BENZYLAMIDE DERIVATIVES AS TRANSFORMING GROWTH FACTOR I RECEPTOR INHIBITORS-BETA / ALK5

Abstract

The present invention relates to benzylamide derivatives of formula (I) (I) with processes for the manufacture of said compounds; with pharmaceutical compositions containing said compounds and with said compounds used for treating pathological conditions or diseases that may be improved by inhibition of the transforming growth factor-β receptor I (TGFβRI) / ALK5, such as diseases and disorders associated with fibrotic conditions of the gastrointestinal system, skin and eyes, with methods for the treatment and / or prevention of said diseases or pathological conditions and with combinations including said compounds and further including other therapeutic agents in therapeutically effective amounts useful for the treatment of said diseases or pathological conditions.

Description

The present invention relates to readily substituted benzylamide derivatives, as potent inhibitors of transforming growth factor-β receptor I kinase, (also named activin receptor-like kinase 5) (TGFβRI) / ALK5. The present invention also relates to a procedure for preparing the compounds; pharmaceutical compositions comprising effective amounts of these compounds; the use of the compounds to prepare a medicament for the treatment of pathological conditions or diseases that may be aggravated by inhibition of transforming growth factor-β receptor I (TGFβRI) / ALK5, such diseases or disorders being associated with fibrotic conditions of the gastrointestinal system, skin and eyes. Background of the Invention Transforming growth factor-β (TGF-β) belongs to the TGF-β superfamily, which consists of TGF-βΙ, TGF^2, TGF-β3, among other proteins. TGF-β is involved in many cellular processes, including cell proliferation, cell migration, invasion, epithelial-mesenchymal transition, extracellular matrix production, and immune suppression. TGF-β and its receptors are often chronically overexpressed in various human diseases, including cancer, inflammation, tissue fibrosis, and autoimmunity. Therefore, blocking the TGF-β signaling pathway is considered an attractive target for drug development. (Heldin CH et al., Signaling Receptors for TGF-β Family Members, Cold Spring Harb Perspect Biol, 2016, doi: 10.1101 / cshperspect.a022053). TGF-β signals through two related transmembrane serine / threonine kinase receptors, type I and type II. Following binding of TGF-β to the constitutively active type II receptor, the type I receptor (also called activin receptor-like kinase 5 (ALK5)) is phosphorylated and creates a binding site for Smad2 and Smad3 proteins, which are further phosphorylated. The phosphorylated Smad2 / Smad3 proteins form a heteromeric complex with Smad4, which translocates into the nucleus, assembles with specific DNA-binding cofactors and comodulators, and binds to the promoters of TGF-β target genes involved in cell differentiation, proliferation, apoptosis, migration, and extracellular matrix production. (Akhurst RJ et al., Targeting the TGF-β signaling pathway in disease, Nature / Reviews, OCTOBER 2012, VOLUME 11). In most cell types, activin receptor-like kinase 5 (ALK5) (also known as TGFeRl) is the primary TGFe receptor I, activated by TGF-β via TGFe receptor II. This interaction requires both extracellular and intracellular domains for signal transduction. ALK5 and TGFe receptor II proteins can also form active heterooligomeric complexes in the absence of ligand. These complexes are capable of transducing basal signals when the receptors are coexpressed due to their intrinsic affinity for interaction. (Bierie B. et al., TGF-β: the molecular Jekyll and Hyde of cancer, Nature Reviews, Cancer, Volume 6, July 2006). The functional TGFeRII-TGFeRI (ALK5) heteromeric signaling complex is commonly associated with human cancers, and it regulates the activation of downstream Smad-dependent and Smad-independent pathways. In fact, numerous studies have identified mutations in components associated with the TGF-β pathway, which correlate with cancer incidence and prognosis in many human tissues. Overexpression of TGF-βΙ has been associated with breast, colon, esophageal, gastric, hepatocellular, lung, and pancreatic cancers. Importantly, overexpression of TGF-βΙ in human cancers correlates with tumor progression, metastasis, angiogenesis, and poor prognostic outcomes. Cancer Currently, the TGF-β pathway has been targeted using strategies that include modifying immune components or delivering small molecule inhibitors and soluble protein or antisense compound inhibitors. Immunotherapy strategies have been used to target the TGF-β pathway in animal models. Immunotherapy strategies typically reduce TGF-β signaling in an immune component prior to reconstitution in a tumor-bearing recipient, thereby allowing a productive interaction with cancer cells. Alternatively, systemic delivery of compounds used to inhibit TGF-β typically abrogates all host-tumor interactions regulated by TGF-β, including those involving immune suppression, angiogenesis, stromal-epithelial cross-talk, and tumor cell-autonomous signaling. Because of the immune-mediated disease and lethality associated with genetic ablation or inhibition of TGF-β signaling in mice, it is unclear whether inhibition of this pathway to treat cancer would be compatible with patient survival when delivered over a sustained duration in vivo.However, it has recently been shown that a lifetime exposure to systemic soluble TGF-β inhibitors in mouse models does not produce significant adverse effects. These studies have shown that specific inhibition of TGF-β should be compatible with long-term survival when administered to humans for a sustained duration in vivo. (Yang, Y. et al., Lifetime exposure to a soluble TGF-β antagonist protects mice against metastasis without adverse side effects, J. Clin. Invest. 109:1607-1615 (2002)) and (Ruzek M. et al., Minimal Effects on Immune Parameters Following Chronic Anti-TGF-β Monoclonal Antibody Administration to Normal Mice, Immunopharmacology and Immunotoxicology Vol. 25, No. 2, pages 235-257, 2003). In the tumor microenvironment, TGF-β signaling affects several cell types such as immune cells, cancer-initiating cells, endothelial cells, and fibroblasts. The overall effect of these microenvironmental changes results in tumor progression and metastasis. TGF-β signaling is present in most malignancies, such as hepatocellular carcinoma, pancreatic cancer, and myelodysplastic syndromes. Because of this prominent role, several small molecule inhibitors have been developed to block the TGF-β signaling pathway with the aim of reducing tumor growth. (Rodon, J. et al., First-inhuman Dose Study of the Novel Transforming Growth Factor-β Receptor I Kinase Inhibitor LY2157299 Monohydrate in Patients with Advanced Cancer and Glioma, American Association for Cancer Research, November 25, 2014; doi: 10.1158 / 1078-0432.CCR-14-1380). Hepatocellular carcinoma (HCC) is a highly aggressive cancer that is the third most common cause of tumor-related death in the United States and Europe. Current therapeutic options are invasive and aim to physically remove or destroy the tumor mass. However, recurrence and / or subsequent metastatic spread are common and negatively impact survival. The overall prognosis remains poor, and little progress has been made in identifying treatment options. In HCC patients, TGF-β has been reported to be overexpressed in the blood and urine, which is associated with a poorer prognosis and survival and therefore represents a marker of this cancer. It has been shown that TGF-β plays a key role in modulating HCC aggressiveness by triggering epithelial-to-mesenchymal transition (EMT) in cells.These studies have suggested that