SGK1-inhibitor compounds and use thereof for the treatment of diseases

Abstract

The present invention relates to a series of compounds with an indazole structural core, which are capable of inhibiting the SGK1 enzyme. Accordingly, the invention also relates to the use of these compounds to treat neurodegenerative and / or cardiovascular diseases involving this enzyme, such as Parkinson's disease, Alzheimer's disease, myocardial infarction or high blood pressure.

Description

[0001] SGK1 INHIBITING COMPOUNDS AND THEIR USE FOR THE TREATMENT OF DISEASES

[0002] The present invention relates to a series of indazole-derived compounds that have the ability to inhibit serum glucocorticoid-induced kinase 1 (SGK1) enzyme, and are therefore useful for the treatment of neurodegenerative and cardiovascular diseases in which this enzyme is involved, such as Parkinson's disease, Alzheimer's disease, myocardial infarction, or hypertension.

[0003] BACKGROUND OF THE INVENTION

[0004] Serum glucocorticoid-induced kinase 1 (SGK1) is a serine / threonine kinase belonging to the AGC kinase family. SGK1 is regulated by serum glucocorticoid levels and is also stimulated by other factors such as DNA damage, oxidative stress, and excessive glucose concentrations, among others. This variety of stimuli promotes the translocation of SGK1 between the cytoplasm and the nucleus, although it is primarily found on the mitochondrial surface, remaining accessible for activation by cytoplasmic kinases.

[0005] SGK1 function is altered in neurodegenerative pathologies such as amyotrophic lateral sclerosis (Lang F et al. J Physiol. 2010 Sep 15;588(Pt 18):3349-54) or Parkinson's disease (Kwon OC et al. EMBO Mol Med. 2021 Apr 9;13(4):e13076). Overexpression of SGK1 has also been observed in the hippocampus of mice, triggering neurodegeneration, cognitive impairment, and increased phosphorylation of the tau protein at the Ser214 epitope, which is highly associated with tauopathies such as Alzheimer's disease (Elahi M et al. Hum Mol Genet. 2021 Aug 28;30(18):1693-1710). These data allow us to consider SGK1 as a possible therapeutic target for different pathological situations, especially in neurodegeneration, a field yet to be explored (see also the following document: Martinez A. et al. Expert Opinion on Therapeutic Targets, 2020, 24:3, 231-243).

[0006] Furthermore, SGK1 also appears to play an important role in cardiovascular diseases, where its activity is associated with oxidative stress and inflammation. Thus, SGK1 regulates endothelial dysfunction, cardiac and vascular remodeling, and water and sodium retention (Lee SG et al. BMC Med 2022, 20:309; Aneesh B et al. JCI Insight. 2022, 7(19):e160885), making it a very attractive therapeutic target for myocardial infarction and systemic and pulmonary hypertension (Rodor J e f a / , Cardiovasc Res, 2022, 118(11):2519-2534; Cai M e f a / . Rev Port Cardiol. 2022, 41(4):271-279). Recently, cardiovascular risk factors have been shown to contribute to the development of neurodegenerative pathologies such as Parkinson's disease, being related to a high risk of coronary pathologies, ischemia and heart failure (Grosu L et al. Biomed Rep. 2023, 18(3):25).

[0007] Some prior art documents disclose SGK1 inhibitor compounds as potential neuroprotective agents, as is the case in the document: Maestro I et al. J Enzyme Inhib Med Chem. 2023; 38(1): 2153841. The documents Geldenhuys, WJ et al. Bioorganic & Medicinal Chemistry Letters, 22(17), 5675-5678 and US2013102586A1 also disclose kinase inhibitors for use in the treatment of neurodegenerative diseases.

[0008] However, to date, SGK1 has been studied primarily in other pathological contexts such as cancer or chronic diseases, and its inhibitors have shown poor permeability to the blood-brain barrier (Jang H et al. Front Pharmacol. 2022 Nov 15; 13: 1036844). Only compounds that modulate SGK1 activity while remaining permeable to the blood-brain barrier will have the potential to represent a good therapeutic option for the treatment of neurodegenerative diseases.

[0009] Given the increasing incidence of neurodegenerative and cardiovascular diseases due to increased life expectancy in today's society, the search for treatments for these diseases has become a priority. Since there is a need for advantageous therapeutic agents, the design and synthesis of SGK1-selective molecules capable of penetrating the central nervous system (CNS) for the treatment of neurodegenerative and cardiovascular diseases, such as those proposed in the present invention, is of vital importance.

[0010] DESCRIPTION OF THE INVENTION

[0011] The present invention relates to compounds with an indazole core structure, hereinafter referred to as the compounds of the invention, and to their use. These compounds exhibit activity as selective inhibitors of SGK1, a kinase involved in signaling pathways that are impaired in neurodegenerative and cardiovascular diseases. Furthermore, the compounds of the present invention have the ability to cross the blood-brain barrier (BBB), as will be demonstrated in the examples provided.

[0012] Therefore, in a first aspect, the present invention relates to a compound of formula (I): or a pharmaceutically acceptable salt thereof, where

[0013] X is selected from N and CH,

[0014] R1 is selected from H and optionally substituted C1-C4 alkyl,

[0015] R2 is selected from aryl and heteroaryl, optionally substituted,

[0016] R3 is selected from H and halogen, and where the compound is not the following:

[0017] In a preferred embodiment, X is CH.

[0018] In a preferred embodiment, Ri is H.

[0019] In another preferred embodiment, Ri is an unsubstituted C1-C4 alkyl or one substituted with at least one group selected from: halogen, -OH, -COOH, -COOR, -NH2, -NHR, or -NRR', R and R' being independently C1-C4 alkyl, and combinations thereof. More preferably, R1 is a C1-C4 alkyl substituted with an amino group, whether a primary, secondary, or tertiary amino group, and, even more preferably, with an -N(CH3)2 group. In another preferred embodiment, R2 is selected from aryl and heteroaryl groups optionally substituted with at least one group selected from: halogen, -NO2, C1-C4 alkyl, -NH2, -CN, -OH, -COOH, -COOR, R being a C1-C4 alkyl, and combinations thereof. More preferably, R2 is selected from aryl and heteroaryl optionally substituted by at least one group selected from: halogen, -NO2, C1-C4 alkyl, and combinations thereof.

[0020] In another preferred embodiment, R2 is an unsubstituted phenyl or a substituted phenyl. More preferably, R2 is a phenyl substituted by at least one substituent selected from: halogen, NO2, C1-C4 alkyl, and combinations thereof.

[0021] In another preferred embodiment, R2 is an unsubstituted heteroaryl radical or one preferably substituted with at least one halogen, NO2, C1-C4 alkyl, or combinations thereof. In a more preferred embodiment, the heteroaryl (substituted or unsubstituted) is selected from furyl, naphthyl, and pyridyl.

[0022] In a preferred embodiment, Rses H.

[0023] In another preferred embodiment, Rs is a halogen, more preferably Cl.

[0024] In another preferred embodiment, the compound of formula (I) is selected from the following list:

[0025] A second aspect of the invention relates to the compound of formula (I) indicated above, or to a pharmaceutically acceptable salt thereof, where X, Ri, R2, and R3 are as defined in the first aspect of the invention, for use as a medicament. Another aspect of the invention relates to the compound of formula (I) indicated above, or to a pharmaceutically acceptable salt thereof, where X, Ri, R2, and R3 are as defined in the first aspect of the invention, for use in the treatment and / or prevention of neurodegenerative or cardiovascular diseases.

[0026] Cardiovascular diseases are all those diseases that affect the heart and / or blood vessels. Cardiovascular diseases also include heart disease, which affects the heart but not the blood vessels; and diseases that affect the blood vessels exclusively, such as aneurysms, arteritis, stenosis, sclerosis, vagal congestion, atherosclerosis, thromboembolism, etc. They can have a congenital, hypertensive, ischemic, or inflammatory origin.Among cardiovascular diseases we can name stroke, pulmonary thromboembolism, coronary infarction (Acute Myocardial Infarction), coronary artery disease (coronary heart disease or ischemic heart disease), heart failure, hypertensive heart disease, cardiomyopathy, heart rhythm disorders (both tachyarrhythmias and bradyarrhythmias, both supraventilator and ventilator, including disorders of genetic origin such as long QT syndrome), congenital heart disease, valvular heart disease (including that caused by bacteria, such as streptococci), aneurysms (of the aorta, abdominal, cerebral, etc.) and pseudoaneurysms, Marfan syndrome, peripheral vascular disease and atherosclerosis.

[0027] In a preferred embodiment of the use of the compound of formula (I), the neurodegenerative disease is selected from Alzheimer's disease, Parkinson's disease, Pick's disease, progressive supranuclear palsy, corticobasal degeneration, frontotemporal dementia, chromosome 17-linked parkinsonism, argyrophilic dementia, post-encephalitic parkinsonism, primary age-related tauopathy, and Lewy body dementia.

[0028] In a more preferred embodiment of the use of the compound of formula (I), the neurodegenerative disease is Parkinson's disease.

[0029] In another more preferred embodiment of the use of the compound of formula (I), the neurodegenerative disease is Alzheimer's disease. In a preferred embodiment of the use of the compound of formula (I), the cardiovascular disease is selected from stroke, myocardial infarction, pulmonary hypertension, systemic hypertension, long QT syndrome, and ventricular arrhythmia. More preferably, the cardiovascular disease is selected from myocardial infarction, pulmonary hypertension, and systemic hypertension.

[0030] Another aspect of the invention relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein X, Ri, R2 and R3 are as defined in the first aspect of the invention, and, optionally, pharmaceutically acceptable excipients, adjuvants and / or vehicles.

[0031] In a preferred embodiment, said pharmaceutical composition further comprises another active ingredient.

[0032] The compounds described in the present invention, their pharmaceutically acceptable salts, and the pharmaceutical compositions containing them can be used in conjunction with other drugs to provide combination therapy. These additional drugs may form part of the same pharmaceutical composition or, alternatively, may be provided as a separate composition for administration, whether or not concurrent with the pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof.

[0033] Another aspect of the invention relates to a method of treating and / or preventing neurodegenerative and / or cardiovascular diseases comprising administering to a subject a therapeutically effective amount of a compound of formula (I) as described in the first aspect of the present invention.

[0034] A final aspect of the present invention relates to the use of a compound of formula (I) as described in the first aspect of the present invention for the preparation of a medicament for use in the treatment and / or prevention of neurodegenerative and / or cardiovascular diseases.

[0035] The compounds of the invention, in their therapeutic use or as part of a pharmaceutical composition, may be in crystalline form as free compounds or as solvates, and it is intended that both forms are within the scope of the present invention. In this sense, the term “solvate,” as used herein, includes both pharmaceutically acceptable solvates, i.e., solvates of the compound of formula (I) that may be used in the preparation of a medicament, and pharmaceutically unacceptable solvates, which may be useful in the preparation of pharmaceutically acceptable solvates or salts. In one particular embodiment, the solvate is a hydrate. The solvates may be obtained by conventional solvation methods well known to those skilled in the art.

[0036] The present invention encompasses all isomers of compounds of formula (I), that is, all geometric, tautomeric, and optical forms, and mixtures thereof (e.g., racemic mixtures). When there are more than one chiral center in the compounds, the present invention includes within its scope all possible diastereomers, including mixtures thereof. The different isomeric forms can be separated or resolved from one another by conventional methods, or any given isomer can be obtained by conventional synthetic methods or by stereospecific, stereoselective, or asymmetric synthesis.

[0037] The compounds of formula (I) for therapeutic use or as part of a pharmaceutical composition are prepared in solid form or aqueous suspension in a pharmaceutically acceptable diluent. These preparations may be administered by any appropriate route of administration, for which purpose the preparation shall be formulated in the pharmaceutical form suitable for the chosen route of administration. In one particular embodiment, the administration of the compound of formula (I) provided by this invention is effected orally, topically, rectally, or parenterally (including subcutaneous, intraperitoneal, intradermal, intramuscular, intravenous, etc.). The various pharmaceutical forms for administering medications and the excipients necessary for obtaining them are widely known to those skilled in the art.

[0038] Unless otherwise stated, the compounds of the invention also include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having such a structure, except for the substitution of a hydrogen atom by a deuterium or tritium atom, or the substitution of a carbon atom by a carbon atom enriched in 13 Co 14 C or a nitrogen enriched in 15 N, are within the scope of this invention. Definitions:

[0039] In the present invention, the term “C1-C4 alkyl” refers to an aliphatic chain radical, linear or branched, having from 1 to 6 carbon atoms, preferably between 1 and 4 carbon atoms such as, for example, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, tere-butyl, sec-butyl, n-pentyl, n-hexyl.

[0040] The term “halogen” refers, in the present invention, to fluorine, bromine, chlorine or iodine.

[0041] The term “aryl” in the present invention refers to an aromatic carbocyclic chain, having from 6 to 12 carbon atoms, which may be a single or multiple ring, in the latter case with separate and / or fused rings. A non-limiting example of an aryl group is a phenyl group.

[0042] The term “heteroaryl” refers to an aromatic carbocyclic chain radical with 5 to 10 members in which at least one carbon atom of the ring or rings has been replaced by a heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur. The heteroaryl may be a monocyclic or bicyclic ring system, which may include fused ring systems. Examples of heteroaryl radicals include, but are not limited to, imidazole, pyrrole, pyridine, pyridazine, piperidine, pyrazine, quinoline, indole, thiophene, furan, oxazole, and pyrazole.

[0043] The term “treatment or prevention” as used herein, unless otherwise indicated, means to reverse, alleviate, inhibit the progression of, or prevent the disorder or condition to which it applies in such terms, or one or more symptoms of such disorder or condition.

[0044] The term “excipients, adjuvants, and / or vehicles” refers to molecular entities or substances with which the active ingredient is administered. Such excipients, adjuvants, or pharmaceutical vehicles may be sterile liquids, such as water and oils, including petroleum-based or those of animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and similar substances; excipients; disintegrants; wetting agents; or diluents. Suitable pharmaceutical excipients and vehicles are described in “Remington’s Pharmaceutical Sciences” by EW Martin.

[0045] The term “therapeutically effective amount” means the amount of a compound needed to be effective in treating or preventing a disease, disorder, or condition.

[0046] Throughout the description and claims, the word "comprises" and its variations are not intended to exclude other technical features, additives, components, or steps. For those skilled in the art, other objects, advantages, and features of the invention will become apparent partly from the description and partly from the practice of the invention. The following examples and figures are provided for illustrative purposes and are not intended to limit the scope of the present invention.

[0047] BRIEF DESCRIPTION OF THE FIGURES

[0048] Figure 1: Neuroprotection of SGK1 inhibitor compounds against okadaic acid (OA). Viability was normalized to control data. GSK650394, a commercial SGK1 inhibitor, was used as a control at 10 pM. All compounds were tested at 5 pM except for compound 41, which was used at 1 pM. #, OA vs. Control; *, OA vs. OA + compound. *, p < 0.05; **, p < 0.01; ***, p < 0.001; ****, p < 0.0001. The mean of 6 independent experiments is shown along with the standard error of the mean.

[0049] Figure 2: In vivo study of an SGK1 inhibitor. Experimental design based on stereotactic administration of an rAAV9-a-SYN viral vector m(Fig 2A); results of the motor asymmetry assay based on the elevated body swing test (Fig 2B); immunohistochemistry against anti-tyrosine hydroxylase (TH), to assess the loss of dopaminergic neuronal (DAergic) cell bodies in the Substantia Nigra (Fig 2C); stereological count of TH neuronal loss (Fig 2D); Th mRNA levels, by qPCR (Fig 2E).

[0050] Figure 3. Quantification of tau levels in the SH-SY5Y cell line in the presence of SGK1 inhibitors. A) Total tau levels. B) p-Ser396 tau levels. C) p-Ser396 tau levels normalized to total tau levels. D) p-Ser214 tau levels normalized to the loading control. E) Representative immunoblot from the Western blot experiments. Tideglusib and GSK (GSK650394) at 10 pM were used as positive controls. Inhibitors were evaluated at 5 pM except for compound 41 (1 pM). n > 3 biological replicates. Statistical significance was calculated using ANOVA with Dunnett's post-hoc correction. * p-value < 0.05, ** p-value < 0.01, *** p-value < 0.001, **** p-value < 0.0001. ns: no significant differences.

[0051] Figure 4. In vivo and in vitro study of the protective role of SGK1 inhibitors on the pulmonary endothelium and inflammation. (A) Experimental design based on intratracheal administration of LPS; (B) results of neutrophil infiltrate analysis (Ly6G+ tide) by flow cytometry in bronchoalveolar lavage (BAL) and by western blot in lung lysate; (C) results of VCAM-1 expression analysis in lung lysate; (D) results of the in vitro assay of VCAM-1 expression in human pulmonary arterial endothelial cells (HPAEC) by fluorescence microscopy. Data are represented as mean ± standard error of the mean. *p<0.05, **p<0.01, ***p<0.001, and ****p<0.0001 were analyzed using one-way ANOVA adjusted with Fisher's LSD multiple comparisons method.

