New derivatives useful as antibacterial agents

Abstract

The invention relates to new derivatives useful as antibacterial agents, specifically to a compound of formula (I) for use to treat and / or prevent a disease caused by a bacterium, in particular wherein the disease is caused by a gram-negative bacterium, such as Acinetobacter baumannii or Escherichia coli, wherein group R1-R4, X and Y have the meaning defined in the description. Formula (I)

Description

[0001] DESCRIPTION

[0002] New derivatives useful as antibacterial agents

[0003] The present invention relates to a compound of formula I for the treatment and / or prevention of a disease caused by a bacterium, in particular where the disease is caused by a gram-negative bacterium such as Acinetobacter baumanii and Escherichia coli.

[0004] BACKGROUND OF THE INVENTION

[0005] Gram-negative bacilli are highly efficient at acquiring antimicrobial resistance through genomic, transcriptomic, and proteomic changes (see Kung VL, Ozer EA, Hauser AR. The accessory genome of Pseudomonas aeruginosa. Microbiol Mol Biol Rev. 2010;74(4):621-41 ; and Yelin I, Kishony R. Antibiotic Resistance. Cell. 2018;172(5):1136-1136. e1 ). The problem of antimicrobial resistance is compounded by the immediate threat of a reduction in the discovery and development of new antibiotics, as highlighted by the World Health Organization (WHO) (Tacconelli E, Carrara E, Savoldi A, et al. Discovery, research, and development of new antibiotics: the WHO priority list of antibiotic-resistant bacteria and tuberculosis. Lancet Infect Dis. 2018;18(3):318-327) and other European institutions (see, e.g., Árdal C, Baraldi E, Ciabuschi F, et al. To the G20: incentivizing antibacterial research and development. Lancet Infect Dis. 2017;17(8):799-801 ).Consequently, new solutions are urgently needed in the field of antimicrobial therapy, such as the development of new therapeutic strategies such as the use of non-antibiotic agents and / or the repurposing of drugs for use as monotherapy or in combination with one of the few clinically relevant antibiotics.

[0006] Therefore, it would be desirable to have new antibacterial agents with improved properties for the treatment and / or prevention of a bacterial disease caused by gram-negative bacteria.

[0007] DESCRIPTION OF THE INVENTION

[0008] The present invention presents a family of compounds that possess antibacterial activity against reference strains of A. baumannii and E. coli with a minimum inhibitory concentration (MIC) between 4 and 64 μg / mL. They also exhibit activity against colistin-resistant clinical strains of A. baumannii and E. coli.

[0009] In a first aspect, the present invention relates to a compound of formula I: or a pharmaceutically acceptable salt thereof, wherein:

[0010] X represents S or O;

[0011] Y represents CH or N;

[0012] R 1 represents phenyl or C1-C4 alkyl, where the phenyl group is optionally substituted by a halogen group, preferably where the halogen group is Cl, and where C1-C4 alkyl is substituted by a phenyl group or a Cy group 1 ;

[0013] Cy 1 represents a 6-membered saturated heterocycle containing 1 or 2 heteroatoms in its structure selected from N and O, which is bonded to the rest of the molecule by any available C or N atom and which is optionally substituted by a benzyl group, preferably Cy 1represents a 6-membered saturated heterocycle containing 1 N in its structure, which is linked to the rest of the molecule by an available C atom and which is optionally substituted by a benzyl group, and more preferably Cy 1 represents N-benzylpiperidine; and each R 2 , R 3 and R 4 independently represent H or a group provided that one of each R 2 , R 3 and R 4 is distinct from H and the other two groups are H, for use for the treatment and / or prevention of a disease caused by a bacterium, preferably for the treatment and / or prevention of a disease caused by a gram-negative bacterium, and more preferably where the bacterium is A. baumanii and E. coli.

[0014] In another embodiment the invention relates to the compound of formula I for the use defined above, where R 1represents C1-C4 alkyl substituted by a phenyl group. In another embodiment, the invention relates to the compound of formula I for the use defined above, wherein:

[0015] R 1 represents C1-C4 alkyl substituted by a Cy group 1 ; and

[0016] Cy 1 represents a 6-membered saturated heterocycle containing 1 or 2 heteroatoms in its structure selected from N and O, which is bonded to the rest of the molecule by any available C or N atom and which is optionally substituted by a benzyl group, preferably Cy 1 represents a 6-membered saturated heterocycle containing 1 N in its structure, which is linked to the rest of the molecule by an available C atom and which is optionally substituted by a benzyl group, and more preferably Cy 1 represents N-benzylpiperidine.

[0017] In another embodiment the invention relates to the compound of formula I for the use defined above, where:

[0018] X represents S; and

[0019] And it represents CH.

[0020] In another embodiment the invention relates to the compound of formula I for the use defined above, where:

[0021] X represents O; and

[0022] And it represents CH.

[0023] In another embodiment the invention relates to the compound of formula I for the use defined above, where:

[0024] X represents S; and

[0025] And it stands for N.

[0026] In another embodiment the invention relates to the compound of formula I for the use defined above, where:

[0027] X represents S or O;

[0028] Y represents CH or N;

[0029] R 1represents phenyl or C1-C4 alkyl, where the phenyl group is optionally substituted by a halogen group, preferably where the halogen group is Cl, and where C1-C4 alkyl is substituted by a phenyl group or a Cy group 1 ; and each R 2 , R 3 and R 4 independently represent H or a group provided that one of each R 2 , R 3 and R 4 is distinct from H and the other two groups are H.

[0030] In another embodiment the invention relates to the compound of formula I for the use defined above, where:

[0031] X represents S;

[0032] And it stands for CH;

[0033] R 1 represents phenyl or C1-C4 alkyl, where the phenyl group is optionally substituted by a halogen group, preferably where the halogen group is Cl, and where C1-C4 alkyl is substituted by a phenyl group or a Cy group 1 ; and each R2 , R 3 and R 4 independently represent H or a group , provided that one of each R 2 , R 3 and R 4 is distinct from H and the other two groups are H.

[0034] In another embodiment, the invention relates to the compound of formula I for the use defined above, wherein the compound of formula I is selected from:

[0035] N-Phenyl-5-(2-(piperidin-4-yloxy)phenyl)thiophene-2-carboxamide (55);

[0036] N-(4-Chlorophenyl)-5-(2-(piperidin-4-yloxy)phenyl)thiophene-2-carboxamide (56);

[0037] N-(3-Chlorophenyl)-5-(2-(piperidin-4-yloxy)phenyl)thiophene-2-carboxamide (57);

[0038] N-Phenethyl-5-(2-(piperidin-4-yloxy)phenyl)thiophene-2-carboxamide (58);

[0039] N-(2-(1-Benzylpiperidin-4-yl)ethyl)-5-(2-(piperidin-4-yloxy)phenyl)thiophene-2-carboxamide (59);

[0040] N-Phenyl-5-(3-(piperidin-4-yloxy)phenyl)thiophene-2-carboxamide (60);

[0041] N-(4-Chlorophenyl)-5-(3-(piperidin-4-yloxy)phenyl)thiophene-2-carboxamide (61);

[0042] N-(3-Chlorophenyl)-5-(3-(piperidin-4-yloxy)phenyl)thiophene-2-carboxamide (62);

[0043] N-Phenyl-5-(4-(piperidin-4-yloxy)phenyl)thiophene-2-carboxamide (63);

[0044] N-(3-Chlorophenyl)-5-(4-(piperidin-4-yloxy)phenyl)thiophene-2-carboxamide (64);

[0045] N-(2-(1-Benzylpiperidin-4-yl)ethyl)-5-(4-(piperidin-4-yloxy)phenyl)thiophene-2-carboxamide (65);

[0046] N-Phenyl-2-(4-(piperidin-4-yloxy)phenyl)thiazol-5-carboxamide (66);

[0047] N-(2-(1-Benzylpiperidin-4-yl)ethyl)-2-(4-(piperidin-4-yloxy)phenyl)thiazol-5-carboxamide (67);

[0048] N-Phenyl-5-(4-(piperidin-4-yloxy)phenyl)furan-2-carboxamide (68);

[0049] N-(3-Chlorophenyl)-5-(4-(piperidin-4-yloxy)phenyl)furan-2-carboxamide (69);

[0050] N-(2-(1-Benzylpiperidin-4-yl)ethyl)-5-(4-(piperidin-4-yloxy)phenyl)furan-2-carboxamide (70);

[0051] N-Phenethyl-2-(2-(piperidin-4-yloxy)phenyl)thiazole-5-carboxamide (71);

[0052] N-Phenyl-2-(3-(piperidin-4-yloxy)phenyl)thiazole-5-carboxamide (72);

[0053] N-(4-Chlorophenyl)-5-(2-(piperidin-4-yloxy)phenyl)furan-2-carboxamide (73); N-Phenyl-5-(2-(piperidin-4-yloxy)phenyl)furan-2-carboxamide (74);

[0054] N-(2-(1-Benzylpiperidin-4-yl)ethyl)-5-(2-(piperidin-4-yloxy)phenyl)furan-2-carboxamide (75);

[0055] N-Phenethyl-5-(2-(piperidin-4-yloxy)phenyl)furan-2-carboxamide (76); and N-Phenyl-5-(3-(piperidin-4-yloxy)phenyl)furan-2-carboxamide (77).

[0056] In another embodiment, the invention relates to a compound of formula II: or a pharmaceutically acceptable salt thereof, wherein:

[0057] X represents S or O;

[0058] Y represents CH or N;

[0059] R1 represents phenyl or C1-C4 alkyl, where the phenyl group is optionally substituted by a halogen group, preferably where the halogen group is Cl, and where C1-C4 alkyl is substituted by a phenyl group or a Cy group 1 ;

[0060] Cy 1 represents a 6-membered saturated heterocycle containing 1 or 2 heteroatoms in its structure selected from N and O, which is bonded to the rest of the molecule by any available C or N atom and which is optionally substituted by a benzyl group, preferably Cy 1 represents a 6-membered saturated heterocycle containing 1 N in its structure, which is linked to the rest of the molecule by an available C atom and which is optionally substituted by a benzyl group, and more preferably Cy 1 represents N-benzylpiperidine; and each R 2 , R 3 and R 4 independently represent H or a group provided that one of each R2 , R 3 and R 4 is distinct from H and the other two groups are H, and with the condition that when X is S, Y is not CH.

[0061] In another embodiment the invention relates to the compound of formula II selected from:

[0062] N-Phenyl-2-(4-(piperidin-4-yloxy)phenyl)thiazole-5-carboxamide (66);

[0063] N-(2-(1-Benzylpiperidin-4-yl)ethyl)-2-(4-(piperidin-4-yloxy)phenyl)thiazole-5-carboxamide (67);

[0064] N-Phenyl-5-(4-(piperidin-4-yloxy)phenyl)furan-2-carboxamide (68);

[0065] N-(3-Chlorophenyl)-5-(4-(piperidin-4-yloxy)phenyl)furan-2-carboxamide (69); N-(2-(1-Benzylpiperidin-4-yl)ethyl)-5-(4-(piperidin-4-yloxy)phenyl)furan-2-carboxamide (70); N-Phenethyl-2-(2-(piperidin-4-yloxy)phenyl)thiazole-5-carboxamide (71);

[0066] N-Phenyl-2-(3-(piperidin-4-yloxy)phenyl)thiazole-5-carboxamide (72);

[0067] N-(4-Chlorophenyl)-5-(2-(piperidin-4-yloxy)phenyl)furan-2-carboxamide (73);

[0068] N-Phenyl-5-(2-(piperidin-4-yloxy)phenyl)furan-2-carboxamide (74);

[0069] N-(2-(1-Benzylpiperidin-4-yl)ethyl)-5-(2-(piperidin-4-yloxy)phenyl)furan-2-carboxamide (75); N-Phenethyl-5-(2-(piperidin-4-yloxy)phenyl)furan-2-carboxamide (76); and N-Phenyl-5-(3-(piperidin-4-yloxy)phenyl)furan-2-carboxamide (77).

[0070] Another aspect of the invention relates to a pharmaceutical composition comprising a compound of formula II or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

[0071] Another aspect of the invention relates to the compound of formula II defined above or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0072] In the above definitions, the term C1-4 alkyl, as a group or part of a group, means a straight or branched chain alkyl group containing from 1 to 4 C atoms and includes the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl groups.

[0073] A halogen group means fluorine, chlorine, bromine or iodine.

[0074] Throughout the present description, the term “treatment” refers to eliminating, reducing, or diminishing the cause or effects of a disease. For the purposes of this invention, treatment includes, but is not limited to, alleviating, diminishing, or eliminating one or more symptoms of the disease; reducing the degree of the disease; stabilizing (i.e., not worsening) the disease state; delaying or slowing the progression of the disease; relieving or improving the disease state; and remitting (whether total or partial).

[0075] As used herein, the term “prevention” refers to preventing the onset of the disease from occurring in a patient who is predisposed or has risk factors, but who is not yet showing symptoms of the disease. Prevention also includes preventing the recurrence of a disease in a subject who has previously suffered from said disease. The present invention also relates to a pharmaceutical composition comprising a compound of the invention (or a pharmaceutically acceptable salt or solvate thereof) and one or more pharmaceutically acceptable excipients. The excipients must be “acceptable” in the sense of being compatible with the other ingredients of the composition and not being harmful to the person taking said composition.

[0076] The compounds of the present invention can be administered in the form of any pharmaceutical formulation, the nature of which, as is well known, will depend on the nature of the active ingredient and its route of administration. In principle, any route of administration can be used, for example, oral, parenteral, nasal, ocular, rectal, and topical.

[0077] Throughout the description and claims, the word "comprises" and its variants 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 be apparent partly from the description and partly from the practice of the invention. The following examples are provided by way of illustration and are not intended to be limiting of the present invention.

[0078] EXAMPLES

[0079] The invention will then be illustrated by tests carried out by the inventors, which demonstrate the effectiveness of the product of the invention.

[0080] Procedures . Analytical grade solvents were used for all reactions. Argon was used to carry out the reactions in an inert atmosphere. The reagents used for the reactions were purchased from Sigma Aldrich or Fluorochem. The reactions under microwave irradiation were carried out in an InitiatorTM device (Biotage®). Melting points were recorded with a Büchi Melting point M-560 apparatus. The NMR spectra of 1 H and 13C were recorded on a Bruker AVI II 300 MHz BACS60 or Bruker AV 500 MHz spectrometer located at the Research Support Center of the Complutense University of Madrid. The abbreviations used are s = singlet, d = doublet, t = triplet, q = quadruplet, dd = doublet of doublets, m = multiplet. Coupling constants (J) are expressed in Hz. Mass spectra were acquired on a Thermo Mod. Finnigan™ LXQ™ spectrometer coupled to a high performance liquid chromatograph (HPLC), using electrospray ionization (ESI). Pre-coated aluminum foils (ALUGRAM® Xtra SIL G / UV254) were used for thin layer chromatography. Column chromatographies were performed on silica gel 60 (Merk) manually or automatically using the IsoleraOne equipment (Biotage®).The exact molecular mass was determined using an Agilent 1200LC liquid chromatograph coupled to an Agilent 6500 mass spectrometer with an ESI / APCI ionization source and a hybrid quadrupole-time-of-flight (QTOF) analyzer located at the Mass Spectrometry Service of the Institute of General Organic Chemistry (IQOG-CSIC). The purity of the final compounds was verified to be >95% by HPLC analysis. The HPLC conditions for purity assessment were as follows: Surveyor HPLC equipped with a Surveyor PDA plus a UV-VIS detector; ZORBAX® SB-C18 column (3.5 µm, 4.6 mm x 50 mm); H2O / CH3CN gradient elution from 100 / 0 to 0 / 100 for 5 min; flow rate 800 µL / min; UV wavelength 254 nm. All final compounds are >95% pure by HPLC-MS.

[0081] Three different gradient conditions were used:

[0082] Gradient I: 23 eC, flow rate of 0.5 mL / min. Gradient elution with mobile phases (A) H2O containing 0.1% volume / volume (v / v) formic acid and (B) CH3CN containing 0.1% (v / v) formic acid. The gradient conditions were initially 5% B, increasing linearly to 95% B over 5 min, remaining at 95% B for 1.45 min, and then decreasing to 10% B over 0.55 min.

[0083] Gradient II: 23 e C, flow rate of 0.8 mL / min. Gradient elution with mobile phases (A) H2O containing 0.1% volume / volume (v / v) formic acid and (B) CH3CN containing 0.1% (v / v) formic acid. The gradient conditions were initially 5% B, increasing linearly to 100% B over 3 min, remaining at 100% B for 1.45 min, and then decreasing to 5% B over 0.55 min.

[0084] Gradient III: 23 eC, flow rate of 0.8 mL / min. Gradient elution with mobile phases (A) H2O containing 0.1% volume / volume (v / v) formic acid and (B) CH3CN containing 0.1% (v / v) formic acid. The gradient conditions were initially 10% B, increasing linearly to 95% B over 5 min, remaining at 95% B for 4 min, and then decreasing to 0% B over 1 min.

[0085] Example 1: Synthesis of compounds of formula (I)

[0086] The final compounds 55-77 have been synthesized, whose antibacterial activity has been evaluated:

[0087] General procedure A for the synthesis of brominated heterocyclic derivatives 1-13.

[0088] X = S; Z = CH X = O; Z = CH X = S; Z = NH

[0089] Scheme 1. Synthesis of brominated derivatives, i) EDCI, HOBt, EtsN, CH2CI2, O e C a ta, 24 hours.

[0090] A solution of the corresponding amine (1.02 equiv.) in CH2CI2 was slowly added to a solution of the corresponding bromocarboxylic acid (1 equiv.), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (2 equiv.), 1-hydroxybenzotriazole (HOBt) (1 or 2 equiv.) and EtsN (3 equiv.) in CH2CI2 at 0 e C. The mixture was stirred for 24 hours at room temperature for all compounds except 11 (5 days) and 12 (4 days). The crude oil was washed with H2O, saturated NH4Cl solution, saturated NaCl solution and then dried over anhydrous Mg2SO4. The drying agent was filtered and the volatiles were evaporated to dryness in vacuo. The resulting residues were purified by flash column chromatography using solvent mixtures as eluents, as indicated in each case.

[0091] 5-Bromo-N-phenylthiophene-2-carboxamide (1). The compound was prepared by the reaction of 5-bromothiophene-2-carboxylic acid (1 mmol, 207 mg), aniline (1.02 mmol, 93 pL), EDCI (1 mmol, 155 mg), EtsN (2 mmol, 278 pL), HOBt (1 mmol, 135 mg) and CH2Cl2 as solvent (5 mL) according to procedure A. Compound 1 was obtained pure after washing. Yield: 170 mg (60%) as a white solid. 1 H NMR (300 MHz, DMSO- d6) 5 10.28 (s, 1 H), 7.87 (d, J = 4.1 Hz, 1 H), 7.75 - 7.64 (m, 2H), 7.43 - 7.27 (m, 3H), 7.19 - 7.03 (m, 1 H). 13 C NMR (75 MHz, DMSO) 5 159.2, 142.3, 138.8, 132.1, 130.3, 129.1, 124.4, 120.8, 1 18.2.

[0092] 5-Bromo-N-(4-chlorophenyl)thiophene-2-carboxamide (2). The compound was prepared by the reaction of 5-bromothiophene-2-carboxylic acid (3 mmol, 621 mg), 4-chloroaniline (3.06 mmol, 398 mg), EDCI (3 mmol, 465 mg), EtsN (6 mmol, 835 pL), HOBt (3 mmol, 405 mg) and CH2Cl2 as solvent (10 mL) according to procedure A. Compound 2 was obtained pure after washing. Yield: 368 mg (39%) as a white solid. 1 H NMR (300 MHz, DMSO-de) 5 10.39 (s, 1 H), 7.85 (d, J = 4.1 Hz, 1 H), 7 .77 - 7.70 (m, 2H), 7.46 - 7.39 (m, 2H), 7.38 (d, J = 4.1 Hz, 1 H). 13 C NMR (75 MHz, CDCI3) 5 158.8, 141.4, 137.4,

[0093] 131.8, 130.1, 128.7 (2C), 127.6, 121.9 (2C), 118.1.

