A GRK2 PROTEIN INHIBITOR COMPOUND AND A PHARMACEUTICAL COMPOSITION COMPRISING IT

Abstract

Compounds that inhibit the GRK2 protein are disclosed. In particular, a compound that inhibits the GRK2 protein is disclosed, having the formula (1), where atom X is selected from carbon and nitrogen, and R¹ is selected from the methylcarboxylate and 1,3,4-oxadiazol-2-yl groups, and wherein the compound is selected from methyl 4-(naphthalene-2-amido)benzoate and N-[4-(1,3,4-oxadiazol-2-yl)phenyl]quinolin-3-carboxamide. Pharmaceutical compositions comprising at least one compound of formula (1) are also disclosed. Claim 1: A GRK2 protein inhibitor compound conforming to formula (1), characterized in that atom X is selected from carbon and nitrogen, and R¹ is selected from the methylcarboxylate and 1,3,4-oxadiazol-2-yl groups, and wherein the compound is selected from methyl 4-(naphthalene-2-amido)benzoate and N-[4-(1,3,4-oxadiazol-2-yl)phenyl]quinolin-3-carboxamide.

Description

A GRK2 PROTEIN INHIBITOR COMPOUND AND A PHARMACEUTICAL COMPOSITION COMPRISING IT The present invention relates to a compound that inhibits the GRK2 protein. In particular, it relates to a compound that inhibits the GRK2 protein according to formula I. Formula I: atom X is selected from carbon and nitrogen, and Ri is selected from the methylcarboxylate and 1,3,4-oxadiazol-2-yl groups, and wherein the compound is selected from methyl 4-(naphthalene-2-amido)benzoate and N-[4-(1,3,4-oxadiazol-2-yl)phenyl]quinolin-3-carboxamide. In a preferred embodiment of the invention, the GRK2 protein inhibitor compound is methyl 4-(naphthalene-2-amido)benzoate. Background of the invention The GRK2 protein is a key protein kinase in the regulation of a large family of membrane receptors known as G protein-coupled receptors (GPCRs). The main function described for GRK2 is the physiological inhibition of these receptors once they have been activated. IF-2019-79523174-APN-ANP#INPI Page 1 of 39. Sustained stimulation. This phenomenon is known as desensitization and allows cells to dynamically inactivate GPCR-dependent signaling pathways when necessary. The GRK2 protein is involved in the regulation of GPCRs linked to cellular responses to adrenaline, histamine, serotonin, acetylcholine, and angiotensin, among others. For this reason, excessive GRK2 activity has been associated with numerous pathologies, and the development of GRK2 inhibitors is of interest for their pharmacological treatment. In particular, much effort has been dedicated to the search for GRK2 inhibitors for the treatment of cardiac pathologies in which this kinase is known to be overactivated. However, the search for inhibitors has always focused on identifying compounds capable of blocking GRK2-mediated kinase or receptor phosphorylation activity.Today, it is known that the GRK2 protein can not only phosphorylate receptors but also inactivate them through its RGS domain by blocking the interaction between the receptor and the G protein through which it signals or transfers the stimulus into the cell to generate a biological response. The present invention consists of the development of a new class of compounds capable of inhibiting the action of the GRK2 RGS domain with high specificity and selectivity. Although the GRK2 protein kinase has been proposed as a target for the development of pharmacological inhibitors, to date only compounds that act by inhibiting the kinase activity (phosphorylation of other proteins) of GRK2 have been proposed. However, to date, no compounds that inhibit the activity (or the RGS domain) of GRK2 have been proposed. IF-2019-79523174-APN-ANP#INPI Page 2 of 39 domain) GRK2 RGS (regulator of signaling through G protein). Brief description of the invention The present invention relates to a compound that inhibits the GRK2 protein. In particular, it relates to a compound that inhibits the GRK2 protein according to formula I. Formula I: atom X is selected from carbon and nitrogen, and . ( Ri is selected from the methylcarboxylate and 1,3,4-oxadiazol-2-yl groups, and wherein the compound is selected from methyl 4-(naphthalene-2-amido)benzoate and N-[4-(1,3,4-oxadiazol-2-yl)phenyl]quinolin-3-carboxamide. In a preferred embodiment of the invention, the GRK2 protein inhibitor compound is methyl 4-(naphthalene-2-amido)benzoate. Brief description of the figures Figure 1 shows the potentiating effect of the comparator compounds C2, C3, C4 and C5 and of the compound according to invention L96B on the capacity of IF-2019-79523174-APN-ANP#INPI Page 3 of 39 H2 receptor response to histamine, a GPCR associated with the Gas-adenylate cyclase-cAMP signaling cascade that is desensitized by GRK2, in HEK293 cells that overexpress rH2. Figure 2 shows the lack of effect of the comparator compounds C2, C3, C4, C5 and the compound according to invention L96B on the responsiveness of rH2 when the effect is evaluated in HEK293 cells expressing a variant of GRK2 having a mutated RGS domain. Figure 3 shows the potentiating effect of the compounds of the invention at a concentration of 100nM on the responsiveness of the H2 receptor to histamine, a GPCR associated with the Gas-adenylate cyclase-cAMP signaling cascade that is desensitized by GRK2, in U937 cells that endogenously express rH2. Figure 4 shows that in the cell line Ά549, the release of Ca2+ in response to rHl stimulation is greater when the cells were treated with the compound according to invention L96B. Figure 5 shows that treatment with a compound according to the invention significantly increases the expression of the monocyte terminal differentiation marker CD88 in a leukemic cell line by inhibiting GRK2 desensitization of rH2 and consequently enhancing the cAMP response to histamine. Figure 6 shows the potentiating effect of the compound of the invention L96B on the cAMP responsiveness of β-adrenergic receptors to isoproterenol in rat cardiomyocytes, whose activity is essential for cardiac function. IF-2019-79523174-APN-ANP#INPI Page 4 of 39 Figure 7 shows that the comparator compound C2 exhibited significant cytotoxicity compared to the DMSO control starting at a concentration of 10 µM. However, the compound of the invention L96B did not affect cell viability at the tested concentrations. Thus, the advantage of the compound of the invention L96B over the comparative commercial compound C2 is highlighted, with respect to potential toxic effects on the human liver. Detailed description of the invention Given that GRK2 is a protein of great physiological relevance and participates in the inactivation of numerous