[0052] Figure 5. A) Schematic of the experimental protocol used in an angiotensin II-induced hypertension model with subcutaneous pumps. The drugs were administered intraperitoneally (ip) one day before subcutaneous implantation of the angiotensin II mini-pumps. B) Effect of compounds 41 and 54 on systolic blood pressure values ​​in control mice or mice infused with angiotensin II (1.44 mg / kg / day, 14 days). C) Effect of compounds 41 and 54 on acetylcholine-induced relaxation values ​​in phenylephrine-precontracted aortic segments from control mice or mice infused with angiotensin II (1.44 mg / kg / day, 14 days). *P<0.05 vs. control, +P<0.05 vs. angiotensin II, by two-way ANOVA and Bonferroni post-test. Number of mice: control: 9; control + 41 : 6; control+54:6; angiotensin II: 9; angiotensin 11 + 41 : 9; angiotensin II + 54:9.

[0053] EXAMPLES

[0054] The invention will then be illustrated by means of tests carried out by the inventors, which demonstrate the effectiveness of the product of the invention.

[0055] Example 1. Synthesis of A / -(1H-indazol-5-yl)-4-phenyl-1H-pyrrole-3-carboxamide derivatives (36-49)

[0056] 24-35 36-49

[0057] General procedure for the synthesis of methyl (E)-3-phenylacrylate derivatives (1-11)

[0058] The corresponding (E)-3-phenylacrylic acid (1 equiv) is dissolved in methanol (MeOH) (2 mL / mmol). Immediately afterward, at room temperature, trimethylsilyl chloride (TMSCI) (2.2 equiv) is added dropwise. The reaction is allowed to continue stirring for 24 hours at room temperature. The MeOH is evaporated under reduced pressure, and the resulting crude solution is dissolved in ethyl acetate (EtAc) (2 mL / mmol). The solution is washed with water (2 mL / mmol x 3), the organic phase is dried over anhydrous sodium sulfate, filtered, and finally evaporated under reduced pressure, yielding the corresponding (E)-3-phenylacrylate.

[0059] (E)-3-(2-Bromophenyl)methyl acrylate (1).

[0060] (E)-3-(2-bromophenyl)acrylic acid (13.2 mmol, 3.0 g) and TMSCI (29.1 mmol, 3.7 mL) were used, obtaining (E)-3-(2-bromophenyl)methyl acrylate as a brown oil (2.973 g, Rto = 93%).

[0061] 1H NMR (300 MHz, DMSO-cfe) 5 7.94 (dd, J = 7.5, 1.8 Hz, 1 H), 7.89 (d, J = 15.7 Hz, 1 H), 7.72 (dd, J = 8.0, 1.3 Hz, 1 H), t 0.6 Hz, 1 H), 7.37 (td, J = 7.7, 1.9 Hz, 1 H), 6.69 (d, J = 15.9 Hz, 1 H), 3.75 (s, 3H). 13 C NMR (75 MHz, DMSO-cfe) 5 166.2, 141.9, 133.3, 133.2, 132.1 , 128.5, 128.3, 124.6, 121.0, 51.7. HPLC-MS [M + H] + = 240.9, T R = 3.90 (95%).

[0062] (E)-3-(3-Bromophenyl)methyl acrylate (2).

[0063] (E)-3-(3-bromophenyl)acrylic acid (13.2 mmol, 3.0 g) and TMSCI (29.1 mmol, 3.7 ml_) were used, obtaining (E)-3-(3-bromophenyl)methyl acrylate as a white solid (2.61 g, 82% yield).

[0064] 1 H NMR (300 MHz, DMSO-cfe) 5 7.98 (t, J = 1.7 Hz, 1 H), 7.74 (d, J = 7.8 Hz, 1 H), 7.64 (d, J = 16.1 Hz, 1 H), 7.61 (ddd, J = 7.9, 1 Hz, 1 Hz). 7.38 (t, J = 7.8 Hz, 1 H), 6.73 (d, J = 16.1 Hz, 1 H), 3.73 (s, 3H). 13C MRI (75 MHz, DMSO-cfe) 5 166.4, 142.9, 136.5, 133.0, 130.9, 130.8, 127.3, 122.3, 119.5, 51.6. HPLC-MS [M + H] + = 241.0, TR = 3.90 (99%).

[0065] (E)-3-(4-Bromophenyl)methylacrylate (3).

[0066] If you use (E)-3-(4-bromophenyl)acrylic acid (13.2 mmol, 3.0 g) and TMSCI (29.1 mmol, 3.7 mL), obtain methyl (E)-3-(4-bromophenyl)acrylate as a white solid (2.456 g, Rto = 77%).

[0067] 1 H NMR (300 MHz, DMSO-cfe) 5 7.69 (d, J = 8.5 Hz, 2H), 7.64 (d, J = 16.4 Hz, 2H), 7.62 (d, J = 8.6 Hz, 2H), 6.69 (d, J = 16.1 Hz, 1 H), 3.73 (s, 3H). 13 C NMR (75 MHz, DMSO- cfe) 5 166.5, 143.2, 133.3, 131.9, 130.3, 123.8, 118.7, 51.5. HPLC-MS [M + H] + = 241.0, TR = 3.92 (99%).

[0068] (E)-3-(2-Chlorophenyl)methylacrylate (4).

[0069] (E)-3-(2-chlorophenyl)acrylic acid (16.4 mmol, 3.0 g) and TMSCI (36.4 mmol, 4.6 mL) were used, obtaining (E)-3-(2-chlorophenyl)methyl acrylate as a white solid (3.001 g, Rto = 92%).

[0070] 1 H NMR (300 MHz, DMSO-cfe) 5 7.95 (dd, J = 7.5, 1.9 Hz, 1 H), 7.92 (d, J = 16.0 Hz, 1 H), 7.55 (dd, J = 7.9, 1.5 Hz, 1 H), 7.45 (td, J = 7.6, 2.0 Hz, 1 H), 7.40 (td, J = 7.4, 1.4 Hz, 1 H), 6.69 (s, 1 H), 3.75 (s, 3H). 13 C NMR (75 MHz, DMSO-cfe) 5 166.3, 139.2, 133.7, 131.9, 131.6, 130.0, 128.3, 127.8, 120.9, 51.7. HPLC-MS [M+H] + = 197.1 , TR = 3.84 (99%).

[0071] (E)-3-(4-Chlorophenyl)methyl acrylate (5).

[0072] (E)-3-(4-chlorophenyl)acrylic acid (27.4 mmol, 5.0 g) and TMSCI (60.2 mmol, 7.6 mL) were used, obtaining (E)-3-(4-chlorophenyl)methyl acrylate as a white solid (4.600 g, Rto = 85%).

[0073] 1H NMR (300 MHz, DMSO-cfe) 5 7.76 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 16.0 Hz, 1 H), 7.48 (d, J = 8.4 Hz, 2H), 6.67 (d, J = 16.0 Hz, 3.3 Hz). 3H). 13 C NMR (75 MHz, DMSO- cfe) 5 166.5, 143.1 , 135.0, 133.0, 130.1 , 128.9, 118.7, 51.5. HPLC-MS [M + H] + = 197.1 , TR = 3.90 (99%).

[0074] (E)-3-(4-Fluorophenyl)methyl acrylate (6). (E)-3-(4-fluorophenyl)acrylic acid (9.15 mmol, 1.5 g) and TMSCI (20.1 mmol, 2.6 mL) were used, yielding methyl (E)-3-(4-fluorophenyl)acrylate as a white solid (1.40 g, R to 8%).

[0075] 1 H NMR (300 MHz, DMSO-cfe) 5 7.81 (dd, J = 8.5, 5.5 Hz, 2H), 7.67 (d, J = 16.1 Hz, 1 H), 7.26 (t, J= 8.8 Hz, 2H), 6.62 (d, J= 16.1 Hz, 3.1 Hz). (s, 3H). 13 C NMR (75 MHz, DMSO- cfe) 5 166.6, 163.3 (d, J = 250.3 Hz), 143.3, 130.9, 130.7 (d, J = 7.1 Hz), 117.7, 115.9 (d, J = 2.6 ), 15.5 Hz. HPLC-MS [M + H] + = 181.1 , T R = 3.60 (99%).

[0076] (E)methyl-3-(4-Nitrophenyl)acrylate (7).

[0077] (E)-3-(4-nitrophenyl)acrylic acid (5.17 mmol, 1.0 g) and TMSCI (11.39 mmol, 1.5 mL) were used, obtaining (E)-3-(4-nitrophenyl)methyl chloride as a yellowish solid (0.520 g, Rto = 49%).

[0078] 1 H NMR (300 MHz, DMSO-cfe) 5 8.24 (d, J = 8.9 Hz, 2H), 8.01 (d, J = 8.7 Hz, 2H), 7.78 (d, J = 16.1 Hz, 1 H), 6.87 (d, J = 16.1 Hz, 1 H), 3.76 (s, 3H). 13 C NMR (75 MHz, DMSO-d6) 5 166.2, 148.1, 142.0, 140.4, 129.5, 123.9, 122.1, 51.8. HPLC-MS [M+H] + = 208.1 , TR = 3.51 (97%).

[0079] (E)methyl-3-(4-lsopropylphenyl)acrylate (8).

[0080] (E)-3-(4-isopropylphenyl)acrylic acid (5.26 mmol, 1.0 g) and TMSCI (11.56 mmol, 1.5 mL) were used, obtaining (E)-3-(4-isopropylphenyl)methyl acrylate as a white solid (1.040 g, Rto = 97%).

[0081] 1H NMR (300 MHz, DMSO-cfe) 5 7.63 (d, J = 16.0 Hz, 1 H), 7.63 (d, J = 8.3 Hz, 2H), 7.29 (d, J = 8.3 Hz, 2H), 6.58 (d, J = 16.0 Hz, 3.2 Hz), 7.2 Hz. 3H), 2.91 (hept, J = 6.9 Hz, 1 H), 1.20 (d, J = 6.9 Hz, 6H). 13 C NMR (75 MHz, DMSO-cfe) 5 166.8, 151.2, 144.5, 131.7, 128.5, 126.9, 116.8, 51.4, 33.4, 23.6. HPLC-MS [M + H] + = 205.1 , TR = 4.18 (99%).

[0082] (E)-3-(p-Tolyl)methyl acrylate (9).

[0083] (E)-3-(p-tolyl)acrylic acid (12.3 mmol, 2.0 g) and TMSCI (27.1 mmol, 3.4 mL) were used, yielding methyl (E)-3-(p-tolyl)acrylate as a white solid (2,033 g, yield = 4%). 1 H NMR (300 MHz, DMSO-cfe) 5 7.63 (d, J = 16.3 Hz, 1 H), 7.60 (d, J = 8.2 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 6.57 (d, J = 16.1 Hz, 1 Hz, 3.1 Hz). 3H), 2.33 (s, 3H). 13 C NMR (75 MHz, DMSO-cfe) 5 166.8, 144.5, 140.5, 131.3, 129.5, 128.4, 116.7, 51.4, 21.0. HPLC- MS [M + H] + = 177.1 , T R = 3.81 (99%).

[0084] (E)-3-(2,4-Dimethylphenyl)methyl acrylate (10).

[0085] (E)-3-(2,4-dimethylphenyl)acrylic acid (5.5 mmol, 1.0 g) and TMSCI (12.5 mmol, 1 .6 m L) were used, obtaining (E)-3-(2,4-dimethylphenyl)acrylic acrylic acid as a (1.14 g) brown acetic acid. Rto = 94%).

[0086] 1 H NMR (300 MHz, DMSO-cfe) 5 7.83 (d, J = 16.0 Hz, 1 H), 7.62 (d, J = 7.8 Hz, 1 H), 7.08 (s, 1 H), 7.05 (d, J = 8.1 Hz, 1 H), J H), 3.72 (s, 3H), 2.35 (s, 3H), 2.28 (s, 3H). 13 C NMR (75 MHz, DMSO-cfe) 5 167.2, 142.1 , 140.6, 137.8, 131.9, 130.3, 127.6, 127.0, 118.1 , 51.9, 21.3, 19.7. HPLC-MS [M + H] + = 191.2, T R = 4.00 (88%).

[0087] (E)-3-(3,4-Dichlorophenyl)methyl acrylate (11).

[0088] (E)-3-(3,4-dimeth¡lphen¡l)acrylic acid (9.2 mmol, 2.0 g) and TMSCI (20.3 mmol,

[0089] 2.6 mL), obtaining methyl (E)-3-(3,4-dichlorophenyl)achlate as a white solid (1.824 g, Rto = 86%).

[0090] 1 H NMR (300 MHz, DMSO-cfe) 5 8.07 (d, J = 2.0 Hz, 1 H), 7.74 (dd, J = 8.5, 1.9 Hz, 1 H), 7.68 (d, J = 8.4 Hz, 1 H), 7.64 (d, J = 16.1 Hz, 1 H), 6.77 (d, J = 16.2 Hz, 1H), 3.73 (s, 3H). 13 C NMR (75 MHz, DMSO-cfe) 5 166.3, 141.9, 134.9, 132.7, 131.8, 131.0, 130.1, 128.3, 120.1, 51.6. HPLC-MS [M+H] + = 231.0, TR = 4.08 (99%).

[0091] General procedure for the synthesis of methyl 4-(phenyl)-1H-pyrrole-3-carboxylate derivatives (12-23)

[0092] A mixture of 1-((isocyanomethyl)sulfonyl)-4-methylbenzene (TosMic) (1.1 equiv) and the corresponding (E)-3-methyl acrylate (1.0 equiv) is dissolved in anhydrous dimethylformamide (DMF) (1.5 mL / mmol) under an argon atmosphere. The solution is added dropwise to a mixture of sodium hydride (NaH) (3 equiv, 60% dispersion) in anhydrous DMF (3.3 mL / mmol) at 0 °C. After the addition, the reaction is stirred for 1 hour at room temperature, then 2 mL of water are added, the mixture is diluted in EtAc (2 mL / mmol), and vigorously washed with a mixture of water and NaCl-saturated water (1:1, 2 mL / mmol x 5) to remove the DMF. Finally, the organic phase is dried over anhydrous sodium sulfate, filtered and vacuum evaporated, yielding the corresponding methyl 4-phenyl-1 / 7-pyrrole-3-carboxylate.

[0093] 4-Phenyl-1H-pyrrole-3-methyl carboxylate (12).

[0094] TosMic (10.2 mmol, 2.0 g), methyl (E)-3-phenylcarboxylate (9.2 mmol, 1.5 g) and NaH (27.8 mmol, 1.1 g) were used, obtaining methyl 4-phenyl-1 / 7-pyrrole-3-carboxylate as a brown solid (1.369 g, Rto = 74%).

[0095] 1 H NMR (300 MHz, DMSO-cfe) 5 11.55 (s, 1 H), 7.49 (dd, J = 3.1, 2.2 Hz, 1 H), 7.44 (dd, J = 8.3, 1.3 Hz, 2H), 7.30 (t, J = 7.3 Hz, 2H), 7.24 - 7.18 (m, 1H), 6.94 (t, J = 2.4 Hz, 1H), 3.63 (s, 3H). 13 C NMR (75 MHz, DMSO-cfe) 5 164.5, 135.0, 128.8, 127.6, 125.9, 125.8, 125.2, 119.1, 111.6, 50.4. HPLC-MS [M+H] + = 202.1 , T R = 3.23 (99%).

[0096] 4-(2-Bromophenyl)-1H-pyrrole-3-methyl carboxylate (13).

[0097] TosMic (4.6 mmol, 0.9 g), methyl (E)-3-(2-bromophenyl)carboxylate (1) (4.1 mmol, 1.0 g) and NaH (12.4 mmol, 0.5 g) were used, obtaining methyl 4-(2-bromophenyl)-1 / 7-pyrrole-3-carboxylate as a brown solid (0.846 g, Rto = 73%).

[0098] 1 H NMR (300 MHz, DMSO-cfe) 5 11.55 (s, 1 H), 7.61 (dd, J = 7.9, 0.9 Hz, 1 H), 7.46 (dd, J = 3.1 , 2.2 Hz, 1 H), 7.36 - 7.25 (m, dd, J = 7.20). 8.0, 7.0, 2.3 Hz, 1 H), 6.83 (t, J = 2.4 Hz, 1 H), 3.54 (s, 3H). 13 C NMR (75 MHz, DMSO-cfe) 5 164.1 , 136.8, 132.1 , 131.9, 128.3, 126.8, 124.5, 124.3, 123.7, 119.4, 113.4, 50.3. HPLC-MS [M + H] + = 280.0, TR = 3.34 (99%).

[0099] 4-(3-Bromophenyl)-1H-pyrrole-3-methyl carboxylate (14).