[0094] 5-Bromo-N-(3-chlorophenyl)thiophene-2-carboxamide (3). The compound was prepared by reaction of 5-bromothiophene-2-carboxylic acid (1.5 mmol, 310 mg), 3-chloroaniline (1.53 mmol, 194 mg), EDCI (1.5 mmol, 233 mg), EtsN (3 mmol, 417 pL), HOBt (1.5 mmol, 203 mg) and CH2Cl2 as solvent (6 mL) according to procedure A. Purification: Hex / AcOEt (9:1). Yield: 190 mg (40%) as white solid. 1 H NMR (300 MHz, DMSO-de) 5 10.41 (s, 1 H), 7.91 - 7.82 (m, 2H), 7.63 (ddd, J = 8.2, 2.1, 1.0 Hz, 1 H), 7.43 - 7.35 (m, 2H), 7.17 (ddd, J = 8.0, 2.1, 1.0Hz, 1H). 13 C NMR (75 MHz, DMSO-d6) 5 158.9, 141 .3,

[0095] 139.9, 133.0, 131.8, 130.4, 130.3, 123.6, 119.7, 118.6, 118.3.

[0096] 5-Bromo-N-phenethylthiophene-2-carboxamide (4). The compound was prepared by the reaction of 5-bromothiophene-2-carboxylic acid (3 mmol, 621 mg), 2-phenethylamine (3.06 mmol, 383 pL), EDCI (3 mmol, 465 mg), Et3N (6 mmol, 835 pL), HOBt (3 mmol, 405 mg) and CH2Cl2 as solvent (10 mL) according to procedure A. Compound 4 was obtained pure after washing. Yield: 253 mg (56%) as a white solid. 1 H NMR (300 MHz, DMSO-de) 5 8.68 (t, J = 5.7 Hz, 1 H), 7.55 (d, J = 4.0 Hz, 1 H), 7.34 - 7.16 (m, 6H), 3.43 (dt, J = 8.0, 6.2 Hz, 2H), 2.81 (dd, J = 8.2, 6.6Hz, 2H). 13 C NMR (75 MHz, DMSO-d6) 5

[0097] 159.9, 141.9, 139.3, 131.5, 128.7 (2C), 128.5, 128.4 (2C), 126.2, 1 16.5, 40.8, 35.1.

[0098] N-(2-(1-Benzylpiperidin-4-yl)ethyl)-5-bromothiophene-2-carboxamide (5). The compound was prepared by the reaction of 5-bromothiophene-2-carboxylic acid (2 mmol, 414 mg), 2-(1-benzylpiperidin-4-yl)ethan-1-amine (2.04 mmol, 445 mg), EDCI (2 mmol, 310 mg), Et3N (4 mmol, 557 pL), HOBt (2 mmol, 270 mg) and CH2Cl2 as solvent (6 mL) according to procedure A. Compound 5 was obtained pure after washing. Yield: 643 mg (79%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) 5 8.51 (t, J = 5.6 Hz, 1 H), 7.56 (d, J = 4.0 Hz, 1 H), 7.34 - 7.21 (m, 7H), 3.42 (s, 2H), 3.24 (q, J = 6.7 Hz, 2H), 2.83 - 2.71 (m, 2H), 1 .94 - 1 .82 (m, 2H), 1 .69 - 1 .60 (m, 2H), 1 .47 - 1 .39 (m, 2H), 1 .33 - 1 .22 (m, 1 H), 1 .22 - 1 .08 (m, 2H). 13 C NMR (75 MHz, DMSO-d6) 5 159.8, 142.1, 138.7,

[0099] 131.4, 128.7 (2C), 128.4, 128.1 (2C), 126.7, 116.4, 62.5, 53.2 (2C), 36.8, 35.8, 32.9, 31.8 (2C).

[0100] 2-Bromo-N-phenylthiazole-5-carboxamide (6). The compound was prepared by reaction of 2-bromothiazole-5-carboxylic acid (4.81 mmol, 1 g), aniline (4.90 mmol, 457 mg), EDCI (4.81 mmol, 919 mg), EtsN (9.62 mmol, 1.34 mL), HOBt (4.81 mmol, 649 mg) and CH2Cl2 as solvent (15 mL) according to procedure A. Purification: Hex / AcOEt (7:3). Yield: 313 mg (23%) as white solid. 1 H NMR (300 MHz, DMSO-de) 5 10.48 (s, 1 H), 8.46 (s, 1 H), 7.72 - 7.65 (m, 2H), 7.41 - 7.32 (m, 2H), 7.18 - 7.09 (m, 1 H). 13 C NMR (75 MHz, DMSO-d6) 5 157.3, 143.8, 140.4, 139.9, 138.0, 128.8 (2C), 124.4, 120.5 (2C).

[0101] 2-Bromo-N-phenethylthiazole-5-carboxamide (7). The compound was prepared by reaction of 2-bromothiazole-5-carboxylic acid (4.81 mmol, 1 g), 2-phenethylamine (4.90 mmol, 614 pL), EDCI (4.81 mmol, 919 mg), EtsN (9.62 mmol, 1.34 mL), HOBt (4.81 mmol, 649 mg) and CH2Cl2 as solvent (15 mL) according to procedure A. Purification: Hex / AcOEt (7:3). Yield: 619 mg (41%) as white solid. 1 H NMR (300 MHz, DMSO-de) 5 8.87 (t, J = 5.7 Hz, 1 H), 8.18 (s, 1 H), 7.34 - 7.16 (m, 5H), 3.45 (ddd, J = 8.3, 7.1, 5.7 Hz, 2H), 2.82 (dd, J = 8.2, 6.6Hz, 2H). 13 C NMR (75 MHz, DMSO-d6) 5 158.5, 142.7, 139.7,

[0102] 139.5, 139.1, 128.6 (2C), 128.4 (2C), 126.2, 40.8, 34.9.

[0103] N-(2-(1-Benzylpiperidin-4-yl)ethyl)-2-bromothiazole-5-carboxamide (8). The compound was prepared by the reaction of 2-bromothiazole-5-carboxylic acid (4.81 mmol, 1 g), 2-(1-benzylpiperidin-4-yl)ethan-1-amine (4.90 mmol, 1.1 g), EDCI (4.81 mmol, 919 mg), EtsN (9.62 mmol, 1.34 mL), HOBt (4.81 mmol, 649 mg) and CH2Cl2 as solvent (15 mL) according to procedure A. Compound 8 was obtained pure after washing. Yield: 668 mg (34%) as a white solid. 1 H NMR (300 MHz, DMSO-de) 6 8.72 (s, 1 H), 8.19 (s, 1 H), 7.34 - 7.22 (m, 5H), 3.46 (s, 2H), 3.24 (q, J = 6.6 Hz, 2H), 2.88 - 2.72 (m, 2H), 2.03 - 1 .84 (m, 2H), 1 .74 - 1 .57 (m, 2H), 1 .44 (q, J = 6.7 Hz, 2H), 1 .36 - 1 .24 (m, 1 H), 1 .24 - 1 .06 (m, 2H). 13C NMR (75 MHz, DMSO-de) 5 158.4, 142.7, 139.8, 139.4, 138.4, 128.9 (2C), 128.1 (2C), 126.9, 62.3, 53.1 (2C), 36.8, 35.6, 32.7, 31.6 (2C). 5-Bromo-N-phenylfuran-2-carboxamide (9). The compound was prepared by reaction of 5-bromofuran-2-carboxylic acid (5.23 mmol, 1.0 g), aniline (5.33 mmol, 480 pL), EDCI (10.46 mmol, 2.0 g), EtsN (10.46 mmol, 1.5 mL), HOBt (5.23 mmol, 705 mg) and CH2CI2 as solvent (17 mL) according to procedure A. Purification: Hex / AcOEt (9:1). Yield: 1.1 g (68%) as white solid. 1 H NMR (300 MHz, DMSO-de) 5 10.34 (s, 1 H), 7.79 - 7.74 (m, 2H), 7.46 - 7.31 (m, 3H), 6.84 (d, J = 3.6 Hz, 1 H). 13 C NMR (75 MHz, DMSO-de) 155.1, 149.3, 138.3, 128.7 (2C), 125.3, 123.9, 120.5 (2C), 117.1, 114.3.

[0104] 5-Bromo-N-(4-chlorophenyl)furan-2-carboxamide (10). The compound was prepared by the reaction of 5-bromofuran-2-carboxylic acid (5.23 mmol, 1.0 g), 4-chloroaniline (5.33 mmol, 677 mg), EDCI (10.46 mmol, 2.0 g), EtsN (10.46 mmol, 1.5 mL), HOBt (10.46 mmol, 1.41 g) and CH2Cl2 as solvent (17 mL) according to procedure A. Purification: CH2Cl2 / MeOH (95:5). Yield: 1.1 g (80%) as a white solid. 1 H NMR (300 MHz, DMSO-de) 5 10.34 (s, 1 H), 7.82 - 7.70 (m, 2H), 7.46 - 7.31 (m, 3H), 6.84 (d, J = 3.6 Hz, 1 H). 13 C NMR (75 MHz, DMSO) 5 155.1, 149.0, 137.3, 128.6 (2C), 127.6, 125.6, 121.9 (2C), 1 17.4, 1 14.4.

[0105] 5-Bromo-N-(3-chlorophenyl)furan-2-carboxamide (11). The compound was prepared by reaction of 5-bromofuran-2-carboxylic acid (7.85 mmol, 1.5 g), 3-chloroaniline (8.01 mmol, 1.02 g), EDCI (7.85 mmol, 1.22 g), EtsN (15.7 mmol, 2.2 mL), HOBt (7.85 mmol, 1.06 mg) and CH2Cl2 as solvent (16 mL) according to procedure A for 5 days. Purification: Hex / AcOEt (9:1). Yield: 760 mg (32%) as orange solid. 1 H NMR (300 MHz, DMSO-de) 5 10.36 (s, 1 H), 7.90 (t, J = 2.0 Hz, 1 H), 7.67 (ddd, J = 8.2, 2.0, 1.0 Hz, 1 H), 7.44 - 7.32 (m, 2H), 7.16 (ddd, J = 8.0, 2.1 , 1 .0 Hz, 1 H), 6.85 (d, J = 3.6 Hz, 1 H). 13 C NMR (75 MHz, DMSO-de) 5 155.2, 148.9, 139.8, 132.9, 130.4, 125.7, 123.6, 119.8, 118.7, 1 17.6, 1 14.4.

[0106] N-(2-(1-Benzylpiperidin-4-yl)ethyl)-5-bromofuran-2-carboxamide (12). The compound was prepared by reacting 5-bromofuran-2-carboxylic acid (7.85 mmol, 1.5 g), 2-(1-benzylpiperidin-4-yl)ethan-1-amine (8.01 mmol, 1.75 g), EDCI (7.85 mmol, 1.22 g), EtsN (15.7 mmol, 2.2 mL), HOBt (7.85 mmol, 1.06 g) and CH2Cl2 as solvent (22 mL) according to procedure A for 4 days. Compound 12 was obtained pure after washing. Yield: 2.2 g (73%) as orange solid. 1 H NMR (300 MHz, DMSO-de) 6 8.39 (t, J = 5.7 Hz, 1 H), 7.34 - 7.20 (m, 5H), 7.09 (d, J = 3.5 Hz, 1 H), 6.73 (d, J = 3.5 Hz, 1 H), 3.42 (s, 2H), 3.27 - 3.17 (m, 2H), 2.82 - 2.72 (m, 2H), 1 .94 - 1 .81 (m, 2H), 1 .70 - 1 .60 (m, 2H), 1 .47 - 1 .37 (m, 2H), 1 .30 - 1 .19 (m, 1 H), 1 .18 - 1 .07 (m, 2H). 13 C NMR (75 MHz, DMSO-de) 5 156.5, 149.9, 138.5, 128.8 (2C), 128.1 (2C), 126.8, 124.1, 115.5, 113.9, 62.5, 53.2 (2C), 36.2, 35.9, 32.8, 31.8 (2C).

[0107] 5-Bromo-N-phenethylfuran-2-carboxamide (13). The compound was prepared by the reaction of 5-bromofuran-2-carboxylic acid (5.23 mmol, 1.0 g), 2-phenethylamine (5.33 mmol, 646 mg), EDCI (5.24 mmol, 1.0 g), Et3N (10.46 mmol, 1.5 mL), HOBt (5.24 mmol, 707 mg) and CH2Cl2 as solvent (15 mL) according to procedure A. Purification: Hex / AcOEt (9:1). Yield: 964 mg (63%) as yellow oil. 1 H NMR (300 MHz, DMSO-de) 5 8.51 (t, J = 5.7 Hz, 1 H), 7.35 - 7.14 (m, 5H), 7.10 (d, J = 3.5 Hz, 1 H), 6.73 (d, J = 3.5 Hz, 1 H), 3.48 - 3.37 (m, 2H), 2.86 - 2.76 (m, 2H). 13 C NMR (75 MHz, DMSO-d6) 5 156.6, 149.8, 139.3, 128.6 (2C), 128.3 (2C), 126.1, 124.2, 115.6, 1 13.9, 35.0.

[0108] General procedure B for the synthesis of 14-30 hydroxylated heterocycles.

[0109] X = S; Z = CH X = O; Z = CH X = S; Z = NH

[0110] Scheme 2. Synthesis of hydroxylated derivatives. i) Pd(PPh3)4, Na2CO3, toluene / H20 / EtOH (2:1,5:1), 120 e C (MW), 20 minutes.

[0111] The corresponding borane derivative (1.2 equiv.) was added to a previously degassed solution of the corresponding carboxamide (1 equiv.), Na2CO3 (2.2 equiv.) and Pd(PPh3)4 (0.05 equiv.) in a toluene / H2O / EtOH 2:1,5:1 mixture. The mixture was bubbled with argon for 15 minutes and then heated under microwave irradiation (MW) for 20 minutes at 120 ° C. e C. The crude oil was washed with a 1:1 H2O / AcOEt solution and extracted with AcOEt. The organic layer was washed with a 1:1 solution of saturated NaCl / H2O and then dried over anhydrous Mg2SO4. The resulting residues were purified by flash column chromatography using solvent mixtures as eluents as indicated in each case.

[0112] 5-(2-Hydroxyphenyl)-N-phenylthiophen-2-carboxamide (14). The compound was prepared by reaction of 5-bromo-N-phenylthiophene-2-carboxam¡de (1) (1 .48 mmol, 417 mg), Na2CO3(3.26 mmol, 345 mg), Pd(PPh3)4(0.074 mmol, 87 mg), 2-(4,4,5,5-tetramethyl-1 ,3,2-1). dioxaborolan-2-yl)phenol (1 .77 mmol, 372 pL) and a mixture of toluene (3.1 ml_), H2O (2.33 mL) and EtOH (1 .57 mL) as solvent according to procedure B. Purification: Hex / AcOEt (6:4). Yield: 118 mg (27%) as yellow solid. Pf 251 - e C. 1 H NMR (300 MHz, DMSO-d6) 5 10.53 (s, 1 H), 10.16 (s, 1 H), 7.99 (d, J = 4.1 Hz, 1 H), 7.79 - 7.72 (m, 3 H), 7.70 (d, J = 4.1 Hz, 1 H), 7.40 - 7.33 (m, 2H), 7.21 (ddd, J = 8.7, 7.2, 1.6 Hz, 1 H), 7.14 - 7.06 (m, 1 H), 7.00 (dd, J = 8.2, 1.2 Hz, 1 H), 6.91 (ddd, J = 8.3, 7.3, 1.2 Hz, 1 H). 13C NMR (75 MHz, DMSO-d6) 5 160.3, 153.8, 144.6, 138.9, 138.2, 129.4, 128.8, 128.7 (2C), 127.6, 124.8, 123.6, 120.3 (2C), 119.9, 1 19.6, 116.4. HRMS (ESI) cale, for C17H14NO2S [M + H] + 296.0740; found 296.0733. HPLC-MS (gradient I) (M + H)+ = 296, t R = 3.38 min (99%).

[0113] N-(4-Chlorophenyl)-5-(2-hydroxyphenyl)thiophene-2-carboxamide (15). The compound was prepared by the reaction of 5-bromo-N-(4-chlorophenyl)thiophene-2-carboxamide (2) (1.16 mmol, 368 mg), Na2CO3 (2.55 mmol, 270 mg), Pd(PPh3)4 (0.058 mmol, 68 mg), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1.4 mmol, 293 pL) and a mixture of toluene (2 mL), H2O (1.5 mL) and EtOH (1 mL) as solvent according to procedure B. Purification: Hex / AcOEt (9:1). Yield: 100 mg (26%) as a yellow solid. Pf 272 - 274 e C. 1H RMN (300 MHz, DMSO-d6) 5 10,56 (s, 1 H), 10,29 (s, 1 H), 7,98 (d, J = 4,1 Hz, 1 H), 7,82 - 7,73 (m, 3H), 7,70 (d, J = 4,1 Hz, 1 H), 7,46 - 7,37 (m, 2H), 7,20 (ddd, J = 8,3, 7,3, 1 ,6 Hz, 1 H), 6,99 (dd, J = 8,2, 1 ,2 Hz, 1 H), 6,90 (ddd, J = 8,3, 7,2, 1 ,2 Hz, 1 H). 13 C RMN (75 MHz, DMSO-d6) 5 160,3, 153,8, 144,8, 137,9, 137,7, 129,4, 129,0, 128,5 (2C), 127,5, 127,1 , 124,8, 121 ,7 (2C), 119,8, 119,6, 116,4. HRMS (ESI) cale, para CI7HI3CINO2S [M + H]+ 330,0350; encontrado 330,0335. HPLC-MS (gradiente III) (M + H)+ = 330, t R = 5,63 min (98%).

[0114] N-(3-Chlorophenyl)-5-(2-hydroxyphenyl)thiophen-2-carboxamide (16). The compound was prepared by reaction of 5-bromo-N-(3-chlorophenyl)thiophene-2-carboxam¡de (3) (0.84 mmol, 265 mg), Na2CO3(1 .84 mmol, 195 mg), Pd(PPh3)4(0.042 mmol, 49 mg), 2-(4,4,5,5-tetramethyl- 1). ,3,2-dioxaborolan-2-yl)phenol (1 ,00 mmol, 211 pL) and a mixture of toluene (2 mL), H2O (2.5 mL) and EtOH (1 mL) as solvent according to procedure B. Purification: Hex / AcOEt (9:1 ). Yield: 120 mg (44%) as white solid. Pf 246-248 e C. 1 H NMR (300 MHz, DMSO-d6) 5 10.56 (s, 1 H), 10.31 (s, 1 H), 8.00 (d, J = 4.1 Hz, 1 H), 7.94 (t, J = 2.0 Hz, 1 H,), 7.77 (dd, J = 7.9, 1 .7 Hz, 1 H), 7.73 - 7.67 (m, 2H), 7.39 (t, J = 8.1 Hz, 1 H), 7.24 - 7.13 (m, 2H), 7.01 (dd, J = 8.2, 1 .2 Hz, 1 H), 6.91 (ddd, J = 7.8, 7.2, 1 .2 Hz, 1 H). 13C NMR (75 MHz, DMSO-d6) 5 160.5, 153.8, 145.0, 140.4, 137.5, 132.9, 130.4 (2C), 129.5, 129.2, 127.6, 124.8, 123.2, 119.8, 119.6, 118.5, 116.4. HRMS (ESI) cal. for C17H13CINO2S [M+H] + 330.0350; found 330.0348. HPLC-MS (gradient III) (M + H) + = 330, t R = 5.65 min (96%).