receptors, its dysregulation is associated with the development of various pathologies such as hypertension, heart failure, Alzheimer's disease, rheumatoid arthritis, cystic fibrosis, and cancer, among others. In all cases, the signaling of a receptor (different for each pathology) is altered due to the overactivation of GRK2, so inhibiting this protein would result in relief of the pathological condition or its reversal. Therefore, to date, there is a need to develop new GRK2 inhibitors that can be used in the treatment or management of the aforementioned pathologies. However, there are numerous suppliers that provide molecular tools to laboratories conducting research in the area of ​​biomedical sciences and that might also be interested in marketing these molecules for conducting in vitro, in vivo or ex vivo experimental assays where it is useful to inhibit the RGS domain of GRK2. IF-2019-79523174-APN-ANP#INPI Page 5 of 39 Thus, the present invention relates to compounds that inhibit the GRK2 protein. In particular, it relates to a compound that inhibits the GRK2 protein according to formula I. Formula I wherein atom X is selected from carbon and nitrogen, and Ri is selected from the methylcarboxylate and 1,3,4-oxadiazol-2-yl groups. In particular, the compound of the invention is selected from the compounds methyl 4-(naphthalene-2-amido)benzoate and N-[4-(1,3,4-oxadiazol-2-yl)phenyl]quinolin-3-carboxamide. In a preferred embodiment of the invention, the GRK2 protein inhibitor compound is methyl 4-(naphthalene-2-amido)benzoate. In one particular embodiment, the compound of the invention conforms to formula II EITHER IF-2019-79523174-APN-ANP#INPI Page 6 of 39 Formula II In another particular embodiment, the compound of the invention corresponds to formula III Formula III Another object of the invention is a pharmaceutical composition comprising at least one GRK2 protein inhibitor and pharmaceutically acceptable excipients. In one particular embodiment of the invention, the pharmaceutical composition comprises methyl 4-(naphthalene-2-amido)benzoate and pharmaceutically acceptable excipients. In another particular embodiment of the invention, the pharmaceutical composition comprises N-[4-(1,3,4-oxadiazol-2-yl)phenyl]quinolin-3-carboxamide. A person skilled in the art will be able to select the most appropriate excipients for the composition of the invention, according to the chosen route of administration. Pharmaceutical compositions comprising one or more of the compounds of the invention in combination with other therapeutically active substances are also considered to be within the scope of the present invention. In particular, it is contemplated that the pharmaceutical composition of the invention can be administered by route. IF-2019-79523174-APN-ANP#INPI Page 7 of 39 oral, parenteral, or transdermal. In particular, this composition may be in the form of a liquid, suspension, tablet, capsule, coated tablet, injectable solution, or transdermal patch. Within the scope of the invention, the possibility of formulating the compositions of the invention to release in a controlled manner at least one of the compounds with inhibitory activity against a GRK2 cellular protein corresponding to formulas I, II, and III is also contemplated. A person skilled in the art will be able to formulate the composition of the invention according to the selected route of administration. The present invention also covers pharmaceutical compositions comprising at least one compound of formula I, II or III in combination with other therapeutically active substances, which together with the compounds of the invention can provide an additive or synergistic therapeutic effect such as, for example, gemcitabine, capecitabine, decitabine, paclitaxel and docetaxel or other antitumor agents. In another particular embodiment of the invention, the pharmaceutical composition comprises the therapeutically active substances encapsulated within liposomes or microspheres. A person skilled in the art may, taking into account the available literature related to this type of encapsulation, determine the necessary parameters and excipients. Furthermore, another object of the invention is a method for treating an indication mediated by a GRK2 cellular protein, which comprises administering to a patient in need of such treatment a safe and effective amount of at least one compound according to the invention. IF-2019-79523174-APN-ANP#INPI Page 8 of 39 In another embodiment of the invention, the described inhibitors may be used in basic research as pharmacological tools to further the understanding of biological, physiological, and pathological processes in which GRK2 is involved through its RGS domain, such as desensitization mechanisms of various GPCRs. In this way, they will allow the identification and assignment of differential functions to the different domains of GRK2 in in vitro, in vivo, or ex vivo experimental assays. The compounds of the invention may be of interest for the treatment or prevention of heart failure (HF), cardiac hypertrophy, and hypertension, as well as for cardiovascular complications in individuals with type 2 diabetes. HF is characterized by elevated sympathetic nervous system activity. The resulting high levels of catecholamines have been associated with increased expression and activity of GRK2 in various tissues. In the heart, this overexpression leads to increased desensitization of GPCRs such as the β-adrenergic receptor and the angiotensin II receptor, which regulate contractility and blood flow to the body, respectively. Furthermore, during myocardial ischemia, an increase in membrane GRK2 activity has been observed, contributing to the inactivation of the β-adrenergic receptor. Cardiac output has been shown to increase following inhibition of GRK2 activity.Furthermore, GRK2 has been shown to play a central role in the regulation of arterial tone mediated by vasoconstrictors. The increase in blood pressure induced by increases in GRK2 is accompanied by vascular thickening and cardiac hypertrophy. In this regard, inhibition of GRK2 activity could reduce the alterations observed in the vasculature of hypertensive patients. IF-2019-79523174-APN-ANP#INPI Page 9 of 39 Furthermore, the compounds of the invention could be used to treat different types of cancer in which an association between GRK2 and cancer development has been established. In this regard, the expression of a peptide inhibitor of GRK2, derived from its carboxy-terminal end (PARKct), showed a delay in the growth of prosthetic tumor cells in vitro