[0100] TosMic (4.6 mmol, 0.9 g), (E)-3-(3-bromophenyl)methyl carboxylate (2) (4.1 mmol, 1.0 g) and NaH (12.4 mmol, 0.5 g) were used, obtaining the 4-(3-bromophenyl)-1 / 7-pyrroboxyl-carboxylic acid as brown methanol (0.836 g, Rto = 72%).

[0101] 1H NMR (300 MHz, DMSO-cfe) 5 11.66 (s, 1 H), 7.67 (t, J = 1.8 Hz, 1 H), 7.51 (t, J = 2.6 Hz, 1 H), 7.45 (dt, J = 7.6, 1.3 Hz, 1 Hz, 7.4 Hz), ddd = 1 Hz. 8.0, 2.0, 1.1 Hz, 1 H), 7.27 (t, J = 7.9 Hz, 1 H), 7.05 (t, J = 2.3 Hz, 1 H), 3.65 (s, 3H). 13 C NMR (75 MHz, DMSO-cfe) 5 164.4, 137.5, 131.2, 129.7, 128.5, 127.7, 126.3, 123.5, 120.9, 119.9, 111.5, 50.5. HPLC-MS [M + H] + = 280.0, TR = 3.53 (98%).

[0102] 4-(4-Bromophenyl)-1H-pyrrole-3-methyl carboxylate (15).

[0103] TosMic (4.6 mmol, 0.9 g), (E)-3-(4-bromophenyl)methyl (3) carboxylate (4.1 mmol, 1.0 g) and NaH (12.4 mmol, 0.5 g) were used, obtaining the 4-(4-bromophenyl)-1 / 7-carboxyl-carboxylic acid as brown methanol (0.783 g, Rto = 67%).

[0104] 1H NMR (300 MHz, DMSO-cfe) 5 11.66 (s, 1 H), 7.67 (t, J = 1.8 Hz, 1 H), 7.51 (t, J = 2.6 Hz, 1 H), 7.45 (dt, J = 7.6, 1.3 Hz, 1 Hz, 7.4 Hz), ddd = 1 Hz. 8.0, 2.0, 1.1 Hz, 1 H), 7.27 (t, J = 7.9 Hz, 1 H), 7.05 (t, J = 2.3 Hz, 1 H), 3.65 (s, 3H). 13 C NMR (75 MHz, DMSO-cfe) 5 164.4, 137.5, 131.2, 129.7, 128.5, 127.7, 126.3, 123.5, 120.9, 119.9, 111.5, 50.5. HPLC-MS [M + H] + = 280.0, TR = 3.55 (98%).

[0105] 4-(2-Chlorophenyl)-1H-pyrrole-3-methyl carboxylate (16).

[0106] TosMic (16.8 mmol, 3.2 g), (E)-3-(2-chlorophenyl)methyl carboxylate (4) (15.2 mmol, 3.0 g) and NaH (45.7 mmol, 1.8 g) were used, obtaining the 4-(2-chlorophenyl)-pyrrolyl-carboxylate / 37-like methyl brown solid (2,500 g, Rto = 70%). 1 H NMR (300 MHz, DMSO-cfe) 5 11.57 (s, 1 H), 7.47 (dd, J = 3.1 , 2.1 Hz, 1 H), 7.45 - 7.40 (m, 1 H), 7.31 - 7.27 (m, 3Hz), 6.27 (m, 3Hz, 2.4 Hz), (2.4 Hz). H), 3.55 (s, 3H). 13C NMR (75 MHz, DMSO-cfe) 5 164.2, 134.7, 133.4, 132.1, 128.8, 128.1, 126.3, 124.4, 121.8, 119.6, 113.5,

[0107] 50.4. HPLC-MS [M + H] + = 236.0, TR = 3.31 (93%).

[0108] 4-(4-Chlorophenyl)-1H-pyrrole-3-methyl carboxylate (17).

[0109] TosMic (11.2 mmol, 2.2 g), methyl (E)-3-(4-chlorophenyl)carboxylate (5) (10.2 mmol, 2.0 g) and NaH (30.5 mmol, 1.2 g) were used, obtaining methyl 4-(4-chlorophenyl)-1 / 7-pyrrole-3-carboxylate as a brown solid (1.830 g, Rto = 76%).

[0110] 1 H NMR (300 MHz, DMSO-cfe) 5 11.61 (s, 1 H), 7.50 (dd, J = 3.1, 2.2 Hz, 1 H), 7.46 (d, J = 8.7 Hz, 2H), 7.35 (d, J = 8.8 Hz, 2H), 6.99 (t, J = 2.4 Hz, 1 H), 3.64 (s, 3H). 13 C NMR (75 MHz, DMSO-cfe) 5 164.4, 133.9, 130.5, 130.5, 127.5, 126.2, 123.8, 119.5, 111.5,

[0111] 50.5. HPLC-MS [M + H] + = 236.0, TR = 3.49 (99%).

[0112] 4-(4-Fluorophenyl)-1H-pyrrole-3-methyl carboxylate (18).

[0113] TosMic (8.7 mmol, 1.7 g), methyl (E)-3-(4-fluorophenyl)carboxylate (6) (7.9 mmol, 1.4 g) and NaH (23.8 mmol, 0.9 g) were used, obtaining methyl 4-(4-fluorophenyl)-1 / 7-pyrrole-3-carboxylate as a brown solid (1.469 g, Rto = 85%).

[0114] 1 H NMR (300 MHz, DMSO-cfe) 5 11.57 (s, 1 H), 7.51 - 7.42 (m, 3H), 7.12 (t, J = 9.0 Hz, 2H), 6.94 (t, J = 2.4 Hz, 1 H), 3.63 (s, 3H). 13 C NMR (75 MHz, DMSO-cfe) 5 164.5, 160.9 (d, J = 242.0 Hz), 131.4 (d, J = 3.1 Hz), 130.6 (d, J = 7.9 Hz), 125.9, 124.1, 119.2, 114.3 (d, J = 21.1 Hz), 111.5, 50.4. HPLC-MS [M+H] + = 220.1 , TR = 3.27 (95%).

[0115] 4-(4-Nitrophenyl)-1H-pyrrole-3-methyl carboxylate (19).

[0116] TosMic (2.8 mmol, 0.5 g), methyl (E)-3-(4-nitrophenyl)carboxylate (7) (2.5 mmol, 0.5 g) and NaH (7.5 mmol, 0.3 g) were used, obtaining methyl 4-(4-nitrophenyl)-1 / 7-pyrrole-3-carboxylate as a brown solid (0.502 g, Rto = 81%).

[0117] 1 H NMR (300 MHz, DMSO-cfe) 5 11.82 (s, 1 H), 8.17 (d, J = 9.0 Hz, 2H), 7.75 (d, J = 9.0 Hz, 2H), 7.58 (dd, J = 3.0, 2.2 Hz, 1 H), 7.22 (t, J = 2.4 Hz, 1 H), 3.67 (s, 3H). 13 C NMR (75 MHz, DMSO-cfe) 5 164.4, 145.3, 142.3, 129.4, 127.0, 123.0, 122.9, 121.1, 111.8, 50.7. HPLC-MS [M+H] + = 247.1 , TR = 3.26 (95%).

[0118] 4-(4-isopropylphenyl)-1H-methyl pyrrole-3-carboxylate (20).

[0119] TosMic (5.6 mmol, 1.0 g), methyl (E)-3-(4-isopropylphenyl)carboxylate (8) (5.09 mmol, 1.0 g) and NaH (15.3 mmol, 0.6 g) were used, obtaining methyl 4-(4-isopropylphenyl)-1 / 7-pyrrole-3-carboxylate as a brown solid (0.910 g, Rto = 74%). 1H NMR (300 MHz, DMSO-cfe) 5 11.51 (s, 1 H), 7.46 (dd, J = 3.1 , 2.2 Hz, 1 H), 7.35 (d, J = 8.3 Hz, 2H), 7.17 (d, J = 8.1 Hz, 2H), 7.17 (d, J = 8.1 Hz, 2.2 Hz). Hz, 1 H), 3.63 (s, 3H), 2.88 (hept, J = 6.9 Hz, 1 H), 1 .22 (d, J = 7.0 Hz, 6H). 13 C NMR (75 MHz, DMSO-cfe) 5 164.5, 145.9,

[0120] 132.5, 128.7, 125.7, 125.5, 125.2, 118.9, 111.5, 50.4, 33.1 , 24.0. HPLC-MS [M + H] + = 244.1 , R t = 3.74 (99%).

[0121] 4-(p-Tolyl)-1H-pyrrole-3-methyl carboxylate (21).

[0122] TosMic (12.5 mmol, 2.4 g), (E)-3-(p-tolyl)methyl carboxylate (9) (11.3 mmol, 2.0 g) and NaH (34.0 mmol, 1.3 g) were used, obtaining the 4-(p-tolyl)-1 H-pyrrol boxyl-3 as methanol brown (2,156 g, Rto = 88%).

[0123] 1 H NMR (300 MHz, DMSO-cfe) 5 11.50 (s, 1 H), 7.46 (dd, J = 3.1 , 2.2 Hz, 1 H), 7.32 (d, J = 8.0 Hz, 2H), 7.10 (d, J = 7.9 Hz, 29.2 Hz), J Hz, 1 H), 3.62 (s, 3H), 2.30 (s, 3H).13 C NMR (75 MHz, DMSO-c) 5 164.5;

[0124] 111.6, 50.4, HPLC-MS [M + H] + = 216.1 , T R = 3.39 (90%).

[0125] Methyl 4-(2,4-Dimethylphenyl)-1H-pyrrole-3-carboxylate (22).

[0126] TosMic (5.8 mmol, 1.1 g), (E)-3-(2,4-dimethylphen¡l)carbox¡late (10) (5.2 mmol, 1.0 g) and NaH (15.8 mmol, 0.6 g) were used, affording 4-(2,4-dimethylphenyl)-1 H-pyrrole-3-1. methyl carboxylate as brown solid (0.810 g, Rto = 67%).

[0127] 1 H NMR (300 MHz, DMSO-cf) 5 11.50 (s, 1 H), 7.47 (dd, J = 3.1 , 2.2 Hz, 1 H), 7.02 - 6.94 (m, 2H), 6.91 (d, J = 7.7 Hz, 1 H), 6.69 (t, J = 2.3 Hz, 1). H), 3.55(s, 3H), 2.27(s, 3H), 2.07(s, 3H). 13 C NMR (75 MHz, DMSO-c) 5 164.4;

[0128] 124.6, 124.2, 118.8, 113.2, 50.2, 20.7, HPLC-MS [M + H] += 230.1 , TR = 3.53 (83%).

[0129] 4-(3,4-Dichlorophenyl)-1H-pyrrole-3-methyl carboxylate (23).

[0130] TosMic (6.5 mmol, 1.4 g), (E)-3-(3,4-dichlorophenyl)methyl carboxylate (11) (7.1 mmol, 1.5 g) and NaH (19.5 mmol, 0.78 g) were used, affording the of methyl as brown solid (0.994 g, Rto = 57%).

[0131] 1 H NMR (300 MHz, DMSO-cfe) 5 11.73 (s, 1 H), 7.74 (d, J = 2.1 Hz, 1 H), 7.55 (d, J = 8.4 Hz, 1 H), 7.52 (dd, J= 3.0, 2.3 Hz, 1 Hz), J = 4, 48, dd. 2.1 Hz, 1 H), 7.11 (t, J = 2.4 Hz, 1 H), 3.66 (s, 3H). 13 C NMR (75 MHz, DMSO-cfe) 5 164.4, 135.8, 130.2, 130.2, 129.6, 128.9, 128.3, 126.5, 122.5, 120.2, 111.5, 50.6. HPLC-MS [M + H] + = 270.0, R t = 3.72 (99%).

[0132] General procedure for the synthesis of 4-phenyl-1H-pyrrole-3-carboxylic acid derivatives (24-35) A mixture of the corresponding methyl 4-phenyl-1 / 7-pyrrole-3-carboxylate (1.0 equiv) and sodium hydroxide (NaOH) (10 equiv) is dissolved in a 1:1 solution of MeOH / water (1.5 mL / mmol). The reaction is heated under reflux for 2 hours. After this time, the mixture is diluted in water (10 mL / mmol), washed with EtAc (1 mL / mmol), and the aqueous phase is acidified with 37% hydrochloric acid (HCl) to a pH of 2-3. The precipitate formed is filtered, yielding the corresponding 4-phenyl-1 / 7-pyrrole-3-carboxylic acid.

[0133] 4-phenyl-1H-pyrrole-3-carboxylic acid (24).

[0134] Methyl 4-phenyl-1 / 7-pyrrole-3-carboxylate (12) (5.0 mmol, 1.0 g) and NaOH (49.7 mmol, 2.0 g) were used, yielding 4-phenyl-1 / 7-pyrrole-3-carboxylic acid as a white solid (0.640 g, Rto = 69%).

[0135] 1H NMR (300 MHz, DMSO-cfe) 5 11.54 (s, 1 H), 11.45 (s, 1 H), 7.51 - 7.41 (m, 3H), 7.29 (t, J = 7.4 Hz, 2H), 7.23 - 7.16 (m, 1 H), 6.91 (t, J = 2.3 Hz, 1 H). 13 C MRI (75 MHz, DMSO-cfe) 5 165.7, 135.3, 128.8, 127.5, 126.0, 125.7, 125.2, 119.0, 112.6. HPLC-MS [M + H] + = 188.1 , TR = 2.74 (99%).

[0136] 4-(2-bromophenyl)-1H-pyrrol-3-carboxylic acid (25).

[0137] If you use 4-(2-bromophenyl)-1 / 7-pyrrol-3-carboxyl methyl (13) (1.79 mmol, 0.5 g) and NaOH (17.9 mmol, 0.7 g), obtain the 4-(2-bromophenyl)-1 / 7-pyrrol-3-carboxyl acid as a white solid (0.270 g, Rto = 57%).

[0138] 1 H NMR (300 MHz, DMSO-cfe) 5 11.43 (s, 2H), 7.59 (dd, J = 7.9, 0.8 Hz, 1 H), 7.40 (dd, J = 3.0, 2.2 Hz, 1 H), 7.34 - 7.25 (m, 2H), 7.18 (ddd, J = 7.9, 6.6, 2.6 Hz, 1 H), 6.78 (t, J = 2.3 Hz, 1 H). 13C NMR (75 MHz, DMSO-cfe) 5 165.2, 137.2, 132.1, 131.8, 128.1, 126.7, 124.6, 124.3, 123.8, 119.2, 114.5. HPLC-MS [M+H] + = 266.0, TR = 2.89 (99%).

[0139] 4-(3-bromophenyl)-1H-pyrrole-3-carboxylic acid (26).

[0140] Methyl 4-(3-bromophenyl)-1 / 7-pyrrole-3-carboxylate (14) (1.79 mmol, 0.5 g) and NaOH (17.9 mmol, 0.7 g) were used, obtaining 4-(3-bromophenyl)-1 / 7-pyrrole-3-carboxylic acid as a yellowish solid (0.302 g, Rto = 64%).

[0141] 1 H NMR (300 MHz, DMSO-cfe) 5 11.67 (s, 1 H), 11.55 (s, 1 H), 7.68 (t, J = 1.7 Hz, 1 H), 7.50 - 7.43 (m, 2H), 7.38 (ddd, J = 8.0, 2.0, 1.1 Hz, 1 H), 7.25 (t, J = 7.9 Hz, 1 H), 7.02 (t, = 2.4 Hz, 1 H). 13 C NMR (75 MHz, DMSO-cfe) 5 165.5, 137.8, 131.2, 129.6, 128.3, 127.8, 126.3, 123.5, 120.9, 119.7, 112.6. HPLC-MS [M+H] + = 265.9, TR = 3.04 (99%).

[0142] 4-(4-Bromophenyl)-1H-pyrrole-3-carboxylic acid (27). Methyl 4-(4-Bromophenyl)-1 / 7-pyrrole-3-carboxylate (15) (1.79 mmol, 0.5 g) and NaOH (17.9 mmol, 0.7 g) were used, obtaining 4-(4-Bromophenyl)-1 / 7-pyrrole-3-carboxylic acid as a yellowish solid (0.343 g, Rto = 72%).

[0143] 1 H NMR (300 MHz, DMSO-cfe) 5 11.67 (s, 1 H), 11.55 (s, 1 H), 7.68 (t, J = 1.7 Hz, 1 H), 7.50 - 7.43 (m, 2H), 7.38 (ddd, J = 8.0, 2.0, 1.1 Hz, 1 H), 7.25 (t, J = 7.9 Hz, 1 H), 7.02 (t, = 2.4 Hz, 1 H). 13 C NMR (75 MHz, DMSO-cfe) 5 165.5, 137.8, 131.2, 129.6, 128.3, 127.8, 126.3, 123.5, 120.9, 119.7, 112.6. HPLC-MS [M+H] + = 266.0, TR = 3.05 (99%).

