (90 mg, 0.15 mmol) was dissolved in 1,4-dioxane to obtain a 0.05 M solution under a nitrogen atmosphere. One equivalent of boron fluoride etherate (BF3-Et2O) (1 eq) was added to the solution. The reaction tube was sealed and the reaction was shaken at 20 eC for 14h. In this first stage, the reaction represented in Figure 26 was promoted, where the compound (3S,4aR,6aR,7S,8S,10aR,10bS,12aS)-3,7,10a,10b,12a-pentamethyl-6-oxo-8-(prop-1-en-2-yl)-7-(4-trifluoromethylphenyl)-1H-pyrazol-5-yl)ethyl)-1,2,3,4,4a,6,6a,7,8,9,10,10a,10b,11,12,12a-methyl hexadecahydrochrysene-3-carboxylate of formula (IV) was obtained. j.2) The mixture was neutralized with 5 mL of an aqueous solution saturated in sodium bicarbonate (NaHCO3). Five milliliters of dichloromethane were added and the phases were separated. The aqueous phase was extracted twice more with 5 milliliters of dichloromethane. The organic layers were combined and dried with sodium sulfate. The solution was filtered through filter paper and concentrated by vacuum distillation. Compound (IV) was purified by silica gel chromatography using a mixture of hexane, ethyl acetate, and dichloromethane in proportions (5:1:0) as the eluent.5) a (2: 1: 1), obtaining 31 mg (yield 35%) (3S,4aR,6aR,7S,8S,10aR,10bS,12aS)-3,7,10a,10b,12a-pentamethyl-6- oxo-8-(prop-1 -en-2-yl)-7-(4-trifluoromethylphenyl)-1 H-pyrazol-5-yl)ethyl)-1 ,2, 3, 4, 4a, 6, 6a, 7, 8, 9,10, 10a,10b,1 1 ,12,12a-hexadecahidrocñseno-3-carboxylate de methyl de formula (IV).

[0338] Datos físicos:

[0339] Rf (S¡02, Hexane: Ethyl acetate: dichloromethane, 5: 1 : 0.5) = 0.1 .

[0340] 1 H NMR (300 MHz, CDCI3) 5 = 7.96 - 7.76 (m, 2H), 7.69 - 7.48 (m, 2H), 6.38 (s, 1 H), 5.70 (s, 1 H), 4.90 (d, J=2.0, 1 H), 4.75 (d, J=2.3, 1 H), 3.67 (s, 3H), 2.86 - 2.65 (m, 2H), 2.64 - 2.45 (m, 1 H), 2.22 - 1.60 (m, 11 H), 1.62 - 0.94 (m, 20H), 0.96 - 0.72 (m, 6H).

[0341] 13C NMR (75 MHz, CDCI3) 5 200.6 (C=O), 177.0 (C=O), 170.5 (C), 147.1 (C), 136.7 (C), 129.7 (C), 129.2 (C), 128.5 (CH), 128.4 (CH), 126.3 (C), 125.8 (3CH), 122.6 (C), 114.2 (CH2), 101 .5 (CH), 59.7 (CH), 53.2 (CH), 51 .9 (CH3), 51 .4 (CH), 48.5 (C), 45.3 (C), 43.8 (C),

[0342] 41.3 (CH2), 39.3 (C), 38.7 (CH2), 37.9 (CH2), 32.0 (C), 31.5 (CH2), 31.2 (CH2), 28.7 (CH3),

[0343] 28.4 (CH3), 26.5 (CH2), 23.9 (CH2), 23.3 (CH3), 20.8 (CH2), 20.0 (CH3), 18.9 (CH3), 17.8 (CH2), 15.9 (CH3).