inhibition of the TGF-β pathway with small molecule inhibitors may be a promising therapy in HCC patients. (Fransvea, E. et al., Blocking Transforming Growth Factor-β Up-Regulates ECadherin and Reduces Migration and Invasion of Hepatocellular Carcinoma Cells, Wiley InterScience, 2008, doi. 10,1002 / hep,22201). Pancreatic adenocarcinoma is one of the leading causes of cancer death among adults worldwide. For all stages combined, the 5-year survival rate is 5%, and the median survival time after diagnosis is <6 months. At the time of diagnosis, two-thirds of patients have locally advanced or metastatic disease. Even when the patient's cancer appears to be localized to the pancreas and is surgically removed, 70% of patients will develop liver metastases. Therefore, pancreatic cancer presents one of the greatest challenges in cancer research. In particular, human pancreatic cancers expressing high levels of TGF-β have been found to be significantly associated with venous invasion, advanced tumor stage, progressive disease, shorter patient survival, and liver metastases.This production of TGF-β by pancreatic tumors inhibits an effective antitumor immune response by affecting the phenotype and function of dendritic cells in the tumor microenvironment. Studies indicate that inhibition of TGF-β signaling cascades by systemic administration of the small molecule selective TGFRI / II kinase inhibitor LY2109761 suppresses liver and other abdominal metastases in an in vivo model of human pancreatic cancer. (Melisi, D. et al., LY2109761, a novel transforming growth factor β receptor type I and type II dual inhibitor, as a therapeutic approach to suppressing pancreatic cancer metastasis, Mol Cancer Ther 2008;7(4). April 2008). Colorectal cancer, also known as colon cancer, has certain features in the tumor microenvironment, such as a lack of T cell infiltration, low T helper cell type 1 (TH1) activity and low immune cytotoxicity or high TGFβ levels. Recent studies have shown that high TGF-β in the tumor microenvironment represents a key mechanism of immune evasion that promotes T cell exclusion and blocks the acquisition of a TH1 effector phenotype. Therefore, immunotherapies directed against TGF-β signaling could have broad applications in treating patients with advanced colorectal cancer. (Tauriello DVF, et al., TGF-β drives immune evasion in genetically reconstituted colon cancer metastasis, Nature, Published online: 14 February 2018, doi:10.1038 / nature25492). Meningiomas account for approximately 36 percent of primary brain tumors. The lack of appropriate chemotherapies has prompted the search for therapies targeting growth-regulating cytokines. Of these, members of the transforming growth factor-beta (TGF-β) superfamily may be particularly relevant. At higher rates, meningiomas, particularly anaplastic ones, have the highest recurrence rates and the lowest response to any current meningioma therapy. Restoration of TGF-β inhibitory signaling pathways may be a critical component for the development of effective chemotherapies for meningiomas. To date, direct therapeutic options have been limited, in part, due to toxicities associated with reversal of baseline TGF-β inhibition.However, in malignancies where TGF-β switches from inhibitory to tumor-promoting effects, TGF-β signaling can be blocked by small molecule inhibitors of the TGF-β type I receptor. Early studies suggest LY 2157229 (Galunisertib) is effective in blocking the effects of TGF-β. (Johnson, MD Transforming growth factor β family in the pathogenesis of meningiomas, World Neurosurgery, doi: 10.1016 / j.wneu,2017,03,058). Galunisertib is a TGFβRI kinase inhibitor currently under clinical development for various cancers (Herbertz, S et al., Clinical development of galunisertib (LY2157299 monohydrate), a small molecule inhibitor of transforming growth factor-beta signaling pathway, Drug Design, Development and Therapy 2015:9 4479-4499). It inhibits the kinase domain of TGFβRI / Alk5 with an IC50 of 0.172 μΜ, ALK4 with an IC50 of 0.77 μΜ. It also inhibits a range of other kinases with submicromolar IC50s including MINK, TGFβRII, ALK6 and ACVR2B. There are previous reports showing high doses of this compound are associated with adverse effects in mice and dogs. Therefore, great rigor is recommended in the selection of dosing regimens in human subjects to achieve the desired effect with minimal toxicity. This compound is orally available. (Yingling, JMet al, Preclinical assessment of galunisertib (LY2157299 monohydrate), a first-in-class transforming growth factor-β receptor type I inhibitor, Oncotarget. January 23, 2018; 9(6):. 6659-6677). Another TGF-β type I receptor kinase inhibitor under clinical development is EW-7197, which inhibits ALK5 with an IC50 value of 0.013 μΜ in a kinase assay. It is a highly selective ALK5 / ALK4 inhibitor and in pharmacokinetic studies in mice showed an oral bioavailability of 51% with high systemic exposure. (Jin, CH et al., Discovery of N-((4([1,2,4]Triazolo[1,5-α]pyridine-6-yl)-5-(6-methylpyridine-2-yl)1H-imidazol-2-yl)methyl)-2-fluoroaniline (EW-7197): a Highly Potent, Selective, and Orally Bioavailable Inhibitor of TGF-β type I Receptor Kinase as Cancer Immunotherapeutic / Antifibrotic Agent, J. Med. Chem. 2014, 57, 4213-4238). Fibrotic conditions Extensive evidence suggests that the canonical ALK5 / Smad3 pathway is critically involved in the pathogenesis of fibrosis in multiple tissues. Oral administration of a selective low-molecular-weight inhibitor of ALK5 kinase activity inhibits fibrogenesis in a mouse model of progressive TGF-βΙ-induced pulmonary fibrosis. In addition, Smad3-null mice exhibit attenuated fibrosis in various experimental models and are resistant to bleomycin-induced pulmonary fibrosis. Similarly, skin fibrosis following irradiation, renal interstitial fibrosis produced by unilateral ureteral obstruction, and cardiac fibrosis are all attenuated in Smad3-deficient animals. (Biernacka, A. et al., TGF-β signaling in fibrosis, growth factors. October 2011; 29 (5): 196 — 202. doi:10,3109 / 08977194,2011,595714). Inhibitors of the intracellular TGF-β signaling pathway are useful for the treatment of fibroproliferative diseases. Specifically, fibroproliferative diseases include renal disorders associated with dysregulated TGF-β activity and excessive fibrosis, including glomerulonephritis (GN), such as mesangial proliferative GN, immune GN, and crescentic GN. Other renal conditions include diabetic nephropathy, renal interstitial fibrosis, and renal fibrosis in transplant patients. Collagen vascular disorders include progressive systemic sclerosis, polymyositis, and scleroderma. Autoimmune disorders associated with fibroproliferative characteristics include systemic lupus erythematosus and rheumatoid arthritis. Myelofibrosis (MF) is a bone marrow disorder characterized by clonal myeloproliferation, aberrant cytokine production, extramedullary hematopoiesis, and bone marrow fibrosis. Although somatic mutations in Janus Kinase 2 (JAK2), Myeloproliferative Leukemia Virus (MPL), and the Calreticulin (CALR) has been identified in the pathogenesis of these diseases, JAK2 pathway inhibitors have not shown efficacy in improving MF in patients. TGF-β family members are profibrotic cytokines and significant TGF-βΙ isoform up-expression was observed in a large cohort of primary MF patient samples. It has been shown that TGF-βΙ stimulates excessive collagen deposition by mesenchymal stromal cells (MSCs) by activating the TGF-β receptor kinase I (ALK5) / Smad3 pathway. The use of Galunisertib, a clinically active ALK5 inhibitor, significantly improved MF in mouse models. The data demonstrate a role for the malignant hematopoietic stem cell (HSC) / TGF-γ / MSC axis in the pathogenesis of MF and provide a preclinical rationale for ALK5 inhibition as a therapeutic strategy in MF. (Yue, L. et al, Efficacy of ALK5 inhibition in myelofibrosis, JCI Insight. 