[0144] 4-(2-chlorophenyl)-1H-pyrrole-3-carboxylic acid (28).

[0145] Methyl 4-(2-chlorophenyl)-1 / 7-pyrrole-3-carboxylate (16) (10.6 mmol, 2.5 g) and NaOH (106.1 mmol, 4.2 g) were used, obtaining 4-(2-chlorophenyl)-1 / 7-pyrrole-3-carboxylic acid as a yellowish solid (1.700 g, Rto = 72%).

[0146] 1 H NMR (300 MHz, DMSO-cfe) 5 11.49 (s, 1 H), 7.45 - 7.36 (m, 2H), 7.33 - 7.22 (m, 3H), 6.79 (t, J = 2.2 Hz, 1 H). 13 C NMR (75 MHz, DMSO-cfe) 5 165.5, 135.2, 133.5, 132.2, 128.7, 127.8, 126.2, 124.3, 121.8, 119.3, 115.0. HPLC-MS [M+H] + = 222.1 , TR = 2.84 (99%).

[0147] 4-(4-chlorophenyl)-1H-pyrrole-3-carboxylic acid (29).

[0148] Methyl 4-(4-chlorophenyl)-1 / 7-pyrrole-3-carboxylate (17) (7.74 mmol, 1.8 g) and NaOH (77.4 mmol, 3.0 g) were used, obtaining 4-(4-chlorophenyl)-1 / 7-pyrrole-3-carboxylic acid as a white solid (840 mg, Rto = 49%).

[0149] 1H NMR (300 MHz, DMSO-cfe) 5 11.64 (s, 1 H), 11.54 (s, 1 H), 7.49 (d, J = 8.7 Hz, 2H), 7.44 (dd, J = 3.1 , 2.2 Hz, 1 H), d 6.96 (t, J = 2.4 Hz, 1 H). 13 C NMR (75 MHz, DMSO-cfe) 5 165.6, 134.2, 130.5, 130.3, 127.4, 126.2, 123.9, 119.3, 112.6. HPLC-MS [M + H] + = 222.1 , TR = 3.00 (99%).

[0150] 4-(4-fluorophenyl)-1H-pyrrole-3-carboxylic acid (30).

[0151] Methyl 4-(4-fluorophenyl)-1 / 7-pyrrole-3-carboxylate (18) (6.45 mmol, 1.4 g) and NaOH (64.5 mmol, 2.6 g) were used, affording 4-(4-fluorophenyl)-1 / 7-pyrrol-3-carboxylic acid as a brown sodium (0.841 g, Rto = 63%).

[0152] 1 H NMR (300 MHz, DMSO-cfe) 5 11.59 (s, 1 H), 11.46 (s, 1 H), 7.48 (dd, J = 8.8, 5.7 Hz, 2H), 7.43 (t, J = 2.6 Hz, 1 H), t 6.91 (t, J = 2.3 Hz, 1 H). 13C RMN (75 MHz, DMSO-cfe) 5 165.6, 160.8 (d, J = 241.8 Hz), 131.7 (d, J = 3.1 Hz), 130.6 (d, J = 7.9 Hz), 126.0, 124.1, 119.0, 114.2 (d, J = 21.0 Hz), 112.5. HPLC-MS [M + H] + = 206.1 , TR = 2.82 (97%). 4-(4-nitrophenyl)-1H-pyrrole-3-carboxylic acid (31).

[0153] Methyl 4-(4-nitrophenyl)-1 / 7-p¡rrole-3-carboxylate (19) (2.0 mmol, 0.5 g) and NaOH (20.0 mmol, 0.8 g) were used, obtaining 4-(4-nitrophenyl)-1 / 7-p¡rrol-3-carboxylic acid as a yellow solid (128 mg, Rto = 27%).

[0154] 1 H NMR (300 MHz, DMSO-cfe) 5 11.84 (s, 1 H), 11.71 (s, 1 H), 8.16 (d, J = 9.1 Hz, 2H), 7.77 (d, J = 9.1 Hz, 2H), 7.52 (dd, J = 3.0, 2.2 Hz, 1 H), 7.19 (t, J = 2.4 Hz, 1 H). 13 C RMN (75 MHz, DMSO-cfe) 5 165.5, 145.2, 142.6, 129.4, 127.1 , 123.0, 122.9, 121.0, 112.9. HPLC-MS [M + H] + = 233.0, TR = 2.82 (99%).

[0155] 4-(4-isopropylphenyl)-1H-pyrrole-3-carboxylic acid (32).

[0156] Methyl 4-(4-isopropylphenyl)-1 / 7-pyrrole-3-carboxylate (20) (3.7 mmol, 0.9 g) and NaOH (37.4 mmol, 1.5 g) were used, obtaining 4-(4-isopropylphenyl)-1 / 7-pyrrole-3-carboxylic acid as a yellow solid (552 mg, Rto = 64%).

[0157] 1 H NMR (300 MHz, DMSO-cfe) 5 11.52 (s, 1 H), 11.43 (s, 1 H), 7.41 (t, J = 2.4 Hz, 1 H), 7.37 (d, J = 8.2 Hz, 2H), 7.15 (d, J = 8.1 Hz, 2H), 6.86 (t, J = 2.3 Hz, 1 H), 2.87 (hept, J = 6.9 Hz, 1 H), 1.21 (d, J = 6.9 Hz, 6H). 13 C NMR (75 MHz, DMSO-cfe) 5 165.7, 145.7, 132.8, 128.8, 125.9, 125.4, 125.2, 118.8, 112.5, 33.1, 24.0. HPLC-MS [M+H] + = 230.0, TR = 3.25 (98%).

[0158] 4-(p-tolyl)-1H-pyrrole-3-carboxylic acid (33).

[0159] Methyl 4-(p-tolyl)-1 / 7-pyrrole-3-carboxylate (21) (9.9 mmol, 2.0 g) and NaOH (99.4 mmol, 3.9 g) were used, yielding 4-(p-tolyl)-1 / 7-pyrrole-3-carboxylic acid as a yellowish solid (1.044 g, Rto = 52%).

[0160] 1 H NMR (300 MHz, DMSO-cfe) 5 11.51 (s, 1 H), 11.40 (s, 1 H), 7.41 (dd, J = 3.1, 2.2 Hz, 1 H), 7.34 (d, J = 8.0 Hz, 2H), 7.09 (d, J = 7.9 Hz, 2H), 6.85 (t, J = 2.4 Hz, 1H), 2.29 (s, 3H). 13 C NMR (75 MHz, DMSO-cfe) 5 165.7, 134.6, 132.4, 128.7, 128.1, 125.9, 125.2, 118.7, 112.6, 20.7. HPLC-MS [M+H] + = 202.1 , TR = 2.91 (98%).

[0161] 4-(2,4-dimethylphenyl)-1H-pyrrole-3-carboxylic acid (34).

[0162] Methyl 4-(2,4-dimethylphenyl)-1 / 7-pyrrole-3-carboxylate (22) (3.4 mmol, 790 mg) and NaOH (34.5 mmol, 1.3 g) were used, yielding 4-(2,4-dimethylphenyl)-1 / 7-pyrrole-3-carboxylic acid as a yellow solid (452 ​​mg, Rto = 61%).

[0163] 1 H NMR (300 MHz, DMSO-cfe) 5 11.35 (s, 1 H), 7.40 (t, = 2.5 Hz, 1 H), 7.00 - 6.94 (m, 2H), 6.89 (d, J = 7.8 Hz, 1 H), 6.64 (t, J = 2.3 Hz, 1 H), 2.27 (s, 3H), 2.08 (s, 3H). 13C NMR (75 MHz, DMSO-c) 5 165.5; HPLC-MS [M + H] + = 216.1, TR = 3.04 (78%). 4-(3,4-dichlorophenyl)-1H-pyrrole-3-carboxylic acid (35).

[0164] Methyl 4-(3,4-dichlorophenyl)-1 / 7-p¡rrol-3-carbox¡late (23) (3.5 mmol, 950 mg) and NaOH (35.2 mmol, 1.4 g) were used, obtaining the 4-(3,4-dichlorophenyl)-1 / 7-pyrrol-3- carboxylic acid as a brown solid (272 mg, Rto = 30%).

[0165] 1 H NMR (300 MHz, DMSO-cf) 5 11.60 (s, 1 H), 7.75 (d, J = 1.9 Hz, 1 H), 7.54 (d, J = 8.3 Hz, 1 H), 7.49 - 7.45 (m, 2 H), 7.08 (t, J = 2.4 Hz, 1 H). 13 C NMR (75 MHz, DMSO-c) 5 165.5; HPLC-MS [M + H] + = 244.1, TR = 3.37 (95%).

[0166] General procedure for synthesis of A / -(1H-indazol-5-yl)-4-phenyl- 1H-pyrrol-3-carboxamide derivatives (36-49)

[0167] Procedure A. A mixture of the corresponding 4-phenyl-1 / 7-pyrrole-3-carboxylic acid (1.0 equiv), the amine indicated in each case (1.1 equiv), and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) (1.3 equiv) is dissolved in anhydrous tetrahydrofuran (THF) (5 mL / mmol) under an argon atmosphere. When the mixture is completely dissolved, N,V-diisopropylethylamine (DIPEA) (1.5 equiv) is added dropwise. The reaction is stirred for 2 hours or until exhaustion of the limiting reagent by monitoring using thin-layer chromatography (TLC) at room temperature. The THF is evaporated under vacuum, the crude is dissolved in EtAc (10 mL / mmol), and washed with water (3 x 10 mL / mmol). Subsequently, the organic phase is dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude oil obtained is purified by column chromatography with dichloromethane:methanol (DCM:MeOH 30:1).

[0168] Procedure E: A mixture of the appropriate 4-phenyl-1 / 7-pyrrole-3-carboxylic acid (1.0 equiv), the suitable amine (1.2 equiv), A / -(3-dimethylaminopropyl)-A / '-ethylcarbodiimide (EDC) (1 equiv), 4-dimethylaminopyridine (DMAP) (2 equiv), hydroxybenzotriazole (HOBT) (0.1 equiv), and DIPEA (5 equiv) is dissolved in anhydrous acetonitrile (CH3CN) (5 mL / mol) under an argon atmosphere. The reaction is stirred for 2 hours or until exhaustion of the limiting reagent by monitoring using thin-layer chromatography at room temperature. The CH3CN is evaporated under vacuum, the crude is dissolved in EtAc (10 mL / mmol), and washed with water (3 x 10 mL / mmol). The organic phase is dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product obtained is purified by column chromatography (DCM:MeOH 30:1). Procedure C. A mixture of the corresponding 4-phenyl-1 / 7-pyrrole-3-carboxylic acid (1.0 equiv) is dissolved in a mixture of anhydrous DCM / THF 2:1 (5 mL / mmol) under an argon atmosphere.Once dissolved, thionyl chloride (SOCh) (2.0 equiv) is added and the reaction is allowed to proceed at room temperature with stirring for 1 hour. The solvent is then evaporated under reduced pressure, and the crude is redissolved in anhydrous THF (2 mL / mmol). Triethylamine (TEA) (1 equiv) and the corresponding amine (1 equiv) are added, and the reaction is allowed to proceed overnight under an argon atmosphere. The THF is evaporated under vacuum, the crude is dissolved in EtAc (10 mL / mmol), and washed with water (3 x 10 mL / mmol). The organic phase is then dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The resulting crude is purified by column chromatography (DCM:MeOH 30:1) followed by TLC purification.

[0169] A / -(1 H-lndazol-5-yl)-4-phenyl-1 H-pyrrole-3-carboxamide (36)

[0170] Procedure B. 4-Phenyl-1 / 7-pyrrol-3-carboxylic acid (24) (150 mg, 0.80 mmol), 1 / 7-¡ndazol-5-amine (117 mg, 0.88 mmol), EDC (184 mg, 0.96 mmol), HOBT (10 mg, 0.08 mmol), DMAP (117) was used mg, 0.96 mmol) and DIPEA (517 mg, 698 pL, 4.00 mmol), obtaining the desired compound as a brown solid (30 mg. Rto = 12%).

[0171] 1 H NMR (500 MHz, Acetone-d6) 5 12.12(s,1H), 10.63(s,1H), 8.45(s,1H), 8.20(s,1H), 7.97(s,1H), 7.56(d,J=7.3Hz,2H), 7.50(t,J= 2.6 Hz, 1 H), 7.46 (d, J = 8.9 Hz, 1 H), 7.37 (t, J = 7.6 Hz, 2 H), 7.33 (dd, J = 8.9, 2.0 Hz, 1 H), 7.28 (t, J = 7.5 Hz, 1 H), 6.98 (t, J = 2.4 Hz, 1 H). 13 C NMR (125 MHz, Acetone-c) 5 164.2; 119.0, 110.7, 110.6. HPLC-MS [M + H] + = 303.2, T R = 2.68 (97%). HRMS (ESI) m / z: [M + Na]+ caled, for Ci8Hi4N4ONa 325.1060; found 325.1055.

[0172] 4-(2-Bromophenyl)- / V-(1 H-indazol-5-yl)-1 H-pyrrole-3-carboxamide (37)

[0173] Procedure A. 4-(2-bromophenyl)-1 / 7-pyrrole-3-carboxyl¡co (25) acid (200 mg, 0.75 mmol), 1 / 7-¡ndazol-5-amine (110 mg, 0.82 mmol), BOP (432 mg, DIPEA (1045 mmol) and 1045 mmol) were used. mg, 195 pL, 1.13 mmol), obtaining the desired compound as a brown solid (43 mg. Rto = 15%).

[0174] 1 H NMR (500 MHz, DMSO-cfe) 5 12.91 (s, 1 H), 11.39 (s, 1 H), 9.45 (s, 1 H), 8.08 (s, 1 H), 7.96 (s, 1 H, 9), 7.61 (d, J = 8.0), J = 1 Hz, 7.5 ( Hz 2.4 Hz, 1 H), 7.47 (dd, J = 8.8, 1.5 Hz, 1 H), 7.43 (d, J = 8.8 Hz, 1 H), 7.37 - 7.32 (m, 2H), 7.20 (ddd, J = 8.9, 6.3, 2.8 Hz, J = 8.8 Hz), 7.8 Hz. 2.2 Hz, 1 H). 13 C NMR (125 MHz, DMSO-cfe) 5 162.8, 137.2, 136.6, 133.2, 132.7, 132.2, 132.0, 127.9, 126.8, 124.3, 120.6, 119.0, 118.4, 109.9, 109.7. HPLC-MS [M + H] + = 381.1 , T R = 2.78 (96%). HRMS (ESI) m / z: [M + Na] +caled, for Ci8Hi3BrN4ONa 403.0165; found 403.0153.

[0175] 4-(3-Bromophenyl)-A / -(1 H-indazol-5-yl)-1 H-pyrrole-3-carboxamide (38)

[0176] Procedure A. 4-(3-bromophenyl)-1 / 7-pyrrole-3-carboxyl¡co (26) acid (200 mg, 0.75 mmol), 1 / 7-indazole-5-amine (110 mg 0.82 mmol), BOP (432 mg, 0.98 mmol DI, and 145 mmol PEA) were used 195 pL, 1.13 mmol), obtaining the desired compound as a brown solid (55 mg. Rto = 19%).

[0177] 1 H NMR (300 MHz, Acetone-cfe) 5 12.12 (s, 1 H), 10.68 (s, 1 H), 8.84 (s, 1 H), 8.25 (s, 1 H), 7.99 (d, J = 0.7 Hz, 1 H), t 7.59 - 7.47 (m, 4H), 7.39 (ddd, J = 8.0, 2.0, 1.1 Hz, 1 H), 7.27 (t, J = 7.8 Hz, 1 H), 7.09 (t, J = 2.4 Hz, 1 H). 13 C NMR (75 MHz, in Acetone) 5 164.3, 139.2, 138.3, 134.5, 134.0, 132.2, 130.6, 121.7, 119.7, 119.4, 111.0, 110.6. HPLC-MS [M + H] + = 381.2, TR = 3.04 (95%). HRMS (ESI) m / z [M + Na]+ caled, for Ci8Hi3BrN4ONa 403.0165; found 403.0158.

[0178] 4-(4-Bromophenyl)- / V-(1H-indazol-5-yl)-1H-pyrrol-3-carboxamide (39) .

[0179] Procedure A. 4-(4-Bromophenyl)-1 / 7-pyrrol-3-carboxyl¡ic acid (27) (200 mg, 0.75 mmol), 1 / 7-¡ndazol-5-amine (110 mg, 0.82 mmol), BOP (432 mg, 0.98 mmol) and DI PEA (145 mg, 195) were used pL, 1.13 mmol), obtaining the desired compound as a brown solid (49 mg. Rto = 17%).