[0344] IC50 frente a células HeLa: 4.2 |iM

Claims

CLAIMS 1. Compound obtainable by chemical modification of glycyrrhetinic acid, of formula (I), or where, R 1 is selected from the group consisting of hydrogen, methyl, benzyl, branched or unbranched alkyl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, allyl, propargyl, substituted or unsubstituted heteroaryl; Ar 1is selected from a group consisting of phenyl optionally substituted with one, two, three or four substituents selected from -F, Cl, -Br, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or a five-membered aromatic heterocycle containing one, two or three nitrogen atoms optionally substituted with one, two or three groups selected from -F, Cl, -Br, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or a five-membered aromatic heterocycle containing a oxygen or sulfur atom, optionally containing a nitrogen atom and optionally substituted with one, two, or three groups selected from -F, Cl, -Br, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or a six-membered nitrogen-containing aromatic heterocycle containing one, two, three, or four nitrogen atoms and optionally substituted with one, two, or three groups selected from -F, Cl, -Br, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or a naphthalene ring optionally substituted with one, two, three, or four substituents selected from -F, Cl, -Br, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or a quinoline ring optionally substituted with one, two,three or four substituents selected from -F, Cl, -Br, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or an isoquinoline ring optionally substituted with one, two, three or four substituents selected from -F, Cl, -Br, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or an indole ring optionally substituted with one, two, three or four substituents selected from -F, Cl, -Br, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or a condensed aromatic bicycle containing two, three or four nitrogen atoms optionally substituted with one, two, three or four substituents selected from -F,Cl, -Br, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl; and, R 2 is selected from the group consisting of phenyl optionally substituted with one, two, three or four substituents selected from -F, Cl, -Br, -I, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or a five-membered aromatic heterocycle containing one, two or three nitrogen atoms optionally substituted with one, two or three groups selected from -F, Cl, -Br, -I, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or a five-membered aromatic heterocycle containing one oxygen or sulfur atom, optionally containing one nitrogen atom and optionally substituted with one, two, or three groups selected from -F, Cl, -Br, -I, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or a six-membered aromatic heterocycle containing one, two, three, or four nitrogen atoms ... or three groups selected from -F, Cl, -Br, -I, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl,or a naphthalene ring optionally substituted with one, two, three, or four substituents selected from -F, Cl, -Br, -I, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or a quinoline ring optionally substituted with one, two, three, or four substituents selected from -F, Cl, -Br, -I, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or an isoquinoline ring optionally substituted with one, two, three or four substituents selected from -F, Cl, -Br, -I, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or an indole ring optionally substituted with one, two,three or four substituents selected from -F, Cl, -Br, -I, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or a condensed aromatic bicycle containing two, three, or four nitrogen atoms optionally substituted with one, two, three, or four substituents selected from -F, Cl, -Br, -I, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl.

2. Compound according to claim 1 of formula (I) or formula (II), or formula (III), or formula (IV) characterized in that R 1 It's methyl.

3. A pharmaceutical preparation comprising, among other components, a therapeutically effective amount of a compound according to any of the formulas (I), (II), (III) or (IV) or a pharmaceutically acceptable salt, solvate or prodrug thereof, together with one or more pharmaceutically acceptable excipients or diluents.