and prevented the formation of prosthetic tumors in vivo in xenotransplantation models. GRK2 was also found to be overexpressed in samples from patients with pancreatic ductal adenocarcinoma (PDAC). Studies of GRK2 expression in various breast cancer-derived cell lines, mammary glands from animal models, and patient samples revealed increased levels of this protein. In this context, xenotransplantation of breast cancer cells overexpressing GRK2 resulted in larger and earlier tumors compared to the control group, while inhibition of its expression prevented breast tumor formation in these models. Regarding ovarian cancer, elevated GRK2 expression was observed in the KGN cell line, derived from granulosa cell tumors, and also in primary and metastatic tumors from patients.This is consistent with GRK2's desensitizing function on the follicle-stimulating hormone receptor, which modulates granulosa cell proliferation and differentiation and is involved in ovarian cancer development, suggesting that exacerbated desensitization of this receptor could be part of the pathogenesis of ovarian cancer. Regarding acute myeloid leukemia, the balance between cAMP production, degradation, and exclusion has been shown to be essential for cell proliferation / differentiation. An increase in... IF-2019-79523174-APN-ANP#INPI Page 10 of 39. Intracellular cAMP levels are desirable for differentiation therapy. Thus, histamine stimulation (acting through the H2 / Gs receptor) in conjunction with GRK2 inhibitors would increase intracellular cAMP levels to induce the desired differentiation. On the other hand, Alzheimer's disease (AD) is a neurodegenerative disorder in which altered GRK2 expression is an early event in its pathogenesis and precedes the cognitive impairments that characterize the disease. GRK2 protein and mRNA levels have been found to be increased in post-mortem hippocampi and lymphocytes of AD patients, as well as in rat models of chronic cerebral hypoperfusion. Although the signaling pathways that are altered have not yet been fully elucidated, it is known that GRK2 participates in the desensitization of metabotropic glutamate receptors 1 and 5 and the muscarinic MI receptor, all of which are implicated in the development of AD. Therefore, it is anticipated that the described GRK2 inhibitors may offer a potential therapeutic option. Furthermore, the GRK2 protein is an important regulator of immune cell responses to inflammation, as it phosphorylates numerous chemokine and chemotactic receptors responsible for leukocyte trafficking to inflammatory sites and the release of T cells from lymphoid organs. While the pathogenesis of rheumatoid arthritis (RA), in its complexity, involves various cell types, synovial fibroblasts are responsible for the development of an invasive phenotype. These produce cytokines that perpetuate inflammation and proteases that destroy cartilage. It has been shown that during development IF-2019-79523174-APN-ANP#INPI Page 11 of 39 of the inflammatory process in rat models of CIA (collagen-induced arthritis): GRK2 levels in synovial fibroblasts are increased as the condition progresses, and GRK2 inhibitors are able to reverse this effect. On the other hand, GRK2 inhibition with paroxetine demonstrated an attenuation of CIA symptoms by reducing T-cell infiltration into the synovial tissue. The specialized literature has published results showing a decrease in GRK2 levels in blood mononuclear cells of rheumatoid arthritis. On the other hand, cystic fibrosis (CF) is a disease caused by mutations in the gene that codes for the CFTR protein (CF transmembrane conductance regulator) and is characterized by abnormal, excessively thick, and viscous secretions that primarily affect the lungs. The CFTR protein is located in the apical membrane of epithelial cells involved in exocrine secretion and acts as a cAMP-dependent chloride channel. Thus, the composition of luminal airway secretions is regulated by the activity of the β2-adrenergic receptor (P2AR), which is coupled to the cAMP pathway. In airway samples from patients with cystic fibrosis, a reduction in the density of this receptor, as well as an overexpression of GRK2, has been observed. Consistent with these findings, cultures of these epithelial cells showed reduced chloride secretion in response to isoproterenol.Thus, the inhibition of GRK2 would be a potential target to increase adenylate cyclase activity in response to activation of the β2 adrenergic receptor. On the other hand, sepsis is a complex clinical syndrome that results from a harmful host response to IF-2019-79523174-APN-ANP#INPI Page 12 of 39. Infection. Polymorphonuclear neutrophils (PMNs) are the first line of defense in the host against microorganisms, being recruited to inflammatory sites by chemoattractants such as leukotriene B4 (LTB4) and chemokines. Once migrated, these leukocytes are capable of phagocytosis and generating large quantities of reactive oxygen and nitrogen species, such as hydrogen peroxide and nitric oxide, which are crucial products for the microbicidal activity of these cells. Given that neutrophils play a crucial role in controlling the infectious process, it can be hypothesized that impaired neutrophil migration may exacerbate infections. The data suggest that endogenous mediators produced during sepsis can continuously activate circulating neutrophils, leading to the activation of GRK2, which in turn can induce neutrophil desensitization to chemoattractants.Inhibition of GRK2 could be beneficial by restoring the migratory capacity of neutrophils. Finally, multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. The infiltration of activated T lymphocytes and macrophages into the brain and spinal cord is a major factor in the pathogenesis of this disease. In a mouse model of MS, a more benign course of the disease has been demonstrated in GRK2+ / - mice. Furthermore, it has been shown that GRK2 expression is reduced during the remission phase in MS patients, suggesting that the reduction of GRK2 activity during MS may be a novel target for therapy. IF-2019-79523174-APN-ANP#INPI Page 13 of 39 Thus, considering that the inhibition of GRK2 activity would be beneficial in the control and / or treatment of the disorders and diseases mentioned above, the inventors herein postulate that the compounds of the invention would be usable in the control and / or treatment of said disorders and diseases. In particular, it is proposed that the compounds of the invention are useful in the treatment and / or control of heart disease, various types