2017;2(6):e90932; doi.org / 10.1172 / jci.insight,90932). In addition, there are studies that have investigated the therapeutic potential of TGF-β inhibitors in preventing postoperative peritoneal adhesion band formation, and the results showed that these types of compounds significantly attenuated adhesion band formation by inhibiting inflammation, oxidative stress, down-regulation of proinflammatory genes and suppression of fibrosis and profibrotic molecules. (Soleimani, A. et al., Novel oral transforming growth factor-β signaling inhibitor potently inhibits postsurgical adhesion band formation, J Cell Physiol. 2019;1—9). Several small molecules that inhibit ALK5 have been developed and have shown encouraging results in animal models of renal fibrosis. However, questions remain about the homeostatic role of ALK5 signaling, and therefore the safety implications of targeting this enzyme. One study showed that immunohistochemical analysis revealed that in the heart, ALK5 expression is unique to the valves. Two compounds (AZ12601011 and AZ12799734) were tested in mice. Microscopic evaluation revealed heart valve lesions in response to treatment with either compound. Both compounds induced histopathological heart valve lesions characterized by hemorrhage, inflammation, degeneration, and proliferation of valve interstitial cells. Pathology was observed in all animals, at all doses tested, and occurred in four heart valves.Analysis of ALK5 in mouse hearts revealed expression in the valves, but not in the myocardium. Compared with control animals, ALK5 protein levels were unchanged in the heart valves of treated animals. These findings suggest that TGF-β signaling through ALK5 plays a critical role in maintaining heart valve integrity. (Anderton MJ et al., Induction of Heart Valve Lesions by Small-Molecule ALK5 Inhibitors, Toxicologic Pathology, 39: 916924, 2011). Additionally, another ALK-5 inhibitor, Galunisertib, was tested in rats and dogs. In both, the heart and large blood vessels were identified as the primary target organs for toxicity. Cardiovascular findings in F344 rats treated with LY2157299 included degenerative and inflammatory valve lesions (valvulopathy), myocardial degeneration and necrosis, aortitis with rupture, vasculitis / perivasculitis, and increased heart weight. (Stauber et al, Nonclinical Safety Evaluation of A Transforming Growth Factor β Receptor I Kinase Inhibitor in Fischer 344 Rats and Beagle Dogs, J Clin Pract. 2014, 4:3). Irritable bowel disease (IBD) In the intestine, many immune and non-immune cells produce TGF-βΙ, and nearly all mucosal cells are targeted by the cytokine. TGF-βΙ is secreted as part of a latent complex, which includes latency-associated peptide (LAP) and latent TGF-β binding protein. Data emerging from these studies clearly indicate that transforming growth factor β1 is one of the key molecules involved in the regulation of epithelial cell biology and immunity in the intestine. These studies confirm the important role of TGF-βΙ in maintaining intestinal homeostasis and suggest that impaired function of this cytokine may contribute to triggering and / or amplifying deleterious signals in the intestine (Troncone E. et al., Transforming Growth Factor-ei / Smad7 in intestinal immunity, inflammation, and cancer, Front. Immunol. 9:1407, 2018). To date, researchers have studied inflammatory mechanisms to alleviate and inhibit intestinal fibrosis. However, anti-inflammatory agents have various problems and limitations in eliminating or treating fibrosis in inflammatory bowel disease (IBD). Therefore, to treat fibrotic diseases, approaches to anti-fibrotic mechanisms should be explored. Many publications have shown that molecules related to TGF-β signaling are involved in fibrosis, making them an important target in the development of intestinal fibrosis because they are correlated with the complex and diverse signaling pathways that regulate the development of intestinal fibrosis in IBD. Therefore, TGF-β signaling is a potential strategy to treat and alleviate fibrosis in several fibrotic diseases, including IBD. (Yun SMdkk, The Molecular Mechanism of Transforming Growth Factor-β Signaling for Intestinal Fibrosis: A Mini-Review, Frontiers in. Pharmacology, Mini-Review, diterbitkan: 27 Februari 2019; Binabaj M.M dkk, EW- 7197 prevents ulcerative colitis- associated fibrosis and inflammation, J Cell Physiol. 2018; 1 — 8). Penyakit-penyakit mata Transforming growth factor-β (TGF-β) may play a role in the pathogenesis of primary open-angle glaucoma (POAG). TGF-β has been implicated in the pathogenesis of POAG, and potential areas for targeting TGF-β include production, activation, downstream signaling, and local regulation. High levels of TGF-β are found in ocular fluid and in reactive optic nerve astrocytes in patients with glaucoma. Although recent research has revealed many unknowns, a deeper understanding of the cellular signaling pathways of TGF-β is needed to design potential TGF-β intervention strategies. (Wang, J. et al., Targeting Transforming Growth Factor-b Signaling in Primary Open-Angle Glaucoma, J Glaucoma 2017; 26:390-395). Ocular diseases associated with a fibroproliferative condition include retinal reattachment surgery accompanying proliferative vitreoretinopathy, cataract extraction with intraocular lens implantation, and post-glaucoma draining surgery associated with excessive TGF-βΙ production. The authors of the present invention have developed readily substituted benzylamide derivatives as potent inhibitors of the TGF-β signaling pathway, particularly as transforming growth factor-β receptor-like kinase 5 / activin (TGFeRl / ALK5) inhibitors, which have low systemic exposure that facilitates the avoidance of significant and well-known side effects. Therefore, the present invention discloses ALK5 inhibitors with low systemic exposure that provide a good therapeutic window. Brief Description of the Invention In one aspect (aspect 1), the present invention refers to readily substituted benzylamide derivatives of formula (I): Where: - R1independently represents 1 or 2 clusters selected from: a) halogen atoms, b) linear C1-C6 alkyl substituted by 1, 2 or optionally 3 halogen atoms, c) cyano group, d) C1-C3 alkoxy, e) -COOH, - R2 represents a cluster selected from: a) hydrogen atoms, b) C1-C3 alkyl, c) C3-C4 cycloalkyl, - R3 represents a cluster selected from: a) C1-C3 alkyls optionally substituted by 1, 2 or 3 halogen atoms, b) hydrogen atoms, c) halogen atoms, - R4 and R5 independently represent a cluster selected from: a) hydrogen atoms, b) C1-C3 alkyls optionally substituted by 1, 2 or 3 halogen atoms, c) halogen atoms, - n has a value of 0, 1 or 2 and its salts are pharmaceutically acceptable. In a second aspect, the present invention relates to processes for the preparation of the compounds of aspect 1. In a third aspect, the present invention relates to pharmaceutical compositions comprising a compound of aspect 1 and a diluent or carrier of the pharmaceutical aspect. In a fourth aspect, the present invention relates to pharmaceutical compositions according to the third aspect described above which further comprise a therapeutically effective amount of a therapeutic agent selected from agents useful for the treatment of gastrointestinal diseases, such as inflammatory bowel diseases among which there are Crohn's disease and ulcerative colitis, liver fibrosis and cancer, in particular gastric cancer, esophageal cancer and colorectal cancer; fibrotic skin diseases, such as scleroderma, nephrogenic scarring dermopathy, mixed connective tissue