[0180] 1 H NMR (300 MHz, DMSO-cfe) 5 12.93 (s, 1 H), 11.42 (s, 1 H), 9.74 (s, 1 H), 8.15 (s, 1 H), 8.00 (s, 1 H), 7.52 (dd, J = 8.9, 1 .8 Hz, 1 H), 7.49 -1. 7.41 (m, 5H), 7.07 (t, J = 2.3 Hz, 1 H). 13 C NMR (75 MHz, DMSO-c) 5 163.7; 117.5, 110.0, HPLC-MS [M + H] + = 381.2, TR = 3.05 (95%). HRMS (ESI) m / z: [M + Na] + caled, for Ci8Hi3BrN4ONa; 403.0165 found

[0181] 4-(2-Chlorophenyl)- / V-(1H-indazol-5-yl)-1H-pyrrole-3-carboxamide (40)

[0182] Procedure A. 4-(2-Chlorophenyl)-1 / 7-pyrrol-3-carboxyl¡ic acid (28) (500 mg, 2.12 mmol), 1 / 7-¡ndazol-5-amine (311 mg, 2.33 mmol), BOP (1.2 g, 2.76 mmol) and DIPEA (411 mg, 554) were used pL, 3.18 mmol), obtaining the desired compound as a white solid (275 mg. Rto = 36%).

[0183] 1 H NMR (300 MHz, DMSO-cfe) 5 12.90 (s, 1 H), 11.39 (s, 1 H), 9.50 (s, 1 H), 8.08 (s, 1 H), 7.96 (s, 1 H), 7.55 (dd, = 2.9, 2.1 Hz, 1 H), 7.47 (dd, J = 9.0, 1.7 Hz, 1 H), 7.43 - 7.39 (m, 2H), 7.38 - 7.33 (m, 1 H), 7.32 - 7.22 (m, 2H), 6.88 (t, J = 2.3 Hz, 1 H). 13 C NMR (75 MHz, DMSO-c) 5 163.0; 119.2, 118.7, 109.9, 109.7. HPLC-MS [M + H] + = 337.1 , T R = 2.48 (99%). HRMS (ESI) m / z: [M + Na] +caled, for Ci8Hi3CIN4ONa 359.0670; found 359.0667.

[0184] 4-(4-Chlorophenyl)-A / -(1 H-indazol-5-yl)-1 H-pyrrole-3-carboxamide (41 )

[0185] Procedure A. 4-(4-chlorophenyl)-1 / 7-pyrrole-3-carboxylic acid (29) (500 mg, 2.12 mmol), 1 / 7-indazol-5-amine (311 mg, 2.33 mmol), BOP (1.2 g, 2.76 mmol) and DIPEA (411 mg, 554 pL, 3.18 mmol) were used, obtaining the desired compound as a white solid (152 mg. Rto = 21%).

[0186] 1 H NMR (300 MHz, DMSO-cfe) 5 12.93 (s, 1 H), 11.42 (s, 1 H), 9.73 (s, 1 H), 8.16 (s, 1 H), 8.00 (s, 1 H), 7.58 - 7.42 (m, 5H), 7.33 (d, J = 8.7 Hz, 2H), 7.07 (t, J = 2.3 Hz, 1 H). 13 C NMR (75 MHz, DMSO-cfe) 5 163.7, 136.8, 134.5, 133.3, 132.7, 130.0, 129.7, 127.7, 122.7, 122.7, 122.1, 121.0, 118.5, 117.5, 110.0, 109.8. HPLC-MS [M+H] + = 337.1, TR = 3.02 (99%). HRMS (ESI) m / z [M + Na] + caled, for Ci8Hi3CIN4ONa 359.0670; found 359.0664.

[0187] 4-(4-Fluorophenyl)-A / -(1H-indazol-5-yl)-1H-pyrrole-3-carboxamide (42)

[0188] Procedure A. 4-(4-fluorophenyl)-1 / 7-pyrrol-3-carboxyl¡ic acid (30) (400 mg, 1.95 mmol), 1 / 7-¡ndazol-5-amine (286 mg, 2.15 mmol), BOP (1.1 g, 2.54 mmol), and DIPEA (378 mg, 510) were used pL, 2.93 mmol), obtaining the desired compound as a grayish solid (475 mg. Rto = 76%).

[0189] 1 H NMR (300 MHz, DMSO-cfe) 5 12.92 (s, 1 H), 11.37 (s, 1 H), 9.68 (s, 1 H), 8.15 (s, 1 H), 8.00 (s, 1 H), 7.56 - 7.42 (m, 5 H), 7.11 (t, J = 9.0 Hz, 2H), 7.01 (t, J = 2.3 Hz, 1 H). 13 C NMR (75 MHz, DMSO-c) 5 163.8, 160.6 (d, J = 241.6 Hz), 136.7, 133.3, 132.8, 132.0 (d, J = 3.1 Hz), 129.9 (d, J = 7.8 Hz). 121.9, 121.0, 118.2, 117.4, 114.4 (d, J = 21.0 Hz), 110.0, 109.8. HPLC-MS [M + H] + = 321.2, TR = 2.90 (99%). HRMS (ESI) m / z: [M + Na] + caled, for Ci8Hi3FN4ONa 343.0966; found 343.0961.

[0190] A / -( 1 H-indazol-5-yl)-4-(4-nitrophenyl)-1 H-pyrrole-3-carboxamide (43)

[0191] Procedure A. 4-(4-nitrophenyl)-1 / 7-p¡rrol-3-carboxylic acid (31) (128 mg, 0.55 mmol), 1 / 7-¡ndazol-5-amine (81 mg, 0.61 mmol), BOP (107 mg, 0.72 mmol) and DIPEA were used. (107 mg, 144 pL, 0.83 mmol), obtaining the desired compound as a yellow solid (52 mg. Rto = 27%).

[0192] 1 H NMR (300 MHz, DMSO-cfe) 5 12.94 (s, 1 H), 11.64 (s, 1 H), 9.89 (s, 1 H), 8.18 (s, 1 H), 8.15 (d, J = 9.1 Hz, 2H), 8.01 (s, 17 H), J = 77 (7). 9.0 Hz, 2H), 7.58 - 7.52 (m, 2H), 7.47 (d, J = 8.9 Hz, 1 H), 7.31 (t, J = 2.4 Hz, 1 H). 13 C NMR (75 MHz, DMSO-cfe) 5 163.5, 144.9, 143.0, 136.8, 133.3, 132.6, 128.4, 123.1 , 123.0, 122.7, 117.9, 110.2,

[0193] 109.8. HPLC-MS [M + H] + = 348.2, T R = 2.87 (99%). HRMS (ESI) m / z: [M + Na] + caled, for CisH NsOsNa 370.0911 ; found 370.0909.

[0194] A / -( 1 H-lndazol-5-yl)-4-(4-isopropylphenyl)-1 H-pyrrole-3-carboxamide (44)

[0195] Procedure C. 4-(4-isopropylphenyl)-1 / 7-pyrrole-3-carboxylic acid (32) (400 mg, 1.74 mmol), 1 / 7-indazole-5-amine (231 mg, 1.74 mmol), SOCh (415 mg, 233 mmol, 1.74 mmol) and 23 mL were used. TEA (176 mg, 242 pL, 1.74 mmol), obtaining the desired compound as a red solid (80 mg. Rto = 13%).

[0196] 1 H NMR (300 MHz, DMSO-cfe) 5 12.93 (s, 1 H), 11.31 (s, 1 H), 9.63 (s, 1 H), 8.15 (s, 1 H), 8.00 (s, 1 H), 7.50 (dd, J = 9.0, J = 9.0, 1.7 Hz, 7.5 Hz). J = 9.0 Hz, 1 H), 7.44 (t, J = 2.4 Hz, 1 H), 7.39 (d, J = 8.2 Hz, 2H), 7.16 (d, J = 8.2 Hz, 2H), 6.96 (t, J = 2.3 Hz, 1 H), 6.96 (t, J = 2.3 Hz, 1 H). H), 1 .21 (d, J = 6.9 Hz, 6H). 13 C NMR (75 MHz, DMSO-cfe) 5 163.9, 145.5,

[0197] 136.7, 133.3, 133.0, 132.8, 128.1 , 125.7, 123.9, 122.7, 121.7, 121 .0, 117.9, 117.6, 109.9,

[0198] 109.8, 33.1 , 24.0. HPLC-MS [M + H]+ = 345.2, TR = 3.30 (95%). HRMS (ESI) m / z: [M + Na] + caled, for C2iH2oN4ONa 367.1529; found 367.1523.

[0199] A / -( 1 H-\ ndazol -5-i I )-4-(p-to I i I )-1 H-pyrrole-3-carboxamide (45)

[0200] Procedure A. 4-(p-tolyl)-1 / 7-pyrrole-3-carboxyl¡co (33) acid (400 mg, 1.99 mmol), 1 / 7-¡ndazol-5-amine (291 mg, 2.18 mmol), BOP (1.1 g, 2.58 mmol) and DIPEA (38 mmol) were used. 520 pL, 2.99 mmol), obtaining the desired compound as a white solid (144 mg. Rto = 24%).

[0201] 1 H NMR (300 MHz, DMSO-cfe) 5 12.92 (s, 1 H), 11.31 (s, 1 H), 9.61 (s, 1 H), 8.15 (s, 1 H), 7.99 (s, 1 H), 7.49 (dd, J = 9.0, J = 9.7, 1 Hz, 7.4 d). J = 8.6 Hz, 1 H), 7.42 (t, J = 2.4 Hz, 1 H), 7.37 (d, J = 8.1 Hz, 2H), 7.09 (d, J = 7.9 Hz, 2H), 6.97 (t, J = 2.3 Hz, 1 H), 2. 38 (s). 13C NMR (75 MHz, DMSO-c) 5 163.9; 109.8, 109.8, HPLC-MS [M + H] + = 317.2, TR = 2.99 (99%). HRMS (ESI) m / z: [M + Na] + caled, for Ci9Hi6N4ONa 339.1216; found 339.1214.

[0202] 4-(2,4-Dimethylphenyl)- / V-(1H-indazol-5-yl)-1H-pyrrole-3-carboxamide (46)

[0203] Procedure A. 4-(2,4-dimethylphen¡l)-1 / 7-p¡rrol-3-carboxyl¡ic acid (34) (400 mg, 1.86 mmol), 1 / 7-¡ndazol-5-amine (272 mg, 2.04 mmol), BOP (1.1 g, 2.42 mmol), and DIPEA (360 mg, 360 mg) were used. 486 pL, 2.79 mmol), obtaining the desired compound as a white solid (105 mg. Rto = 17%). 1H RMN (300 MHz, DMSO-cfe) 5 12.91 (s, 1 H), 11.32 (s, 1 H), 9.05 (s, 1 H), 8.02 (s, 1 H), 7.95 (s, 1 H), 7.54 (t, J = 2.2 Hz, 1 H), 7.41 (d, J = 8.9 Hz, 1 H), 7.29 (dd, J = 8.9, 1 .8 Hz, 1 H), 7.07 (d, J = 7.6 Hz, 1 H), 7.02 (s, 1 H), 6.96 (d, J = 7.6 Hz, 1 H), 6.72 (t, J = 2.2 Hz, 1 H), 2.29 (s, 3H), 2.13 (s, 3H). 13 C RMN (75 MHz, DMSO-cfe) 5 163.1 , 136.7, 136.5, 135.4, 133.2, 132.7, 132.6, 130.4, 130.1 , 125.7, 123.0, 122.7, 121.2, 120.7, 118.3, 118.2, 109.8, 109.6, 20.7, 20.1. HPLC-MS [M + H] + = 331.2, TR = 3.15 (99%). HRMS (ESI) m / z [M + Na] + caled, para C2oHisN40Na 353.1373; encontrada 353.1369.

[0204] A / -(4-Cloro-1 H-indazol-5-il)-4-(4-clorofenil)-1 H-pirrol-3-carboxamida (47)

[0205] Procedure A. 4-(4-Chlorophenyl)-1 / 7-pyrrol-3-carboxylic acid (29) (133 mg, 0.60 mmol), 4-chloro-1 / 7-indazol-5-amine (121 mg, 0.72 mmol), BOP (345 mg, 0.78 mmol) and DI PEA (116 mg, 0.72 mmol) were used. 157 pL, 0.90 mmol) obtaining the desired compound as a white solid (97 mg. Rto = 44%).

[0206] 1 H NMR (300 MHz, DMSO-cf) 5 13.39 (s, 1 H), 11.48 (s, 1 H), 9.30 (s, 1 H), 8.11 (s, 1 H), 7.71 - 7.45 (m, 5H), 7.34 (d, J = 8.2 Hz, 2H), 7.06 (t,J). = 2.4 Hz, 1 H). 13 C NMR (75 MHz, DMSO) 5 164.2;

[0207] 122.6, 119.7, 119.4, 116.9, 109.4. HPLC-MS [M + H] + = 371.1, TR = 3.29 (95%). HRMS (ESI) m / z: [M + Na]+ caled, for C18H12CI2N4ONa 393.0286; found 393.0281.

[0208] 4-(3,4-Dichlorophenyl)-A / -(1H-indazol-5-yl)-1H-pyrrol-3-carboxamide (48)

[0209] Procedure A. 4-(3,4-Dichlorophenyl)-1 / 7-p¡rrol-3-carboxyl¡ic acid (35) (250 mg, 0.98 mmol), 1 / 7-¡ndazol-5-amine (143 mg, 1.07 mmol), BOP (561 mg, 1.27 mmol), and DIPEA (190 mg, 1.07 mmol) were used. 256 pL, 1.47 mmol), obtaining the desired compound as a brown solid (206 mg. Rto = 57%).

[0210] 1 H NMR (300 MHz, DMSO-cf) 5 12.94 (s, 1 H), 11.52 (s, 1 H), 9.79 (s, 1 H), 8.15 (d, J = 1.0 Hz, 1 H), 8.01 (s, 1 H), 7.78 (d, J = 1.9 Hz, 1 H), 7.57 -1. 7.44 (m, 5H), 7.19 (t, J = 2.4 Hz, 1 H). 13 C NMR (75 MHz, DMSO-c) 5 163.6;

[0211] 129.6, 128.3, 127.7, 122.7, 122.5, 121.5, 121.1 , 119.3, 117.4, 110.2, 109.9. HPLC-MS [M + H] + = 371.1, TR = 3.19 (99%). HRMS (ESI) m / z: [M + Na] + caled, for CisHi2Cl2N4ONa 393.0280; found 393.0277.

[0212] A / -( 1 Hindazol-5-iI)-4-(pyridin-3-iI)-1H-pyrrol-3-carboxamide (49)

[0213] Procedure A. 4-(Pyridin-3-yl)-1 / 7-pyrrol-3-carboxylic acid (113 mg, 0.6 mmol), 1 / 7-¡ndazol-5-amine (96 mg, 0.72 mmol), BOP (345 mg, 0.78 mmol) and DIPEA (116 mg, 157 pL, 0.90) were used mmol), obtaining the desired compound as a brown solid (71 mg. Rto = 39%). 1 H NMR (300 MHz, DMSO-cf) 5 12.95 (s, 1 H), 11.53 (s, 1 H), 9.77 (s, 1 H), 8.69 (dd, J = 2.3, 0.9 Hz, 1 H), 8.38 (dd, J = 4.8, 1.7 Hz, 1 H), 8.16 (dd, 1 H). J = 1.9, 0.8 Hz, 1 H), 8.01 (d, J = 1.0 Hz, 1 H), 7.89 (ddd, J = 7.9, 2.3, 1.7 Hz, 1 H), 7.59 (dd, J = 3.0, 2.1 Hz, 1 H), 7.54 (dd, J = 9.0, 1 .9). Hz, 1 H), 7.47 (dt, J = 8.9, 1.0 Hz, 1 H), 7.32 (ddd, J = 7.9, 4.8, 0.9 Hz, 1 H), 7.15 (t, J = 2.3 Hz, 1 H). 13 C NMR (75 MHz, DMSO) 5 164.0; 117.9, 110.6, 110.3. HPLC-MS [M + H] + = 304.2, T R = 1.91 (95%). HRMS (ESI) m / z: [M + Na] +caled, for Ci7Hi3N5ONa 326.1018; found 326.1014.

[0214] Example 2. Synthesis of Af-methylpyrrole derivatives 53 and 54

[0215] T a amb. 2h

[0216] 53-54

[0217] Synthesis of methyl 1-methyl-1H-pyrrole-3-carboxylate (50)

[0218] The corresponding methyl 4-phenyl-1 / 7-pyrrole-3-carboxylate (1.0 equiv) is dissolved in anhydrous DMF (1.5 mL / mmol) under an argon atmosphere. At 0 °C, NaH (60% dispersion, 1.3 equiv) dissolved in anhydrous DMF is added dropwise. Methyl iodide (CH3I) (2 equiv) is then added, and the reaction is allowed to proceed for 2 hours at room temperature. Subsequently, 2 mL of water are added, the mixture is diluted in EtAc (10 mL / mmol), and vigorously washed with a mixture of water and NaCl-saturated water (1:1, 10 mL / mmol x 5) to remove the DMF. Finally, the organic phase is dried over anhydrous sodium sulfate, filtered, and evaporated under vacuum. The compound is purified by column chromatography with a mixture of hexane and ethyl acetate (Hex:AcOEt 7:3) to obtain the corresponding methyl 4-phenyl-1-methyl-1 / 7-pyrrole-3-carboxylate.