4. Use of the pharmaceutical preparation of claim 3 to prepare a medicament with antitumor activity.

5. Method for the preparation of glycyrrhetinic acid derivatives comprising the following steps: a) mixing glycyrrhetinic acid of formula (0) with an alcohol or an alkyl halide with an effective amount of an acid or a base and an effective amount of a solvent to promote the following chemical esterification reaction to obtain the compound of formula (V) where, R 1is selected from the group consisting of hydrogen, methyl, benzyl, branched or unbranched alkyl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, allyl, propargyl, substituted or unsubstituted heteroaryl; b) purify the mixture by means of purification that removes the solvent and means of separation that separates the compound of formula (V); c) mixing the separated compound of formula (V) with an effective amount of an oxidizing agent and an organic solvent to promote the following chemical reaction for the synthesis of the compound of formula (VI) where, R 1is selected from the group consisting of hydrogen, methyl, benzyl, branched or unbranched alkyl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, allyl, propargyl, substituted or unsubstituted heteroaryl; d) purifying the mixture by means of purification that removes the solvent and means of separation that separates the compound of formula (VI); e) mixing the separated compound of formula (VI) with an organic solvent, an arylsulfonylhydrazide of formula Ar 2 -SG>2NHNH2 and an acid, to promote the following chemical condensation reaction to obtain the N-arylsulfonylhydrazone compound of formula (Vil) where, R 1 is selected from the group consisting of hydrogen, methyl, benzyl, branched or unbranched alkyl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; and Ar 2is selected from the group consisting of phenyl, optionally substituted with one, two, three, four or five identical or different substituents, selected from methyl, linear alkyl, branched alkyl, O-alkyl, -CF3, -NO2, F, Cl, Br, CN, or phenyl; f) purifying the mixture by purification means that remove the solvent and separation means that separate the compound of formula (Vil) and, alternatively g.1) mixing the / V-arylsulfonylhydrazone compound of formula (Vil) with an effective amount of an aromatic compound of formula Ar 1 -X in the presence of an effective amount of a base, a catalytically effective amount of a palladium catalyst, an effective amount of water, and an effective amount of an organic solvent at a temperature between 20 e C and 150 e C for a period of time between 3h and 24h to promote the following chemical reaction for the synthesis of the compound of formula (I) R 1 is selected from the group consisting of hydrogen, methyl, benzyl, branched or unbranched alkyl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; Ar 1 is selected from a group consisting of phenyl optionally substituted with one, two, three or four substituents selected from -F, Cl, -Br, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or a five-membered aromatic heterocycle containing one, two, or three nitrogen atoms optionally substituted with one, two, or three groups selected from -F, Cl, -Br, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or a five-membered aromatic heterocycle containing one oxygen or sulfur atom, optionally containing one nitrogen atom and optionally substituted with one, two, or three groups selected from -F, Cl, -Br, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or a six-membered nitrogen-containing aromatic heterocycle containing one, two,three or four nitrogen atoms and optionally substituted with one, two, or three groups selected from -F, Cl, -Br, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or a naphthalene ring optionally substituted with one, two, three, or four substituents selected from -F, Cl, -Br, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or a quinoline ring optionally substituted with one, two, three, or four substituents selected from -F, Cl, -Br, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or an isoquinoline ring optionally substituted with one, two,three or four substituents selected from -F, Cl, -Br, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or an indole ring optionally substituted with one, two, three or four substituents selected from -F, Cl, -Br, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or a condensed aromatic bicycle containing two, three or four nitrogen atoms optionally substituted with one, two, three or four substituents selected from -F, Cl, -Br, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl; X is selected from the group Cl, Br, I, triflate, mesylate, tosylate, nonaflate; and Ar 2 is selected from the group consisting of phenyl, optionally substituted with one, two, three, four or five identical or different substituents, methyl, linear alkyl, branched alkyl, O-alkyl, -CF3, -NO2, F, Cl, Br, CN, or phenyl; h.1) purifying the mixture by means of purification that removes the solvent and means of separation that separates the compound of formula (I) or, alternatively g.2) mixing the N-arylsulfonylhydrazone compound of formula (Vil) with an effective amount of a terminal alkyne compound of formula R 2 -C=CH in the presence of an effective amount of a base and an effective amount of a solvent at a temperature between 20 e C and 150 e C for a period of time between 3h and 24h to promote the following chemical reaction for the synthesis of the compound of formula (II) where, R 1is selected from the group consisting of hydrogen, methyl, benzyl, branched or unbranched alkyl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; R 2 is selected from the group consisting of phenyl optionally substituted with one, two, three or four substituents selected from -F, Cl, -Br, -I, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or a five-membered aromatic heterocycle containing one, two, or three nitrogen atoms optionally substituted with one, two, or three groups selected from -F, Cl, -Br, -I, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or a five-membered aromatic heterocycle containing one oxygen or sulfur atom, optionally containing one nitrogen atom and optionally substituted with one, two, or three groups selected from -F, Cl, -Br, -I, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or a six-membered aromatic heterocycle containing one, two, three, or four nitrogen atoms and optionally substituted with one, two, or three groups selected from -F, Cl, -Br, -I, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2,linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or a naphthalene ring optionally substituted with one, two, three or four substituents selected from -F, Cl, -Br, -I, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or a quinoline ring optionally substituted with one, two, three or four substituents selected from -F, Cl, -Br, -I, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or an isoquinoline ring optionally substituted with one, two, three, or four substituents selected from -F, Cl, -Br, -I, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino,dialkylamino, CO2R, CONH2, CONH-alkyl, or an indole ring optionally substituted with one, two, three or four substituents selected from -F, Cl, -Br, -I, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or a condensed aromatic bicycle containing two, three or four nitrogen atoms optionally substituted with one, two, three or four substituents selected from -F, Cl, -Br, -I, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl; and, Ar 2is selected from the group consisting of phenyl, optionally substituted with one, two, three, four or five equal or different substituents selected from methyl, linear alkyl, branched alkyl, O-alkyl, -CF3, -NO2, F, Cl, Br, CN, phenyl; h.2) purify the mixture by means of purification that remove the solvent and means of separation that separate the compound of formula (II).

6. Method according to claim 5 characterized in that in step e) the organic solvent is a mixture of dichloromethane and methanol, the acid is sulfuric acid and in that the chemical reaction is promoted at a temperature between 40 and 70 e C for a period of time between 1 and 12 hours.