[0115] 5-(2-Hydroxyphenyl)-N-phenethylthiophene-2-carboxamide (17). The compound was prepared by the reaction of 5-bromo-N-phenethylthiophene-2-carboxamide (4) (2.23 mmol, 692 mg), Na2CO3 (4.91 mmol, 520 mg), Pd(PPh3)4 (0.114 mmol, 131 mg), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (2.68 mmol, 561 pL) and a mixture of toluene (4 mL), H2O (3 mL) and EtOH (2 mL) as solvent according to procedure B. Compound 17 was obtained pure after washing. Yield: 263 mg (45%) as a white solid. Mp 200-202 e C. 1H RMN (300 MHz, DMSO-d6) 5 10,42 (s, 1 H), 8,53 (t, J = 5,7 Hz, 1 H), 7,72 - 7,64 (m, 2H), 7,58 (d, J = 4,0 Hz, 1 H), 7,34 - 7,13 (m, 6H), 6,97 (dd, J = 8,2, 1 ,2 Hz, 1 H), 6,87 (td, J = 7,5, 1 ,3 Hz, 1 H), 3,46 (dt, J = 8,0, 6,1 Hz, 2H), 2,84 (dd, J = 8,3, 6,6 Hz, 2H). 13 C RMN (75 MHz, DMSO-d6) 5 161 ,4, 153,7, 143,4, 139,5, 138,3, 129,1 , 128,6 (2C), 128,3 (2C), 127,6, 126,1 , 124,7, 120,0, 119,5, 116,3, 40,7, 35,2. HRMS (ESI): cale, para C19H18NO2S [M + H]+ 324,1053; encontrado 324,1043. HPLC-MS (gradiente III) (M + H)+ = 324, tñ= 5,08 min (99%).

[0116] <h2 style=";text-align:left;direction:ltr">N-(2-(1-Bencilpiperidin-4-il)etil)-5-(2-hydroxifenil)tiofeno-2-carboxamida (18). The composition is prepared for the reaction of N-(2-(1-bencilpiperidin-4-il)etil)-5-bromotiofeno-2-carboxamida (5) (1.47 mmol, 601 mg), Na2CO3(3.23 mmol, 343 mg), Pd(PPh3)4(0.074 mmol, 87 mg), 2-(4,4,5,5-tetrametil-1,3,2-dioxaborolan-2-il)fenol (1,77 mmol, 371 pL) and toxin (4 mL (2 mL)) from the product. Purification: Rendimiento: 116 mg (20%) como solid wood PF 185 - 187<h2 style=";text-align:left;direction:ltr"> e <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> DMSO-d6) 5 10.42 (s, 1 H), 8.37 (t, J = 5.6 Hz, 1 H), 7.73 - 7.64 (m, 2H), 7.58 (d, J = 4.0 Hz, 1 H), 7.35 - 7.20 (m, 5H), 7.16 (td, J = 7.7, 7.2, 1.6 Hz, 1 H), 6.97 (dd, J = 8.2, 1.2 Hz, 1 H), 6.87 (td, J = 7.5, 1.2 Hz, 1 H), 3.45 (s, 2H), 3.29 - 3.21 (m, 2H), 2.89 - 2.69 (m, 2H,) 2,03 - 1.81 (m, 2H), 1.73 - 1.61 (m, 2H), 1.52 - 1.38 (m, 2H), 1.37 - 1.24 (m, 1H), 1.23 - 1.08 (m, 2H).<h2 style=";text-align:left;direction:ltr"> 13C NMR (75 MHz, DMSO-d6) 5 161.3, 153.7, 143.2, 138.5, 129.1, 128.8, 128.1 (2C), 127.6, 127.4, 126.9, 124.7, 120.0, 119.5, 1 16.3, 62.4, 53.2 (2C), 36.7, 36.0, 32.9, 31.8 (2C). HRMS (ESI) cale, for C25H29N2O2S [M + H]+ 421 .1944; found 421 ,1946. HPLC-MS (gradient III) (M+H) + = 421 , tñ= 2.49 min (99%).

[0117] 5-(3-Hydroxyphenyl)-N-phenylthiophene-2-carboxamide (19). The compound was prepared by the reaction of 5-bromo-N-phenylthiophene-2-carboxamide (1) (1.42 mmol, 404 mg), Na2CO3 (2.84 mmol, 301 mg), Pd(PPh3)4 (0.070 mmol, 80 mg), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1.56 mmol, 344 mg) and a mixture of toluene (3.1 mL), H2O (2.33 mL) and EtOH (1.57 mL) as solvent according to procedure B. Purification: Hex / AcOEt (9:1). Yield: 180 mg (43%) as a yellow solid. 1H NMR (300 MHz, DMSO-de) 5 10.24 (s, 1 H), 9.71 (s, 1 H), 8.02 (d, J = 4.0 Hz, 1 H), 7.82 - 7.67 (m, 2 H), 7.55 (d, J = 3.9 Hz, 1 H), 7.37 (dd, J = 8.5, 7.3 Hz, 2H), 7.27 (t, J = 7.8 Hz, 1 H), 7.18 (ddd, J = 7.7, 1 .8, 1 .1 Hz, 1 H), 7.15 - 7.08 (m, 2H), 6.81 (ddd, J = 8.0, 2.4, 1 .1 Hz, 1 H). 13 C NMR (75 MHz, DMSO-d6) 5 160.1 , 158.4 , 149.0 , 139.2 , 139.1 , 134.6 , 130.8 , 130.7 , 129.1 , 124.7 , 124.2 , 120.8 , 1 17.0.1 16.3, 1 12.8.

[0118] N-(4-Chlorophenyl)-5-(3-hydroxyphenyl)thiophen-2-carboxamide (20). The compound was prepared by reaction of 5-bromo-N-(4-chlorophenyl)thiophene-2-carboxam¡de (2) (1 .28 mmol, 404 mg), Na2CO3(2.82 mmol, 298 mg), Pd(PPh3)4(0.065 mmol, 75 mg), 3-(4,4,5,5-tetramethyl- 1). ,3,2-dioxaborolan-2-yl)phenol (1 .54 mmol, 338 mg) and a mixture of toluene (3.1 mL), H2O (2.33 mL) and EtOH (1 .57 mL) as solvent according to procedure B. Purification: Hex / AcOEt (9:1 ). Yield: 180 mg (43%) as yellow solid. Pf decomposes. 1H NMR (300 MHz, DMSO-d6) 5 10.35 (s, 1 H), 9.71 (s, 1 H), 8.00 (d, J = 4.0 Hz, 1 H), 7.83 to 7.73 (m, 2H), 7.55 (d, J = 3.9, 7.8 Hz), 7.48 Hz (m, 2H), 7.26 (t, J = 7.8 Hz), 7.17 (dt, J = 7.7, 1 .3 Hz, 1 H), 7.10 (t, J = 2.1 Hz, 1 H), 6.80 (ddd, J = 8.0, 2.4, 1 Hz, 1 Hz). 13 C NMR (75 MHz, DMSO-d6) 5 159.7, 157.9, 148.8, 138.2, 137.7, 134.1 , 130.4, 128.6 (2C), 127.4, 124.3, 12.8 (16.6), 15.9, 112.4. HRMS (ESI) cale, for Ci7Hi3NO2SCI [M + H]+ 330.0350; found 330.0355. HPLC-MS (gradient II) (M + H) + = 330, t R = 3.56 min (99%).

[0119] N-(3-Chlorophenyl)-5-(3-hydroxyphenyl)thiopheno-2-carboxamide (21). The compound was prepared by reaction of 5-bromo-N-(3-chlorophenyl)thiophene-2-carboxam¡da

[0120] (3) (0.32 mmol, 101 mg), Na2CO3(0.71 mmol, 75 mg), Pd(PPh3)4(0.016 mmol, 19 mg), 3-(4,4,5,5-tetramethyl-1 ,3,2-doxaborolan-2-yl)phenol (0.98 mmol, 85 mg) and a mixture of toluene (2). mL), H2O (1 .5 mL) and EtOH (1 mL) as solvent according to procedure B. Purification: Hex / AcOEt (1 :1 ). Yield: 68 mg (64%) as white solid. Pf 190 - e C. 1 H NMR (300 MHz, DMSO-d6) 5 10.37 (s, 1 H), 9.70 (s, 1 H), 8.01 (d, J = 3.9 Hz, 1 H), 7.92 (t, J = 2.0 Hz, 1 H), 7.72 - 7.63 (m, 1 H), 7.55 (d, J = 4.0 Hz, 1 H), 7.39 (t, J = 8.1 Hz, 1 H), 7.26 (m, 1 H), 7.21 - 7.14 (m, 2 H), 7.13 - 7.08 (m, 1 H), 6.83 - 6.77 (m, 1 H). 13 C NMR (75 MHz, DMSO-d6) 5 159.9, 157.9, 149.0, 140.2, 137.9, 134.0, 132.9, 130.6, 130.4, 130.4, 124.3, 123.4, 119.6, 118.6. 116.6, 115.9, 1 12.4. HRMS (ESI) lime, for Ci7Hi3NO2SCI[M + H]+ 330.0350; found 330.0347. HPLC-MS (gradient II) (M + H)+ = 330, t R= 3.61 min (99%). 5-(4-Hydroxyphenyl)-N-phenylthiopheno-2-carboxamide (22). The compound was prepared by reaction of 5-bromo-N-phenylthiophene-2-carboxam¡da (1) (2.0 mmol, 574 mg), Na2CO3(4.0 mmol, 424 mg), Pd(PPh3)4(0.05 mmol, 58 mg), 4-(4,5,5,5-tetramethyl ,3,2-dioxaborolan- 2-¡l)phenol (2.2 mmol, 484 mg) and a mixture of toluene (4 mL), H2O (3 mL) and EtOH (2 mL) as solvent according to procedure B. Purification: Hex / AcOEt (9:1 ). Yield: 336 mg (57%) as white solid. 1 H NMR (300 MHz, DMSO-d6) 5 10.17 (s, 1 H), 9.84 (s, 1 H), 7.98 (d, J = 4.0 Hz, 1 H), 7.82 to 7.67 (m, 2H), 7.64 to 7.50 (m, 2.4 Hz, 2H), Hz, 1 H), 7.40 - 7.32 (m, 2H), 7.17 - 7.02 (m, 1 H), 6.96 - 6.75 (m, 2H). 13 C NMR (75 MHz, DMSO-d6) 5 160.3, 158.6, 149.7, 139.3, 137.5, 130.7, 129.1 , 127.7, 124.6, 124.1 , 122.9, 120.6, 12.7.4.

[0121] N-(3-Chlorophenyl)-5-(4-hydroxyphenyl)thiophen-2-carboxamide (23). The compound was prepared by reaction of 5-bromo-N-(3-chlorophenyl)thiophene-2-carboxam¡de (3) (1 .27 mmol, 400 mg), Na2CO3(2.78 mmol, 295 mg), Pd(PPh3)4(0.065 mmol, 75 mg), 4-(4,4,5,5-tetramethyl- 1). ,3,2-dioxaborolan-2-yl)phenol (1 .52 mmol, 334 mg) and a mixture of toluene (3.1 mL), H2O (2.33 mL) and EtOH (1 .57 mL) as solvent according to procedure B. Purification: Hex / AcOEt (9:1 ). Yield: 73 mg (18%) as yellow solid. Pf decomposes. 1 H NMR (300 MHz, DMSO-d6) 5 10.31 (s, 1 H), 9.84 (s, 1 H), 7.97 (d, J = 4.0 Hz, 1 H), 7.91 (t, J = 2.0 Hz, 1 H), 7.67 (ddd, J = 8.3, 2.1 , 1 ,0 Hz, 1 H), 7.61 - 7.54 (m, 2H), 7.43 (d, J = 4.0 Hz, 1 H), 7.38 (t, J = 8.1 Hz, 1 H), 7.15 (ddd, J = 8.0, 2.1 , 0.9 Hz, 1 H), 6.88 - 6.81 (m, 2H). 13C NMR (75 MHz, DMSO-d6) 5 159.9, 158.2, 149.8, 140.3, 136.4, 132.9, 130.7, 130.4, 127.3 (2C), 126.9, 124.0, 123.3, 122.6, 1 19.6, 118.5, 115.9 (2C). HRMS (ESI) calc. for Ci7Hi3NO2SCI [M+H] + 330.0350; found 330.0346. HPLC-MS (gradient II) (M + H)+ = 330, t R = 3.50 min (99%).

[0122] 2-(2-Hydroxyphenyl)-N-phenethylthiazole-5-carboxamide (24). The compound was prepared by the reaction of 2-bromo-N-phenethylthiazole-5-carboxamide (7) (1.90 mmol, 593 mg), Na2CO3 (4.19 mmol, 444 mg), Pd(PPh3)4 (0.097 mmol, 1.12 mg), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (2.29 mmol, 479 pL) and a mixture of toluene (2.66 mL), H2O (2 mL) and EtOH (1.33 mL) as solvent according to procedure B. Purification: Hex / AcOEt (8:2). Yield: 266 mg (43%) as a yellow solid. Pf 175 - 177 e C. 1H RMN (300 MHz, DMSO-d6) 5 11 ,32 (s, 1 H), 8,76 (t, J = 5,6 Hz, 1 H), 8,40 (s, 1 H), 8,16 (dd, J = 7,9, 1 ,7 Hz, 1 H), 7,39 - 7,17 (m, 6H), 7,05 (d, J = 7,4 Hz, 1 H), 7,01 - 6,93 (m, 1 H), 3,55 - 3,44 (m, 2H), 2,85 (t, J = 7,4 Hz, 2H). 13 C RMN (75 MHz, DMSO- d6) 5 165,6, 160,3, 155,3, 142,1 , 139,4, 134,5, 131 ,7, 128,7 (2C), 128,4 (2C), 127,5, 126,2, 1 19,6, 119,1 , 116,5, 40,8, 35,1. HRMS (ESI) m / z: [M + H]+ cale, para C18H17N2O2S 325,1005; encontrado 325,1005. HPLC-MS (gradiente II) (M + H) + = 325, t R = 3,72 min (99%).

[0123] 2-(3-Hydroxyphenyl)-N-phenylthiazol-5-carboxamide (25). The compound was prepared by reaction of 2-bromo-N-phenylthiazol-5-carboxam¡de (6) (2.21 mmol, 622 mg), Na2CO3(2.66 mmol, 282 mg), Pd(PPh3)4 (0.11 1 mmol, 128 mg), 3-(4,4,5,5-tetramethyl-1 ,3,2-1). dioxaborolan-2-yl)phenol (2.66 mmol, 584 mg) and a mixture of toluene (4 mL), H2O (3 mL) and EtOH (2 mL) as solvent according to procedure B. Purification: Hex / AcOEt (7:3). Yield: 309 mg (47%) as brown solid. 1 H NMR (300 MHz, DMSO-de) 5 10.45 (s, 1 H), 9.87 (s, 1 H), 8.66 (s, 1 H), 7.78 - 7.63 (m, 3H), 7.46 - 7.31 (m, 5H), 7.14 (t, J = 7.4 Hz, 1 H), 6.99 - 6.91 (m, 1 H). 13 C NMR (75 MHz, DMSO-d6) 5 170.9, 158.5, 157.9, 144.8, 138.4, 135.4, 133.7, 130.6, 128.8 (2C), 124.1 , 120.4 (2C), 1 18.3. 117.5, 1 12.8. HPLC-MS (gradient II) (M + H)+ = 297, t R = 3.31 min (90%).

[0124] 5-(2-Hydroxyphenyl)-N-phenylfuran-2-carboxamide (26). The compound was prepared by reaction of 5-bromo-N-phenylfuran-2-carboxamide (9) (3.38 mmol, 900 mg), Na2CO3(7.44 mmol, 789 mg), Pd(PPh3)4 (0.17 mmol, 196 mg), 2-(4,4,5,5-tetramethyl-1 ,3,2-1). dioxaborolan-2-yl)phenol (4.06 mmol, 850 pL) and a mixture of toluene (4 mL), H2O (3 mL) and EtOH (2 mL) as solvent according to procedure B. Purification: Hex / AcOEt (7:3). Yield: 780 mg (83%) as white solid. Pf 168 - e C. 1 H NMR (300 MHz, DMSO-de) 5 10.38 (s, 1 H), 10.14 (s, 1 H), 8.09 (dd, J = 7.9, 1 .7 Hz, 1 H), 7.80 - 7 .77 (m, 2H), 7.41 - 7.33 (m, 3H), 7.26 -1. 7.18 (m, 1 H), 7.15 - 7.09 (m, 2H), 7.02 - 6.92 (m, 2H). 13 C NMR (75 MHz, DMSO-d6) 5 156.2, 154.4, 152.7, 145.3, 138.5, 129.5, 128.6 (2C), 126.4, 123.8, 120.7 (2C), 1 19.2, 117.1 , 1 16.3, 1 16.1 , 111 .3. HRMS (ESI) calc, for CI7HI4NO3[M + H]+ 280.0968; detected 280.0967. HPLC-MS (gradient II) (M + H)+ = 280, time = 3.25 min (95%).

[0125] N-(4-Chlorophenyl)-5-(2-hydroxyphenyl)furan-2-carboxamide (27). The compound was prepared by reaction of 5-bromo-N-(4-chlorophenyl)furan-2-carboxamide (10) (3.58 mmol, 1 .07 g), Na2CO3(7.88 mmol, 835 mg), Pd(PPh3)4(0.18 mmol, 208 mg), 2-(4,4,5,5-tetramethyl- 1). ,3,2-dioxaborolan-2-yl)phenol (4.30 mmol, 900 pL) and a mixture of toluene (4 mL), H2O (3 mL) and EtOH (2 mL) as solvent according to procedure B. Purification: Hex / AcOEt (8:2). Yield: 750 mg (64%) as white solid. 1 H NMR (300 MHz, DMSO-de) 5 10.39 (s, 1 H), 10.25 (s, 1 H), 8.07 (dd, J = 7.9, 1 .7 Hz, 1 H), 7.81 (d, J = 9.0 Hz, 2H), 7.46 - 7.38 (m, 3H), 7.26 -1. 7.18 (m, 1 H), 7.12 (d, J = 3.6 Hz, 1 H), 7.02 - 6.91 (m, 2H). 13 C NMR (75 MHz, DMSO-de) 5 156.2, 154.4, 152.9, 145.0, 137.5, 129.6, 128.5 (2C), 127.4, 126.4, 122.1 (2C), 119.2, 1 17.4, 1 16.2. 116.1 , 11 1 .3. HPLC-MS (gradient II) (M + H)+ = 314, t R = 3.68 min (99%).

[0126] <h2 style=";text-align:left;direction:ltr">N-(2-(1-Bencilpiperidin-4-il)etil)-5-(2-hydroxifenil)furan-2-carboxamida (28). The composition is prepared for the reaction of N-(2-(1-bencilpiperidin-4-il)etil)-5-bromofuran-2-carboxamida (12) (3.52 mmol, 1.38 g), Na2CO3(7.75 mmol, 822 mg), Pd(PPh3)4(0.176 mmol, 203 mg), 2-(4,4,5,5-tetrametil-1,3,2-dioxaborolan-2-il)fenol (4.23 mmol, 860 pL) and toxin (6 mL), H2O (4.5 mL) and EtOH (3 mL) combined with the procedure B. Purification: CH2CI2 / MeOH (95:5). Rendimiento: 1.1 g (80%) combined with salted amarillo.<h2 style=";text-align:left;direction:ltr"> 1 <h2 style=";text-align:left;direction:ltr"> H RMN (300 MHz, DMSO-d6) 5 10.35 (s, 1 H), 8.41 (t, J = 5.8 Hz, 1 H), 8.00 (dd, J = 7.9, 1 .7 Hz, 1 H), 7.34 - 7.19 (m, 6H), 7.11 (d, J = 3.5 Hz, 1 H), 7.02 (d, J = 3.5 Hz, 1 H), 6.98 - 6.92 (m, 1 H), 6.92 - 6.87 (m, 1 H), 3.43 (s, 2H), 3.34 - 3.23 (m, 2H), 2.83 - 2.74 (m, 2H), 1 .96 - 1 ,85(m, 2H), 1.73 - 1.62 (m, 2H), 1.53 - 1.42 (m, 2H), 1.36 - 1.26 (m, 1H), 1.27 - 1.16 (m, 2H).<h2 style=";text-align:left;direction:ltr"> 13 <h2 style=";text-align:left;direction:ltr"> C RMN (75 MHz, DMSO-d6) 157,4, 153,9, 151,4,<h2 style=";text-align:left;direction:ltr">

[0127] 145.6, 138.2, 128.9, 128.5 (2C), 127.8 (2C), 126.5, 125.8, 1 18.8, 116.2, 115.8, 1 14.9,

[0128] 110.6, 62.1, 52.9 (2C), 40.1, 35.9, 32.6 (2C), 31.5. HPLC-MS (gradient I) (M + H)+ = 405, t R = 3.74 min (95%).