[0219] Methyl 4-(3,4-Dichlorophenyl)-1-methyl-1H-pyrrole-3-carboxylate (50) Methyl 4-(3,4-Dichlorophenyl)-1 / 7-pyrrole-3-carboxylate (23) (500 mg, 1.76 mmol), CH3I (0.22 mL, 3.52 equiv) and NaH in 60% dispersion (91 mg, 2.29 mmol) were used to obtain a white solid (332 mg, Rto 66%).

[0220] 1 H NMR (300 MHz, DMSO-cfe) 5 7.71 (d, J = 2.0 Hz, 1 H), 7.56 (d, J = 8.4 Hz, 1 H), 7.53 (d, J = 2.4 Hz, 1 H), 7.42 (dd, J = 8.4, 2.1 Hz, 1 H), 7.09 (d, J = 2.4 Hz, 1H), 3.67 (s, 3H), 3.65 (s, 3H). 13 C NMR (75 MHz, DMSO-cfe) 5 164.0, 135.4, 130.2, 130.2, 129.9, 129.7, 128.8, 128.4, 123.9, 122.8, 111.2, 50.6, 36.2. HPLC-MS [M+H] + = 284.0, TR = 4.01 (95%)

[0221] Synthesis of 1-methyl-1H-pyrrole-3-carboxylic acid derivatives (51-52)

[0222] A mixture of the corresponding methyl 4-phenyl-1-methyl-1 / 7-pyrrole-3-carboxylate (1.0 equiv) and NaOH (10 equiv) is dissolved in a 1:1 solution of MeOH / water (1.5 mL / mmol). The reaction is heated under reflux for 2 hours. After this time, the mixture is diluted in water (10 mL / mmol), washed with ethyl acetate, and the aqueous phase is acidified with 37% fuming hydrochloric acid to a pH of 2–3. The precipitate formed is filtered, yielding the corresponding 4-phenyl-1-methyl-1 / 7-pyrrole-3-carboxylic acid.

[0223] 4-(3,4-Dichlorophenyl)-1-methyl-1H-pyrrole-3-carboxylic acid (51)

[0224] Methyl 4-(3,4-dichlorophenyl)-1-methyl-1 / 7-pyrrole-3-carboxylate (50) (1.06 mmol, 300 mg) and NaOH (10.5 mmol, 422 mg) were used, obtaining 4-(3,4-dichlorophenyl)-1-methyl-1 / 7-pyrrole-3-carboxylic acid as a white solid (266 mg, Rto = 93%).

[0225] 1H NMR (300 MHz, DMSO-cfe) 5 11.76 (s, 1 H), 7.72 (d, J = 2.0 Hz, 1 H), 7.54 (d, J = 8.3 Hz, 1 H), 7.48 - 7.42 (m, 2H), 7.05 (d, J = 2.5 Hz, 1 H), 3.66 (s, 3H). 13 C NMR (75 MHz, DMSO-cfe) 5 165.1 , 135.7, 130.2, 130.1 , 130.0, 129.7, 128.8, 128.2, 123.8, 122.8, 112.3, 36.1. HPLC-MS [M + H] + = 270.0, TR = 3.46 (95%).

[0226] 4-(4-chlorophenyl)-1-methyl-1H-pyrrol-3-carboxylic acid (52)

[0227] If you use methyl 4-(4-chlorophenyl)-1-methyll-1 / 7-p¡rrol-3-carboxyl (2.0 mmol, 500 mg) and NaOH (20 mmol, 800 mg), obtain 4-(4-dichlorophenyl)-1-methyl-1 / 7-pyrrol-3-carboxylic acid as a white solid (376 mg, Rto = 80%).

[0228] 1 H NMR (300 MHz, DMSO-cfe) 5 11.68 (s, 1 H), 7.47 (d, J = 8.6 Hz, 2H), 7.44 (d, = 2.5 Hz, 1 H), 7.38 - 7.22 (m, 2H), 6.94 (d, J = 2.5 Hz, 1 H), 3.67 (s, 3H). 13 C NMR (75 MHz, DMSO) 5 165.7, 134.3, 130.9, 130.8, 130.2, 128.0, 124.7, 123.6, 112.8, 36.6.

[0229] Synthesis of A / -(1H-indazol-5-yl)-4-phenyl-1-methyl-1H-pyrrole-3-carboxamide derivatives (53-54) A mixture of the corresponding 4-phenyl-1-methyl-1 / 7-pyrrole-3-carboxylic acid (1.0 equiv), the amine indicated in each case (1.1 equiv) and BOP (1.3 equiv) is dissolved in anhydrous THF (5 mL / mmol) under an argon atmosphere. When the mixture is completely dissolved, A / ,V-diisopropylethylamine (DIPEA) (1.5 equiv) is added dropwise. The reaction is stirred for 2 hours or until exhaustion of the limiting reagent by monitoring by TLC at room temperature. The THF is evaporated under vacuum, the crude is dissolved in EtAc (10 mL / mmol) and washed with water (3 x 10 mL / mmol). Subsequently, the organic phase is dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The resulting crude is purified using column chromatography (DCM:MeOH 30:1).

[0230] 4-(4-Chlorophenyl)- / V-(1 H-indazol-5-yl)-1 -methyl-1 H-pyrrole-3-carboxamide (53)

[0231] 4-(4-chlorophenyl)-1-methyl-1 / 7-p¡rrol-3-carboxylic acid (52) (141 mg, 0.60 mmol), 1 / 7-¡ndazol-5-amine (96 mg, 0.72 mmol), BOP (345 mg, 0.78 mmol), and DIPEA (116 mg, 157) were used pL, 0.90 mmol), obtaining the desired compound 53 as a brown solid (107 mg. Rto = 51 %).

[0232] 1 H NMR (300 MHz, DMSO-cf) 5 12.94 (s, 1 H), 9.75 (s, 1 H), 8.16 (s, 1 H), 8.01 (s, 1 H), 7.54 - 7.44 (m, 4H), 7.37 - 7.31 (m, 2H), 7.04 (d, J = 2.3 Hz, 1 H), 3.71(s, 3H). 13 C NMR (75 MHz, DMSO-c) 5 163.8; 110.3, 36.5. HPLC-MS [M + H] + = 351.2, TR = 3.26 (95%). HRMS (ESI) m / z [M + Na] + caled, for Ci9Hi5CIN4ONa 373.0832; found 373.0825.

[0233] 4-(3,4-Dichlorophenyl)- / V-(1H-indazol-5-yl)-1-methyl-1H-pyrrole-3-carboxamide (54) .

[0234] 4-(3,4-dichlorophenyl)-1-methyl-1 / 7-p¡rrol-3-carboxylic acid (51) (200 mg, 0.74 mmol), 1 / 7-¡ndazol-5-amine (108 mg, 0.81 mmol), BOP (425 mg, 0.96 mmol), and DIPEA (143 mg, 0.81 mmol) were used. 193 pL, 1.11 mmol), obtaining the desired compound 54 as a white solid (84 mg. Rto = 30%).

[0235] 1 H NMR (300 MHz, DMSO-cf) 5 12.94 (s, 1 H), 9.80 (s, 1 H), 8.14 (s, 1 H), 8.01 (s, 1 H), 7.75 (d, J = 2.0 Hz, 1 H), 7.57 - 7.42 (m, 5 H), 7.16 (d, J = 2.3 Hz, 1 H), 3.70 (s, 3H). 13 C NMR (75 MHz, DMSO-c) 5 163.2; 121.0, 117.4, 110.1, 109.9, HPLC-MS [M + H] + = 385.1, TR = 3.43 (95%). HRMS (ESI) m / z: [M + Na] + caled, for C HuCh^ONa; 407.0437 found 407.0432. il)- / V-(1H-indazol-5-i I )-1H-pyrrole-3-carboxamide

[0236] Following procedure A of the general synthesis of A / -(1 / 7-indazol-5-yl)-4-phenyl-1 H-pyrrole-3-carboxamide. First, 5-(4-(4-chlorophenyl)-1 / 7-pyrrole-3-carboxamido)-1 / 7-indazol-1-carboxylate of tert-butyl (55) was synthesized. For this purpose, 4-(4-chlorophenyl)-1 / 7-pyrrole-3-carboxylic acid (29) (173 mg, 0.78 mmol), 5-amino-1 / 7-indazol-1- tere-butyl carboxylate (200 mg, 0.86 mmol), BOP (448 mg, 1.01 mmol) and DIPEA (201 mg, 272 pL, 1.56 mmol) were used, obtaining the desired compound as a white solid (151 mg. Rto = 44%).

[0237] 1 H NMR (300 MHz, DMSO-cfe) 5 11.48 (s, 1 H), 9.96 (s, 1 H), 8.38 (d, J = 0.8 Hz, 1 H), 8.32 (d, J = 1.3 Hz, 1 H), 7.99 (d, J = 9.0 Hz, 1 H), 7.76 (dd, J = 9.1 , 2.0 Hz, 1 H), 7.53 (dd, J = 3.0, 2.1 Hz, 1 H), 7.50 (d, J = 8.8 Hz, 2H), 7.33 (d, J = 8.8 Hz, 2H), 7.08 (t, J = 2.4 Hz, 1 H), 1.65 (s, 9H). 13C RMN (75 MHz, DMSO-cfe) 5 163.9, 148.5, 139.9, 135.9, 135.2, 134.4, 130.1 , 129.8, 127.7, 125.9, 122.9, 122.6, 122.5, 118.7, 117.1 , 113.9, 110.7, 84.3, 27.7. HPLC-MS [M + H] + = 473.3, Rt = 3.76 (99%).

[0238] Subsequently, cesium carbonate (CS₂CO₃) (135 mg, 0.42 mmol), potassium iodide (KI) (10 mg, 0.06 mmol), and 3-chloro- / V, / V-dimethylpropan-1-amine (51 mg, 55 mL, 0.42 mmol) are added to a solution of 5-(4-(4-chlorophenyl)-1 / 7-pyrrole-3-carboxamide)-1 / 7-indazol-1-carboxylate (55) (140 mg, 0.32 mmol) in DMF (2 mL). The mixture is heated for 18 hours at 80 °C. It is then allowed to cool to room temperature, and 20 mL of EtAc are added. The DMF is removed by vigorous extraction with a 1:1 mixture of water and water saturated with NaHCl. The organic phase is dried, filtered, and the solvent is evaporated under reduced pressure. The resulting crude is dissolved in a mixture of dichloromethane and trifluoroacetic acid (DCM / TFA) (4:1, 5 mL) and stirred for 6 hours at room temperature. Then, water (10 mL) and a saturated sodium bicarbonate (NaHCl) solution are added until a basic pH is reached.The mixture is extracted with EtAc (3 x 10 mL), and the organic phase is washed with saturated NaHCO3 solution (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and removed under reduced pressure. The crude product obtained is purified by column chromatography using a DCM / MeOH mixture as eluent (from 10:0 to 9:1), yielding the desired compound 56 as a white solid (21 mg, Rto = 16%).

[0239] 1 H NMR (300 MHz, DMSO-cfe) 5 12.94 (s, 1 H), 9.72 (s, 1 H), 8.14 (s, 1 H), 8.00 (s, 1 H), 7.55 - 7.41 (m, 5H), 7.33 (d, J = 8.7 Hz, 2H), 7.10 (d, J = 2.2 Hz, 1 H), 3.97 (t, J = 7.0 Hz, 2H), 2.33 (t, J = 6.8 Hz, 2H), 2.23 (s, 6H), 2.04 - 1.89 (m, 2H). 13 C NMR (75 MHz, DMSO-efe) 5 163.3, 136.8, 134.1, 133.3, 132.7, 130.1, 129.6, 127.7, 124.7, 122.8, 122.7, 121.4, 121.0, 117.3, 110.0, 109.8, 55.6, 47.1, 44.8, 28.2. HPLC-MS [M+H] + = 422.3, T R = 2.45 (95%). HRMS (ESI) m / z: [M + H] +caled, for C23H24CIN5O 422.1742; found 422.1735.

[0240] Example 4. Synthesis of 4-(3-chlorophenyl)- / V-(1H-indazol-5-yl)-1H-pyrrole-3-carboxamide

[0241] To a solution of (E)-3-(3-chlorophenyl)acrylic acid (430 mg, 2.35 mmol) and tert-butyl 5-amino-1 / 7-indazol-1-carboxylate (500 mg, 2.14 mmol) in 10 mL of anhydrous DMF, O-(1 / 7-benzothazol-1-yl)-A / ,A / ,A / ',A / '-tetramethyluronium hexafluorophosphate (HBTII) (1.2 g, 3.22 mmol) and DIPEA (830 mg, 1.1 mL, 6.42 mmol) were added. The mixture was stirred for 2 hours at room temperature under an argon atmosphere, diluted in EtAc (20 mL), and vigorously washed with a mixture of water and NaCl-saturated water (1:1, 20 mL x 5) to remove the DMF. The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The crude was purified on a silica gel column chromatographic (DCM:MeOH 90:1) yielding tere-butyl (E)-5-(3-(3-chlorophenyl)acrylamide)-1 / 7-indazol-1-carboxylate (57) as a white solid (532 mg, Rto = 62%).

[0242] 1H RMN (300 MHz, DMSO-cfe) 5 10.45 (s, 1 H), 8.43 (d, J = 0.7 Hz, 1 H), 8.40 (d, J = 1.5 Hz, 1 H), 8.04 (d, J = 9.0 Hz, 1 H), 7.78 - 7.70 (m, 2H), 7.65 - 7.57 (m, 2H), 7.52 - 7.44 (m, 2H), 6.91 (d, J = 15.8 Hz, 1 H), 1.65 (s, 9H). 13 C RMN (75 MHz, DMSO-cfe) 5 163.3, 148.5, 140.0, 138.6, 137.0, 135.5, 135.2, 133.7, 130.8, 129.4, 127.4, 126.2, 125.9, 123.9, 122.0, 114.3, 110.6, 84.4, 27.7. HPLC-MS [M + H - terc] + = 342.1 , R t = 3.05 (90%).

[0243] For the synthesis of 4-(3-chlorophenyl)-A / -(1 / 7-indazol-5-yl)-1 / 7-pyrrole-3-carboxamide, TosMic (304 mg, 1.56 mmol) and (E)-5-(3-(3-chlorophenyl)acnlamido)-1 / 7-indazol-1-tert-butyl carboxylate (310 mg, 0.78 mmol) are dissolved in 5 mL of anhydrous DMF and NaH in 60% dispersion (94 mg, 2.34 mmol) in an argon atmosphere is added slowly at 0 °C. The mixture is stirred for 1 h at room temperature and then 2 mL of water are added to stop the reaction. The sample is diluted in 20 mL of EtAc and washed vigorously with a mixture of water and NaCl-saturated water (1:1, 20 mL x 5). The phase is dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude is purified by column chromatography with a toluene-hexane mixture (TokHex 8:2) followed by TLC purification, yielding the desired compound 58 as a brown solid (7 mg, Rto = 3%).

[0244] 1H NMR (500 MHz, DMSO-cfe) 5 12.93 (s, 1 H), 11.46 (s, 1 H), 9.74 (s, 1 H), 8.15 (s, 1 H), 8.00 (s, 1 H), 7.58 (t, J = 1 .8, 1 H), Jdd = 7.5 (Hz, 1 H). 8.9, 1 .5 Hz, 1 H), 7.49 (t, J = 2.4 Hz, 1 H), 7.48 - 7.43 (m, 2H), 7.31 (t, J = 7.8 Hz, 1 H), 7.22 (ddd, J = 8.0, 2.0, 1.0 Hz, 7.1 Hz). J = 2.3 Hz, 1 H). 13 C NMR (125 MHz, DMSO-cfe) 5 163.7, 137.8, 136.8, 133.3,

[0245] 132.7, 132.4, 129.5, 127.6, 126.6, 125.1 , 122.7, 122.4, 122.2, 121.1 , 118.9, 117.5, 110.1 ,

[0246] 109.8. HPLC-MS [M + H + = 337.1 , R t = 2.86 (98%). HRMS (ESI) m / z: [M + Na] + caled, for CisH CIN^Na 359.0670; found 359.0666.