of cancer, inflammatory diseases, Alzheimer's disease (AD), rheumatoid arthritis, cystic fibrosis (CF), sepsis, and multiple sclerosis (MS). A particularly preferred object of the present invention is a pharmaceutical composition comprising a compound of formula II or a compound of formula III, one of its salts, one of its prodrugs, or one of its pharmaceutically acceptable derivatives. However, the invention also encompasses pharmaceutical compositions comprising one or more of such compounds according to the invention, in combination with one or more second therapeutically active substances. According to the present invention, the term "administer" and variants thereof (e.g., the administration of a compound) with reference to a compound of the invention means introducing a compound, a prodrug, a salt, or a pharmaceutically acceptable derivative of the compound of the invention into the system of the animal or human requiring such treatment. When a compound of the invention, a salt, or a pharmaceutically acceptable derivative of the compound of the invention is provided in combination with one or more other IF-2019-79523174-APN-ANP#INPI Page 14 of 39 active agents (for example, another therapeutically active substance that has a complementary or synergistic therapeutic effect to that of the compound of the invention), administration and its variants shall each be understood as including the sequential and concurrent introduction of the compound, the salt, the derivative or the prodrug thereof and of the other agents. For the purposes of the present invention, the term "patient" includes humans. However, it should be understood that the compounds can also be administered to other animals, particularly mammals and other organisms. Thus, the methods are applicable to both human therapy and veterinary applications. Therefore, in some particular embodiments, the compounds are for administration to mammals, and in other embodiments, they are for administration to humans. According to the present invention, a pharmaceutically acceptable salt or derivative of a compound means a salt or derivative that is pharmaceutically acceptable and possesses the desired pharmacological activity of the starting compound. It is understood that pharmaceutically acceptable salts or derivatives are non-toxic. Further information concerning suitable pharmaceutically acceptable salts or derivatives can be found in Remington: The Science and Practice of Pharmacy, 21st ed., Pharmaceutical Press, London, England, 2011, which is incorporated herein by reference. It is also understood that the compounds of the invention may have one or more pharmaceutically acceptable salts or derivatives associated with them. IF-2019-79523174-APN-ANP#INPI Page 15 of 39 A prodrug refers to compounds that are transformed (typically rapidly) in vivo to obtain the starting compound of the above formula, for example, by hydrolysis in the blood. A person skilled in the art will know how to prepare prodrugs from the compounds of the invention in accordance with appropriate practices. A therapeutically effective amount, or a safe and effective amount, is a quantity of a compound of the invention that, when administered to a patient, effectively treats a particular disease. The quantity of a compound of the invention that constitutes a therapeutically effective amount will vary depending on several factors, including the activity, metabolic stability, excretion rate, and duration of action of the compound; the patient's age, weight, general health, sex, diet, and species; the mode and timing of administration of the compound; the concurrent administration of adjuvants or additional therapies; and the severity of the disease for which the therapeutic effect is sought. The therapeutically effective amount, or the safe and effective amount, for a given circumstance can be determined without further experimentation.In preferred embodiments, the acceptable dosage range is from 10 mg to 500 mg every 24 hours, orally, intramuscularly, or intravenously. As is known in the art, adjustments are made for systemic versus localized release, age, weight, general health, sex, diet, and species of the patient, as well as the mode and timing of administration, concurrent administration of adjuvants or additional therapeutically active ingredients, and the severity of the disease for which the effect is desired. IF-2019-79523174-APN-ANP#INPI Page 16 of 39. The therapeutic effect is sought, may be necessary, and will be verifiable through routine experimentation. The effective amounts or doses of the compounds of the present invention can be determined by routine methods, such as modeling, dose escalation, or clinical trials, taking into account routine factors. The actual dosage levels of the active ingredients in pharmaceutical compositions may vary. In general, an appropriate daily dose of a compound and / or of the compositions and methods according to the present invention will be the amount of the compound that provides the lowest effective dose that produces the desired therapeutic effect. The compounds of the invention can be administered to a patient by any acceptable route of administration. Acceptable routes of administration include, but are not limited to, oral, parenteral, transdermal, endocervical, endosinusal, enteral, intra-abdominal, intra-arterial, intrabronchial, intracerebral, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, nasal, nasogastric, buccal, percutaneous, epidural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transmucosal, transtracheal, and ureteral routes. urethral and vaginal. The compounds of the invention can be administered in any acceptable solid dosage form, IF-2019-79523174-APN-ANP#INPI Page 17 of 39 semi-solid, liquid or gaseous. Acceptable dosage forms include, but are not limited to, tablets, capsules, solutions, sprays, creams, emulsions, gases, gels, granules, liniments, lotions, suppositories, ointments, pastes, powders, suspensions, syrups and tablets. A dosage form of the invention may comprise only one compound of the invention, or the compound of the invention may be formulated together with conventional excipients, pharmaceutical carriers, adjuvants, and / or other medicinal or pharmaceutical agents. Acceptable excipients include, but are not limited to, (a) anti-adherents, such as croscarmellose sodium, crospovidone, sodium starch glycolate, microcrystalline cellulose, starch, and talc; (b) binders, such as cellulose, gelatin, hydroxypropyl cellulose, lactose, polyethylene glycol, polyvinylpyrrolidone, sorbitol, starch, and