disease, scleromyxedema, scleredema and eosinophilic fasciitis; fibrotic eye diseases such as dry eye, age-related macular degeneration, corneal and conjunctival scarring, post-cataract fibrosis, proliferative vitreoretinopathy and proliferative diabetic retinopathy. In a fifth aspect, the present invention relates to the use of the compound in aspect 1 in making a medicament for the treatment and / or prevention of a disease or pathological condition that can be improved by inhibition of transforming growth factor-β receptor I (TGF^RI) / ALK5, such as gastrointestinal diseases, such as inflammatory bowel diseases among which there are Crohn's disease and ulcerative colitis, liver fibrosis and cancer, in particular gastric cancer, esophageal cancer and colorectal cancer; fibrotic skin diseases, such as scleroderma, nephrogenic scarring dermopathy, mixed connective tissue disease, scleromyxedema, scleredema and eosinophilic fasciitis; fibrotic eye diseases such as dry eye, age-related macular degeneration, corneal and conjunctival scarring, post-cataract fibrosis, proliferative vitreoretinopathy and proliferative diabetic retinopathy. In a sixth aspect, the present invention relates to methods for the treatment and / or prevention of diseases or pathological conditions that can be improved by inhibition of transforming growth factor-β receptor I (TGFeRI) / ALK5, such as gastrointestinal diseases, such as inflammatory bowel diseases among which there are Crohn's disease and ulcerative colitis, liver fibrosis and cancer, in particular gastric cancer, esophageal cancer and colorectal cancer; fibrotic skin diseases, such as scleroderma, nephrogenic scarring dermopathy, mixed connective tissue disease, scleromyxedema, scleredema and eosinophilic fasciitis; fibrotic eye diseases such as dry eye, age-related macular degeneration, corneal and conjunctival scarring, post-cataract fibrosis, proliferative vitreoretinopathy and proliferative diabetic retinopathy. In a seventh aspect, the present invention relates to a combination product of the compound of the first aspect described above with one or more therapeutic agents known to be useful in the treatment of selected diseases such as gastrointestinal diseases, such as inflammatory bowel diseases among which there are Crohn's disease and ulcerative colitis, liver fibrosis and cancer, in particular gastric cancer, esophageal cancer and colorectal cancer; fibrotic skin diseases, such as scleroderma, nephrogenic scarring dermopathy, mixed connective tissue disease, scleromyxedema, scleredema and eosinophilic fasciitis; fibrotic eye diseases such as dry eye, age-related macular degeneration, corneal and conjunctival scarring, post-cataract fibrosis, proliferative vitreoretinopathy and proliferative diabetic retinopathy. In an eighth aspect, the present invention relates to the compound of aspect 1 for use in the treatment and / or prevention of a disease or pathological condition that can be improved by inhibition of transforming growth factor-β receptor I (TGFpRI) / ALK5, such as gastrointestinal diseases, such as inflammatory bowel diseases among which there are Crohn's disease and ulcerative colitis, liver fibrosis and cancer, in particular gastric cancer, esophageal cancer and colorectal cancer; fibrotic skin diseases, such as scleroderma, nephrogenic scarring dermopathy, mixed connective tissue disease, scleromyxedema, scleredema and eosinophilic fasciitis; fibrotic eye diseases such as dry eye, age-related macular degeneration, corneal and conjunctival scarring, post-cataract fibrosis, proliferative vitreoretinopathy and proliferative diabetic retinopathy. In a particular embodiment, the compounds of formula (I) have a low systemic exposure after oral, topical or ocular administration, due to their very low metabolic stability, leading to the formation of inactive metabolites. For this reason, these compounds are particularly suitable for the treatment of diseases such as gastrointestinal diseases, including inflammatory bowel diseases among which there are Crohn's disease and ulcerative colitis, liver fibrosis and cancer, in particular gastric cancer, esophageal cancer and colorectal cancer; fibrotic skin diseases, such as scleroderma, nephrogenic scarring dermopathy, mixed connective tissue disease, scleromyxedema, scleredema and eosinophilic fasciitis; fibrotic eye diseases such as dry eye, age-related macular degeneration, corneal and conjunctival scarring, post-cataract fibrosis, proliferative vitreoretinopathy and proliferative diabetic retinopathy. As stated previously, the benzylamide derivatives of the present invention are useful in the treatment or prevention of diseases known to be susceptible to improvement by treatment with transforming growth factor-β receptor I (TGFpRI) / ALK5 inhibitors, such as gastrointestinal diseases, such as inflammatory bowel diseases among which Crohn's disease and ulcerative colitis, liver fibrosis and cancer, in particular gastric cancer, esophageal cancer and colorectal cancer; fibrotic skin diseases, such as scleroderma, nephrogenic scarring dermopathy, mixed connective tissue disease, scleromyxedema, scleredema and eosinophilic fasciitis; fibrotic eye diseases such as dry eye, age-related macular degeneration, corneal and conjunctival scarring, post-cataract fibrosis, proliferative vitreoretinopathy and proliferative diabetic retinopathy. Accordingly, the derivatives of the invention and pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising such compounds and / or salts thereof, may be used in a method of treating pathological conditions or diseases of the human body which comprises administering to a subject requiring such treatment, an effective amount of the benzylamide derivatives of the invention or a pharmaceutically acceptable salt thereof. As used herein, the term Ca-Cb alkyl includes linear or branched radicals, having a carbon atom to b carbon atom. Preferred radicals have from 1 to 6 carbon atoms, more preferably from 1 to 4 carbon atoms. Examples of linear or branched alkyl groups are methyl, ethyl, n-propyl, iso-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, pentyl and hexyl. As used herein, the term linear or branched Ca-Cb alkoxy is used to designate radicals containing Ca-Cb alkyl radicals linked to an oxygen atom (CxH2x+1-O-). Preferred radicals have from 1 to 6 carbon atoms, more preferably from 1 to 4 carbon atoms. Preferred alkoxy radicals include, for example, methoxy, ethoxy, n-propoxy, ipropoxy. As used herein, the term halogen atom includes chlorine, fluorine, bromine, and iodine atoms, preferably fluorine, chlorine, and bromine atoms. The term halo, when used as a prefix, has the same meaning. As a mere example, haloalkyl means an alkyl substituted by one or more halogen atoms. As used herein, some atoms, radicals, chains or cycles present in the general structures of the invention are optionally substituted. This means that the atoms, radicals, chains or cycles may be substituted or not substituted at any position by one or more, for example 1, 2, 3 or 4 substituents, wherein the hydrogen atoms bonded to the unsubstituted atoms, radicals, chains or cycles are replaced by chemically acceptable atoms, radicals, chains or cycles. When there are two or more substituents, each substituent may be the same or different. As used herein, the term pharmaceutically acceptable salt is used to designate salts with a pharmaceutically acceptable acid or base. Pharmaceutically acceptable acids include inorganic acids, for example, hydrochloric, sulfuric, phosphoric, diphosphoric, hydrobromic, hydroiodic and nitric acids and organic acids, for example, citric, fumaric, maleic, malic, mandelic, ascorbic, oxalic, succinic, tartaric, benzoic, acetic, methanesulfonic, ethanesulfonic, benzenesulfonic