[0129] 5-(2-Hydroxyphenyl)-N-phenethylfuran-2-carboxamide (29). The compound was prepared by the reaction of 5-bromo-N-phenethylfuran-2-carboxamide (13) (3.22 mmol, 964 mg), Na2CO3 (7.08 mmol, 751 mg), Pd(PPh3)4 (0.16 mmol, 189 mg), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (3.86 mmol, 849 mg) and a mixture of toluene (4 mL), H2O (3 mL) and EtOH (2 mL) as solvent according to procedure B. Purification: Hex / AcOEt (7:3). Yield: 850 mg (86%) as a white solid. 1 H NMR (300 MHz, DMSO-de) 5 10.30 (s, 1 H), 8.55 (t, J = 5.8 Hz, 1 H), 8.04 - 7.93 (m, 1 H), 7.35 - 7.15 (m, 6H), 7.12 (d, J = 3.5 Hz, 1 H), 7.03 (d, J = 3.5 Hz, 1H), 6.99 - 6.88 (m, 2H), 3.56 - 3.42 (m, 2H), 2.95 - 2.79 (m, 2H). 13C NMR (75 MHz, DMSO-d6) 5157.7, 154.2, 151.7, 145.8, 139.4, 129.3, 128.6(2C), 128.4(2C), 126.1(2C), 1 19.1 , 1 16.4, 1 16.1 , 1 15.4, 1 10.9, 40.2,

[0130] 5-(3-Hydroxyphenyl)-N-phenylfuran-2-carboxamide (30). The compound was prepared by reaction of 5-bromo-N-phenylfuran-2-carboxamide (9) (3.76 mmol, 1 g), Na2CO3(4.51 mmol, 478 mg), Pd(PPh3)4(0.18 mmol, 217 mg), 3-(4,4,5,5-tetramethyl-1 ,3,2-1). dioxaborolan-2-yl)phenol (4.51 mmol, 478 mg) and a mixture of toluene (4 mL), H2O (3 mL) and EtOH (2 mL) as solvent according to procedure B. Purification: Hex / AcOEt (9:1 ). Yield: 528 mg (50%) as yellow solid. 1 H NMR (300 MHz, DMSO-de) 5 10.17 (s, 1 H), 9.67 (s, 1 H), 7.81 - 7.72 (m, 2H), 7.42 - 7.35 (m, 5H), 7.32 - 7.23 (m, 1 H), 7.18 - 7.07 (m, 2H), 6.85 - 6.77 (m, 1 H). 13 C NMR (75 MHz, DMSO-d6) 5 157.8, 156.1 , 155.4, 146.5, 138.5, 130.5, 130.0, 128.6 (2C), 123.8, 120.6 (2C), 1 16.9, 115.9. 115.5, 111.2,

[0131] General procedure C for the synthesis of protected heterocyclic derivatives 31-48.

[0132] X = S; Z = CH X = O; Z = CH X = S; Z = NH

[0133] Scheme 3. Synthesis of protected heterocyclic derivatives, i) DIAD, PPh3, THF, 0 e C a ta

[0134] To a solution of PPh3 (1.3 eq) in THF at 0 °C was added diisopropyl azodicarboxylate (DIAD) (1.3 eq), except for the synthesis of 42 where di-(4-chlorobenzyl) azodicarboxylate (DCAD) was used. The mixture was stirred at room temperature until a white cloud appeared. After cooling again to 0 °C, a solution of the hydroxyphenyl precursors (1 equiv.) and the corresponding protected pipenidine (1.3 equiv.) in THF was added. The mixture was stirred for the time indicated in each case. The volatiles were evaporated to dryness in vacuo and the resulting residues were purified by flash column chromatography using the solvent mixtures indicated in each case as eluents.

[0135] 4-(2-(5-(Phenylcarbamoyl)thiophen-2-yl)phenoxy)piperidin-1 -terre-butyl carboxylate (31 ). The compound was obtained by reaction of 5-(2-hydroxyphenyl)-N-phenyl-thiophene-2-carboxamide (14) (3.0 mmol, 886 mg), 4-hydroxypiperidine-1 -tert-butyl carboxylate (3.6 mmol, 724 mg), DIADL (3.9 mmol, 768 pmol), PPh3(3.9 mmol, 1 .02 g) and 20 mL of THF following general procedure C for 24 hours. Purification: Hex / AcOEt (1 :1 ). Yield: 1 .0 g (70%) as white solid. 1 H NMR (300 MHz, DMSO-d6) 5 10.19 (s, 1 Hz), 8.01 (d, J = 4.1 Hz, 1 H), 7.86 (dd, J = 7.9, 1 .6 Hz, 1 H), 7.79 - 7.72 (m, 2, 7.0 Hz), 1 H), 7.41 - 7.30 (m, 3H), 7.29 - 7.22 (m, 1 H), 7.16 - 7.00 (m, 2H), 4.83 (dt, J = 7.8, 4.0 Hz, 1 H), 3.71 (ddd, J = 1.5, 6.3, 4.7 Hz), H 3.33 - 3.19 (m 2H), 2.11 - 1 .90 (m, 2H), 1 .69 (dt, J = 8.7, 5.9 Hz, 2H), 1 .42 (s, 9H). 13C NMR (75 MHz, DMSO-d6) 5 160.2, 153.8, 152.8, 143.6, 138.9, 138.8, 129.6, 128.6 (2C), 128.5, 128.2, 125.6, 123.6, 122.3, 121 ,1, 120.3 (2C), 114.2, 78.8, 72.9, 39.5 (2C), 30.3 (2C), 28.1 (3C).

[0136] tert-buty Io 4-(2-(5-((4-Chlorophenyl)carbamoyl)thiophen-2-yl)phenoxy)piperidine-1-carboxylate

[0137] (32). The compound was obtained by reaction of N-(4-chlorophenyl)-5-(2-hydroxyphenyl)thiophene-2-carboxamide (15) (3.61 mmol, 1.19 g), tert-butyl 4-hydroxypiperidine-1-carboxylate (3.96 mmol, 798 mg), DIAD (4.69 mmol, 925 pL), PPhs (4.69 mmol, 1.23 g) and 20 mL of THF following general procedure C for 24 hours. Purification: Hex / AcOEt (1:1). Yield: 296 mg (76%) as a white solid. 1H RMN (300 MHz, DMSO-de) 5 10,31 (s, 1 H), 7,99 (d, J = 4,1 Hz, 1 H), 7,89 - 7,82 (m, 1 H), 7,81 - 7,73 (m, 2H), 7,70 (d, J = 4,1 Hz, 1 H), 7,46 - 7,36 (m, 2H), 7,38 - 7,31 (m, 1 H), 7,31 - 7,22 (m, 1 H), 7,08 - 7,01 (m, 1 H), 4,87 - 4,79 (m, 2H), 3,77 - 3,64 (m, 2H), 3,32 - 3,19 (m, 2H), 2,04 - 1 ,92 (m, 2H), 1 ,77 - 1 ,59 (m, 2H), 1 ,41 (s, 9H). 13 C RMN (75 MHz, DMSO-d6) 5 160,3, 153,8, 152,9, 143,9, 138,5, 137,8, 129,7, 128,8, 128,6 (2C), 128,2, 127,3, 125,6, 122,3, 121 ,8 (2C), 121 ,1 , 1 14,2, 78,8, 28,1 (3C).

[0138] 4-(2-(5-((3-Clorofenil)carbamoil)tiofen-2-il)fenoxi)piperidin-1 -carboxilato de tere-butilo

[0139] (33). The compound was obtained by reaction of N-(3-chlorophenyl)-5-(2-hydroxyphenyl)thiophene-2-carboxamide (16) (0.34 mmol, 1.12 mg), tert-butyl 4-hydroxypiperidine-1-carboxylate (0.44 mmol, 89 mg), DIAD (0.44 mmol, 87 pL), PPhs (0.44 mmol, 1.15 mg) and 3 mL of THF following general procedure C for 3 days. Purification: Hex / AcOEt (8:2). Yield: 169 mg (97%) as a white solid. 1 H NMR (300 MHz, DMSO-de) 5 10.34 (s, 1 H), 8.00 (d, J = 4.1 Hz, 1 H), 7.95 - 7.91 (m, 1 H), 7.89 - 7.83 (m, 1 H), 7.71 (d, J = 4.1 Hz, 1 H), 7.69 - 7.64 (m, 1H), 7.42 - 7.32 (m, 2H), 7.29 - 7.23 (m, 1H), 7.19 - 7.13 (m, 1H), 7.09 - 7.01 (m, 1H), 4.89 - 4.77 (m, 1H), 3.78 - 3.63 (m, 2H), 3.31 - 3.19 (m, 2H), 2.06 - 1 .92 (m, 2H), 1 .74 - 1 .60 (m, 2H), 1 .41 (s, 9H). 13 C NMR (75 MHz, DMSO-de) 5 160.4, 153.8, 152.9, 144.0, 140.3, 138.3, 132.9, 130.4, 129.8, 128.9, 128.2, 125.6, 123.3, 122.2, 121,1, 1 19.6, 1 18.5, 1 14.2, 78.8, 73.1, 38.7 (2C) 30.4 (2C), 28.1 (3C).

[0140] 4-(2-(5-(Phenethylcarbamoyl)thiophen-2-yl)phenoxy)piperidine-1-carboxylic acid tert-butyl ester (34). The compound was obtained by reaction of 5-(2-hydroxyphenyl)-N-phenethylthiophene-2-carboxamide (17) (0.82 mmol, 265 mg), 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (1.05 mmol, 211 mg), DIAD (1.05 mmol, 210 pL), PPhs (1.05 mmol, 275 mg) and 7 mL of THF following general procedure C for 24 hours. Compound 34 was obtained pure after washing. Yield: 237 mg (57%) as a white solid. 1 H NMR (300 MHz, DMSO-de) 5 8.56 (t, J = 5.6 Hz, 1 H), 7.79 (dd, J = 7.9, 1.6 Hz, 1 H), 7.68 (d, J = 4.1 Hz, 1 H), 7.58 (d, J = 4.1 Hz, 1 H), 7.37 - 7.17 (m, 7H), 7.02 (ddd, J = 8.0, 7.2, 1.2 Hz, 1 H), 4.86 - 4.72 (m, 1 H), 3.76 - 3.63 (m, 2H), 3.54 - 3.40 (m, 2H), 3.30 - 3.14 (m, 2H), 2.94 - 2.79 (m, 2H), 2.04 - 1 .90 (m, 2H), 1 .77 - 1 .57 (m, 2H), 1 .41 (s, 9H). 13C NMR (75 MHz, DMSO-d6) 5 161.4, 153.8, 152.7, 142.4, 139.4, 139.1, 129.4, 128.7 (2C), 128.4 (2C), 128.2, 127.3, 126.1, 125.4, 122.5, 121,1, 1 14.2, 78.8, 72.9, 40.8, 35.3, 30.4 (2C), 28.1 (3C).

[0141] tert-Butyl 4-(2-(5-((2-(1-Benzylpiperidin-4-yl)ethyl)carbamoyl)thiophen-2-yl)phenoxy)piperidine-1-carboxylate (35). The compound was prepared by reacting N-(2-(1-benzylpiperidin-4-yl)ethyl)-5-(2-hydroxyphenyl)thiophene-2-carboxamide (18) (1.66 mmol, 700 mg), tert-butyl 4-hydroxypiperidine-1-carboxylate (2.16 mmol, 434 mg), DIAD (2.16 mmol, 426 pL), PPhs (2.16 mmol, 434 mg) and 15 mL of THF following general procedure C for 24 hours. Purification: CHsCh / MeOH (9:1 ). Yield: 160 mg (16%) as white solid. 1H RMN (300 MHz, DMSO-d6) 5 10,02 (s, 1 H), 7,94 (d, J = 4,1 Hz, 1 H), 7,83 (dd, J = 7,9, 1 ,7 Hz, 1 H), 7,66 (d, J = 4,1 Hz, 1 H), 7,58 (d, J = 9,0 Hz, 2H), 7,34 (ddd, J = 8,8, 7,3, 1 ,7 Hz, 1 H), 7,25 (d, J = 8,2 Hz, 1 H), 7,06 - 7,02 (m, 1 H), 6,96 - 6,92 (m, 2H), 4,89 - 4,75 (m, 1 H), 3,78 - 3,72 (m, 4H), 3,72 - 3,66 (m, 2H), 3,30 - 3,21 (m, 2H), 3,1 1 - 3,04 (m, 4H), 2,03 - 1 ,94 (m, 2H), 1 ,71 - 1 ,62 (m, 2H), 1 ,41 (s, 9H). 13 C RMN (75 MHz, DMSO-d6) 5 159,7, 153,8, 152,8, 147,5, 143,1 , 139,3, 130,9, 129,5, 128,2, 127,9, 125,6, 122,4, 121 ,5 (2C), 121 ,1 , 1 15,2 (2C), 114,2, 78,8, 72,9, 66,1 (2C), 48,8 (2C), 39,9 (2C), 30,4 (2C), 28,1 (3C).

[0142] 4-(3-(5-(Phenylcarbamoyl)thiophen-2-yl)phenoxy)piperidine-1-carboxylic acid tert-butyl ester (36). The compound was obtained by reaction of 5-(3-hydroxyphenyl)-N-phenylthiophene-2-carboxamide (19) (1.70 mmol, 502 mg), 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (2.2 mmol, 447 mg), DIAD (2.2 mmol, 437 pL), PPhs (2.2 mmol, 582 mg) and 15 mL of THF following general procedure C for 24 hours. Purification: Hex / AcOEt (9:1). Yield: 568 mg (70%) as a white solid. 1 H NMR (300 MHz, Chloroform-d) 5 8.0 (s, 1 H), 7.68 - 7.58 (m, 3H), 7.41 - 7.26 (m, 4H), 7.26 - 7.21 (m, 1 H), 7.19 - 7.12 (m, 2H), 6.91 (d, J = 8.0, 1 H), 4.54 (dt, J = 7.1, 3.6 Hz, 1 H), 3.80 - 3.66 (m, 2H), 3.48 - 3.29 (m, 2H), 2.03 - 1 .87 (m, 2H), 1 .86 - 1 .71 (m, 2H), 1 .50 (s, 9H). 13 C NMR (75 MHz, CDCI3) 5 160.3, 158.1, 155.3, 149.8, 138.4, 138.1, 135.2, 130.7, 129.7, 129.5 (2C), 124.9, 124.2, 120.7 (2C), 1 19.4, 1 16.4, 1 14.5, 80.1, 72.7, 41.0 (2C), 30.9 (2C), 28.9 (3C).

[0143] tert-Butyl 4-(3-(5-((4-Chlorophenyl)carbamoyl)thiophen-2-yl)phenoxy)piperidine-1-carboxylate (37). The compound was obtained by reaction of N-(4-chlorophenyl)-5-(3-hydroxyphenyl)thiophene-2-carboxamide (20) (1.71 mmol, 564 mg), tert-butyl 4-hydroxypiperidine-1-carboxylate (2.2 mmol, 447 mg), DIAD (2.2 mmol, 437 pL), PPh3 (2.2 mmol, 582 mg) and 15 mL of THF following general procedure C for 2 days. Purification: Hex / AcOEt (9:1). Yield: 603 mg (69%) as a white solid. 1 H NMR (300 MHz, DMSO-de) 5 10.35 (s, 1 H), 8.01 (d, J = 4.0 Hz, 1 H), 7.81 - 7.74 (m, 2H), 7.65 (d, J = 4.0 Hz, 1 H), 7.47 - 7.39 (m, 2H), 7.38 - 7.27 (m, 3H) 1.41 (s, 9H). 13C NMR (75 MHz, DMSO-d6) 5 159.7, 157.5, 153.9, 148.4, 138.5, 137.7, 134.4, 130.5, 130.4, 128.6 (2C), 127.4, 124.8, 121.8 (2C), 118.4, 1 16.2, 1 13.2, 78.7, 71.9, 30.7 (2C), 28.1 (3C).

[0144] tert-Butyl 4-(3-(5-((3-Chlorophenyl)carbamoyl)thiophen-2-yl)phenoxy)piperidine-1-carboxylate (38). The compound was obtained by reaction of N-(3-chlorophenyl)-5-(3-hydroxyphenyl)thiophene-2-carboxamide (21) (0.62 mmol, 206 mg), tert-butyl 4-hydroxypiperidine-1-carboxylate (0.81 mmol, 163 mg), DIAD (0.81 mmol, 160 pL), PPh3 (0.81 mmol, 213 mg) and 10 mL of THF following general procedure C for 24 hours. Purification: Hex / AcOEt (9:1 ). Yield: 139 mg (44%) as a white solid. 1H NMR (300 MHz, DMSO-de) 6 10.38 (s, 1 H), 8.02 (d, J = 4.1 Hz, 1 H), 7.92 (t, J = 2.0 Hz, 1 H), 7.70 - 7.64 (m, 2H), 7.44 - 7.28 (m, 4H), 7.20 - 7.15 (m, 1H), 7.06 - 6.99 (m, 1H), 4.73 - 4.62 (m, 1H), 3.75 - 3.61 (m, 2H), 3.29 - 3.15 (m, 2H), 2.02 - 1.87 (m, 2H), 1.64 - 1.47 (m, 2H), 1.41 (s, 9H). 13 C NMR (75 MHz, DMSO-d6) 5 159.8, 157.5, 153.9, 148.6, 140.2, 138.3, 134.3, 132.9, 130.6, 130.4, 124.9, 123.4, 1 19.6, 118.5, 118.5, 116.2, 1 13.2, 78.7, 71.9, 30.4 (2C), 28.1 (3C).

[0145] 4-(4-(5-(Phenylcarbamoyl)thiophen-2-yl)phenoxy)piperidine-1-carboxylic acid tert-butyl ester (39). The compound was obtained by reaction of 5-(4-hydroxyphenyl)-N-phenylthiophene-2-carboxamide (22) (3.61 mmol, 1.06 g), 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (3.96 mmol, 798 mg), DIAD (4.69 mmol, 925 pL), PPh3 (4.69 mmol, 1.23 g) and 20 mL of THF following general procedure C for 24 hours. Purification: Hex / AcOEt (7:3). Yield: 811 mg (47%) as a white solid.1 H RMN (300 MHz, DMSO-d6) 5 10,20 (s, 1 H), 8,00 (d, J = 4,0 Hz, 1 H), 7,77 - 7,71 (m, 2H), 7,67 (d, J = 8,8 Hz, 2H), 7,50 (d, J = 4,0 Hz, 1 H), 7,36 (dd, J = 8,6, 7,3 Hz, 2H), 7,15 - 7,03 (m, 3H), 4,63 (dt, J = 8,1 , 4,2 Hz, 1 H), 3,72 - 3,63 (m, 2H), 3,24 - 3,17 (m, 2H), 2,02 - 1 ,81 (m, 2H), 1 ,54 (dt, J = 8,5, 4,1 Hz, 2H), 1 ,42 (s, 9H). 13 C RMN (75 MHz, DMSO-d6) 5 160,0, 157,7, 154,2, 148,8, 139,0, 137,9, 130,6, 128,9 (2C), 127,5 (2C), 126,1 , 123,9, 123,5, 120,6 (2C), 116,7 (2C), 79,0, 72,3, 40,6 (2C), 30,6 (2C), 28,4 (3C).

[0146] 4-(5-((3-Chlorophenyl)carbamoyl)thiophen-2-yl)phenoxy)piperidine-1-carboxylic acid tert-butyl ester (40). The compound was obtained by reaction of N-(3-chlorophenyl)-5-(4-hydroxyphenyl)thiophene-2-carboxamide (23) (0.88 mmol, 290 mg), 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (1 .14 mmol, 229 mg), DIAD (1 .14 mmol, 226 pL), PPh3 (1 .14 mmol, 289 mg) and 5 mL of THF following general procedure C for 24 hours. Purification: Hex / AcOEt (9:1). Yield: 252 mg (56%) as a white solid. 1 H NMR (300 MHz, DMSO-de) 5 10.33 (s, 1 H), 7.99 (d, J = 4.0 Hz, 1 H), 7.91 (t, J = 2.0 Hz, 1 H), 7.72 - 7.62 (m, 3H), 7.51 (d, J = 3.9 Hz, 1 H), 7.39 (t, J = 8.1 Hz, 1 H), 7.20 - 7.13 (m, 1 H), 7.1 1 - 7.02 (m, 2H), 4.68 - 4.55 (m, 1 H), 3.74 - 3.60 (m, 2H), 3.27 - 3.12 (m, 2H), 1 .99 - 1 .83 (m, 2H), 1 .61 - 1 .47 (m, 2H), 1 .41 (s, 9H). 13C NMR (75 MHz, DMSO-d6) 5 159.9, 157.5, 153.9, 149.0, 140.3, 137.1, 132.9, 130.7, 130.4, 127.3 (2C), 125.7, 123.3 (2C), 1 19.6, 118.5, 1 16.5 (2C), 78.8, 72.0, 30.3 (2C), 28.1 (3C).