xylitol; (c) coatings, such as cellulose and shellac; (d) disintegrants, such as cellulose, polyvinylpyrrolidone, sodium carboxymethyl cellulose, methylcellulose, microcrystalline cellulose and sodium starch glycolate and starch;(e) Fillers, such as calcium carbonate, cellulose, dibasic calcium phosphate, and mannitol; (f) Flavoring / aroma agents; (g) Coloring agents; (h) Glidants, such as calcium stearate and colloidal silicon dioxide; (i) Lubricants, such as calcium stearate, magnesium stearate, polyethylene glycol, and talc; and (j) Preservatives, such as citric acid, vitamin C, and vitamin E. Pharmaceutical carriers include soluble polymers; IF-2019-79523174-APN-ANP#INPI Page 18 of 39 microparticles made of polymers, natural or synthetic, insoluble or biodegradable, microcapsules, lipoproteins, liposomes and micelles. A pharmaceutical composition of the invention shall contain a therapeutically effective amount of a compound of the invention, a prodrug, a derivative, or a pharmaceutically acceptable salt thereof, with the remainder of the pharmaceutical composition consisting of one or more pharmaceutically acceptable excipients. Typically, a compound of the invention, a prodrug, a derivative, or a pharmaceutically acceptable salt thereof shall be present in a proportion of between 1% and 99% by weight of the pharmaceutically acceptable composition, with the remainder of the pharmaceutical composition consisting of one or more pharmaceutically acceptable excipients.Typically, a compound of the invention, an individual stereoisomer thereof, or a mixture of stereoisomers thereof, a prodrug, a derivative, or a pharmaceutically acceptable salt thereof, shall be in a proportion of between 5% and 75% by weight of the pharmaceutically acceptable composition, with the remainder of the pharmaceutical composition consisting of one or more pharmaceutically acceptable excipients. Methods for preparing the dosage forms of the invention are known, or shall be apparent to those skilled in the art; see, for example, Remington: The Science and Practice of Pharmacy, 21st ed. (Pharmaceutical Press, London, England, 2011). A therapeutically effective amount of a compound of the invention will vary depending on a number of factors, including the activity, metabolic stability, excretion rate, and duration of action of the compound. IF-2019-79523174-APN-ANP#INPI Page 19 of 39 age, weight, general health, sex, diet and species of the patient, the mode and time of administration of the compound, the presence of adjuvants, of additional therapeutically active ingredients in the composition and the severity of the disease for which the therapeutic effect is sought. The present invention also covers the processes usable in obtaining the compounds of Formula I, II and III of the invention and the intermediate compounds usable in said process. Examples Example 1 Synthesis of methyl 4-(2-naphthamide)benzoate (L96B) Step a: 4.0 g (29.2 mmol) of 4-aminobenzoic acid were dissolved in 40 mL of MeOH. This solution was cooled to 0°C, 2.5 equivalents of SOCl₂ were added dropwise, and the mixture was refluxed for 2.5 h under vigorous stirring. The solvent was then evaporated, the mixture was neutralized with saturated NaHCO₃ solution, and extracted with EtAc. The organic phase was washed with saturated NaCl, dried with anhydrous Na₂SC₄, and the solvent was evaporated under reduced pressure. Purification of the crude residue by column chromatography (n-hexane / EtAc) yielded methyl 4-aminobenzoate in 70% (3.1 g). Step b: Subsequently, 500 mg (3.31 mmol) of the product obtained in Step a was dissolved in CH2Cl2, triethylamine (3 equivalents) was added, and to this solution 569 mg (3.31 mmol) of 2-naphthoic acid was added. Then SOCl2 was added dropwise at room temperature under 21 IF-2019-79523174-APN-ANP#INPI Page 20 of 39. Vigorous stirring was carried out until the reaction was complete. The solvent was evaporated under reduced pressure, the residue was dissolved in CH2Cl2 and washed with 1 N HCl, dry NaCl, 1 N NaOH, and finally with dry NaCl. It was dried with anhydrous Na2SC4, and the solvent was evaporated under reduced pressure. Purification of the crude residue by column chromatography (CH2Cl2) yielded methyl 4-(2-naphthamide)benzoate (L96B) in 69% (700 mg). Pf: 142°C MS (ESI) m / z for M+H+: 291.0890. XH-NMR (500 MHz, CDCI3): 3.92 (CH3, 3H, s); 7.57-7.63 (2 H, m) ; 7.80 (2H, d, J = 8.7 Hz) ; 7.90-7.93 (2 H, m) ; 7.95 (2H, t, J = 8.2 Hz); 8.08 (2H, d, J = 8.7.Hz); 8.16 (NH, 1H, s); 8.39 (1 H, s). 13C-NMR (125 MHz, CDCI3): 52.2 (CH3); 119.4; 123.5; 126.0; 127.3; 127.9; 128.0; 128.3; 129.1; 129.2;' 131.1; 131.8; 132.7; 135.2; 142.3; 166.0 (CO amide); 166.7 (CO ester). Example 2 Synthesis of N-[4-(1,3,4-oxadiazol-2-yl)phenyl]quinoline-3 carboxamide (L94C). Following a procedure similar to that described in Example 1 but using, in Step b, 3-quinolinecarboxylic acid, methyl 4-(quinolin-3-carboxamido)benzoate (L94A) was obtained. This last compound (200 g, 0.66 mmol) was dissolved in MeOH, 5 mL of hydrazine hydrate solution was added, and the mixture was stirred until the reaction was complete. The solvent was evaporated under reduced pressure. Purification of the crude residue by crystallization with CH₂Cl₂ yielded N-(4-(hydrazinocarbonyl-1)phenyl)quinolin-3-carboxamide in 50% yield (100 mg). Finally, 25 IF-2019-79523174-APN-ANP#INPI Page 21 of 39 mg (80 pinol) of the product obtained in the previous step was added to 3 mL of trimethyl orthoformate and heated under reflux with vigorous stirring until the reaction was complete. The solvent was evaporated under reduced pressure. Purification of the crude residue by washing with ethyl ether and subsequent recrystallization with CH2Cl2 yielded N-[4-(1,3,4-oxadiazol-2-yl)phenyl]quinoline-3-carboxamide(L94C) with an overall yield of 15%. Pf:202°C . MS (ESI) m / z for M+H+: 317.10390. XH-NMR (300 MHz, DMSO-d6):7.65-7.82 (7H, m); 8.20 (1H, d, J = 7.9 Hz); 8.37 (1H, d, J = 7.9 Hz); 8.73 (1H, s); 9.25 (1H, s); 9.51 (NH, 1H, s). 