[0247] Example 5. Synthesis of At- indazol-5-yl)-4-(naphthalene-1-yl)-1H-pyrrole-3-carboxamide (60)

[0248] For the synthesis of (E)- / V-(1 / 7-indazol-5-yl)-3-(naphthalen-1-yl)acrylamide (59), 500 mg (2.52 mmol) of (E)-3-(naphthalen-1-yl)acrylic acid was dissolved in 5 mL of anhydrous DMF under an argon atmosphere. After dissolution, DI PEA (977 mg, 1.3 mL, 7.56 mmol) was added dropwise and allowed to react for 15 minutes. Then, a mixture dissolved in anhydrous DMF of HBTU (1.435 g, 3.78 mmol) and 1 / 7-indazol-5-amine (369 mg, 2.77 mmol) was added and allowed to react for 2 hours. Subsequently, 20 mL of AcOEt was added and 20 mL of water were added, causing the precipitation of the compound in the form of a white solid (412 mg, Rto 52%).

[0249] 1 H NMR (300 MHz, DMSO-cfe) 5 13.02 (s, 1 H), 10.32 (s, 1 H), 8.43 - 8.32 (m, 2H), 8.26 (d, J = 8.8 Hz, 1 H), 8.08 - 7.98 (m, 3H), 7.86 (d, J = 7.2 Hz, 1H), 7.69 - 7.51 (m, 5H), 6.95 (d, J = 15.5 Hz, 1H). 13C RMN (75 MHz, DMSO-cfe) 5 163.3, 137.0, 136.2, 133.5, 133.4, 132.3, 132.0, 130.8, 129.8, 128.7, 127.0, 126.3, 125.8, 125.5, 124.7, 123.3, 122.8, 120.3, 110.3, 109.8. HPLC-MS [M + H] + = 314.2, T R = 3.53 (93%).

[0250] For the synthesis of A / -(1 / 7-indazol-5-yl)-4-(naphthalen-1-yl)-1 / 7-pyrrole-3-carboxamide (60), a mixture of TosMic (550 mg, 2.82 mmol) and (E)- / V-(1 / 7-indazol-5-yl)-3-(naphthalen-l-yl)acrylamide (59) (400 mg, 1.28 mmol) was dissolved in anhydrous DMF under an argon atmosphere. At 0 °C, 60% NaH dispersion dissolved in anhydrous DMF was added dropwise. The reaction was carried out for 1 hour. After the addition, the reaction is carried out for 1 hour at room temperature. Subsequently, 2 mL of water are added, the mixture is diluted in 25 mL of EtAc, and vigorously washed with a mixture of water and NaCl-saturated water (1:1, 20 mL x 5) to remove the DMF. Finally, the organic phase is dried over anhydrous sodium sulfate, filtered, and evaporated under vacuum. The compound is purified using two consecutive column chromatography (DCM:MeOH 30:1 and Hex:EtAc 8:2), yielding compound 60 as a white solid (30 mg, 7% yield). 1H NMR (300 MHz, Acetone-cfe) 5 12.02 (s, 1 H), 10.83 (s, 1 H), 8.06 - 7.96 (m, 2H), 7.93 (d, J = 8.3 Hz, 1 H), 7.85 (s, 1 Hz), 7.8 (s, 1 Hz, 1, 1 Hz). H), 7.71 (dd, J = 3.2, 2.2 Hz, 1 H), 7.69 - 7.60 (m, 3H), 7.55 - 7.40 (m, 2H), 7.26 (d, J = 8.9 Hz, 1 H), 6.99 (t, J = 2.4), Hz, J 8.9, 2.0 Hz, 1 H). 13 C NMR (75 MHz, Acetone-cfe) 5 163.2, 138.0, 134.8, 134.3, 134.3, 134.2, 133.3, 129.4, 129.1 , 128.8, 127.1 , 12.17 , 19.6 126.4, 124.1 , 123.9, 121.5, 120.8, 120.8, 120.3, 110.6, 110.2. HPLC-MS [M + H] + = 353.2, T R = 3.02 (99%). HRMS (ESI) m / z: [M + Na] + black, for C22H16N4O2; 375.1216 found 375.1208.

[0251] Example 6. Synthesis of pyrazole derivatives.

[0252] T a with. 4 p.m.

[0253] 67–69

[0254] Synthesis of Arylpyrazole Carboxylate Derivatives (61-63)

[0255] To a mixture of the corresponding nitro derivative (1 equiv) and ethyl diazoacetate (4 equiv) at room temperature, ethylamine (0.2 equiv) is added and left to react for 24 h. The volatile compounds are then removed under reduced pressure. The residue is washed with a DCM / Hex 8:2 mixture, and the resulting solid residue is used in the next stage.

[0256] Ethyl 4-Phenyl-1H-pyrazole-3-carboxylate (61).

[0257] (E)-2-(nitrovinyl)benzene (150 mg, 1 mmol) is dissolved in ethyl diazoacetate (0.5 mL, 4 mmol). The mixture is then mixed with ethylamine (27 mL, 0.2 mmol) to obtain ethyl 4-phenyl-1 / 7-pyrazol-3-carboxylate.

[0258] 1 H NMR (400 MHz, CDCh) 5 9.47 (brs, 1 H), 7.86 (s, 1 H), 7.52-7.54 (m, 2H), 7.32-7.45 (m, 3H), 4.36 (q, J= 7.1 Hz, 2H), 1.28 (t, J= 7.1 Hz, 3H).

[0259] Ethyl 4-(4-Fluorophenyl)-1H-pyrazole-3-carboxylate (62).

[0260] Dissolve (E)-1-fluoro-4-(2-nitrovinyl)benzene (1.02 g, 6 mmol) in ethyl diazoacetate (19.2 mL, 24 mmol). Tnyethylamine (0.16 mL, 1.2 mmol) was added to the mixture to obtain ethyl 4-(4-fluorophenyl)-1 / 7-pyrazole-3-carboxylate.

[0261] 1 H NMR (400 MHz, CDCh) 5 7.61 (s, 1 Hz), 7.37-7.42 (m, 2H), 7.02 (t, J= 8.7 Hz, 2H), 4.22 (q, J= 7.1 Hz, 2H), 1.19 (t, J= 7.1 Hz, 3H).

[0262] 4-Furan-2-yl-1H-pyrazole-3-ethyl carboxylate (63).

[0263] (E)-2-(2-nitrovinyl)furan (1.02 g, mmol) is dissolved in ethyl diazoacetate (19.2 mL, 24 mmol). Tnethylamine (0.16 mL, 1.2 mmol) was added to the mixture to obtain ethyl 4- furan-2-yl-1 / 7-pyrazole-3-carboxylate.

[0264] 1 H NMR (500 MHz, CDCh) 6 8.12 (s, 1 Hz), 7.45 (t, J= 1.7 Hz, 1 H), 7.09 (d, J= 3.3 Hz, 1 H), 6.49 (dd, J= 3.3, 1 .7 Hz, 1 5 Hz, 4 Hz, 7.2 Hz). 2H), 1.45 (t, J= 7.2 Hz, 3H).

[0265] Synthesis of arylpyrazole carboxylic acid derivatives (64-66)

[0266] The corresponding ethyl arylpyrazole carboxylates are dissolved in 37% HCl (10 mL / 3 mmol) and heated under reflux for 4 hours. The mixture is then allowed to cool to room temperature and the volume is concentrated to half. The resulting solid is filtered and dried to obtain the corresponding acid.

[0267] 4-phenyl-1H-pyrazole-3-carboxylic acid (64).

[0268] Ethyl 4-phenyl-1 / 7-pyrazol-3-carboxylate (61) (660 mg, 3 mmol) and 37% HCI (10 mL) were used to obtain 4-phenyl-1 / 7-pyrazol-3-carboxylic acid in the form of a white solid (366 mg, Rto 66%)

[0269] 1 H NMR (300 MHz, DMSO-cfe) 5 7.95 (s, 1 H), 7.50 (m, 2H), 7.37 (m, 2H), 7.29 (m, 1 H), 3.76 (s, 3H).

[0270] 4-(4-fluorophenyl)-1H-pyrazole-3-carboxylic acid (65).

[0271] Ethyl 4-(4-fluorophenyl)-1 / 7-pyrazol-3-carboxylate (62) (700 mg, 3 mmol) and 37% HCI (10 mL) were used to obtain 4-(4-fluorophenyl-1 / 7-pyrazol-3-carboxylic acid in the form of a white solid (410 mg, Rt: 65%)

[0272] 1 H NMR (300 MHz, DMSO-cfe) 5 7.88 (s, 1 H), 7.64 - 7.50 (m, 2H), 7.20 (t, J = 8.9 Hz, 2H).

[0273] 4-furan-2-yl-1H-pyrazole-3-carboxylic acid (66).

[0274] Ethyl 4-furan-2-yl-1 / 7-pyrazol-3-carboxylate (63) (600 mg, 3 mmol) and HCI (10 mL) were used to obtain 4-furan-2-yl-1 / 7-pyrazol-3-carboxylic acid in the form of a white solid (178 mg, Rt: 33%)

[0275] 1 H NMR (300 MHz, DMSO-cfe) 5 13.53 (brs, 2H), 8.02 (s, 1 H), 7.67 (d, J = 1.7 Hz, 1 H), 7.06 (d, J = 3.4 Hz, 1 H), 6.54 (dd, J = 3.4, 1.8 Hz, 1 H). Synthesis of pyrazolyl carboxamide derivatives (67-69)

[0276] A solution of the corresponding arylpyrazole carboxylic acid (1 equiv), 1 / 7-indazol-5-amine (1.2 equiv), and BOP (1.2 equiv) is added to 3 mL of anhydrous THF, along with DIPEA (1.3 equiv), at room temperature and stirred for 16 hours under an argon atmosphere. Subsequently, H₂O (15 mL) is added, and the mixture is extracted with EtAc (3 x 15 mL). The organic phase is washed with NaCl-saturated water (15 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product is purified by column chromatography using DCM / MeOH eluents (100:0 to 90:10).

[0277] A / -(1 H-lndazol-5-yl)-4-phenyl-1 H-pyrazole-3-carboxamide (67)

[0278] 4-phenyl-1 / 7-pyrazol-3-carboxylic acid (64) (113 mg, 0.6 mmol), 1 / 7-indazol-5-amine (96 mg, 0.72 mmol), BOP (318 mg, 0.72 mmol) and DIPEA (136 pL, 0.78 mmol) were used, obtaining compound 67 as a white solid (69 mg. Rto = 38%).

[0279] 1H NMR (300 MHz, DMSO-cfe) 5 13.46 (s, 1 H), 12.99 (s, 1 H), 10.21 (s, 1 H), 8.28 (d, J =

[0280] 1.8 Hz, 1 H), 8.16 (s, 1 H), 8.04 (s, 1 H), 7.70 - 7.59 (m, 3H), 7.50 (d, J = 8.8 Hz, 1 H), 7.36 (t, J = 7.6 Hz, 2H), 7.36 (t, J = 7.6 Hz, 2H), 7.2. Hz, 1 H). 13 C NMR (75 MHz, DMSO) 5 162.1 , 143.6, 137.4, 133.9, 132.8, 132.5, 129.9, 128.8, 128.5, 126.9, 123.2, 12.3, 21.5, 11.5. 110.4. HPLC-MS [M + H] + = 304.1 , T R = 2.83 (95%). HRMS (ESI) m / z [M + Na] + caled, para C^H^NsONa 326.1018; found 326.1011.

[0281] 4-(4-Fluorophenyl)-A / -(1 H-indazol-5-yl)-1 H-pyrazol-3-carboxamide (68)

[0282] 4-Fluorophenyl-1 H-pyrazol-3-carboxylic acid (65) (123 mg, 0.6 mmol), 1 / 7- indazol-5-amine (96 mg, 0.72 mmol), BOP (318 mg, 0.72 mmol) and DIPEA (1, 380 mmol) were used, obtaining p. the compound 68 as a white solid (77 mg. Rto = 40%).

[0283] 1H NMR (300 MHz, DMSO-cfe) 5 13.49 (s, 1 H), 12.99 (s, 1 H), 10.20 (s, 1 H), 8.28 (d, J =

[0284] 1.9 Hz, 1 H), 8.16 (s, 1 H), 8.04 (s, 1 H), 7.72 - 7.61 (m, 3H), 7.50 (d, 7 = 8.8 Hz, 1 H), 7.20 (t, J= 8.9 Hz, 2H). 13 C NMR (75 MHz, DMSO) 5 162.0, 160.0, 143.3, 137.5, 133.9, 132.4, 130.9, 130.0, 129.2, 123.2, 121.6, 121.4, 11.3, 11.3. 110.4. HPLC-MS [M + H] + = 322.1 , TR = 2.91 (95%). HPLC-MS [M + H] + = 322.1 , TR = 2.91 (95%). HRMS (ESI) m / z: [M + Na] + caled, for Ci7Hi2FN5ONa 344.0924; found 344.0921.

[0285] 4-(Furan-2-yl)-A / -(1 H-indazol-5-yl)-1 / 7-pyrazol-3-carboxamide (69)

[0286] 4-furan-2-yl-1 / 7-pyrazol-3-carboxylic acid (66) (107 mg, 0.6 mmol), 1 / 7- indazole-5-amine (96 mg, 0.72 mmol), BOP (318 mg, 0.72 mmol) and DIPEA (318 mg, 0.78 mmol), obtaining compound 69 as a white solid (58 mg. Rto = 33%). 1H NMR (300 MHz, DMSO-cfe) 5 13.62 (s, 1 H), 13.00 (s, 1 H), 10.17 (s, 1 H), 8.30 (d, J = 1.8 Hz, 1 H), 8.23 ​​(d, J = 1.4 Hz, 1 Hz, 1 H), 8.23 ​​(d, J = 1.4 Hz, 1 H), 7.75 - 7.61 (m, 2H), 7.51 (d, J = 8.9 Hz, 1 H), 7.13 (d, J = 3.3 Hz, 1 H), 6.52 (dd, J = 3.3, 1.9 Hz, 1 H). 13 C NMR (75 MHz, DMSO) 5 161.3, 147.3, 142.0, 141.9, 137.5, 133.9, 132.3, 128.7, 123.2, 121.8, 113.6, 11.9, 11.4, 11.4. 108.7. HPLC-MS [M + H] + = 294.1 , T R = 2.79 (95%). HRMS (ESI) m / z: [M + Na] + caled, for CisHuNsC^Na 316.0810; found 316.0803.

[0287] Example 7. Enzymatic inhibition of SGK1

[0288] The inhibition of the compounds was evaluated using the Kinase-Glo luminescence assay (Zegzouti H, et al. Assay Drug Dev Technol. 2009;7(6):560-572). The luciferin-luciferase system required for the assay (ref. V6711), as well as the recombinant SGK1 protein and the substrate peptide (ref. V2911), were obtained from Promega (Promega Biotech Ibérica, SL). ATP was purchased from Thermo Fisher Scientific (ref. R0441). The buffer solution used contained 40 mM Ths (pH 7.5), 20 mM MgCh, and 0.1 mg mL⁻¹. 1BSA and 50 pM DTT were used. Inhibition assays were performed in 96-well plates with a total volume of 40 pL. To calculate the activity of the compounds, they were initially tested at a concentration of 10 pM, starting from a 10 mM solution of the compound in DMSO. The necessary dilutions were made so that the final DMSO concentration did not exceed 1%. The amount of enzyme used per well was 50 ng, while the peptide was used at a final concentration of 25 pM. The ATP concentration used was 1 pM. The reaction was incubated for 1 hour at 30 °C, and the reaction was stopped by adding 40 pL of Kinase-Glo reagent. After incubation of this reaction for 10 minutes, the luminescence signal generated was measured using the GloMax® Discover Microplate Reader (Promega, ref. GM3000). The maximum enzyme activity (in the absence of the inhibitor) was calculated by the difference between the total ATP and the ATP consumed.The inhibition of the compounds was calculated based on this maximum activity. For those compounds with inhibition greater than 50% at 10 pM, an inhibition curve was designed to calculate the IC50. The IC50 was defined as the concentration of each compound that reduces enzyme activity by 50% compared to the maximum enzyme activity. The data are summarized in Table 1.

[0289] Example 8. Blood-Brain Barrier Permeability. Blood-brain barrier (BBB) ​​passage was predicted using the PAMPA methodology (Parallel Artificial Membrane Permeability Assay) (Di L, et al. Eur J Med Chem. 2003;38(3):223-232). This technique consists of an artificial system of parallel plates separated by a membrane coated with porcine brain lipid that mimics the BBB. To validate the study, 10 FDA-approved commercial drugs with known human permeability were used: enoxacin, hydrocortisone, desipramine, caffeine, ofloxacin, piroxicam, testosterone, promazine, verapamil, and atenolol. The study compounds and controls (1-2 mg) were dissolved in 5 mL of the assay buffer: phosphate-buffered saline (PBS, pH 7.4) and ethanol (EtOH) in a specific ratio. 70:30.Next, they were filtered and subsequently scanned with the Varioskan™ ultraviolet (UV) reader (Thermo Fisher) from wavelength 220 to 400, resulting in a spectrum for each compound in which the wavelengths at which each one absorbs were identified.