[0147] 4-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)piperidine-1-carboxylate (41 ). The compound was obtained by reaction of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1.36 mmol, 300 mg), tert-butyl 4-hydroxypiperidine-1-carboxylate (1.77 mmol, 356 mg), DIAD (1.77 mmol, 349 pL), PPh3 (1.77 mmol, 465 mg) and 5 mL of THF following general procedure C for 24 hours. Purification: Hex / AcOEt (9:1 ). Yield: 228 mg (42%) as a white solid. 1 H NMR (300 MHz, DMSO-de) 5 7.59 (d, 2H), 6.96 (d, 2H), 4.69 - 4.54 (m, 1 H), 3.75 - 3.54 (m, 2H), 3.26 - 3.10 (m, 2H), 1 .99 - 1 .81 (m, 2H), 1 .60 - 1 .45 (m, 2H), 1 .40 (s, 9H), 1 .27 (s, 12H). 13C NMR (75 MHz, DMSO-d6) 5 159.6, 153.9, 136.3 (2C), 115.1 (2C), 83.3 (2C), 78.7, 71.6, 30.3 (2C), 28.1 (3C), 24.7 (4C).

[0148] 4-(2-(5-(Phenethylcarbamoyl)thiazol-2-yl)phenoxy)piperidine-1-carboxylic acid tert-butyl ester (42). The compound was obtained by reaction of 2-(2-hydroxyphenyl)-N-phenethylthiazole-5-carboxamide (24) (0.75 mmol, 242 mg), 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (0.97 mmol, 195 mg), di-(4-chlorobenzyl)azodicarboxylate (DCAD) (0.97 mmol, 356 mg), PPh3 (0.97 mmol, 254 mg) and 8 mL of THF following general procedure C for 24 hours. Purification: Hex / AcOEt (9:1). Yield: 78 mg (20%) as a white solid. 1 H NMR (300 MHz, DMSO-de) 5 8.76 (t, 1 H), 8.41 (s, 1 H), 8.32 (dd, J = 6.1 Hz, 1 H), 7.53 - 7.45 (m, 1 H), 7.39 - 7.20 (m, 6H), 7.14 - 7.08 (m, 1 H), 4.98 - 4.88 (m, 1H), 3.86 - 3.74 (m, 2H), 3.52 - 3.42 (m, 2H), 3.29 - 3.17 (m, 2H), 2.89 - 2.79 (m, 2H), 2.14 - 2.01 (m, 2H), 1 .76 - 1 .67 (m, 2H), 1 ,42 (s, 9H). 13C NMR (75 MHz, DMSO-de) 5 163.8, 160.3, 153.9, 142.2, 139.3, 134.9, 131.8, 128.7 (2C), 128.4 (2C), 128.1, 126.2, 121.7, 120.9, 1 13.9, 78.9, 73.8, 40.8, 35.1, 30.6 (2C), 28.1 (3C). tert-Butyl 4-(3-(5-(Phenylcarbamoyl)thiazol-2-yl)phenoxy)piperidine-1-carboxylate (43). The compound was obtained by reaction of 2-(3-hydroxyphenyl)-N-phenylthiazole-5-carboxamide (25) (0.84 mmol, 240 mg), tert-butyl 4-hydroxypiperidine-1-carboxylate (1 .1 mmol, 221 mg), DIAD (1 .1 mmol, 217 pL), PPhs (1 .1 mmol, 288 mg) and 4 mL of THF following general procedure C for 4 days. Purification: Hex / AcOEt (1 :1 ). Yield: 76 mg (19%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) 5 10.47 (s, 1 H), 8.68 (s, 1 H), 7.77 - 7.68 (m, 2H), 7.62 - 7.53 (m, 2H), 7.49 - 7.42 (m, 1 H), 7.42 - 7.34 (m, 2H), 7.21 - 7.10 (m, 2H), 4.78 - 4.67 (m, 2H), 3.74 - 3.60 (m, 2H), 3.29 - 3.14 (m, 2H), 1 .99 - 1 .85 (m, 2H), 1 .67 - 1 .51 (m, 2H), 1 .41 (s, 9H). 13C NMR (75 MHz, DMSO-d6) 5 170.5, 158.4, 157.5, 153.9, 144.7, 138.3, 135.8, 133.9, 130.8, 128.8 (2C), 124.2, 120.5 (2C), 119.3, 118.8, 113.4, 78.7, 72.1, 30.3 (2C), 28.1 (3C).

[0149] 4-(2-(5-(Phenylcarbamoyl)furan-2-yl)phenoxy)piperidine-1-carboxylic acid tert-butyl ester (44). The compound was obtained by reaction of 5-(2-hydroxyphenyl)-N-phenylfuran-2-carboxamide (26) (2.73 mmol, 760 mg), 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (3.54 mmol, 710 mg), DIAD (3.54 mmol, 696 pL), PPhs (3.54 mmol, 930 mg) and 10 mL of THF following general procedure C for 24 hours. Purification: Hex / AcOEt (9:1). Yield: 740 mg (59%) as a white solid. 1 H NMR (300 MHz, DMSO-de) 5 10.15 (s, 1 H), 8.16 (d, J = 6.1 Hz, 1 H), 7.80 - 7.73 (m, 2H), 7.44 - 7.32 (m, 4H), 7.29 - 7.22 (m, 1 H), 7.17 - 7.06 (m, 3H), 4.73 - 4.72 (m, 1 H), 3.79 - 3.64 (m, 2H), 3.27 - 3.14 (m, 2H), 2.07 - 1 .93 (m, 2H), 1 .75 - 1 .58 (m, 2H), 1 .41 (s, 9H). 13C NMR (75 MHz, DMSO-de) 5 153.8, 153.5, 151.9, 145.6, 138.4, 129.8, 128.6 (2C), 127.1, 123.8, 120.7 (3C), 118.6, 117.0, 113.8, 1 11.9, 78.8, 72.7, 30.5 (2C), 28.1 (3C).

[0150] tert-Butyl 4-(2-(5-((4-Chlorophenyl)carbamoyl)furan-2-yl)phenoxy)piperidine-1-carboxylate (45). The compound was obtained by reaction of N-(4-chlorophenyl)-5-(2-hydroxyphenyl)furan-2-carboxamide (27) (2.23 mmol, 700 mg), tert-butyl 4-hydroxypiperidine-1-carboxylate (2.90 mmol, 584 mg), DIAD (2.90 mmol, 570 pL), PPhs (2.90 mmol, 761 mg) and 16 mL of THF following general procedure C for 2 days. Purification: Hex / AcOEt (7:3). Yield: 40 mg (4%) as a yellow solid. 1 H NMR (300 MHz, DMSO-de) 6 10.27 (s, 1 H), 8.15 (dd, J = 7.8, 1.7 Hz, 1 H), 7.84 - 7.78 (m, 2H), 7.45 - 7.39 (m, 3H), 7.37 - 7.33 (m, 1 H), 7.28 - 7.21 (m, 1H), 7.13 - 7.06 (m, 2H), 4.77 (m, 1H), 3.77 - 3.62 (m, 2H), 3.27 - 3.11 (m, 2H), 2.07 - 1.96 (m, 2H), 1.74 - 1.55 (m, 2H), 1.41 (s, 9H).13 C NMR (75 MHz, DMSO-de) 5 156.1, 153.8, 153.5, 152.1, 145.3, 137.4, 129.8, 128.5 (2C), 127.5, 127.1, 122.1 (2C), 120.7, 1 18.6, 117.3, 1 13.8, 1 11 .9, 78.8, 72.8, 39.5 (2C), 30.5 (2C), 28.1 (3C). tert-Butyl 4-(2-(5-((2-(1-Benzylpiperidin-4-yl)ethyl)carbamoyl)furan-2-yl)phenoxy)piperidine-1-carboxylate (46). The compound was obtained by reaction of N-(2-(1-benzylpiperidin-4-yl)ethyl)-5-(2-hydroxyphenyl)furan-2-carboxamide (28) (1.73 mmol, 617 mg), tert-butyl 4-hydroxypiperidine-1-carboxylate (2.25 mmol, 400 mg), DIAD (2.25 mmol, 440 pL), PPh3 (2.25 mmol, 520 mg) and 16 mL of THF following general procedure C for 2 days. Purification: CFhCh / MeOH (95:5). Yield: 250 mg (28%) as yellow solid. 1<h2 style=";text-align:left;direction:ltr">H RMN (300 MHz, DMSO-d6) 5 8.47 - 8.40 (m, 1 H), 8.11 - 8.06 (m, 1 H), 7.35 - 7.19 (m, 7H), 7.12 (d, J = 3.6 Hz, 1 H), 7.09 - 7.01 (m, 1 H), 6.99 (d, J = 3.6 Hz, 1 H), 4.83 - 4.71 (m, 1 H), 3.76 - 3.64 (m, 2H), 3.44 (s, 2H), 3.29 - 3.17 (m, 4H), 2.85 - 2.71 (m, 2H), 2.05 - 1 .87 (m, 4H), 1,72 - 1.57 (m, 4H), 1.52 - 1.31 (m, 11H), 1.24 - 1.15 (m, 2H).<h2 style=";text-align:left;direction:ltr"> 13 <h2 style=";text-align:left;direction:ltr"> C RMN (75 MHz, DMSO-d6) 157.5, 153.8, 153.3, 150.9, 146.2, 129.4, 128.8, 128.1 (5C), 126.8, 120.6, 1 18.8, 1 15.3, 1 13.8, 1 11 ,5, 78,8, 72,7, 62,5, 53,2 (2C), 40,2 (2C), 36,2, 32,9, 31,8 (2C), 30,5 (2C), 28,1 (3C).<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0151] <h2 style=";text-align:left;direction:ltr"> 4-(2-(5-(Fenetilcarbamoil)furan-2-il)fenoxi)piperidin-1-carboxilato de terc-butilo (47). The composition is due to the reaction of 5-(2-hydroxifenil)-N-fenetilfurano-2-carboxamide<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0152] (29) (2.83 mmol, 850 mg), 4-hidroxipiperidina-1 -carboxylate of terc-butyl (3.68 mmol, 740 mg), DIAD (3.68 mmol, 726 pL), PPh3 (3.68 mmol, 743 mg) and 10 mL of THF following the general procedure C during 4 days. Purification: Hex / AcOEt (6:4). Yield: 791 mg (59%) as amarillo aceite. 1 H NMR (300 MHz, DMSO-de) 5 8.57 (t, J = 5.8 Hz, 1 H), 8.08 (dd, J = 7.8, 1 .7 Hz, 1 H), 7.38 - 7.16 (m, 7H), 7.14 (d, J = 3.5 Hz, 1 H), 7.1 1 - 7.03 (m, 1 H), 7.00 (d, J = 3.5 Hz, 1 H), 4.83 - 4.68 (m, 1 H), 3.77 - 3.63 (m, 2H), 3.56 - 3.42 (m, 2H), 3.27 - 3.13 (m, 2H), 2.92 - 2.77 (m, 2H), 2.09 - 1.92 (m, 2H), 1.69 - 1.55 (m, 2H), 1.41 (s, 9H). 13 C NMR (75 MHz, DMSO-d6) 5 157.6, 153.8,

[0153] 153.4, 151.0, 146.1, 139.4, 129.5, 128.6 (2C), 128.4 (2C), 126.7, 126.1, 120.6, 1 18.8,

[0154] 115.4, 113.8, 11 1 .6, 78.8, 72.7, 40.2, 35.3, 30.5 (2C), 28.1 (3C).

[0155] 4-(3-(5-(Phenylcarbamoyl)furan-2-yl)phenoxy)piperidine-1-carboxylate tert-butyl (48). The compound was obtained by reaction of 5-(3-hydroxyphenyl)-N-phenylfuran-2-carboxamide

[0156] (30) (1.79 mmol, 500 mg), tert-butyl 4-hydroxypiperidine-1-carboxylate (2.33 mmol, 469 mg), DIAD (2.33 mmol, 459 pL), PPh3 (2.33 mmol, 61 1 mg) and 8 mL of THF following general procedure C for 5 days. Purification: Hex / AcOEt / CH2Cl2 (5:2:3). Yield: 192 mg (23%) as a yellow solid. 1 H NMR (300 MHz, DMSO-de) 5 10.20 (s, 1 H), 7.81 - 7.71 (m, 2H), 7.60 - 7.50 (m, 2H), 7.45 - 7.33 (m, 4H), 7.21 (d, J = 3.6 Hz, 1 H), 7.17 - 7.08 (m, 1H), 7.07 - 7.00 (m, 1H), 4.73 - 4.59 (m, 1H), 3.78 - 3.61 (m, 2H), 3.26 - 3.09 (m, 2H), 2.03 - 1.84 (m, 2H), 1.65 - 1.47 (m, 2H), 1.41 (s, 9H). 13C NMR (75 MHz, DMSO-d6) 5 157.4, 156.0, 154.9, 153.9, 146.7, 138.4, 130.7, 130.2, 128.6 (2C), 123.9, 120.7 (2C), 117.2, 117.0, 115.7, 112.4, 108.3, 78.7, 72.0, 30.4 (2C), 28.1 (3C).

[0157] General procedure D for the synthesis of protected heterocyclic derivatives 49-54.

[0158] Scheme 4. Synthesis of protected heterocyclic derivatives, i) Pd(PPh3)4, Na2CO3, toluene / H20 / EtOH (2:1, 5:1), 120 e C (MW), 20 minutes.

[0159] For the synthesis of a thiophene and all protected para-substituted thiazole and furan precursors, an alternative procedure was employed. The compound 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)piperidine-1-carboxylate (41) (1 equiv.) was added to a previously degassed solution of the corresponding carboxamide (1 equiv.), Na2CO3 (2.2 equiv.) and Pd(PPh3)4 (0.05 equiv.) in a mixture of toluene / H2O / EtOH 2:1 , 5:1. The mixture was bubbled with argon for 15 minutes and then heated under microwave irradiation (MW) for 20 minutes at 120 °C. e C. The crude oil was washed with a 1:1 H2O / AcOEt solution and extracted with AcOEt. The organic phase was washed with a 1:1 solution of saturated NaCl / H2O and then dried over anhydrous Mg2SO4. The resulting residues were purified by flash column chromatography using solvent mixtures as eluents as indicated in each case.

[0160] Tere-butyl 4-(4-(5-((2-Benzylpiperidin-4-yl)ethyl)carbamoyl)thiophene-2-yl)phenoxy)piperidin-1 carboxylate (49). The compound was obtained by reaction of N-(2-(1-benzylpiperidin-4-yl)ethyl)-5-bromothiophene-2-carboxamide (5) (0.74 mmol, 300 mg), Na2CC>3 (1.64 mmol, 163 mg), Pd(PPh3)4 (0.037 mmol, 43 mg), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)piperidine-1-carboxylate (41) (0.74 mmol, 300 mg) and a mixture of toluene (4 mL), H2O (3 mL) and EtOH (2 mL) as solvent according to procedure D. Compound 49 was obtained pure after washing. Yield: 438 mg (98%) as a yellow solid. 1H RMN (300 MHz, DMSO-d6) 5 8,47 - 8,36 (m, 1 H), 7,68 (d, J = 3,9 Hz, 1 H), 7,64 - 7,60 (m, 2H), 7,38 (d, J = 3,9 Hz, 1 H), 7,32 - 7,24 (m, 5H), 7,06 - 7,01 (m, 2H), 4,66 - 4,56 (m, 1 H), 3,74 - 3,59 (m, 2H), 3,42 (s, 2H), 3,30 - 3,15 (m, 4H), 2,81 - 2,72 (m, 2H), 1 ,94 - 1 ,82 (m, 4H), 1 ,69 - 1 ,61 (m, 2H), 1 ,58 - 1 ,51 (m, 2H), 1 ,49 - 1 ,42 (m, 1 H), 1 ,40 (s, 9H), 1 ,18 - 1 ,09 (m, 4H). 13 C RMN (75 MHz, DMSO-d6) 5 160,8, 157,2, 153,9, 147,2, 138,7, 138,1 , 128,7 (2C), 128,1 (3C), 127,1 , 126,7 (2C), 126,0, 123,0, 116,4 (2C), 78,7, 71 ,9, 62,5, 53,3 (2C), 40,3 (2C), 36,8, 36,0, 31 ,9 (2C), 30,3, 28,1 (3C), 21 ,9 (2C).

[0161] 4-(4-(5-(Phenylcarbamoyl)thiazol-2-yl)phenoxy)piperidine-1-carboxylic acid tert-butyl ester (50). The compound was obtained by reaction of 2-bromo-N-phenylthiazole-5-carboxamide (6) (0.28 mmol, 79 mg), Na2CO3 (0.57 mmol, 60 mg), Pd(PPh3)4 (0.014 mmol, 17 mg), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)piperidine-1-carboxylate (41) (0.28 mmol, 114 mg) and a mixture of toluene (2 mL), H2O (1.5 mL) and EtOH (1 mL) as solvent according to procedure D. Compound 50 was obtained pure after washing. Yield: 57 mg (42%) as brown solid. 1 H NMR (500 MHz, DMSO-de) 5 10.41 (s, 1 H), 8.62 (s, 1 H), 7.99 - 7.93 (m, 2H), 7.72 (d, J = 7.6 Hz, 2H), 7.41 - 7.35 (m, 2H), 7.18 - 7.10 (m, 3H), 4.75 - 4.65 (m, 1H), 3.74 - 3.63 (m, 2H), 3.26 - 3.15 (m, 2H), 2.01 - 1 .89 (m, 2H), 1 .60 - 1 .51 (m, 2H), 1 .41 (s, 9H). 13C NMR (126 MHz, DMSO-de) 5 170.7, 159.4, 158.5, 153.9, 144.7, 138.4, 134.5, 128.7 (2C), 128.3 (2C), 125.4, 124.0, 120.4 (2C), 116.3 (2C), 78.7, 72.2, 40.1 (2C), 30.2 (2C), 28.0 (3C).