13C-NMR (75 MHz, DMSO-d6): 123.3; 123.3; 123.6; 125.1; 126.1; 127.1; 127.1; 128.5; 128.7; 128.9; 131.6; 137.4; 143.0; 145.8; 149.9; 151.0; 162.2; 163.9. Example 3 Potentiating effect of inhibitors on the response of a receptor associated with the Gas-adenylate cyclase-cAMP pathway The inhibitory activity of the compounds of the invention and of the following compounds belonging to the Enamine library was studied: COMPOUNDS ACCORDING TO THE INVENTION L96B: methyl 4-(naphthalene-2-amido)benzoate L94C: N-[4-(1,3,4-oxadiazol-2-yl)phenyl]quinoline-3carboxamide TESTED COMPOUNDS BELONGING TO THE ENAMINE LIBRARY IF-2019-79523174-APN-ANP#INPI Page 22 of 39 C4: 3-(naphthalen-2-yl)-1-[3-(IH-pyrazol-l-yl) piperidin-l-yl]propan-l-one C2: 3-(l-acetyl-2,3-dihydro-H-indol-5-yl)-1(quinolin-8-yl)urea C3: 2,7-dimethyl-N-[3-(1,3,4-oxadiazol-2-yl)phenyl]quinoline-3-carboxamide C5: 2-(4-oxo-3,4-dihydrophthalazin-l-yl)-N-(quinolin5-yl) acetamide CIO: N-(2,3-dihydro-lH-inden-l-yl) —3—[5—(4 — methylphenyl)-1,3,4-oxadiazol-2-yl]propanamide To evaluate the effect of GRK2 RGS domain inhibitors, a cell model derived from transfected HEK293 cells was obtained. These cells overexpress the histamine H2 receptor (rH2), a G protein-coupled receptor (GPCR) of the Gs type that, when activated, promotes cAMP synthesis and is inactivated by desensitization mediated by the G protein stimulation regulatory domain (RGS) of GRK2. The resulting clone not only overexpresses rH2 but also overexpresses a dominant-negative mutant of GRK2, the GRK2-K220R variant, which cannot phosphorylate GPCRs but can inactivate them through its RGS domain. In this system, the desensitizing effect of the GRK2 RGS domain on the cAMP response of rH2 is evident. In response to pretreatment with a compound, an enhancement of the cAMP response to the agonist could be associated with an inhibition of desensitization mediated by the RGS domain of GRK2. Clones derived from HEK293 cells were obtained by stable and sequential transfection with the pcDNA3.IZeo(+)-HARH2 and pcDNA3-GRK2K220R plasmids using the K2 Transfection System reagent (BIONTEX), following the manufacturer's instructions and employing, for a plate of IF-2019-79523174-APN-ANP#INPI Page 23 of 39 35 mm diameter plates, mixture A of 2.7 pg of total DNA and 150 µA of DMEM base, and mixture B of 6 µA of K2 transfection reagent and 150 µA of DMEM base. The following day, the cells were plated into 96-well plates with 0.3 ml of complete DMEM per well. For clone selection, the cells were incubated in medium supplemented with the selection agent (Zeocin 50 pg / ml or 2 mg / ml geneticin), following a limit dilution protocol. According to this protocol, the cells were counted and plated by performing serial dilutions, resulting in wells with 1000, 100, 10, and 1 cell. Every other day, the medium was renewed by replacing 100 µA of each well with 100 µA of fresh medium of the same composition. After 3 weeks, several antibiotic-resistant clones were selected, and plasmid expression was subsequently analyzed by Western blot. The clones were maintained in adhesion in an incubator with a humidified atmosphere, containing 5% CO2, at 37°C, in DMEM medium supplemented with 10% FBS, gentamicin 50 pg / ml, geneticin 0.8 mg / ml and zeocin 50 pg / ml. The cells were subcultured by adding a 0.05% trypsin solution and 0.3 mM EDTA. To evaluate the effect of GRK2 inhibitor compounds, clones were plated in 48-well plates at 50% confluence. After 24 h, cells were pretreated in minimal medium at 37 °C for 40 min with the commercial compounds (C2, C3, C4, and C5) at concentrations of 10 µM or 100 µM, or with the compound according to invention L96B at concentrations of 100 µM or 1 µM. An equivalent amount of DMSO was used as a negative control. IF-2019-79523174-APN-ANP#INPI Page 24 of 39 The cells were then incubated for 3 min with IBMX, a phosphodiesterase inhibitor that prevents the degradation of the produced cAMP, and subsequently stimulated for 9 min with the rH2-Gas-adenylate cyclase-cAMP signaling pathway using the specific rH2 agonist, amtamine, at a concentration of 10 µM. The cells were then resuspended in absolute ethanol. This was evaporated, and cAMP levels were determined. The quantification of cAMP in the samples was performed using an adaptation of the binding protein technique according to Davio et al, 1995. Figure 1 shows the potentiating effect of commercial compounds C2, C3, C4, and C5 and of compound L96B according to the invention on the responsiveness of the H2 receptor to histamine, a GPCR associated with the gas-adenylate cyclase-cAMP signaling cascade that is desensitized by GRK2. (Blank bars represent baseline cAMP levels and dashed bars represent the response of the H2 receptor to 10 µM of its specific agonist, histamine. *p<0.05 compared to cells stimulated in the absence of inhibitor) Example 4 Selectivity of the effect of inhibitors. To evaluate the specificity of the effect of the compounds on the RGS domain of GRK2, assays were performed on a second system that overexpresses rH2 and a dominant-negative construct of GRK2 double mutant GRK2K220R / R106A that lacks both kinase activity and action IF-2019-79523174-APN-ANP#INPI Page 25 of 39. Desensitizing via the RGS domain. In this case, overexpression of the inactive variant of GRK2 prevents regulation of the rH2 response. The R106A mutation, which inactivates the RGS domain, is redundant to the effect of a potential inhibitor, thus constituting the selectivity control of the model and allowing us to discern whether the potentiation of the receptor response occurred as a result of inhibition of the RGS domain, or as a result of the compound's non-specific action on an unintended target. Compounds that also raise cAMP levels in this control system are considered to have non-specific action. Figure 2 shows the lack of effect of the comparator compounds C2, C3, C4, C5 and the compound according to invention L96B on the responsiveness of rH2 when the effect is evaluated in HEK293 cells expressing a GRK2 variant having a mutated RGS domain. (Blank bars correspond to baseline cAMP levels and dashed bars to the rH2 response to 10uM of its specific agonist, amtamine; "a" indicates that there are no significant differences between the stated values.) The potentiating effect of compounds C2, C3, C4, C5, and L96B does not occur in clones derived from HEK293 cells that stably express rH2 and a double mutant variant of GRK2 deficient in both kinase activity and RGS activity. Since this latter mutation is redundant to the effect of a potential inhibitor of the RGS domain of GRK2, this system allows us to discern whether the potentiation of the rH2 response resulted from inhibition of the RGS domain or from a nonspecific action of the compound on an unintended target. IF-2019-79523174-APN-ANP#INPI Page 26 of 39 To evaluate the effect of GRK2 inhibitor compounds on the cAMP response under more physiological conditions, we determined the cAMP response in U937 cells that were not translocated because they endogenously express rH2. 