or ptoluenesulfonic. Pharmaceutically acceptable bases include alkali metals (e.g., sodium or potassium), alkaline earth metal hydroxides (e.g., calcium or magnesium), and organic bases, for example, alkyl amines, arylalkyl amines and heterocyclic amines. Other preferred salts according to the present invention are quaternary ammonium compounds in which an anion equivalent (Xn) corresponds to the positive charge of the N atom. X-n may be an anion of various mineral acids such as, for example, chloride, bromide, iodide, sulfate, nitrate, phosphate, or an anion of an organic acid such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, methanesulfonate and p-toluenesulfonate. X-n is preferably an anion selected from chloride, bromide, iodide, sulfate, nitrate, acetate, maleate, oxalate, succinate or trifluoroacetate. More preferably, X- is chloride, bromide, trifluoroacetate or methanesulfonate. According to one embodiment of the invention in the compounds of formula (I), each R1 independently represents a halogen atom. In a preferred embodiment, n is 0 or n is 1 or 2 and each R represents a halogen atom. In a more preferred embodiment, n is 1 or 2 and each R represents a fluorine atom or a chlorine atom. According to one embodiment of the invention in the compounds of formula (I), R2 represents a hydrogen atom. According to one embodiment of the invention in compounds of formula (I), R3 represents a group selected from C1-C3 alkyl optionally substituted by 1, 2 or 3 halogen atoms, and hydrogen atoms. In a preferred embodiment, R3 represents hydrogen or a C1-C3 alkyl. In a preferred embodiment, R3 represents hydrogen, a methyl group or an ethyl group, more preferably hydrogen or a methyl group. According to one embodiment of the invention in the compounds of formula (I), R4 represents a hydrogen atom. According to one embodiment of the invention in the compounds of formula (I), R2, R4and R5represent hydrogen atoms. According to one embodiment of the invention in the compounds of formula (I), n is 0 or n is 1 or 2 and each R1 independently represents a halogen atom, R2, R4 and R5 independently represent hydrogen atoms, and R3 represents a group selected from a methyl group, an ethyl group and a hydrogen atom. In a preferred embodiment, n is 0 or n is 1 or 2 and each R1 represents a halogen atom and R3 represents a methyl group. In a more preferred embodiment, n is 1 or 2 and each R1 independently represents a fluorine atom or a chlorine atom. Certain individual compounds of the present invention include: N-benzyl-2-(3-(pyridine-2-yl)-4-(quinoline-4-yl)-1H-pyrazol1-yl)acetamide N-(4-fluorobenzyl)-2-(3-(pyridine-2-yl)-4-(quinoline-4-yl)1H-pyrazole-1-yl)acetamide N- (4-chlorobenzyl)-2-(3-(pyridine-2-yl)-4-(quinoline-4-yl)-1Hpyrazol-1-yl)acetamide N- (4-bromobenzyl)-2-(3-(pyridine-2-yl)-4-(quinoline-4-yl)-1Hpyrazol-1-yl)acetamide N- (4-cyanobenzyl)-2-(3-(pyridine-2-yl)-4-(quinoline-4-yl)-1Hpyrazol-1-yl)acetamide N- (4-methoxybenzyl)-2-(3-(pyridine-2-yl)-4-(quinoline-4-yl)1H-pyrazol-1-yl)acetamide N- (4-methylbenzyl)-2-(3-(pyridine-2-yl)-4-(quinoline-4-yl)-1Hpyrazol-1-yl)acetamide N-(4 - (tert-butyl)benzyl)-2-(3-(pyridine-2-yl)-4-(quinoline-4yl)-1H-pyrazol-1-yl)acetamide N -benzyl-2-(3-(6-methylpyridine-2-yl)-4-(quinoline-4-yl)-1Hpyrazol-1-yl)acetamide N- (3-methylbenzyl)-2-(3-(pyridine-2-yl)-4-(quinoline-4-yl)-1Hpyrazol-1-yl)acetamide N- (3-fluorobenzyl)-2-(3-(pyridine-2-yl)-4-(quinoline-4-yl)1H-pyrazol-1-yl)acetamide N-(3-chlorobenzyl)-2-(3-(pyridine-2-yl)-4-(quinolin-4-yl)-1Hpyrazol-1-yl)acetamide N- (3-cyanobenzyl)-2-(3-(pyridine-2-yl)-4-(quinoline-4-yl)-1Hpyrazol-1-yl)acetamide N- (2-methylbenzyl)-2-(3-(pyridine-2-yl)-4-(quinoline-4-yl)-1Hpyrazol-1-yl)acetamide N- (2-methylbenzyl)-2-(3-(6-methylpyridine-2-yl)-4-(quinoline-4yl)-1H-pyrazol-1-yl)acetamide N- (2-fluorobenzyl)-2-(3-(pyridine-2-yl)-4-(quinoline-4-yl)1H -pyrazol-1-yl)acetamide N- (2-fluorobenzyl)-2-(3-(6-methylpyridine-2-yl)-4-(quinoline4-yl)-1H -pyrazol-1-yl)acetamide N -benzyl-2-(3-(6-ethylpyridine-2-yl)-4-(quinoline-4-yl)-1Hpyrazol-1-yl)acetamide 2- (3-(6-ethylpyridine-2-yl)-4-(quinoline-4-yl)-1H-pyrazol-1yl)-N-(2-methylbenzyl)acetamide N- (4-methylbenzyl)-2-(3-(6-methylpyridine-2-yl)-4-(quinoline-4yl)-1H-pyrazol-1-yl)acetamide N- (2-chlorobenzyl)-2-(3-(pyridin-2-yl)-4-(quinoline-4-yl)-1Hpyrazol-1-yl)acetamide N- (2-chlorobenzyl)-2-(3-(6-methylpyridine-2-yl)-4-(quinoline-4yl)-1H-pyrazol-1-yl)acetamide N-(2,6-difluorobenzyl)-2-(3-(pyridine-2-yl)-4-(quinoline-4yl)-1H -pyrazole-1-yl)acetamide N-(2,6-difluorobenzyl)-2-(3-(6-methylpyridine-2-yl)-4(quinoline-4-yl)-1H -pyrazole-1-yl)acetamide N-(2,6-dimethylbenzyl)-2-(3-(pyridine-2-yl)-4-(quinoline-4yl)-1H -pyrazole-1-yl)acetamide N-(2,6-dimethylbenzyl)-2-(3-(6-methylpyridine-2-yl)-4(quinoline-4-yl)-1H -pyrazole-1-yl)acetamide N-(2-ethylbenzyl)-2-(3-(6-methylpyridine-2-yl)-4-(quinoline-4yl)-1H -pyrazole-1-yl)acetamide N-(2,6-dichlorobenzyl)-2-(3-(6-methylpyridine-2-yl)-4(quinoline-4-yl)-1H -pyrazole-1-yl)acetamide 4-((2-(3-(pyridine-2-yl)-4-(quinolin-4yl)-1H-pyrazol-1-yl)acetamido)methyl)benzoic acid hydrochloride Complete Description of the Invention The compounds of the present invention may be prepared using the procedures described below. To facilitate the description of the procedures, concrete examples have been used but do not limit in any way the scope of the present invention. The synthesis of compound formula (I) is described in Scheme 1. (II) HN n Reagents Stage a) NaH, and conditions: THF, DMF, 0°C to DMF, RT. Compounds of general formula (I) room temperature or Na2CO3, are prepared in several steps from 4-(3-(pyridine-2-yl)-1H-pyrazol-4yl)quinoline derivatives (II) by reaction with the corresponding bromoacetamide (III) (WO 2009123316 A1; Chem. Eur. J., 2013,19(32), 10506 10510). Several 4-(3-(pyridine-2-yl)-1H-pyrazol-4yl)quinoline (II) derivatives are commercially available and others can be prepared in several steps as indicated in scheme 2 (J. Med. Chem. 2004, 47, 4494-4506; WO 2004026302 A1). (VI) Reagents and conditions: Stage b) LiHMDS, THF, -60°C to -10°C. Stage c) compounds where R4 = H. Stage 1. DMF^DMA, AcOH, DMF, RT; Stage 2. N2HvH2O, RT. Compounds in which R2= C3-C4 cycloalkyl is optionally substituted by 1, 2 or 3 groups selected from halogen atoms: step d) R2-CO-N2H3, HCl, THF, 40 °C, according to the following scheme (scheme 2-1). 4-methylquinoline derivatives (IV) were curdled with ethyl 2-pyridinecarboxylate (V) in the presence of lithium bis(trimethylsilyl)amide to provide compounds of formula (VI). Reaction of the derivatives (VI) with dimethylformamide dimethylacetal yielded unisolated enamine intermediates, which were cyclized directly by reaction with hydrazine in the presence of acetic acid to provide pyrazoles of formula (II). Another route to produce compounds of formula (II) is as follows: Scheme 2-1 d) O R5 R3 (IIa) H (II) R4 R5 R2 N H (II) The pyrazole derivatives of formula (IIa) can be halogenated to give the corresponding halogenated compounds. These compounds yield compounds of formula (IIa) with standard halogenating reagents, as succinimide derivatives, after protection of the pyrazole ring nitrogen. A CC coupling followed by deprotection of the pyrazole nitrogen gives derivatives of formula (II). PG = protecting group. The protecting groups were chosen from Tetrahydropyran (THP), tert-butyloxycarbonylo (Boc) and Trityl (Tr) groups. Bromoacetamides of formula (III) are readily synthesized in one step from commercially available amines (VII) by reaction with bromoacetyl bromide of formula (VIII) as indicated in scheme 3 (J. Med. Chem. 2009, 52, 6851 — 6859). Scheme 3 (VIII)0f) (III) Reagents and conditions: Stage f) THF, 0°C to room temperature; or CH2Cl2, DIPEA, 0°C to room temperature. Other amines of