[0162] 4-(4-(5-((2-(1 -Benzylpiperidin-4-yl)ethyl)carbamoyl)thiazol-2-yl)phenoxy)piperidine-1-carboxylic acid tert-butyl ester (51). The compound was obtained by reaction of N-(2-(1-benzylpiperidin-4-yl)ethyl)-2-bromothiazole-5-carboxamide (8) (0.80 mmol, 327 mg), Na2CO3 (1.6 mmol, 170 mg), Pd(PPhs)4 (0.041 mmol, 47 mg), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)piperidine-1-carboxylate (41) (0.80 mmol, 323 mg) and a mixture of toluene (2.67 mL), H2O (2 mL) and EtOH (1.33 mL) as solvent according to procedure D. Purification: CH2Cl2 / MeOH (95:5). Yield: 205 mg (43%) as white solid. 1H RMN (300 MHz, DMSO-d6) 5 8,63 (s, 1 H), 8,33 (s, 1 H), 7,92 - 7,86 (m, 2H), 7,34 - 7,26 (m, 5H), 7,12 - 7,07 (m, 2H), 4,73 - 4,61 (m, 1 H), 3,74 - 3,63 (m, 2H), 3,53 (s, 2H), 3,28 - 3,1 1 (m, 4H), 2,90 - 2,79 (m, 2H), 2,10 - 1 ,88 (m, 4H), 1 ,76 - 1 ,65 (m, 2H), 1 ,58 - 1 ,51 (m, 2H), 1 ,49 - 1 ,44 (m, 2H), 1 ,40 (s, 9H), 1 ,36 - 1 ,28 (m, 1 H), 1 ,26 - 1 ,12 (m, 2H). 13C NMR (75 MHz, DMSO-d6) 5 169.9, 159.7, 159.3, 154.0, 143.6, 134.6, 129.2, 128.3 (2C), 128.2 (4C), 125.5, 116.4 (2C), 78.8, 72.2, 52.9 (2C), 36.9, 35.7, 30.3 (2C), 28.1 (3C). tert-Butyl 4-(4-(5-(Phenylcarbamoyl)furan-2-yl)phenoxy)piperidine-1-carboxylate (52). The compound was obtained by reaction of 5-bromo-N-phenylfuran-2-carboxamide (9) (1.65 mmol, 440 mg), Na2CO3 (3.30 mmol, 350 mg), Pd(PPh3)4 (0.083 mmol, 97 mg), 4-(4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)piperidine-1-carboxylate (41) (1.65 mmol, 665 mg) and a mixture of toluene (4 mL), H2O (3 mL) and EtOH (2 mL) as solvent according to procedure D. Purification: Hex / AcOEt (7:3). Yield: 580 mg (76%) as yellow solid. 1 H NMR (300 MHz, DMSO-d6) 5 10.1 1 (s, 1 H), 7.93 - 7.84 (m, 2H), 7.79 - 7.72 (m, 2H), 7.42 - 7.31 (m, 3H), 7.15 - 7.06 (m, 3H), 7.02 (d, J = 3.6 Hz, 1 H), 4.71 - 4.61 (m, 1 H), 3.74 - 3.62 (m, 2H), 3.28 - 3.12 (m, 2H), 1 .99 - 1 .88 (m, 2H), 1 .61 - 1 .47 (m, 2H), 1 .41 (s, 9H).13 C NMR (75 MHz, DMSO-d6) 5 157.4, 156.1,

[0163] 155.5, 153.9, 145.9, 138.5, 128.6 (2C), 126.3, 123.8, 122.2, 120.6 (2C), 117.1, 1 16.1 (2C), 106.3, 78.7, 71.9, 40.2 (2C), 30.3 (2C), 28.1 (3C).

[0164] 4-(4-(5-((3-Chlorophenyl)carbamoyl)furan-2-yl)phenoxy)piperidine-1-carboxylate tert-butyl (53). The compound was obtained by reaction of 5-bromo-N-(3-chlorophenyl)furan-2-carboxamide (11 ) (0.74 mmol, 223 mg), Na2CO3(1 ,64 mmol, 173 mg), Pd(PPh3)4(0.037 mmol, 43 mg), 4-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)piperidine-1-carboxylate (41 ) (0.74 mmol, 300 mg) and a mixture of toluene (4 mL), H2O (3 mL) and EtOH (2 mL) as solvent according to procedure D. Purification: Hex / AcOEt (9:1 ). Yield: 240 mg (65%) as yellow solid. 1<h2 style=";text-align:left;direction:ltr">H RMN (300 MHz, DMSO-de) 5 10.25 (s, 1 H), 7.93 (t, J = 2.0 Hz, 1 H), 7.91 - 7.86 (m, 2H), 7.74 - 7.69 (m, 1 H), 7.44 - 7.37 (m, 2H), 7.20 - 7.14 (m, 1 H), 7.13 - 7.07 (m, 2H), 7.04 (d, J = 3.7 Hz, 1 H), 4.71 - 4.59 (m, 1 H), 3.73 - 3.62 (m, 2H), 3.27 - 3.15 (m, 2H), 1 .97 - 1 .88 (m, 2H), 1 ,62 - 1 ,48 (m, 2H), 1 ,41 (s, 9H).<h2 style=";text-align:left;direction:ltr"> 13 <h2 style=";text-align:left;direction:ltr"> C RMN (75 MHz, DMSO-d6) 5 158.0, 156.7, 156.2, 154.4, 146.0,<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0165] <h2 style=";text-align:left;direction:ltr"> 140.5, 133.4, 130.8, 126.8 (2C), 123.9, 122.6, 120.4, 1 19.3, 118.2, 116.6 (2C), 106.9, 79.2, 72.4, 30.8 (2C), 28.5 (3C).<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0166] <h2 style=";text-align:left;direction:ltr"> 4-(5-((2-(1 - Bencilpiperidin-4-il)eti l)carbamoil)f uran-2-il)fenoxi)piperidi n- 1 -carboxilato de terc-butilo (54). The composition is due to the reaction of N-(2-(1-bencilpiperidin-4-il)etil)-<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0167] 5-bromofuran-2-carboxamide (12) (0.74 mmol, 290 mg), Na2CO3 (1.64 mmol, 173 mg), Pd(PPh3)4 (0.037 mmol, 43 mg), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)piperidine-1-carboxylate (41) (0.74 mmol, 300 mg), and a mixture of toluene (4 mL), H2O (3 mL), and EtOH (2 mL) as solvent according to procedure D. Purification: CH2Cl2 / MeOH (9:1). Yield: 57 mg (13%) as a yellow solid. 1 1H NMR (300 MHz, DMSO-d6) δ 8.38 (t, J = 5.8 Hz, 1H), 7.85 - 7.78 (m, 2H), 7.31 - 7.28 (m, 5H), 7.11 - 7.08 (m, 1H), 7.08 - 7.03 (m, 2H), 6.91 (d, J = 3.5 Hz, 1H), 4.69 - 4.58 (m, 1H), 3.72 - 3.70 (m, 2H), 3.47 (s, 2H), 3.31 - 3.17 (m, 4H), 2.83 - 2.77 (m, 4H), 1.98 - 1.86 (m, 4H), 1.75 - 1.58 (m, 4H), 1.41 (s, 9H). 13 13C NMR (75 MHz, DMSO-d6) δ 157.6, 157.2, 154.5, 153.9, 146.6, 128.9, 128.2 (4C), 125.9 (3C), 122.4, 116.1 (2C), 115.3, 105.8, 78.8, 71.9, 61.9, 53.2 (2C), 48.6 (2C), 36.1 (2C), 28.1 (3C), 24.7.

[0168] General procedure E for the synthesis of deprotected heterocyclic derivatives 55-77.

[0169] X = S; Z = CH X = O; Z = CH X = S; Z = NH

[0170] Scheme 5. Synthesis of the deprotected derivatives, i) TFA, CH2CI2, rt, 3 hours.

[0171] After obtaining the protected products, deprotection was carried out by stirring them in a 3:2 CH2Cl2 / TFA or 4:1 CH2Cl2 / TFA solution at room temperature for 3 hours, except for 69 (4 days), 70 (3 days), 74 (24 h) and 75 (4 days). Once the deprotection was completed, the solvent was evaporated in vacuo and the product dissolved in CH2Cl2 was basified with NaHCO3 to give the final product in its neutral form. The volatiles were evaporated to dryness in vacuo and the resulting residues were purified by flash column chromatography using solvent mixtures as eluents, as indicated in each case.

[0172] N-Phenyl-5-(2-(piperidin-4-yloxy)phenyl)thiophene-2-carboxamide (55). The compound was prepared by reacting tert-butyl 4-(2-(5-(phenylcarbamoyl)thiophen-2-yl)phenoxy)piperidine-1-carboxylate (31) (0.5 mmol, 302 mg) and a solution of CH2Cl2 (5 mL) and TFA (3.4 mL) following general procedure E. Purification: CH2Cl2 / MeOH (9:1). Yield: 90 mg (35%) as a white solid. Mp 122-124 e C. 1 H NMR (300 MHz, DMSO-d6) 5 10.28 (s, 1 H), 8.07 (d, J = 4.1 Hz, 1 H), 7.87 (dd, J = 7.9, 1.6 Hz, 1 H), 7.81 - 7.73 (m, 2H), 7.70 (d, J = 4.1 Hz, 1 H), 7.41 - 7.31 (m, 3H), 7.29 (d, J = 7.7 Hz, 1 H), 7.12 (d, J = 7.5 Hz, 1 H), 7.07 (dd, J = 7.8, 1 .2 Hz, 1 H), 4.91 (dt, J = 7.9, 4.0 Hz, 1 H), 3.37 - 3.25 (m, 2H), 3.23 - 3.05 (m, 2H), 2.31 - 2.15 (m, 2H), 2.04 - 1 .90 (m, 2H). 13C NMR (75 MHz, DMSO-d6) 5 160.5, 152.8, 143.7, 139.5, 139.2 (2C), 130.1, 129.0 (2C), 128.9, 128.7, 126.1, 124.0, 121.8, 120.6 (2C), 1 14.5, 70.7, 41 .3 (2C), 27.7 (2C). HRMS (ESI) cal. for C22H22N2O2S [M + H]+ 379.1475; found 379.1473. HPLC-MS (gradient II) (M+H) + = 379, t R = 2.86 min (99%).

[0173] N-(4-Chlorophenyl)-5-(2-(piperidin-4-yloxy)phenyl)thiophene-2-carboxamide (56). The compound was obtained by reaction of tert-butyl 4-(2-(5-((4-chlorophenyl)carbamoyl)thiophen-2-yl)phenoxy)piperidine-1-carboxylate (32) (0.46 mmol, 102 mg) and a solution of CH2Cl2 (5 mL) and TEA (3.3 mL) following general procedure E. Compound 56 was obtained pure after extraction with acidic aqueous medium. Yield: 30 mg (16%) as a white solid. Mp 143-145 e C. 1H RMN (300 MHz, DMSO-d6) 5 10,29 (s, 1 H) 7,93 (d, J = 4,1 Hz, 1 H), 7,82 (dd, J = 7,9, 1 ,7 Hz, 1 H), 7,78 - 7,75 (m, 2H), 7,66 (d, J = 4,2 Hz, 1 H), 7,40 - 7,35 (m, 2H), 7,31 (ddd, J = 8,6, 7,2, 1 ,7 Hz, 1 H), 7,21 (d, J = 8,5 Hz, 1 H), 7,01 (t, J =

[0174] 7.4 Hz, 1 H), 4,69 - 4,62 (m, 1 H), 3,02 - 2,93 (m, 2H), 2,62 - 2,53 (m, 2H), 2,01 - 1 ,96 (m, 2H), 1 ,66 - 1 ,57 (m, 2H). 13 C RMN (75 MHz, DMSO-d6) 5 160,6, 152,9, 143,5, 138,7 (2C), 129,4 (2C), 128,4 (2C), 128,0, 126,9, 125,3, 122,5, 122,0 (2C), 120,8, 1 14,3, 74,7, 43,6 (2C), 32,2 (2C). HRMS (ESI) cale, para C22H22CIN2O2S [M + H]+ 413,1085; encontrado 413,1077. HPLC-MS (gradiente II) (M + H) + = 413, t R = 2,69 min (99%).

[0175] N-(3-Chlorophenyl)-5-(2-(piperidin-4-yloxy)phenyl)thiophene-2-carboxamide (57). The compound was obtained by reaction of tert-butyl 4-(2-(5-((3-chlorophenyl)carbamoyl)thiophen-2-yl)phenoxy)piperidine-1-carboxylate (33) (0.33 mmol, 169 mg) and a solution of CH2Cl2 (3 mL) and TFA (2 mL) following general procedure E. Purification: C^Ch / MeOH (9:1 ). Yield: 53 mg (39%) as a white solid. Mp 195 - 197 e C. 1 H NMR (500 MHz, DMSO-d6) 5 10.42 (s, 1 H), 8.06 (d, J = 4.1 Hz, 1 H), 7.96 (t, J = 2.1 Hz, 1 H), 7.86 (dd, J = 7.9, 1.7 Hz, 1 H), 7.73 - 7.68 (m, 2H), 7.38 (t, J = 8.1 Hz, 1 H), 7.33 (ddd, J = 8.7, 7.2, 1 .7 Hz, 1 H), 7.23 (d, J = 8.6 Hz, 1 H), 7.15 (ddd, J = 8.0, 2.1, 0.9 Hz, 1 H), 7.05 - 7.01 (m, 1H), 4.72 - 4.66 (m, 1H), 3.05 - 3.00 (m, 2H), 2.67 - 2.59 (m, 2H), 2.05 - 1 .97 (m, 2H), 1 .69 - 1 .61 (m, 2H). 13C NMR (125 MHz, DMSO-d6) 5 160.5, 152.9, 144.2, 140.4, 138.3, 132.9, 130.3, 129.6, 128.9, 128.1, 125.4, 123.2, 122.3, 120.9, 119.6, 1 18.5, 1 14.3, 74.4,

[0176] 43.4 (2C), 31.9 (2C). HRMS (ESI) m / z: [M + H]+ cale, for C22H22CIN2O2S 413.1085; found 413.1083. HPLC-MS (gradient II) (M + H)+ = 413, t R = 2.72 (99%).

[0177] N-Phenethyl-5-(2-(piperidin-4-yloxy)phenyl)thiophene-2-carboxamide (58). The compound was obtained by reaction of tert-butyl 4-(2-(5-(phenylcarbamoyl)thiophen-2-yl)phenoxy)piperidine-1-carboxylate (34) (0.47 mmol, 237 mg) and a solution of CH2Cl2 (5 mL) and TFA (3.3 mL) following general procedure E. Purification: C^Ch / MeOH (9:1 ). Yield: 30.5 mg (16%) as a yellow solid. Mp decomposes. 1H RMN (300 MHz, DMSO-de) 5 8,56 (t, J = 5,7 Hz, 1 H), 7,78 (dd, J = 7,9, 1 ,7 Hz, 1 H), 7,67 (d, J = 4,0 Hz, 1 H), 7,59 (d, J = 4,0 Hz, 1 H), 7,33 - 7,18 (m, 7H), 7,02 - 6,97 (m, 1 H), 4,66 - 4,56 (m, 1 H), 3,46 (q, J = 6,9, 6,4 Hz, 2H), 3,02 - 2,94 (m, 2H), 2,84 (t, J = 7,5 Hz, 2H), 2,62 - 2,53 (m, 2H), 2,00 - 1 ,94 (m, 2H), 1 ,65 - 1 ,54 (m, 2H). 13 C RMN (75 MHz, DMSO-d6) 5

[0178] 161.5, 152,9, 142,7, 139,5, 139,0, 129,3, 128,7 (2C), 128,4 (2C), 127,9, 127,1 , 126,1 ,

[0179] 125.2, 122,6, 120,8, 114,3, 74,6, 43,7 (2C), 40,8, 35,3, 32,3 (2C). HRMS (ESI) m / z: [M + H] + calc, para C24H27N2O2S 407,1788; encontrado 407,1782. HPLC-MS (gradiente II) (M + H)+ = 407, t R = 2,62 (99%).

[0180] N-(2-(1 -Benzylpiperidin-4-yl)ethyl)-5-(2-(piperidin-4-yloxy)phenyl)thiopheno-2-carboxamide (59). The compound was obtained by reaction of 4-(2-(5-((2-(1 -benzylp¡peridine-4-yl)ethyl)carbamoyl)thiophene-2-yl)phenoxy)piperidin-1 -carboxylate of tere-butyl (35) (0.25 mmol, 1 mL dissolution of 120 mg EA) and (2 mL) following general procedure E. Purification: AcOEt / MeOH (8:2). Yield: 30 mg (24%) as yellow solid. Pf 118 – 120 e C. 1 H NMR (300 MHz, DMSO-d6) 5 8.39 (t, J = 5.7 Hz, 1 H), 7 .77 (dd, J = 7.9, 1 .7 Hz, 1 H), 7.68 (d, J = 4.0 Hz, 1 H), H. 7, 3, 34 (d - 7.26 (m, 5H), 7.26 - 7.18 (m, 2H), 7.02 - 6.97 (m, 1 H), 4.67 - 4.58 (m, 1 H), 3.42 (s, 2H), 3.28 - , 3.23 (m 2H), 2.81 - 2.74 (m, 2H), 2.58 (ddt, 2H), 2.01 - 1 .94 (m, 2H), 1 .92 - 1 .86 (m, 2H), 1 .70 - 1 .64), - 1 .64 (m, 2H 2H), 1 .46 (q, J = 7.0 Hz, 2H), 1 .35 - 1 .26 (m, 1 H), 1 .20 - 1 .12 (m, 2H). 13C NMR (75 MHz, DMSO-d6) 5 161 .3, 152.9, 142.6, 139.2, 138.7, 129.2, 128.7 (2C), 128.1 (2C), 128.0, 127.0, 126.7, 125.2,

[0181] 122.6, 120.8, 1 14.3, 74.5, 62.5, 53.3 (2C), 43.6 (2C), 36.7, 36.0, 32.9, 32.2 (2C), 31.9 (2C). HRMS (ESI) m / z: [M + H] + cale, for C30H38N3O2S 504.2679; found 504.2680. HPLC-MS (gradient II) (M + H)+ = 504, t R = 1.84 min (99%).

[0182] N-Phenyl-5-(3-(piperidin-4-yloxy)phenyl)thiophene-2-carboxamide (60). The compound was obtained by reaction of tert-butyl 4-(3-(5-(phenylcarbamoyl)thiophen-2-yl)phenoxy)piperidine-1-carboxylate (36) (1 mmol, 478 mg) and a solution of CH2Cl2 (8 mL) and TFA (2 mL) following general procedure E. Purification: CH2Cl2 / MeOH (9:1 ). Yield: 121 mg (32%) as a white solid. Mp 151 - 153 e C. 1H RMN (300 MHz, DMSO-d6) 5 10,27 (s, 1 H), 8,05 (d, J = 4,0 Hz, 1 H), 7,81 - 7,70 (m, 2H), 7,65 (d, J = 4,0 Hz, 1 H), 7,43 - 7,32 (m, 3H), 7,32 - 7,24 (m, 2H), 7,21 - 7,05 (m, 1 H), 6,99 (d, J = 8,1 Hz, 1 H), 4,56 (dt, J = 8,8, 4,7 Hz, 1 H), 3,08 - 2,90 (m, 2H), 2,73 - 2,56 (m, 2H), 1 ,96 (dd, J = 12,9, 4,0 Hz, 2H), 1 ,53 (qd, J = 9,2, 4,7 Hz, 2H). 13 C RMN (75 MHz, DMSO-d6) 5 160,0, 157,9, 148,5,

[0183] 139.2, 139,0, 134,8, 130,9, 130,5, 129,0 (2C), 125,1 , 124,1 , 120,7 (2C), 118,6, 1 16,4, 113,4, 73,2, 43,5 (2C), 31 ,9 (2C). HRMS (ESI) m / z: [M + H]+ cale, para C22H23N2O2S 379,1475; encontrado 379,1475. HPLC-MS (gradiente II) (M + H)+ = 379, t R = 2,91 min (99%).

[0184] N-(4-Chlorophenyl)-5-(3-(piperidin-4-yloxy)phenyl)thiophene-2-carboxamide (61). The compound was obtained by reaction of tert-butyl 4-(3-(5-((4-chlorophenyl)carbamoyl)thiophen-2-yl)phenoxy)piperidine-1-carboxylate (37) (1 mmol, 508 mg) and a solution d (2 mL) following general procedure E. Purification: Yield: 137 mg (34%) as a white solid. Mp 169 - 171 e DMSO-de) 5 10.36 (s, 1 H), 8.02 (d, J = 4.0 Hz, 1 H), 7.82 - 7.74 (m, 2H), 7.65 (d, J = 3.9 Hz, 1 H), 7.47 - 7.39 (m, 2H), 7.35 (t, J = 8.1 Hz, 1 H), 7.30 - 7.23 (m, 2H), 7.02 - 6.94 (m, 1 H), 4.64 - 4.37 (m, 1 H), 3.02 - 2.88 (m, 2H), 2.67 - 2.54 (m, 2H), 2.02 - 1 .86 (m, 2H), 1 .58 - 1 .38 (m, 2H). 13C NMR (75 MHz, DMSO-d6) 5 159.7, 157.7, 148.5, 138.4, 137.7, 134.3, 130.5, 130.4, 128.6 (2C), 127.4, 124.8, 121.8 (2C), 1 18.1, 116.1, 1 13.0, 73.5, 43.7 (2C), 32.3 (2C). HRMS (ESI) m / z: [M + H]+ cale, for C22H22CIN2O2S 413.1085; found 413.1088. HPLC-MS (gradient II) (M + H)+ = 413, t R = 2.90 min (99%).