400,000 cells were starved for two hours in the absence of fetal bovine serum, pretreated in minimal medium (RPMI), at 37°C for 40 min, with the compounds of the invention L96B and L94C, at concentrations of 100nM and 10μM. An equivalent amount of vehicle, DMSO, was used as a negative control. The cells were then incubated for 3 min with IBMX ImM, a phosphodiesterase inhibitor that prevents the degradation of the cAMP produced. The rH2-Gas-adenylate cyclase-cAMP signaling pathway was then stimulated for 9 min with the specific rH2 agonist, amtamine, at a concentration of 10 μM. Subsequently, the cells were lysed and resuspended in absolute ethanol. This was evaporated, and the cAMP levels were determined. The quantification of cAMP in the samples was performed using an adaptation of the binding protein technique according to Davio et al, 1995. Figure 3 shows the potentiating effect of the compounds of the invention at a concentration of 100nM on the responsiveness of the H2 receptor to histamine, a GPCR associated with the gas-adenylate cyclase-cAMP signaling cascade that is desensitized by GRK2. (Blank bars correspond to the cAMP response to the H2 receptor agonist amtamine in cells pretreated with DMSO and dashed bars to the cAMP response to the amtamine agonist in cells pretreated with the compounds. *p<0.05; IF-2019-79523174-APN-ANP#INPI Page 27 of 39 **p<0.005 with respect to the stimulated cells in the absence of inhibitor representing 100%) To evaluate the effect of GRK2 RGS domain inhibitors on the response of GPCRs coupled to the intracellular Gq-PLC-calcium signaling pathway, the H1 histamine receptor was used as an example. This receptor, coupled to the Gq protein, promotes the release of calcium from the endoplasmic reticulum into the cell cytoplasm when activated, and is also inactivated by desensitization mediated by the GRK2 RGS domain. The system used to determine this biological activity consists of the A549 lung epithelial cell line, which endogenously expresses rH1 and GRK2. Cytoplasmic calcium levels were evaluated using the fluorescent probe Fura2AM, which binds to the Ca2+ ion, altering its excitation wavelength (λ) from 380 nM (free) to 340 nM (bound). Thus, a calcium receptor response to the stimulus is evidenced by an increase in the fluorescence emitted by Fura2AM in its calcium-bound form and a decrease in the signal emitted by its free form, resulting in an increase in the F340 / F380 fluorescence ratio. A549 cells were plated to 40% confluence in 96-well plates. The following day, they were incubated with 2 mM FURA 2-AM probe and 0.2% pluronic acid in BSS buffer (140 mM NaCl, 3.9 mM KCl, 0.7 mM KH2PO4, 0.5 mM Na2HPO4, A12H2O, 1 mM CaCl2, 0.5 mM MgCl2, 20 mM HEPES, 10 mM glucose, and 0.1% BSA, pH 7.5) for 90 min at 37°C. The cells were then washed twice with BSS. During the last 40 minutes of this incubation, the compound according to invention L96B was added at a concentration of 100 mM. Intracellular calcium levels were recorded at 37°C in real time, alternating the IF-2019-79523174-APN-ANP#INPI Page 28 of 39. Excitations were performed at 340 nm and 380 nm using the FlexStation 3 instrument (MolDev). Fluorescence emission was measured at 505 nm. Histamine ligand at a concentration of 100 µM was pipetted into each well 30 seconds after the start of the reading and without interruption, and Triton X100 detergent 0.1% was added at 180 seconds to estimate the amount of FURA2-AM incorporated by the cells. To evaluate the response in desensitized cells, A549 cells were plated to 40% confluence in 96-well plates. The following day, they were incubated with 2 mM FURA 2-ΆM and 0.2% pluronic acid in BSS for 90 min at 37°C. During the last 10 min of this incubation, histamine α was added to the corresponding wells at a concentration of 33 μM, or vehicle alone. Two washes with BSS were then performed, and the procedure was the same as in the response assays. Figure 4 shows that in the A549 cell line, Ca2+ release in response to rHl stimulation is greater when the cells were treated with the compound according to invention L96B. This indicates less GRK2-mediated rHl inactivation. In turn, this compound inhibits GRK2-mediated Ca2+ desensitization in cells that were pretreated with 33 μM histamine. Example 5 Effect of inhibitors on the differentiation of leukemic cells The induction of cell differentiation is a desirable event for achieving cell maturation and halting the proliferation of leukemic cells. This process is closely related to the generation of IF-2019-79523174-APN-ANP#INPI Page 29 of 39 second messenger cAMP in response to different stimuli. The effect of the compounds on the differentiation of leukemic cells U937 was studied by measuring the expression of the terminal differentiation marker to monocytes CD88 after the combined treatment with histamine (an agent that increases intracellular levels of cAMP, but due to the rapid desensitization of its receptor by GRK2 the cAMP signal is insufficient to induce cell differentiation), compounds C2 and CIO and the compound according to the invention L96B. Leukemic promonocytic U937 cells were cultured in suspension in an incubator with a humidified atmosphere of 5% CO2, at 37°C, in RPMI 1640 medium supplemented with 10% FBS and gentamicin · 50 pg / ml, and maintained at a density of 4.105-l, 6.106 cells / ml. The U937 cells were treated for 48h with a concentration of 100 µM of histamine and 1 µM of compound C2 and CIO or with compound L96B of the invention. The samples were lysed in Laemmli buffer (50 mM Tris-HCl, pH 6.8; 2% SDS; 100 mM 2-mercaptoethanol; 10% glycerol; and 0.05% bromophenol blue), sonicated, and incubated in a water bath for 5 minutes before plating. Protein extracts were analyzed on 12% polyacrylamide gels under denaturing conditions (SDS-PAGE). The electrophoresis buffer used consisted of 25 mM Tris; 192 mM glycine; and 0.1% SDS, pH 8.3. Electrophoresis was performed on minigels at a constant current of 30 mA (BioRad). At the end of the fractionation, the gel was equilibrated in transfer buffer (25 mM Tris HCl, pH 8.3, 150 mM glycine; 20% methanol) for 15 min and transferred to nitrocellulose membranes at 100 V for 1 h at 4°C. The proteins transferred to the membranes were stained in a 0.2% Ponceau; 0.5% acetic acid solution. IF-2019-79523174-APN-ANP#INPI Page 30 of 39: Visualize the total proteins and verify the transfer efficiency in all lanes. Subsequently, the membranes were washed in PBS until the staining disappeared. After treating the membranes with blocking solution (PBS-0.1% Tween20) for 1 h, they were incubated for 1 h with 1 pg / ml of goat anti-CD88 or