[0290] Once the initial concentration of each compound was determined by measuring the absorbance at the established wavelengths (initial absorbance), 180 pL of each sample were added to the 96-well donor plate, the bottom of which is a semipermeable membrane previously coated with 5 pL of porcine brain lipid dissolved in dodecane (20 mg / mL). The 96-well acceptor plate was then filled with 180 pL / well of the assay buffer. The donor plate was then sandwiched over the acceptor plate for 2.30 hours at room temperature in a humid atmosphere.After the incubation period, the donor plate was removed, and the absorbance of the solutions on the acceptor plate was read at the predetermined wavelengths. The effective permeability (Pe) of each compound was calculated based on the correlation established between the experimental Pe and the Pe described in the literature for the 10 control drugs, according to the protocol described in the aforementioned literature (Table 1). This predicts the probability of each compound crossing the blood-brain barrier (BBB), which is classified as high (CNS+), low (CN-), or uncertain (CNS+ / CNS-) (Table 1). Each sample was analyzed at 3 to 5 wavelengths, in triplicate, and in two independent assays. The results are shown as the mean of the two assays with their standard deviation.

[0291] Table 1. Enzyme inhibition and blood-brain barrier (BBB) ​​permeability data of the compounds of the invention. Prediction of BBB passage of the tested compounds: high probability (CNS+), low probability (CNS-), and uncertain probability (CNS+ / CNS-); nd: could not be determined under the experimental conditions.

[0292] Cso refers to the inhibitory concentration needed to inhibit 50% of the kinase activity.

[0293] Pe refers to effective permeability to the blood-brain barrier (BBB) ​​of the compounds; nd refers to not determined due to incompatibility with the conditions of this test.

[0294] Example 9. Neuroprotection against okadaic acid. The neuroprotection of the compounds was tested in the okadaic acid cell model. For this purpose, SH-SY5Y cells were seeded in sterile 96-well plates at a density of 40,000 cells per well in DMEM medium supplemented with 10% FBS and 1% penicillin / streptomycin at 37 °C and 5% CO2. 24 hours after seeding, the cells were incubated for 1 hour with the compounds of interest at the indicated concentration. After this time interval, okadaic acid (Sigma Aldrich, ref. 09381) was added at a final concentration of 30 nM. The final DMSO concentration in the wells did not exceed 1% in any case. 24 hours after treatment, the cells were incubated with a methylthiazolyldiphenyltetrazolium bromide solution (MTT, Merck, ref. M-5666) at a final concentration of 0.5 mg mL' 1The cells were incubated for 3 hours at 37 °C in 5% DMSO. Finally, the cell medium was carefully aspirated, and the formazan crystals were dissolved in 200 pL of DMSO. The UV absorbance signal was measured using a GloMax® Discover Microplate Reader (Promega, ref. GM3000) at 560 nM. The statistical significance of the data was assessed using a one-way ANOVA with Dunnett's post-hoc correction. The data are presented in Figure 1.

[0295] Example 10. In vivo study in a rAAV9-a-SYN model WT (Parkinson's disease)

[0296] To determine whether SGK1 inhibition could have a beneficial effect on the neurodegenerative process of Parkinson's disease (PD), we used a multifactorial murine in vivo model (Lastres-Becker et al., Hum Mol Genet. 2012; 21(14):3173-92.) based on stereotactic administration of a viral vector rAAV9-a-SYN mto overexpress the α-synuclein protein (Figure 2A). Two weeks after injection and on the same day as sacrifice, the animals were evaluated using a double-blind protocol for motor asymmetry based on the elevated body swing test (Figure 2B). The animals injected with rAAV9-α-SYN mThey showed rotation toward the contralateral side. As previously described (Lastres-Becker et al., Antioxid Redox Signal. 2016; 25(2):61-77), these motor alterations indicate a degree of dopaminergic activity, suggesting that the lesion would be large enough to cause motor disability. In contrast, animals treated with the SGK1 inhibitor showed less contralateral rotation, suggesting less neurodegeneration. This finding was confirmed by an immunohistochemical assay against anti-tyrosine hydroxylase (TH) to assess the loss of DAergic neuronal cell bodies in the substantia nigra (Figure 2C). Stereological counting indicated that α-SYN overexpression was present. m It induced a neuronal loss of approximately 70% in TH cells, which was reduced to 40% by treatment with the SGK1 inhibitor (Figure 2D). This finding was also confirmed at the Th mRNA level by qPCR (Figure 2E).

[0297] Example 11. Modulation of phospho-tau levels in cell models (Alzheimer's disease)

[0298] In order to test the potential of SGK1 inhibition as a modulator of the tau protein, the phosphorylation levels of epitopes 396 and 214 were quantified in the SH-SY5Y cell line in the presence of inhibitors 41, 42, 67 and 68. The cells were seeded at a concentration of 5 10 5 cells- m 1Cells were cultured in 6-well plates. 24 h later, the compounds to be evaluated were added at the indicated concentration, and the cells were incubated for 6 h. After lifting and washing the cell pellets, the cells were lysed using 70 pL of buffer containing phosphatase and protease inhibitors on ice with shaking for 15 min. After centrifugation, protein extracts were obtained from the supernatant and quantified using the BCA method. Using the protein extracts, phospho-tau 396 and total tau levels were quantified using two different ELISA kits. 5 and 15 pg of protein extract were used to quantify total tau and p-Ser396 tau levels, and the resulting epitope concentration was normalized according to the amount of extract used. The inhibitors used were able to reduce phospho-tau 396 levels without altering total protein levels (Figure 3A, 3B, 3C).Phospho-tau 214 levels were quantified by Western blot. Protein separation according to molecular weight was performed by electrophoresis on gradient polyacrylamide gels, loading 30 pg per sample. The samples were transferred onto a PDVF membrane and blocked with 5% BSA in TBS-T for 1 h. Subsequently, the membrane was incubated overnight at 4 °C with the p-Ser214 tau antibody. The following day, the membrane was incubated with the HRP-conjugated secondary antibody for 1 h. Finally, the membranes were visualized by chemiluminescence, and the signal was quantified using a luminescence reader. The compounds were able to reduce phospho-tau 214 levels (Figure 3D, 3E). The statistical significance of the data was assessed using a one-way ANOVA with Dunnett's post-hoc correction.

[0299] Example 12. In vivo and in vitro study of inflammatory and endothelial damage (cardiovascular and pulmonary circulation diseases)

[0300] To determine whether SGK1 inhibition could have a beneficial effect on the process of inflammation and vascular damage, and therefore a potential benefit in cardiovascular diseases with a high inflammatory component and endothelial damage such as pulmonary hypertension or myocardial infarction, we used a murine model of acute lung injury in vivo (Clemente-Moragón et al., Eur Heart J. 2020; 41 (46): 4425-4440) based on the administration by tracheal instillation (it) of lipopolysaccharide (LPS, 10mg / Kg), having randomly received the intraperitoneal administration (ip) of the SGK1 inhibitors, compounds 41 and 54 at a dose of 15mg / Kg (Figure 4A).Twenty-four hours after instillation and on the same day as sacrifice, bronchoalveolar lavage fluid was extracted from the animals and evaluated by flow cytometry to characterize and quantify the level of leukocyte infiltration, specifically neutrophils (Figure 4B), the main players in acute inflammation. The lungs were then isolated and rapidly frozen for subsequent analysis of inflammatory markers and endothelial vascular damage using Western blot. Animals treated with SGK1 inhibitors showed less inflammatory cell infiltration in the lungs, particularly neutrophils (CD45). + Ly6G +This finding was confirmed by both experimental techniques (Figure 4B). Furthermore, a lower expression of vascular cell adhesion molecule 1 (VCAM-1) was observed, reflecting the protective effect of these inhibitors against pulmonary endothelial damage induced in this model (Figure 4C). This finding was also confirmed in vitro in a model of TNF-alpha damage in human pulmonary artery endothelial cells. For this model, HPAEC cells were seeded in sterile plates in medium supplemented with 10% FBS and 1% penicillin / streptomycin at 37 °C and 5% CO2. For the pro-inflammatory stimulus, the cells were exposed for 24 hours to TNF-alpha concentrations of 1 and 10 ng / ml, in the presence or absence of the inhibitors (Figure 4D). After 24h, the cells were fixed and stained with an anti-VCAM-1 antibody for study by fluorescence microscopy and quantification using ImageJ.The results showed a reduction in the levels of this adhesion protein, thus confirming the protective role of SGK1 inhibitors on the vascular endothelium.

[0301] Example 13: Analysis of blood pressure and endothelial function in SGK1 inhibitors (cardiovascular diseases)

[0302] This study was conducted in vivo using 12-week-old male C57BL / 6J mice. The mice were randomly divided into six groups: 1) vehicle-treated control group; 2) control group treated with 41 (15 mg / kg / day, 15 days); 3) control group treated with 54 (15 mg / kg / day, 15 days); 4) vehicle + angiotensin II (1.44 mg / kg / day, 14 days) group administered subcutaneously via Alzet model 2002 osmotic minipumps; 5) angiotensin II group treated with 41 (15 mg / kg / day, 15 days); and 6) angiotensin II group treated with 54 (15 mg / kg / day, 15 days).

[0303] Systolic blood pressure was measured by caudal artery plethysmography one week before pump implantation and throughout the experiment. To minimize errors, at least six individual measurements were taken for each animal at each sampling session. After sacrifice, the aorta was isolated, cleaned of fat and connective tissue in a Krebs-Henseleit solution, and vascular function was analyzed that same day.

[0304] To analyze vascular function, 2-mm segments of aorta were mounted on a wire myograph, equilibrated, and then stretched to their optimum internal diameter for the development of active tension. The functional integrity of the arterial segments was assessed by initial exposure to a high-potassium (K+) solution. Concentration-response curves for acetylcholine were then generated in arteries pre-contracted with phenylephrine at a dose that produced approximately 50% of the response to potassium chloride (KCl). Vasodilatory responses were expressed as the percentage of relaxation relative to the pre-contraction. Data are expressed as mean ± standard error of the mean number of animals, calculated using a two-way ANOVA followed by a Bonferroni post-test.

[0305] Angiotensin II infusion increased systolic blood pressure in mice in a time-dependent manner, and this effect was partially prevented by compounds 41 and 54 (Figure 5B). Furthermore, angiotensin II decreased acetylcholine-induced endothelium-dependent relaxant responses in the aorta, an effect that was completely prevented by compounds 41 and 54 (Figure 5C). In control mice, neither compound affected systolic blood pressure or endothelium-dependent vasodilator responses (Figures 5B, C).

[0306] Conclusions

[0307] SGK1 inhibitors, which are permeable to the blood-brain barrier, may be promising drug candidates for the treatment of neurodegenerative diseases characterized by oxidative stress and / or inflammation, such as Parkinson's disease. Furthermore, compounds capable of reducing tau phosphorylation in cellular models may also be good candidates for treating diseases characterized by hyperphosphorylation of this protein, such as Alzheimer's disease.

Claims

CLAIMS 1. Compound of formula (I): or a pharmaceutically acceptable salt thereof, where X is selected from N and CH, R1 is selected from H and optionally substituted C1-C4 alkyl, R2 is selected from aryl and heteroaryl, optionally substituted, R3 is selected from H and halogen, and where the compound is not the following:

2. Compound of formula (I), according to claim 1, where X is CH.

3. Compound of formula (I), according to claim 1 or 2, wherein R1 is H.

4. Compound of formula (I), according to claim 1 or 2, wherein R1 is an unsubstituted or substituted C1-C4 alkyl group, -OH, -COOH, -COOR, -NH2, -NHR or -NRR', R and R' being independently a C1-C4 alkyl group, and combinations thereof.

5. Compound of formula (I), according to any of the preceding claims 1 to 4, wherein R2 is an unsubstituted phenyl or a phenyl substituted by at least one substituent selected from: halogen, -NO2, C1-C4 alkyl, -NH2, -CN, -OH, -COOH, -COOR, R being a C1-C4 alkyl.

6. Compound of formula (I), according to any of the preceding claims 1 to 4, wherein R2 is an unsubstituted or substituted heteroaryl radical with at least one group selected from: halogen, NO2, C1-C4 alkyl, -NH2, -CN, -OH, -COOH, -COOR, R being a C1-C4 alkyl, and combinations thereof.

7. Compound of formula (I), according to any of the preceding claims 1 to 4, wherein R2 is an unsubstituted heteroaryl radical selected from furyl, naphthyl and pyridyl.

8. Compound of formula (I), according to any of the preceding claims 1 to 4, wherein R3 is H.

9. Compound of formula (I), according to any of claims 1 to 4 above, wherein R3 is a Cl.

10. Compound according to claim 1 selected from the following list: A / -(1 / 7-indazol-5-yl)-4-phen i I- 1 / 7-pyrrole-3-carboxamide 4-(2-bromophenyl)-A / -(1 / 7-indazol-5-i I)- 1 / 7-pyrrole-3-carboxamide 4-(3-Bromophenyl)-A / -(1 / 7-indazol-5-i I)- 1 / 7-pyrrole-3-carboxamide 4-(4-Bromophenyl)-A / -(1 / 7-i ndazol-5-i I)- 1 H-pyrrole-3-carboxamide 4-(2-chlorophenyl)-A / -(1 / 7-indazol-5-i I)- 1 / 7-pyrrole-3-carboxamide 4-(3-chlorophenyl)-A / -(1 H-indazol-5-yl)- 1 H-pyrrole-3-carboxamide 4-(4-chlorophenyl)-A / -(1 / 7-indazol-5-i I)- 1 / 7-pyrrole-3-carboxamide 4-(4-Fluorophenyl)-A / -(1 / 7-indazol-5-i I)- 1 / 7-pyrrole-3-carboxamide A / -(1 / 7-indazol-5-yl)-4-(4-n itrofeni I)- 1 / 7-pyrrole-3-carboxamide A / -(1 / 7-indazol-5-yl)-4-(4-isopropylphenyl)-1 / 7-pyrrole-3-carboxamide A / -( 1 / 7-indazol-5-yl)-4-(p-tol i)- 1 / 7-pyrrol-3-carboxamida 4-(2,4-Dimethylphenyl)-A / -(1 / 7-indazol-5-yl)-1 / 7-pyrrol-3-carboxamide N-(4-Chloro-1 / 7-indazol-5-yl)-4-(4-chlorophenyl)-1 / 7-pyrrol-3-carboxamida 4-(3,4-Dichlorophenyl)-A / -(1 / 7-indazol-5-yl)-1 / 7-pyrrol-3-carboxamida N-(1 / 7-indazol-5-yl)-4-(pi rid i n-3-i I)- 1 H-pyrrol-3-carboxamida 4-(4-chlorophenyl)-N-(1 / 7-indazol-5-yl)-1-methyl-1 / 7-pyrrole-3-carboxamide 4-(3,4-dichlorophenyl)-A / -(1 / 7-indazol-5-yl)-1-methyl-1 / 7-pyrrol-3-carboxamida 4-(4-chlorophenyl)-1-(3-(dimethylamino)propyl)-N-(1,7-indazol-5-yl)-1 H-pyrrol-3- carboxamide A / -(1 / 7-indazol-5-yl)-4-(naphthalen-1-yl)-1 / 7-pyrrol-3-carboxamide A / -( 1 / 7-i ndazol-5-yl)-4-phen i I- 1 H-pyrazol-3-carboxamida 4-(4-Fluorophenyl)-A / -(1 / 7-indazol-5-yl)-1 / 7-pyrazol-3-carboxamida 4-(Furan-2-yl)- / V-(1 / 7-i ndazol-5-i I)- 1 H-pyrazol-3-carboxamida.

11. Compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein X, Ri, R2 and R3 are as defined in any one of claims 1 to 10 for use as a medicament.

12. Compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein X, R1, R2 and R3 are as defined in any one of claims 1 to 10 for use in the treatment of a neurodegenerative or cardiovascular disease.

13. Compound for use according to claim 12, wherein the neurodegenerative disease is selected from Alzheimer's disease, Parkinson's disease, Pick's disease, progressive supranuclear palsy, corticobasal degeneration, frontotemporal dementia, chromosome 17-linked parkinsonism, argyrophilic dementia, post-encephalitic parkinsonism, and primary age-related tauopathy.

14. Compound for use according to claim 13, wherein the neurodegenerative disease is Parkinson's disease.

15. Compound for use according to claim 13, wherein the neurodegenerative disease is Alzheimer's disease.

16. Compound for use according to claim 12, wherein cardiovascular disease is selected from stroke, heart attack, pulmonary hypertension, systemic hypertension, long QT syndrome and ventricular arrhythmia.

17. Pharmaceutical composition comprising a compound of formula (I) according to any of claims 1 to 10 together with pharmaceutically acceptable excipients, adjuvants and / or vehicles.