[0185] N-(3-Chlorophenyl)-5-(3-(piperidin-4-yloxy)phenyl)thiophene-2-carboxamide (62). The compound was obtained by reaction of tert-butyl 4-(3-(5-((3-chlorophenyl)carbamoyl)thiophen-2-yl)phenoxy)piperidine-1-carboxylate (38) (0.27 mmol, 139 mg) and a solution of CH2Cl2 (3 mL) and TFA (2 mL) following general procedure E. Purification: C^Ch / MeOH (9:1 ). Yield: 17 mg (16%) as a yellow solid. Mp 150 - 152 e C. 1H RMN (300 MHz, DMSO-de) 5 10,40 (s, 1 H), 8,03 (d, J = 4,0 Hz, 1 H), 7,92 (t, J = 2,1 Hz, 1 H), 7,72 - 7,63 (m, 2H), 7,43 - 7,25 (m, 4H), 7,20 - 7,14 (m, 1 H), 7,03 - 6,95 (m, 1 H), 4,62 - 4,45 (m, 1 H), 3,04 - 2,91 (m, 2H), 2,69 - 2,57 (m, 2H), 2,02 - 1 ,90 (m, 2H), 1 ,58 - 1 ,41 (m, 2H), 1 ,27 - 1 ,10 (m, 1 H). 13 C RMN (75 MHz, DMSO-d6) 5 159,9, 157,6, 148,7, 140,2, 138,3, 134,3, 133,0, 130,6, 130,5, 130,4, 124,8, 123,4, 119,7, 1 18,6, 118,2, 1 16,1 , 1 13,1 , 73,3, 43,5 (2C), 31 ,9 (2C). HRMS (ESI) m / z: [M + H]+ cale, para C22H22CIN2O2S 413,1085; encontrado 413,1080. HPLC-MS (gradiente II) (M + H)+ = 413, t R = 2,75 (99%).

[0186] N -Phenyl-5-(4-(piperidine-4-yloxy)phenyl)thiopheno-2-carboxamide (63). The compound was obtained by reaction of 4-(5-(phenylcarbamoyl)thiophen-2-yl)phenoxy)piperidine-1 -tere-butyl carboxylate (39) (0.20 mmol, 96 mg) and a TFA dissolution (0.8 mL) following Procedure E. 8% white solid. Pf 192 – 194 e C , DMSO-d6) 5 10.22 (s, 1 H), 8.01 (d, J = 4.0 Hz, 1 H), 7.79 - 7.68 (m, 2H), 7.68 - 7.57 (m, 2H), 7.49 (t, J 7, =31, 7.9 Hz, 2H), 7.15 − 7.07 (m, 1 H), 7.07 − 6.94 (m, 2H), 4.69 − 4.38 (m, 1 H), 2.98 (dd, J = 12.6, 4.8 Hz, 8, J =1 =1 ( 2), 2.9 Hz, 2H), 2.04 - 1 .86 (m, 2H), 1 .51 - 1 .38 (m, 2H). 13 C NMR (75 MHz, DMSO-d6) 5 160.1 , 157.9, 148.9, 139.1 , 137.9, 130.7, 129.0 (2C), 127.6 (2C), 125.6, (123.0), 116.7, 73.3, 43.6 (2C), 31 .9 (2C). HRMS (ESI) m / z: [M + H]+ calc, for C22H23N2O2S 379.1475; found 379.1469. HPLC–MS (gradient II) (M + H)+ = 379, t R = 2.82 min (99%).

[0187] N-(3-Chlorophenyl)-5-(4-(piperidin-4-yloxy)phenyl)thiophene-2-carboxamide (64). The compound was obtained by reaction of tert-butyl 4-(5-((3-chlorophenyl)carbamoyl)thiophen-2-yl)phenoxy)piperidine-1-carboxylate (40) (0.42 mmol, 213 mg) and a solution of CH2Cl2 (4 mL) and TEA (1 mL) following general procedure E. Purification: C^Ch / MeOH (9:1 ). Yield: 38 mg (22%) as a white solid. Mp 224 - 226 e C. 1 H NMR (300 MHz, DMSO-d6) 5 10.37 (s, 1 H), 8.02 (d, J = 4.0 Hz, 1 H), 7.92 (t, J = 2.0 Hz, 1 H), 7.73 - 7.61 (m, 3H), 7.50 (d, J = 3.9 Hz, 1 H), 7.39 (t, J = 8.1 Hz, 1 H), 7.20 - 7.13 (m, 1 H), 7.09 - 6.99 (m, 2H), 4.58 - 4.40 (m, 1 H), 3.05 - 2.91 (m, 2H), 2.71 - 2.58 (m, 2H), 2.09 - 1 .87 (m, 2H), 1 ,61 - 1 ,40 (m, 2H). 13C NMR (75 MHz, DMSO) 5 159.9, 157.6, 149.1, 140.3, 137.0, 132.9, 130.8, 130.4, 127.3 (2C), 125.5, 123.3, 123.2, 119.6, 118.5, 116.4 (2C), 72.9, 43.2 (2C), 31.5 (2C). HRMS (ESI) m / z: [M + H]+ cale, for C22H22CIN2O2S 413.1085; found 413.1083. HPLC-MS (gradient I) (M + H)+ = 413, t R = 4.46 (99%).

[0188] N-(2-(1-Benzylpiperidin-4-yl)ethyl)-5-(4-(piperidin-4-yloxy)phenyl)thiophene-2-carboxamide (65). The compound was obtained by reaction of tert-butyl 4-(5-((2-benzylpiperidin-4-yl)ethyl)carbamoyl)thiophen-2-yl)phenoxy)piperidine-1-carboxylate (49) (0.69 mmol, 420 mg) and a solution of CH2Cl2 (8 mL) and TFA (2 mL) following general procedure E. Purification: C^Ch / MeOH (9:1 ). Yield: 10 mg (3%) as an orange solid. Mp. 1H RMN (300 MHz, DMSO-d6) 5 8,42 (t, J = 5,6 Hz, 1 H), 7,69 (d, J = 3,9 Hz, 1 H), 7,64 - 7,59 (m, 2H), 7,39 (d, J = 3,9 Hz, 1 H), 7,33 - 7,24 (m, 5H), 7,09 - 7,02 (m, 2H), 4,69 - 4,61 (m, 1 H), 3,43 (s, 2H), 3,26 - 3,24 (m, 2H), 3,21 - 3,15 (m, 2H), 3,03 - 2,94 (m, 2H), 2,80 - 2,75 (m, 2H), 2,1 1 - 2,04 (m, 2H), 1 ,93 - 1 ,86 (m, 2H), 1 ,82 - 1 ,73 (m, 2H), 1 ,68 - 1 ,64 (m, 2H), 1 ,45 (q, J = 7,0 Hz, 2H), 1 ,20 - 1 ,13 (m, 3H). 13 C RMN (75 MHz, DMSO-d6) 5 160,8, 156,9, 147,1 , 138,2, 128,8, 128,7 (2C), 128,1 (2C), 127,1 , 126,8 (2C), 126,2 (2C), 123,1 , 116,4 (2C), 69,9, 62,5, 53,2 (2C), 41 ,1 (2C), 36,7, 35,9, 31 ,8 (2C), 28,9, 28,1 (2C). HRMS (ESI) m / z: [M + H]+ cale, para C30H38N3O2S 504,2679; encontrado 504,2653. HPLC-MS (gradiente II) (M + H) + = 504, t R= 2.95 min (97%). N-Phenyl-2-(4-(piperidin-4-yloxy)phenyl)thiazole-5-carboxamide (66). The compound was obtained by reaction of tert-butyl 4-(4-(5-(phenylcarbamoyl)thiazol-2-yl)phenoxy)piperidine-1-carboxylate (50) (0.10 mmol, 50 mg) and a solution of CH2Cl2 (4 mL) and TEA (1 mL) following general procedure E. Compound 66 was obtained pure after washing. Yield: 38 mg (97%) as a yellow solid. Mp 159 - 161 e C. 1 H NMR (300 MHz, DMSO-de) 5 10.50 (s, 1 H), 8.66 (s, 1 H), 7.98 - 7.89 (m, 2H), 7.77 - 7.69 (m, 2H), 7.41 - 7.33 (m, 2H), 7.17 - 7.05 (m, 3H), 4.62 - 4.45 (m, 1H), 3.07 - 2.88 (m, 2H), 2.65 - 2.52 (m, 2H), 2.01 - 1 .88 (m, 2H), 1 .56 - 1 .41 (m, 2H). 13 C NMR (75 MHz, DMSO-d6) 5 170.8, 159.6, 158.6, 144.8, 138.5, 134.5, 128.8 (2C), 128.3 (2C), 125.1, 124.0, 120.4 (2C), 116.2 (2C), 73.8, 43.6 (2C), 32.2 (2C). HRMS (ESI) m / z: [M + H]+ cale, for C21 H22N3O2S 380.1427; found 380.1429. HPLC-MS (gradient II) (M + H)+ = 380, tR = 2.49 (96%).

[0189] N-(2-(1-Benzylpiperidin-4-yl)ethyl)-2-(4-(piperidin-4-yloxy)phenyl)thiazole-5-carboxamide (67). The compound was obtained by reaction of tert-butyl 4-(5-((2-(1-benzylpiperidin-4-yl)ethyl)carbamoyl)thiazol-2-yl)phenoxy)piperidine-1-carboxylate (51) (0.32 mmol, 195 mg) and a solution of CH2Cl2 (4 mL) and TFA (1 mL) following general procedure E. Compound 67 was obtained pure after washing. Yield: 91 mg (56%) as a yellow solid. Mp 162-164 e C. 1 H NMR (300 MHz, DMSO-d6) 5 8.61 (s, 1 H), 8.34 (s, 1 H), 7.93 - 7.83 (m, 2H), 7.35 - 7.18 (m, 5H), 7.11 - 7.02 (m, 2H), 4.60 - 4.44 (m, 1 H), 3.42 (s, 2H), 3.27 - 3.22 (m, 2H), 3.04 - 2.90 (m, 2H), 2.84 - 2.70 (m, 2H), 2.68 - 2.54 (m, 2H), 1 .99 - 1 .83 (m, 4H), 1 .72 - 1 .61 (m, 2H), 1 .53 - 1 .41 (m, 4H), 1 .36 - 1 .25 (m, 1 H), 1 .22 - 1 .09 (m, 2H). 13 C NMR (75 MHz, DMSO-d6) 5 169.8, 159.6, 159.4,

[0190] 143.5, 138.7, 134.5, 128.7 (2C), 128.1 (2C), 128.1 (2C), 126.7, 125.2, 116.2 (2C), 73.4,

[0191] 62.5, 53.2 (2C), 43.4 (2C), 36.9, 35.9, 32.9 (2C), 31.8 (2C). HRMS (ESI) m / z: [M + H]+ cale, for C29H37N4O2S 505.2632; found 505.2654. HPLC-MS (gradient II) (M + H)+ = 505, t R = 2.01 (98%).

[0192] N-Phenyl-5-(4-(piperidin-4-yloxy)phenyl)furan-2-carboxamide (68). The compound was obtained by reaction of tert-butyl 4-(4-(5-(phenylcarbamoyl)furan-2-yl)phenoxy)piperidine-1-carboxylate (52) (1.25 mmol, 580 mg) and a solution of CH2Cl2 (4 mL) and TFA (1 mL) following general procedure E. Compound 68 was obtained pure after washing. Yield: 246 mg (50%) as a yellow solid. Mp 169-171 e C. 1H RMN (300 MHz, DMSO-de) 5 10,12 (s, 1 H), 7,96 - 7,84 (m, 2H), 7,81 - 7,71 (m, 2H), 7,42 - 7,32 (m, 3H), 7,15 - 7,04 (m, 3H), 7,01 (d, J = 3,6 Hz, 1 H), 4,63 - 4,49 (m, 1 H), 3,12 - 2,96 (m, 2H), 2,77 - 2,62 (m, 2H), 2,07 - 1 ,90 (m, 2H), 1 ,68 - 1 ,47 (m, 2H). 13 C RMN (75 MHz, DMSO-de) 5 157,5, 156,1 , 155,5, 145,9, 138,5, 128,6 (2C), 126,2 (2C), 123,8, 122,1 , 120,6 (2C), 117,1 , 116,0 (2C), 106,2, 72,5, 42,9 (2C), 31 ,1 (2C). HRMS (ESI) m / z: [M + H] + calc, for C22H23N2O3 363,1703; detectado 363,1703. HPLC-MS (gradiente II) (M + H) + = 363, t R = 2,61 (96%).

[0193] N-(3-Chlorophenyl)-5-(4-(piperidin-4-yloxy)phenyl)furan-2-carboxamide (69). The compound was obtained by reaction of tert-butyl 4-(5-((3-chlorophenyl)carbamoyl)furan-2-yl)phenoxy)piperidine-1-carboxylate (53) (0.47 mmol, 240 mg) and a solution of CH2Cl2 (4 mL) and TEA (1 mL) following general procedure E for 4 days. Purification: CFhCh / MeOH (9:1 ). Yield: 20 mg (12%) as a yellow solid. Mp 127.5-129.5 e C. 1 H NMR (300 MHz, DMSO-d6) 5 10.26 (s, 1 H), 7.95 - 7.93 (m, 1 H), 7.90 - 7.86 (m, 2H), 7.74 - 7.71 (m, 1 H), 7.43 - 7.38 (m, 2H), 7.19 - 7.15 (m, 1 H), 7.11 - 7.06 (m, 2H), 7.03 (d, J = 3.7 Hz, 1 H), 4.61 - 4.53 (m, 1 H), 3.09 - 2.99 (m, 2H), 2.80 - 2.68 (m, 2H), 2.04 - 1 .94 (m, 2H), 1 .63 - 1 ,53 (m, 2H). 13C NMR (75 MHz, DMSO-d6) 5 157.5, 156.2, 155.8, 145.5, 140.1, 132.9, 130.4, 126.3 (2C), 123.4, 122.0, 1 19.9, 118.8, 117.7, 116.1 (2C), 106.3, 72.1, 42.7 (2C), 30.7 (2C). HRMS (ESI): cale, for C22H22CIN2O3 [M + H]+ 397.1313; found 397.1312. HPLC-MS (gradient II) (M + H)+ = 397, t R = 4.09 (99%).

[0194] N-(2-(1-Benzylpiperidin-4-yl)ethyl)-5-(4-(piperidin-4-yloxy)phenyl)furan-2-carboxamide (70). The compound was obtained by reaction of tert-butyl 4-(5-((2-(1-benzylpiperidin-4-yl)ethyl)carbamoyl)furan-2-yl)phenoxy)piperidine-1-carboxylate (54) (0.085 mmol, 50 mg) and CH2Cl2 solution (2.25 L) following general procedure E for 3 days. Purification: ). Yield: 10 mg (24%) as an orange solid. Mp. decomposes. , DMSO-de) 5 8,40 - 8,37 (m, 1 H), 7,83 - 7,81 (m, 2H), 7,34 - 7,26 (m, 4H), 7,25 - 7,21 (m, 1 H), 7,10 (d, J = 3,5 Hz, 1 H), 7,09 - 7,06 (m, 2H), 6,92 (d, J = 3,5 Hz, 1 H), 4,69 - 4,60 (m, 1 H), 3,43 (s, 2H), 3,26 - 3,21 (m, 2H), 3,20 - 3,14 (m, 2H), 3,00 - 2,91 (m, 2H), 2,80 - 2,74 (m, 2H), 2,08 - 2,01 (m, 2H), 1 ,93 - 1 ,86 (m, 2H), 1 ,75 - 1 ,65 (m, 4H), 1 ,48 - 1 ,44 (m, 2H), 1 ,20 - 1 ,14 (m, 3H). 13 C RMN (75 MHz, DMSO-d6) 5 157,6, 156,9, 154,4, 146,6, 138,6, 128,7 (2C), 128,1 (2C), 126,8, 126,0 (2C), 122,6, 1 16,1 (2C), 115,3, 105,9, 70,3, 62,5, 53,2 (2C), 41 ,4 (2C), 36,1 , 32,9, 31 ,8 (2C), 29,1 (2C) 22,1 . HRMS (ESI): cale, para C30H38N3O3 [M + H]+ 488,2908; encontrado 488,2921 . HPLC-MS (gradiente II) (M + H)+ = 488, t R = 2,88 (97%).

[0195] N-Phenethyl-2-(2-(piperidin-4-yloxy)phenyl)thiazole-5-carboxamide (71). The compound was obtained by reaction of tert-butyl 4-(2-(5-(phenethylcarbamoyl)thiazol-2-yl)phenoxy)piperidine-1-carboxylate (42) (0.052 mmol, 26 mg) and a solution of CH2Cl2 (4 mL) and TFA (1 mL) following general procedure E. Compound 71 was obtained pure after work up. Yield: 16.5 mg (77%) as a white solid. Mp 157-159 e C. 1 H NMR (300 MHz, DMSO-de) 5 8.77 (t, J = 5.7 Hz, 1 H), 8.42 (s, 1 H), 8.32 (dd, J = 7.9, 1.8 Hz, 1 H), 7.46 (ddd, J = 8.7, 7.2, 1.8 Hz, 1 H), 7.35 - 7.28 (m, 3H), 7.29 - 7.24 (m, 2H), 7.24

[0196] - 7.19 (m, 1H), 7.11 - 7.05 (m, 1H), 4.78 (dt, J = 9.3, 4.9 Hz, 1H), 3.53 - 3.44 (m, 2H), 3.08 - 3.00 (m, 2H), 2.85 (t, J = 7.5 Hz, 2H), 2.70 - 2.60 (m, 2H), 2.07 - 2.01 (m, 2H), 1 .74 - 1 .61 (m, 2H). 13C NMR (75 MHz, DMSO-d6) 5 164.0, 160.4, 154.1, 142.0, 139.3, 134.9, 131.7, 128.7 (2C), 128.4 (2C), 127.9, 126.2, 121.8, 120.7, 114.0, 75.2, 43.7 (2C), 40.8, 35.1, 32.2 (2C). HRMS (ESI) m / z: [M + H]+ cale, for C23H26N3O2S 408.1740; found 408.1741. HPLC-MS (gradient II) (M + H)+ = 408, t R = 2.54 (99%).

[0197] N-Phenyl-2-(3-(piperidin-4-yloxy)phenyl)thiazole-5-carboxamide (72). The compound was obtained by reaction of tert-butyl 4-(3-(5-(phenylcarbamoyl)thiazol-2-yl)phenoxy)piperidine-1-carboxylate (43) (0.14 mmol, 70 mg) and a solution of CH2Cl2 (3 mL) and TFA (0.75 mL) following general procedure E. Purification: C^Ch / MeOH (9:1 ). Yield: 6 mg (11 %) as a yellow solid. Mp 235 - 237 e C. 1 H NMR (500 MHz, DMSO-d6) 5 10.55 (s, 1 H), 8.74 (s, 1 H), 7.76 - 7.72 (m, 2H), 7.63 - 7.58 (m, 2H), 7.47 (t, J = 8.0 Hz, 1 H), 7.41 - 7.35 (m, 2H), 7.22 - 7.18 (m, 1 H), 7.16 - 7.12 (m, 1 H), 4.82 - 4.72 (m, 1 H), 3.24

[0198] - 3.17 (m, 2H), 3.08 - 2.99 (m, 2H), 2.15 - 2.06 (m, 2H), 1 .86 - 1 .77 (m, 2H). 13 C NMR (125 MHz, DMSO-de) 5 170.3, 158.4, 157.2, 144.9, 138.4, 135.9, 134.0, 130.9, 128.9 (2C), 124.2, 120.4 (2C), 1 18.5, 113.8, 70.0, 40.2 (2C), 27.9 (2C). HRMS (ESI) m / z: [M + H]+ calc, for C21H22N3O2S 380.1427; detected 380.1423. HPLC-MS (gradient II) (M + H)+ = 380, t R = 2.64 (99%).