formula (VII) that are not commercially available can be prepared as indicated in scheme 4. The compounds of formula (IX) where X is are explained below in the Scheme Scheme 4 in several stages as (VII) is synthesized from a compound of a halogen atom, according to 4 below. (IX) h2n (VII) Reagents and conditions: X: halogen atoms Stage g) phthalimide, K2CO3, DMF 50°C, Stage h) Ν2Η4·Η2Ο, EtOH, reflux. The amines of formula (VII) were prepared using the classical conditions of the Gabriel synthesis; which involves the conjugate base reaction of phthalimide and an alkyl halide (IX) followed by subsequent removal of the phthaloyl group with hydrazine to provide the primary amines (VII). Abbreviations In this application the following abbreviations are used, with appropriate definitions: AcOH: Acetic Acid ACVR2B: activin receptor A, type IIB ALKn: activin receptor-like kinase n ATP: adenosine triphosphate Boc2O: t-butyl dicarbonate Clint: Intrinsic cleansing DIPEA: N,N-Diisopropylethylamine DMA: Dimethylacetamide DMAP: 4-Dimethylaminopyridine DME: Dimethoxyethane DMF: Dimethylformamide DMSO: Dimethyl sulfoxide Et3N: Triethylamine EtOAc: Ethyl acetate EtOH: ethanol FBS: Fetal bovine serum1H-NMR: Proton nuclear magnetic resonance K2EDTA: dipotassium ethylenediaminetetraacetic acid salt KOtBu: Potassium tert-butoxide LC: Liquid chromatography LiHMDS: Lithium bis(trimethylsilyl)amide LLOQ: lower limit of quantification MeCN: acetonitrile MeOH: Methanol MS: Mass spectroscopy N2H4^H2O: Hydrazine monohydrate NaCMC: Sodium carboxymethyl cellulose NMP: N-Methyl-2-pyrrolidone PCy3: tricyclohexylphosphine Pd(OAc)2: Palladium (II) acetate Pd / C: Palladium on carbon PPh3: Triphenylphosphine Rt: retention time RT: room temperature TGFe: transforming growth factor-β THF: Tetrahydrofuran THF:EtOH: Tetrahydrofuran:ethanol UPLC: ultra high performance liquid chromatography UV: Ultraviolet Pharmacological activity In vitro enzyme assay: Inhibition of kinase activity TGF3R-1 Human TGFpR-1 inhibition experiments were performed on a white 384-well microplate (Corning 3572) with the ADP-Glo ​​Kinase Assay Kit (Promega V9101) and the TGFeR-1 Kinase Enzyme System (Promega V4092). Test compounds and standard Galunisertib (Cayman 15312), 50 ng / well of TGFpR-1 kinase and 50 μΜ ATP were added in a final volume of 10 pL / well, using the Reaction buffer provided by the kit as the assay buffer. The reaction mixture was incubated with gentle stirring for 120 min at room temperature, after which 10 pL of ADPGlo Reagent was added and incubated with gentle stirring for 40 min at room temperature. 20 pL of Kinase Detection Reagent was added and the plate was incubated with gentle stirring for 30 min at room temperature. Luminescence (1000 ms) was measured in a Perkin Elmer EnSpire Multimode plate reader. Results Table 1 shows the results of the assays described for some of the compounds of the invention below. Table 1 Example Name IC50 Range 1 N-benzyl-2-(3-(pyridine-2yl)-4-(quinoline-4-yl)-1Hpyrazol-1-yl)acetamide A 2 N- (4-fluorobenzyl)-2-(3(pyridin-2-yl)-4-(quinoline-4yl)-1H-pyrazol-1-yl)acetamide B 3 N- (4-chlorobenzyl)-2-(3(pyridine-2-yl)-4-(quinoline-4- B yl)-1H-pyrazol-1-yl)acetamide 4 N- (4-bromobenzyl)-2-(3(pyridin-2-yl)-4-(quinoline-4yl)-1H-pyrazol-1-yl)acetamide B 7 N- (4-methylbenzyl)-2-(3(pyridin-2-yl)-4-(quinolin-4yl)-1H-pyrazol-1-yl)acetamide B 9 N-benzyl-2-(3-(6methylpyridin-2-yl)-4-(quinolin4-yl)-1H-pyrazol-1-yl Acetamide N-10 (3-methylbenzyl)-2-(3(pyridin-2-yl)-4-(quinolin-4yl)-1H-pyrazol-1-yl)acetamide B 11 N- (3-fluorobenzyl)-2-(3(pyridin-2-yl)-4-(quinolin-4yl)-1H-pyrazol-1-yl) (3-chlorobenzyl)-2-(3(pyridin-2-yl)-4-(quinolin-4yl)-1H-pyrazol-1-yl)acetamide B 13 N- (3-cyanobenzyl)-2-(3(pyridin-2-yl)-4-(quinolin-4yl)-1H-pyrazol-1-yl-acetamide 14 N-(2-methylbenzyl)-2-(3(pyridin-2-yl)-4-(quinolin-4yl)-1H-pyrazol-1-yl)acetamide B 15 N- (2-methylbenzyl)-2-(3-(6methylpyridin-2-yl)-4-(3-(6methylpyridin-2-yl)-4-(quinolin4-yl)-1-H (2-fluorobenzyl)-2-(3(pyridin-2-yl)-4-(quinolin-4yl)-1H -pyrazol-1-yl)acetamide B 17 N- (2-fluorobenzyl)-2-(3(6-methylpyridin-2-yl) -4(quinolin-4-yl)-1Hyl-1-pyrazol-18yl acetamide)N -benzyl-2-(3-(6ethylpyridine-2-yl)-4-(quinolin4-yl)-1H-pyrazol-1-yl)acetamide A 19 2-(3-(6-ethylpyridine-2-yl)4-(quinoline-4-yl)-1H-pyrazol-1yl)-N-(2-methylbenzyl)acetamide A 20 N- (4-methylbenzyl)-2-(3-(6methylpyridine-2-yl)-4-(quinoline4-yl)-1H-pyrazol-1-yl)acetamide A 21 N- (2-chlorobenzyl)-2-(3(pyridin-2-yl)-4-(quinolin-4yl)2zol-acetam-1H-pyr (2-chlorobenzyl)-2-(3-(6methylpyridine-2-yl)-4-(quinolin4-yl)-1H-pyrazol-1-yl)acetamide A 23 N- (2,6-difluorobenzyl)-2(3-(pyridine-2-yl)-4-(N-quinolin-1da B-2-yl)-yl - (2,6-difluorobenzyl)-2(3-(6-methylpyridine-2-yl)-4(quinoline-4-yl)-1H-pyrazol-1yl)acetamide A 25 N- (2,6-dimethylbenzyl)-2(3-(pyridin-2-yl)-H-4-pyl-)acetamol14 26 N- (2,6-dimethylbenzyl)-2(3-(6-methylpyridine-2-yl)-4(quinoline-4-yl)-1H-pyrazol-1yl)acetamide A 27 N- (2-ethylbenzyl)-2-(3-(6methylpyridine-2-ino1)H4-(cu -pyrazol-1-yl)acetamide A 28 N- (2,6-dichlorobenzyl)-2(3-(6-methylpyridine-2-yl)-4(quinoline-4-yl)-1H-pyrazol-1yl)acetamide A 29 Hydrochloride of 4- ((2- (3-(pyridin-2-yl)-4-(quinoline4-yl)-1H-pyrazol-1yl)acetamido)methyl)benzoic acid B, Ranges: A: IC50=< 100 nM B: 100nM< IC50< 800 nM Determination of intracellular TGF-beta kinase activity (ALK-5) Experiments were performed on the A549 cell line. 30,000 cells were seeded in 200μl of culture medium (Sigma D6046) supplemented with L-Glutamine (Sigma G7513), Penicillin / Streptomycin (Invitrogen 11058) and FBS (Sigma F9665) in a 96-well microplate (Becton Dickinson 353072). After 16 hours, the medium was changed to serum-free medium. Galunisertib, as a ligand inhibitor (Cayman CAY-15312) and recombinant Human TGF-p2 (R&D Systems 302-B2-002) as an ALK-5 activator, were added to the appropriate wells and incubated following the instructions of the AlpahscreenAlphaLISA® SureFire® Ultra™ pSMAD3(Ser423 / 425) Kit (Perkin Elmer ALSU-PSM3-A500). Results Table 2 shows the results of the assays described for some of the compounds of the invention below. Table 2 Example Name Range IC50 1 N -benzyl-2-(3-(pyridine-2yl)-4-(quinoline-4-yl)-1Hpyrazol-1-yl)acetamide B 9 N-benzyl-2-(3-(6methylpyridine-2-yl)-4-(N-quinoline-A-1-pyrazol)-1 (2-methylbenzyl)-2-(3-(6methylpyridine-2-yl)-4-(quinolin4-yl)-1H-pyrazol-1-yl)acetamide B 19 2-(3-(6-ethylpyridine-2-yl)4-(quinolin-4-yl)-1H-pyramethylbenezyl-12yl N- (4-methylbenzyl)-2-(3-(6methylpyridine-2-yl)-4-(quinoline- A 4-yl)-1H-pyrazol-1-yl)acetamide 22 N- (2-chlorobenzyl)-2-(3-(6methylpyridine-2-yl)-4-(quinoline4-yl)-1H-pyrazol-1-yl)acetamide A 24 N- (2,6-difluorobenzyl)-2(3-(6-methylpyridine-2-yl)-4(quinoline-4-yl)-1H-pyrazol-1yl)acetamide A 26 N- (2,6-dimethylbenzyl)-2-(3(6-methylpyridine-2-yl-tam-1-H-4-)pyraceyl)quinoline 27 N − (2-ethylbenzyl)-2-(3-(6methylpyridine-2-yl)-4-(quinoline4-yl)-1H-pyrazol-1-yl)acetamide A 28 N − (2,6-dichlorobenzyl)-2-(3(6-methylpyridine-2-yl)-4(quinoline-4-yl)-1H-pyrazol-1yl)acetamide B Ranges: A: IC50=< 100 nM B: 100 nM < IC50< 500 nM As can be seen from the results described in the tables above, the compounds of the present invention are potent inhibitors of transforming growth factor-β receptor I (TGFeRI / ALK5). Plasma pharmacokinetic determination This study aimed to investigate the plasma pharmacokinetics of the compounds of the present invention in male Sprague Dawley rats following a single oral administration. Three rats per compound were used in this study. Animals were administered with a suspension formulation of each compound in 0.5% Tween-80 and 99.5% NaCMC (0.5% w / v in RO Water) via the oral route at 5 mg / kg. Blood samples were collected from three rats at each time point in labeled microcentrifuge tubes containing K2EDTA solution as an anticoagulant at 