rabbit anti-beta-tubulin antibody. Detection was performed by incubating with 0.2 pg / ml of peroxidase-conjugated anti-goat or anti-rabbit secondary antibody for 1 h, followed by exposure to a peroxidase substrate and chemiluminescence amplifier solution (Amersham Life Science). The result was visualized by autoradiography. The intensity of the CD88 band was quantified by optical densitometry using ImageJ software and expressed relative to the tubulin value. Results were expressed considering 100% CD88 expression in cells treated with DMSO. Data represent the mean ± SEM of 2 independent experiments (n=2). Figure 5 shows that treatment with a compound according to the invention significantly increases the expression of the monocyte terminal differentiation marker CD88 by inhibiting GRK2 desensitization of rH2 and consequently enhancing the cAMP response to histamine. (Blank bars represent CD88 levels in cells pretreated with histamine (H) and vehicle (DMSO), and dashed bars represent CD88 levels in cells pretreated with histamine (H) and the compounds. *p<0.05) Example 6 IF-2019-79523174-APN-ANP#INPI Page 31 of 39 Effect of the compounds of the invention on the cAMP response of cardiomyocytes stimulated with the β-adrenergic agonist, isoproterenol Beta-adrenergic receptors are responsible for controlling myocardial force and contractility. The function of these receptors is regulated by GRK2, and their desensitization by GRK2 is exacerbated in patients with hypertension or heart failure. Cardiomyocytes were obtained from the ventricles of neonatal Sprague-Dawley rats by proteolytic digestion. Shortly after decapitation, the ventricles were separated and transferred to iced PBS, where they were cut with fine scissors into 1–3 mm³ portions. The resulting tissue was subjected to three rounds of enzymatic digestion in saline solution containing collagenase IV (1 mg / ml). The disaggregated cells were collected by centrifugation at 400 rpm for 5 minutes and maintained in DEM-F12 medium containing 10% FBS, 10 pg / ml insulin, 10 pg / ml holotransferrin, 100 µg bromodeoxyuridine (to prevent proliferation of other cell types), 10,000 U / ml penicillin, and 10 mg / ml streptomycin. The cells were plated on Petri dishes and maintained for 1h at 37 °C in a humidified atmosphere with 5%CC>2. The cells that did not adhere to the plate, corresponding to the cardiomyocytes, were transferred at a density of 0.5×10⁶ cells / well to 12-well multi-plates. All animal work was carried out following the guidelines of the National Institute of Health Guide for the Care and Use of Laboratory Animals (2011) and were approved by the Institutional Committee for the Use and Care of Laboratory Animals of the Faculty of Pharmacy and Biochemistry of the UBA (RES (D) N° 19-16). IF-2019-79523174-APN-ANP#INPI Page 32 of 39 To perform the isoproterenol response assays, cells were starved for 2 h and pretreated for 40 min with the compound according to the invention L96B 100nM or equivalent amounts of DMSO, in minimal medium, at 37°C. The cells were then incubated for 3 min with 1100mM of the phosphodiesterase inhibitor, IBMX, and then stimulated for 9 min with isoproterenol 1100mM to activate cAMP production evoked by β-adrenergic receptors. Subsequently, the cells were resuspended in absolute ethanol. This was evaporated and the cAMP levels determined. The quantification of cAMP in the samples was carried out using an adaptation of the binding protein technique according to Davio et al., 1995. Figure 6 shows the potentiating effect of the compound of the invention L96B on the cAMP response of β-adrenergic receptors to isoproterenol, whose activity is essential for cardiac function. (Blank bars represent the cAMP response to isoproterenol in cells pretreated with DMSO, and dashed bars represent the cAMP response to isoproterenol in cells pretreated with the compound according to the invention L96B. **p<0.005 compared to cells stimulated in the absence of inhibitor) Example 7 Effect of the compounds of the invention on the viability of immortalized human hepatocytes The unexpected toxicity of a compound is the reason why 30% of drug development processes fail. Hepatotoxicity is one of the IF-2019-79523174-APN-ANP#INPI Page 33 of 39 The main forms of toxicity by which drugs affect the body We evaluated the cytotoxicity of inhibitors using the human hepatocyte cell line HEPG2. The cells were plated in a 96-well plate at a density of 22,000 cells / well and incubated for 48 hours with the compounds at concentrations ranging from 0.33 μM to 200 μM. Their viability was then analyzed using the trypan blue exclusion method and Neubauer chamber counting. Figure 7 shows that compound C2 exhibited significant cytotoxicity compared to the DMSO control starting at a concentration of 10 µM. L96B, on the other hand, did not affect cell viability at the tested concentrations. In this respect, the advantage of the invention's compound L96B over the comparative commercial compound C2 is noteworthy in terms of potential toxic effects on the human liver. The EC50 obtained for compound C2 is 10.3 µM ± 3.2 (*p < 0.05; **p < 0.01; ***p < 0.005). Example 8. 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IF-2019-79523174-APN-ANP#INPI Page 39 of 39 Argentine Republic - National Executive Branch 2019 - Year of Exports Additional Signature Sheet Graphic Report Number: IF-2019-79523174-APN-ANP#INPI CITY OF BUENOS AIRES Monday, September 2, 2019 Reference: 20190101103 The document was imported by the GEDO system with a total of 39 page(s). Digitally signed by GESTION DOCUMENTAL ELECTRONICA - GDE DN: cn=ELECTRONIC DOCUMENTARY MANAGEMENT - GDE, c=AR, o=GOVERNMENT SECRETARY OF MODERNIZATION, ou=ADMINISTRATIVE MODERNIZATION SECRETARY, serialNumber=CUIT 30715117564 Date: 2019.09.02 22:53:40 -03'00' Marcelo Esteban Rubino Administrative Assistant National Patent Administration National Institute of Industrial Property Digitally signed by GESTION DOCUMENTAL ELECTRONICA GDE DN: cn=GEST10N DOCUMENTAL ELECTRONICA - GDE, c=AR, o=SECRETARIA DE GOBIERNO DE MODERNIZACION, ou=SECRETARIA DE MODERNIZACION ADMINISTRATIVA, serialNumber=CUIT 30715117564 Date: 2019.09.02 22:53:40 -03'00'

Claims

1. A GRK2 protein inhibitor compound according to formula I (FORMULA), characterized in that atom X is selected from carbon and nitrogen, and R1 is selected from the methylcarboxylate and 1,3,4-oxadiazol-2-yl groups, and wherein the compound is selected from methyl 4-(naphthalene-2-amido)benzoate and N-[4-(1,3,4-oxadiazol-2-yl)phenyl]quinoline-3-carboxamide. Eight claims follow.