[0199] N-(4-Chlorophenyl)-5-(2-(piperidin-4-yloxy)phenyl)furan-2-carboxamide (73). The compound was obtained by reaction of tert-butyl 4-(2-(5-((4-chlorophenyl)carbamoyl)furan-2-yl)phenoxy)piperidine-1-carboxylate (45) (1.1 mmol, 537 mg) and a solution of CH2Cl2 (20 mL) and TFA (5 mL) following general procedure E. Purification: C^Ch / MeOH (9:1 ). Yield: 145 mg (34%) as a white solid. Mp 124.5-126.5 e C. 1 H NMR (300 MHz, DMSO-de) 5 10.31 (s, 1 H), 8.16 (dd, J = 7.8, 1.7 Hz, 1 H), 7.86 - 7.76 (m, 2H), 7.47

[0200] - 7.40 (m, 3H), 7.39 - 7.32 (m, 1H), 7.23 (d, J = 8.3 Hz, 1H), 7.13 - 7.04 (m, 2H), 4.76 - 4.62 (m, 1H), 3.11 - 2.93 (m, 2H), 2.83 - 2.64 (m, 2H), 2.14 - 1 .97 (m, 2H), 1 .75 - 1 .57 (m, 2H). 13 C NMR (75 MHz, DMSO-de) 5 156.2, 153.6, 152.3, 145.3, 137.5, 129.8, 128.6 (2C), 127.5, 127.0, 122.2 (2C), 120.6, 1 18.5, 1 17.3, 113.9, 11 1 .8, 73.1 , 43.0 (2C), 31 .1 (2C). HRMS (ESI): cale, for C22H22CIN2O3 [M + H]+ 397.1313; found 397.1312. HPLC-MS (gradient II) (M + H)+ = 397, t R = 2.78 (99%). N-Phenyl-5-(2-(piperidin-4-yloxy)phenyl)furan-2-carboxamide (74). The compound was obtained by reaction of tert-butyl 4-(2-(5-(phenylcarbamoyl)furan-2-yl)phenoxy)piperidine-1-carboxylate (44) (1 .3 mmol, 600 mg) and a solution of CH 2 1 / 2 mL) following general procedure E for 24 h. Purification: . Yield: 70 mg (16%) as an orange solid. Mp 147.5-149.5 Hz, DMSO-d6) 5 10,23 - 10,16 (m, 1 H), 8,20 - 8,14 (m, 1 H), 7,81 - 7,74 (m, 2H), 7,45 (d, J = 3,6 Hz, 1 H), 7,42 - 7,31 (m, 3H), 7,29 - 7,23 (m, 1 H), 7,17 - 7,08 (m, 2H), 7,07 (d, J = 3,6 Hz, 1 H), 4,90 - 4,75 (m, 1 H), 3,22 - 3,16 (m, 2H), 3,05 - 2,92 (m, 2H), 2,25 - 2,12 (m, 2H), 1 ,94 - 1 ,78 (m, 2H). 13 C RMN (75 MHz, DMSO-d6) 5 156,6, 153,7, 152,4, 146,2, 138,9, 130,3, 129,1 (2C), 127,7, 124,3, 121 ,4, 121 ,2 (2C), 119,1 , 117,4, 114,4, 1 12,2, 71 ,4, 41 ,9 (2C), 28,9 (2C). HRMS (ESI): cale, para C22H23N2O3 [M + H]+ 363,1703; encontrado 363,1703. HPLC-MS (gradiente II) (M + H)+ = 363, t R = 2,61 (99%).

[0201] N-(2-(1 -Benci Ipiperidine n-4-yl)ethyl)-5-(2-(piperidin-4-iloxy)phenyl)fu ran-2-carboxamide (75). The compound was obtained by reaction of 4-(2-(5-((2-(1 -benzylp¡peridin-4-yl)ethyl)carbamoyl)furan-2-yl)phenoxy)piperidin-1 -tere-butyl carboxylate (46) (0.33 mmol, 195 mg dilution CH general procedure E for 4 days Purification: 30 mg (18%) as yellow solid Pf 123.6 - 125.6 Hz, DMSO-d6) 5 8.48 - 8.41 (m, 1 H), 8.1 1 - 8.06 (m, 1 H), 7.36 - 7.26 (m, 5H), 7.25 - 7.18 (m, 2H), 7.0 Hz = 14 (d 7.03 (m, 1 H), 7.00 (d, J = 3.6 Hz, 1 H), 4.73 - 4.66 (m, 1 H), 3.42 (s, 2H), 3.30 - 3.24 (m, 2H), 3.10 - , 3.71 (m 4H), 2.1 1 - 2.02 (m, 2H), 1 .92 - 1 .85 (m, 2H), 1 .74 - 1 .60 (m, 4H), 1 .52 - 1 .43 (m, 2H), 1 .25 H). 13C NMR (75 MHz, DMSO-d6) 5 157.5, 153.3, 151.1, 146.2, 138.7, 129.5 (2C), 128.7, 128.1 (2C), 126.8, 120.6, 118.8, 115.2, 113.8 (2C), 1 11 .42, 72.5, 62.5, 53.2 (2C), 42.7 (2C), 36.2 (2C), 32.9, 31 .9 (2C), 30.5 (2C). HRMS (ESI): cale, for C30H38N3O3 [M + H]+ 488.2908; found 505.3215 (NH4 salt + ). HPLC-MS (gradient II) (M+H) + = 488, t R = 2.04 (98%).

[0202] N-Phenethyl-5-(2-(piperidin-4-yloxy)phenyl)furan-2-carboxamide (76). The compound was obtained by reaction of tert-butyl 4-(2-(5-(phenethylcarbamoyl)furan-2-yl)phenoxy)piperidine-1-carboxylate (47) (1.51 mmol, 743 mg) and TFA solution (2 mL) following general procedure E. Purification: Yield: 124 mg (21 %) as a yellow solid. Mp 200 - 204 e , DMSO-d6) 5 8,62 (t, J = 5,8 Hz, 1 H), 8,09 (dd, J = 7,9, 1 ,7 Hz, 1 H), 7,39 - 7,19 (m, 7H), 7,17 (d, J = 3,5 Hz, 1 H), 7,08 (ddd, J = 8,1 , 7,2, 1 ,1 Hz, 1 H), 6,99 (d, J = 3,6 Hz, 1 H), 4,89 - 4,70 (m, 1 H), 3,57 - 3,42 (m, 2H), 3,19 - 3,09 (m, 2H), 3,00 - 2,81 (m, 4H), 2,22 - 2,05 (m, 2H), 1 ,91 - 1 ,74 (m, 2H). 13 C RMN (75 MHz, DMSO-d6) 5 157,6, 153,1 , 151 ,0, 146,2, 139,4, 129,5, 128,6 (2C), 128,4 (2C), 126,8, 126,1 , 120,8, 1 18,8, 1 15,3, 113,8, 1 11 ,4, 71 ,2, 41 ,7 (2C), 35,3, 28,9 (2C). HRMS (ESI): calc, for C24H27N2O3 [M + H]+ 391 ,2016; detectado 391 ,2012. HPLC-MS (gradiente II) (M + H)+ = 391 , t R = 2,64 (99%).

[0203] N-Phenyl-5-(3-(piperidin-4-yloxy)phenyl)furan-2-carboxamide (77). The compound was obtained by reaction of tert-butyl 4-(3-(5-(phenylcarbamoyl)furan-2-yl)phenoxy)piperidine-1-carboxylate (48) (0.39 mmol, 180 mg) and a solution of CH2Cl2 (4 mL) and TEA (1 mL) following general procedure E. Compound 77 was obtained pure after washing. Yield: 107 mg (76%) as a white solid. Mp 169 - 171 e C. 1 H NMR (300 MHz, DMSO-d6) 5 10.20 (s, 1H), 7.82 - 7.70 (m, 2H), 7.58 - 7.49 (m, 2H), 7.44 - 7.33

[0204] (m, 4H), 7.20 (d, J = 3.7 Hz, 1 H), 7.16 - 7.09 (m, 1 H), 7.04 - 6.97 (m, 1 H), 4.62 - 4.45

[0205] (m, 1 H), 3.08 - 2.91 (m, 2H), 2.75 - 2.58 (m, 2H), 2.05 - 1 .88 (m, 2H), 1 .60 - 1 .43 (m,

[0206] 2H). 13 C NMR (75 MHz, DMSO-d6) 5 157.5, 156.0, 155.0, 146.7, 138.4, 130.7, 130.1,

[0207] 128.6 (2C), 123.9, 120.7 (2C), 117.0, 1 16.9, 1 15.6, 1 12.3, 108.3, 72.9, 43.3 (2C), 31.6 (2C). HRMS (ESI): calc, for C22H23N2O3 [M + H]+ 363.1703; detected 363.1705. HPLC- MS (gradient II) (M + H)+ = 363, t R = 2.64 (99%).

[0208] Example 2. Antibacterial activity in reference strains of A. baumannü and E. coli

[0209] Bacterial strains and growth conditions

[0210] Two gram-negative bacterial reference strains were used: A. baumannü ATCC 17978 and E. coli ATCC 25922. The strains were thawed from a collection stored at -80 e C and grown on sheep blood agar plate (Columbia Agar 5% Sheep Blood, ThermoFisher, Spain) at 37 e C under stirring for 24 hours.

[0211] Microdilution assays

[0212] The MIC, i.e., the minimum concentration of compound necessary to inhibit bacterial growth, was evaluated. For this purpose, microdilution assays were performed in duplicate for the three study strains. This assay was carried out in 96-well U-bottom microplates (Microdur, Spain). The procedure was as follows: first, 100 pL of the study compound was added to the wells of the first column, starting from an initial concentration of 64 or 128 mg / L. Subsequently, 50 pL of Luria Bertani (LB) culture medium was added to the remaining wells, except for those used as sterility and growth controls. After this step, serial dilutions were made.

[0213] Each well was then inoculated with 50 pL of a bacterial culture at a concentration of 1x10 A6 colony-forming units (CFU) / mL, derived from a 0.5 McFarland (McF) suspension. Only 100 pL of medium was added to the sterility control well to ensure it was not contaminated. Bacterial culture, without drug, was added to the growth control well to verify that our strain was growing properly.

[0214] Results

[0215] Table 1

[0216] Example 3. Antibacterial activity in colistin-resistant clinical strains of A. baumannii and E. coli

[0217] Bacterial strains and growth conditions

[0218] Seven colistin-resistant A. baumannii clinical strains and ten colistin-resistant E. coli clinical strains were used. The strains were thawed from a collection stored at -80°C. e C and grown on sheep blood agar plate at 37 e C under stirring for 24 hours.

[0219] Microdilution assays

[0220] The MIC of 1 1 thiophene derivatives was evaluated. Microdilution assays were performed in duplicate for the 17 study strains. This assay was carried out in 96-well U-bottom microplates.

[0221] The procedure was as follows: first, 100 pL of the test compound was added, starting from an initial concentration of 64 or 128 mg / L, to the wells of the first column. Subsequently, 50 pL of LB culture medium was added to the remaining wells, except for those used as sterility and growth controls. After this step, serial dilutions were made.

[0222] Each well was then inoculated with 50 pL of a bacterial culture at a concentration of 1x10 A6 CFU / mL, which comes from a 0.5 McF suspension. Only 100 pL of medium was added to the sterility control well to ensure it was not contaminated. Bacterial culture, without drug, was added to the growth control well to verify that our strain was growing properly. Results

[0223] 5

[0224] MIC (mg / L)

[0225] Pathogen Strain Colistin 55 60 58 56 62 61

[0226] RC-64 32 64 16 64 8 32 16

[0227] Ab11 256 64 32 >64 16 16 4

[0228] Ab20 64 64 32 >64 16 32 1

[0229] A Ab21 128 16 32 16 4 64 >64 baumannii Ab22 128 16 8 32 4 32 16

[0230] Ab99 64 64 32 >64 8 64 64

[0231] Ab113 256 64 32 >64 16 32 >64

[0232] CMIso 128 64 32 >64 16 32 16

[0233] CRA5 8 64 32 64 4 32 32

[0234] CRA7 8 64 >64 64 8 64 464

[0235] Tabla 2

[0236] CMI (mg / L)

[0237] Patógeno Cepa Colistina 64 59 74 73 69

[0238] RC-64 32 >64 >64 64 32 >64

[0239] Ab11 256 8 >64 64 32 >64

[0240] Ab20 64 >64 >64 64 32 >64

[0241] A Ab21 128 >64 >64 64 16 >64 baumannii Ab22 128 >64 >64 64 8 32

[0242] Ab99 64 >64 >64 64 16 64

[0243] Ab113 256 >64 >64 64 16 64

[0244] CMI50 128 >64 >64 64 16 >64

[0245] CRA5 8 >64 >64 >64 16 64

[0246] CRA7 8 >64 >64 64 32 >64

[0247] CRA8 8 >64 >64 64 64 >64

[0248] E. coli

[0249] CRA17 8 >64 >64 64 16 64

[0250] CRA20 8 >64 >64 >64 >64 >64

[0251] CRA32 8 64 >64 64 16 64 CRA57 4 64 >64 >64 8 8

[0252] MCR1 + 4 >64 >64 >64 >64 >64

[0253] R6 MCR1 8 >64 >64 64 >64 32

[0254] CMI50 8 >64 >64 64 64 64

[0255] Table 2 (continued)

Claims

CLAIMS or a pharmaceutically acceptable salt thereof, wherein: X represents S or O; Y represents CH or N; R 1 represents phenyl or C1-C4 alkyl, where the phenyl group is optionally substituted by a halogen group; Cy 1 represents a 6-membered saturated heterocycle containing 1 or 2 heteroatoms in its backbone selected from N and O, which is bonded to the rest of the molecule via any available C or N atom and which is optionally substituted by a benzyl group; and each R 2 , R 3 and R 4 independently represent H or a group provided that one of each R 2 , R 3 and R 4 is distinct from H and the other two groups are H, for use in the treatment and / or prevention of a disease caused by a bacterium.

2. The compound of formula I for use according to claim 1, for the treatment and / or prevention of a disease caused by a gram-negative bacterium.

3. The compound of formula I for use according to any of claims 1 or 2. 2, where the bacteria are A. baumanii and E. coli.

4. The compound of formula I for use according to any of claims 1 to 3. 3, where R 1 represents phenyl optionally substituted by a halogen group.

5. The compound of formula I for use according to claim 4, wherein the halogen is Cl.

6. The compound of formula I for use according to any one of claims 1 to 3, wherein R 1 represents C1-C4 alkyl substituted by a phenyl group.

7. The compound of formula I for use according to claim 1, wherein: R 1 represents C1-C4 alkyl substituted by a Cy group 1 ; and Cy 1 represents a 6-membered saturated heterocycle containing 1 N in its structure, which is linked to the rest of the molecule by an available C atom and which is optionally substituted by a benzyl group.

8. The compound of formula I for use according to any of claims 1 to 7, wherein: X represents S; and And it represents CH.

9. The compound of formula I for use according to any of claims 1 to 7, wherein: X represents O; and And it represents CH.

10. The compound of formula I for use according to any of claims 1 to 7, wherein: X represents S; and And it stands for N.

11. The compound of formula I for use according to claim 1, wherein the compound of formula I is selected from: N-Phenyl-5-(2-(piperidin-4-yloxy)phenyl)thiophene-2-carboxamide (55); N-(4-Chlorophenyl)-5-(2-(piperidin-4-yloxy)phenyl)thiophene-2-carboxamide (56); N-(3-Chlorophenyl)-5-(2-(piperidin-4-yloxy)phenyl)thiophene-2-carboxamide (57); N-Phenethyl-5-(2-(piperidin-4-yloxy)phenyl)thiophene-2-carboxamide (58); N-(2-(1-Benzylpiperidin-4-yl)ethyl)-5-(2-(piperidin-4-yloxy)phenyl)thiophene-2-carboxamide (59); N-Phenyl-5-(3-(piperidin-4-yloxy)phenyl)thiophene-2-carboxamide (60); N-(4-Chlorophenyl)-5-(3-(piperidin-4-yloxy)phenyl)thiophene-2-carboxamide (61 ); N-(3-Chlorophenyl)-5-(3-(piperidin-4-yloxy)phenyl)thiophene-2-carboxamide (62); N-Phenyl-5-(4-(piperidin-4-yloxy)phenyl)thiophene-2-carboxamide (63); N-(3-Chlorophenyl)-5-(4-(piperidin-4-yloxy)phenyl)thiophene-2-carboxamide (64); N-(2-(1-Benzylpiperidin-4-yl)ethyl)-5-(4-(piperidin-4-yloxy)phenyl)thiophene-2-carboxamide (65); N-Phenyl-2-(4-(piperidin-4-yloxy)phenyl)thiazol-5-carboxamide (66); N-(2-(1 -Benzylpiperidin-4-yl)ethyl)-2-(4-(piperidin-4-yloxy)phenyl)thiazol-5-carboxamide (67); N -Phenyl-5-(4-(piperidine-4-yloxy)phenyl)furan-2-carboxamide (68); N-(3-Chlorophenyl)-5-(4-(piperidine-4-yloxy)phenyl)furan-2-carboxamide (69); N-(2-(1 -Benzylpiperidin-4-yl)ethyl)-5-(4-(piperidin-4-yloxy)phenyl)furan-2-carboxamide (70); N-Phenetyl-2-(2-(piperidin-4-yloxy)phenyl)thiazol-5-carboxamide (71); N-Phenyl-2-(3-(piperidin-4-ylox)phenyl)thiazol-5-carboxamide (72); N-(4-Chlorophenyl)-5-(2-(piperidin-4-yloxy)phenyl)furan-2-carboxamide (73); N-Phenyl-5-(2-(piperidine-4-yloxy)phenyl)furan-2-carboxamide (74); N-(2-(1 -Benzylpiperidin-4-yl)ethyl)-5-(2-(piperidin-4-yloxy)phenyl)furan-2-carboxamide (75); N-Phenetyl-5-(2-(piperidine-4-yloxy)phenyl)furan-2-carboxamide (76); y N -Phenyl-5-(3-(piperidin-4-yloxy)phenyl)furan-2-carboxamide ( 77 ).

12. A compound of Formula II: or a pharmaceutically acceptable salt thereof, wherein: X represents S or O; Y represents CH or N; R 1 represents phenyl or C1-C4 alkyl, where the phenyl group is optionally substituted by a halogen group, preferably where the halogen group is Cl, and where C1-C4 alkyl is substituted by a phenyl group or a Cy group 1 ; Cy 1 represents a 6-membered saturated heterocycle containing 1 or 2 heteroatoms in its structure selected from N and O, which are attached to the rest of the molecule by any available C or N atom and which is optionally substituted by a benzyl group, preferably Cy 1 represents a 6-membered saturated heterocycle containing 1 N in its structure, which is linked to the rest of the molecule by an available C atom and which is optionally substituted by a benzyl group, and more preferably Cy 1represents N-benzylpiperidine; and each R 2 , R 3 and R 4 independently represent H or a group , provided that one of each R 2 , R 3 and R 4 is distinct from H and the other two groups are H, and with the condition that when X is S, Y is not CH.

13. The compound of formula II according to claim 12, selected from: N-Phenyl-2-(4-(piperidin-4-yloxy)phenyl)thiazole-5-carboxamide (66); N-(2-(1-Benzylpiperidin-4-yl)ethyl)-2-(4-(piperidin-4-yloxy)phenyl)thiazole-5-carboxamide (67); N-Phenyl-5-(4-(piperidin-4-yloxy)phenyl)furan-2-carboxamide (68); N-(3-Chlorophenyl)-5-(4-(piperidin-4-yloxy)phenyl)furan-2-carboxamide (69); N-(2-(1-Benzylpiperidin-4-yl)ethyl)-5-(4-(piperidin-4-yloxy)phenyl)furan-2-carboxamide (70); N-Phenethyl-2-(2-(piperidin-4-yloxy)phenyl)thiazole-5-carboxamide (71); N-Phenyl-2-(3-(piperidin-4-yloxy)phenyl)thiazole-5-carboxamide (72); N-(4-Chlorophenyl)-5-(2-(piperidin-4-yloxy)phenyl)furan-2-carboxamide (73); N-Phenyl-5-(2-(piperidin-4-yloxy)phenyl)furan-2-carboxamide (74); N-(2-(1-Benzylpiperidin-4-yl)ethyl)-5-(2-(piperidin-4-yloxy)phenyl)furan-2-carboxamide (75); N-Phenethyl-5-(2-(piperidin-4-yloxy)phenyl)furan-2-carboxamide (76); and N-Phenyl-5-(3-(piperidin-4-yloxy)phenyl)furan-2-carboxamide (77).

14. A pharmaceutical composition comprising the compound of formula II according to any of claims 12 or 13, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

15. The compound of formula II according to any of claims 12 or 13, or a pharmaceutically acceptable salt thereof, for use as a medicament.

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