0.25, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours (p.o.). Plasma samples were separated by whole blood centrifugation and stored below -70 ± 10°C until bioanalysis. All samples were processed for analysis by protein precipitation using acetonitrile and analyzed by a suitable LC-MS / MS method for the purpose (LLOQ = 1.01 ng / mL).Pharmacokinetic parameters were calculated using the Phoenix WinNonlin® non-compartmental analyzer (Version 7.0). The main pharmacokinetic parameters obtained from several examples are shown in table 3 below. Table 3 Route Analyte Dose (mg / kg) Tmax (hr) Cmax (ng / mL) AUClast (hr*ng / mL) AUCinf (hr*ng / mL) Example 9 5 0.25 62.83 27.02 27.7 Example 15 5 0.25 75.76 35.09 39.42 PO Example 22 5 0.33 19.97 13.69 15.34 Concentrations can be measured at Example 5 only at 0, 25 and 0.5 hours; not sufficient to calculate PK parameters. Cmax: refers to the maximum plasma drug concentration obtained after oral administration of a drug between the time of dosing and the last observed time point. AUClast: refers to the area under the curve from the time of dosing to the time of last observation that is wider than the limit of quantitation. AUCinf: describes the total exposure to a drug. Tmax: the time after administration of a compound or drug when the maximum plasma concentration is reached. From the PK data presented above, it can be concluded that the compounds of the present invention have a low systemic exposure after oral administration. Determination of metabolic stability levels Recombinant human and mouse microsomes from TebuXenotech were used in the assay. The microsomes contained 0.5 mg / ml protein. The following amounts were added to each well of a 96-well microplate. Blank (μΐ) Rat (μΐ) Human (μΐ) Phosphate buffer Na / K 50 mM pH 7.4 295 301.3 301.3 MgCl2 30 mM 50 50 50 NADP 10 mM 50 50 50 Glucose 6-P 100mM 50 50 50 Glucose 6-P DH 20 U / ml 25 25 25 Water 25 - - Rat microsomes - 18.7 - Human microsomes - - 18.7 Test compound 5 5 5 The plates were incubated at 37°C and 75 μL samples were taken at 0, 10, 20, 40 and 60 min. The samples were transferred to a microplate and 75 μL acetonitrile was added to inactivate the microsomes, and 30 μL H2O to improve the chromatographic conditions and stored at 4°C. When all samples were taken, the plate was centrifuged at 46000 g for 30 min at 15°C. The supernatant was taken and injected in the UPLC-MS / MS. Stationary phase: Acquity UPLC® BEH C18 reversed phase 1.7 μm (2.1 mm x 50 mm) (Waters). Mobile phase: A: 0.1% formate; B: acetonitrile+0.1% formic acid. Flow: 0.6 ml / min. The chromatographic apparatus used was a Waters Acquity UPLC QSM. Compound concentrations were calculated from the UV peak regions. The response was linear in the range of 10 ng / ml to 0.3125 ng / ml. Metabolic stability was calculated from the logarithm of the compound remaining at each evaluated time. Data analysis The data will be fitted to a single-phase exponential decay equation using GraphPad Prism® software. The half-lives (t1 / 2) generated by the software will be reported. The intrinsic scavenging will be calculated using the formula where, k=decay rate constant (min1). Clint = kx volume of reaction mixture (uL) protein content (mg) Example Rat Human % remanence (sampling time 60 min) Clint (μL / min*mg prot) % remanence (sampling time 60 min) Clint (μL / min*mg prot) 20 0.02 381.1 0.01 215.6 22 0.14 644.4 0.03 378.4 24 0.01 359.9 0.05 307.3 26 0.08 825.6 0.05 622.4 27 0.31 600.5 0.53 505.0 The samples analyzed above were unstable in liver microsome assays and showed high clearance in the evaluated species. In an identification, metabolite research identified Compound A. The compound is 2-(3-(6methylpyridine-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetic acid and has the following formula: 1H NMR (300 MHz, MeOD) δ 8.79 (d, J = 4.6 Hz, 1H), 8.42 (br s, 1H), 8, 09 — 7.85 (m, 3H), 7.77 — 7.63 (m, 1H), 7.59 - 7.28 (m, 4H), 7.08 6.96 (m, 1H), 4.97 (s, 2H), 2.08 (s, 3H). HPLC-MS: Rt 13.025 m / z 345.1 (MH+). Compound A was identified as the major metabolite of samples 9, 15, 20, 22, 24 and 26, among others. The activity of Compound A against TGFpR-1 was carried out under the conditions described above, which showed an IC50 greater than 800 nM. The intracellular TGF-beta kinase (ALK-5) activity was also determined, which showed an IC50 greater than 5000 nM. The compounds of the invention have a low systemic exposure after oral, topical or ocular administration, due to their low metabolic stability, so they are particularly suitable for the treatment of diseases such as gastrointestinal diseases, such as inflammatory bowel diseases among which there are Crohn's disease and ulcerative colitis, liver fibrosis and cancer, in particular gastric cancer, esophageal cancer and colorectal cancer; fibrotic skin diseases, such as scleroderma, nephrogenic scarring dermopathy, mixed connective tissue disease, scleromyxedema, scleredema and eosinophilic fasciitis; fibrotic eye diseases such as dry eye, age-related macular degeneration, corneal and conjunctival scarring, post-cataract fibrosis, proliferative vitreoretinopathy and proliferative diabetic retinopathy. Accordingly, the derivatives of the invention and pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising such compounds and / or salts thereof, may be used in a method of treating disorders of the human body which comprises administering to a subject requiring such treatment an effective amount of the benzylamide derivatives of the invention or a pharmaceutically acceptable salt thereof. The present invention also provides pharmaceutical compositions comprising, as an active ingredient, at least a benzylamide derivative of formula (I) or a pharmaceutically acceptable salt thereof in conjunction with, other therapeutic agents a pharmaceutically acceptable excipient such as a carrier or diluent. The active ingredient may comprise 0.001% to 99% by weight, preferably 0.01% to 90% of the composition weight depends on the nature of the formulation and whether further dilution is carried out before application. Preferably, the compounds of formula (I), pharmaceutically acceptable salts and compositions thereof are prepared in a form suitable for oral, topical, ocular, rectal or percutaneous administration. Pharmaceutically acceptable excipients, which are mixed with the active compound or salts of such compound, to form the compositions of the present invention, are well known and the actual excipients used depend, among other things, on the method of administration of the compositions in question. The compounds of formula (I), their pharmaceutical salts and the compositions of the invention are preferably adapted for injection and oral administration. In this regard, the compositions for oral administration may take the form of tablets, inhibitor tablets, sublingual tablets, capsules or liquid preparations, such as mixtures, elixirs, syrups or suspensions, all containing the compounds of the invention; such preparations may be prepared by methods known in the art. Diluents, which may be used in the preparation of the compositions, include those liquid diluents and solid diluents, which are compatible with the active ingredient, together with coloring or flavoring agents, if desired. Tablets or capsules may readily contain from 2 to 500 mg of the active ingredient or an equivalent amount of a salt thereof. Liquid compositions adapted for oral use may be in the form of solutions or suspensions. Solutions may be aqueous solutions of a soluble salt or other derivative of the active compound in contact with, for example, sucrose to form a syrup. Suspensions may include an insoluble active compound of the invention or a pharmaceutically acceptable salt thereof in