7. Method according to claim 5 characterized in that in step g.1) the mixture is heated to a temperature between 70 e C and 150 e C for a period of time between 3h and 24h.

8. Method according to claim 5 characterized in that in step g.1) the mixture comprises 1 equivalent of N-arylsulfonylhydrazone compound of formula (Vil), from 1 to 5 equivalents of aromatic compound of formula Ar 1 -X, from 0.05 to 0.3 equivalents of catalyst, from 1 to 10 equivalents of base and from 1 to 20 equivalents of water.

9. Method according to claim 5 characterized in that in step g.1) the base is selected from the group containing alkoxides and phenoxides of alkali metals.

10. Method according to the preceding claim characterized in that the base is lithium tert-butoxide.

11. Method according to claim 5 characterized in that in step g.1) the base is selected from the group containing alkali metal hydroxides.

12. Method according to claim 5 characterized in that in step g.1) the base is selected from the group containing alkali metal carbonates.

13. Method according to claim 5 characterized in that in step g.1) the palladium catalyst is generated by adding a palladium compound and a ligand to the reaction medium.

14. Method according to claim 13 characterized in that the palladium compound is [tris-di(benzylidene)acetone]dipalladium(0) and the ligand is 2-dicyclohexylphosphine-2',4',6'- triisopropylbiphenyl (X-Phos).

15. Method according to claim 5 characterized in that in step g.2) the mixture is heated to a temperature between 70 and 150 e C for a period of time between 3h and 24h.

16. Method according to claim 5 characterized in that in step g.2) the base is selected from the group of alkali metal carbonates.

17. Method according to claim 5 for preparing glycyrrhetinic acid derivatives of formula (III) and formula (IV) further comprising the following steps subsequent to step h.2): .2) mix the compound of formula (II) with an effective amount of an acid and an effective amount of a solvent under an inert atmosphere at a temperature between 20 e C and 110 e C for a period of time between 1 and 24 h to promote the following chemical reaction of dissolution and synthesis of the compound of formula (III) and of the compound of formula (IV) where, R 1 is selected from the group consisting of hydrogen, methyl, benzyl, branched or unbranched alkyl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; R 2is selected from the group consisting of phenyl optionally substituted with one, two, three or four substituents selected from -F, Cl, -Br, -I, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or a five-membered aromatic heterocycle containing one, two or three nitrogen atoms optionally substituted with one, two or three groups selected from -F, Cl, -Br, -I, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or an aromatic heterocycle of five members containing an oxygen or sulfur atom, optionally containing a nitrogen atom and optionally substituted with one, two or three groups selected from -F, Cl, -Br, -I, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2,-NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or a six-membered aromatic heterocycle containing one, two, three, or four nitrogen atoms and optionally substituted with one, two, or three groups selected from -F, Cl, -Br, -I, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or a naphthalene ring optionally substituted with one, two, three, or four substituents selected from -F, Cl, -Br, -I, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or a quinoline ring optionally substituted with one, two, three, or four substituents selected from -F, Cl, -Br, -I, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl,alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or an isoquinoline ring optionally substituted with one, two, three, or four substituents selected from -F, Cl, -Br, -I, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or an indole ring optionally substituted with one, two, three, or four substituents selected from -F, Cl, -Br, -I, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl, or, a condensed aromatic bicycle containing two, three or four nitrogen atoms optionally substituted with one, two, three or four substituents selected from -F, Cl, -Br, -I, -OH, -O-alkyl, cyano, nitro, -CF3, -OCF3, -OCHF2, linear alkyl, branched alkyl, -NH2, -NH-alkyl, N-dialkyl, alkylamino, dialkylamino, CO2R, CONH2, CONH-alkyl; j.2) purifying the mixture by means of purification that removes the solvent and means of separation that separates the compounds of formula (III) and (IV).

18. Method according to claim 17 characterized in that in step 1.2) the mixture consisting of the compound of formula (II), the acid and the solvent, are kept at room temperature.

19. Method according to claim 17 characterized in that in step 1.2) the acid is boron trifluoride etherate (BF3-OEt2).

20. Method according to claim 5 characterized in that in step e), in step g.1) and in step g.2), Ar2 of the compound with formula (Vil) is 4-tolyl.

21. Method according to claims 5 and 17 characterized in that the purification means and the separation means of any of the stages comprise a liquid-liquid extraction process, solvent evaporation and chromatography.

22. Method according to claim 5 or 17 characterized in that in step g.1), in step g.2) and in step i.2) the solvent is 1,4-dioxane.

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