contact with water, together with a suspending agent or flavoring agent. Compositions for parenteral injection may be prepared from soluble salts, which may or may not be freeze-dried and may be dissolved in a pyrogen-free aqueous medium or other suitable parenteral injection fluid. Effective doses typically range from 2 to 2,000 mg of active ingredient per day. The daily dose may be administered in one or more treatments, preferably from 1 to 4 treatments, per day. The present invention will be further illustrated by the following examples. The following are provided for illustrative purposes and do not limit the scope of the invention in any way. The synthesis of the compounds of the invention is illustrated by the following examples, including the preparation of intermediates, which do not limit the scope of the invention in any way. Example General. Reagents, solvents, and starting products were obtained from commercial sources. The term “concentration” refers to vacuum evaporation using a Buchi rotary evaporator. When indicated, reaction products were purified by flash chromatography on silica gel (40-63 pm) with the indicated solvent systems. Spectroscopic data were measured on a Varian Mercury 300 spectrometer. HPLC-MS was performed on a Waters instrument equipped with an Alliance 2795 separation module, a W 2996 UV-Vis detector, and a ZQ 200 micromass. Intermediate 1: Ethyl 6-methylpicolinate To a solution of 6-methylpicolinic acid (2.0 g, 14.58 mmol) in ethanol (50 mL), sulfuric acid (1.2 mL) was added and the mixture was heated to reflux for 22 h and then concentrated to dryness. The residue was dissolved in water (50 mL), sodium bicarbonate was added to pH 8-9 and extracted with ethyl acetate (3x40 mL). The combined organic layers were dried over sodium sulfate and concentrated to yield a yellow oil (1.88 g, 78%). 1H-NMR (300 MHz, CDCl3): δ =7.95 (d, J = 7.7 Hz, 1H), 7.72 (t, J = 7.7 Hz, 1H), 7.34 (d, J = 7.7 Hz, 1H), 4.49 (q, J = 7.1 Hz, 2H), 2.67 (s, 3H), 1.44 (t, J = 7.1 Hz, 3H). HPLC-MS: Rt 8.258 m / z 166.5 [M+H]+. Intermediate 2: 1-(6-methylpyridine-2-yl)-2-(quinoline-4-yl)ethane-1one To a solution of lepidine (0.500 g, 3.49 mmol) in tetrahydrofuran (10 mL), cooled to -60 °C, lithium bis(trimethylsilyl)amide (10.5 mL, 10.47 mmol of a 1M solution in tetrahydrofuran) was added and the reaction mixture was stirred at low temperature for 30 min. A solution of ethyl 6-methylpicolinate (0.634 g, 3.83 mmol) in tetrahydrofuran (5 mL) was added and the reaction mixture was stirred overnight, allowing the temperature to reach -10 °C. The reaction mixture was quenched with ammonium chloride (aqueous saturated solution) and the solvent was removed under vacuum. The residue was dissolved in ethyl acetate (60 mL) and washed with ammonium chloride (2 x 50 mL, aqueous saturated solution). The organic layer was dried over sodium sulfate and concentrated. The reaction product was purified by flash chromatography on silica gel (40% EtOAc / Hexane) to yield an orange oil (0.423 g, 46%). 1H-NMR (300 MHz, CDCl3): δ =8.84 (d, J = 4.4 Hz, 1H), 8.1388.045 (m, 2H), 7.85 (d, J = 7.6 Hz, 1H), 7.74-7, 66 (m,2H 7.56–7.51 (m, 1H), 7.41 (d, J = 4.4 Hz, 1H), 7.36 (dd, J =7.6, 0.5 Hz, 1H), 5.02 (s, 2H), 2.67 (s,3H). HPLC-MS: Rt 10.077 m / z 262.7 [M+H]+. Intermediate 3: 1-(6-ethylpyridine-2-yl)-2-(quinoline-4-yl)ethane-1 ona HPLC-MS: Rt 10.643 m / z 276.7[M+H]+. Intermediate 4: 4-(3-(6-methylpyridine-2-yl)-1H-pyrazol-4yl)quinoline To a solution of 1-(6-methylpyridine-2-yl)-2-(quinolin4-yl)ethan-1-one (0.420 g, 1.60 mmol) in dimethylformamide (5 mL), acetic acid (0.330 mL, 5.76 mmol) and N,N-dimethylformamidedimethylacetal (0.640 mL, 4.80 mmol) were added and the reaction mixture was stirred at room temperature for 1 h. Hydrazine monohydrate (1.75 mL, 35.84 mmol) was added and the solution was heated at 50 °C for 1 h. The cooled reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL). The organic layer was washed with water (20 mL) and with brine (2x20 mL), dried over sodium sulfate and concentrated. The crude solid was recrystallized from acetonitrile to produce a yellow solid (0.335 g, 73%). 1H-NMR (300 MHz, DMSO-d6): δ =13.63 (br s, 1H), 8.81 (br s, 1H), 8.04 (d, J = 9.6 Hz, 1H), 7.73-7.40 (m, 7H), 7.02 (m,1H), 2.50 (s,3H). HPLC-MS: Rt 9,100 m / z 286.9 [M+H]+. Intermediate 5: 4-(3-(6-ethylpyridine-2-yl)-1H-pyrazol-4yl)quinoline1H-NMR (300 MHz, CDCl3): δ =8.99 (d, J = 4.4 Hz, 1H),8,24 (d, J = 14H), ( ,8, Hz 7.89—7.68 (m, 3H), 7.55—7.41 (m, 2H), 7.30–7.25 (m, 1H), 7.03 (d, J = 7.8 Hz, 1H), 6.66(d, J = 7.8 Hz, 1H), Jq = 2,8 1.31 (t, J = 7.6 Hz, 3H). HPLC-MS: Rt 9.616 m / z 301.2 [M+H]+. Intermediate 6: (2-ethylphenyl)methanamine To a solution of 2-ethylbenzonitrile (0.20 g, 1.52 mmol) in THF (8 mL) cooled to 5°C with the aid of an external ice bath / water bath / external H2O, LiAlH4 (0.28 mg, 7.62 mmol) was added in parts. The reaction mixture was allowed to reach room temperature and stirred for 21 h. H2O (3 mL) and NaOH (1 mL of a 36% aqueous solution) were added to the mixture and stirred for 5 min. The suspension was filtered through Celite washing with EtOAc (15 mL). The mother liquors were concentrated to dryness to give a pink oil (140 mg). The product was used in the next step without additional purification. Intermediate 7: tert-butyl 4-((1,3-dioxisoindolin-2yl)methyl)benzoate To a suspension of phthalimide (0.19 g, 1.32 mmol) and potassium carbonate (0.22 g, 1.59 mmol) in N,N-dimethylformamide (4 mL) was added tert-butyl 4-(chloromethyl)benzoate (0.30 g, 1.32 mmol) and the mixture was heated at 50°C for 20 h. The reaction mixture was cooled to room temperature, diluted with water (30 mL) and brine (20 mL) and extracted with ethyl acetate (2x15 mL). The combined organic extracts were dried over sodium sulfate and concentrated to give a white solid (0.42 g, 95%). 1H-NMR (300 MHz, CDCl3): δ =7.93 (d, J = 8.2 Hz, 2H),7.85 (dd, J = 5.3, 2.9 Hz, 2H), 7.72 (dd, J = 5.3, 2.9 Hz, 2H),7.44 (d, J = 8.2 Hz, 2H), 4.88 (s, 2H), 1.56 (s,9H). Intermediate 8: tert-butyl 4-(aminomethyl)benzoate To a suspension of tert-butyl 4-((1,3dioxoisoindoline-2-yl)methyl)benzoate (0.41 g, 1.23 mmol) in ethanol (5 mL) hydrazine monohydrate (0.12 g, 2.46 mmol) was added and the mixture was refluxed with vigorous stirring for 2 h. The reaction mixture was cooled to room temperature, 6 M hydrochloric acid solution (22%) was added and the solution was heated for a further 5 min. Water (10 mL), ethyl acetate (10 mL) and a 10% dilute hydrochloric acid solution, to achieve pH 1, were added. The layers were separated, and the organic layer was extracted with a 10% dilute hydrochloric acid solution (2x5 mL). The combined aqueous extracts were made basic with a 24% dilute sodium hydroxide solution and extracted with ethyl acetate (2x10 mL). The combined organic extracts were dried over sodium sulfate and concentrated to yield a pale yellow oil (0.12 g, 48%). 1H-NMR (300 MHz, CDCl3): δ =7.84 (d, J = 8.2 Hz, 2H), 7.24 (d, J = 8.2 Hz, 2H), 3.81 (s, 2H), 1.48 (s, 9H). Intermediate 9: N-benzyl-2-bromoacetamide To a solution of benzylamine (1.5 g, 14.00 mmol) in THF (15 mL), cooled to 5°C with the aid of an external ice / water bath, bromoacetyl bromide (1.46 mL, 16.80 mmol) was added and the reaction mixture was stirred for 22 h, allowing it to reach room temperature. The resulting suspension was filtered and the mother liquors were concentrated to dryness. The crude residue was purified by flash chromatography on silica gel (30%^50% EtOAc / Hexane) to yield a white solid (1.33 g, 42%). HPLC-MS: Rt 8.327 m / z 226.0-228.1 [MH]-. The following intermediates, from Intermediate 10 to Intermediate 26, are prepared by following the procedure described for Intermediate 9. Intermediate 10: 2-bromo-N -(4-fluorobenzyl)acetamide HPLC-MS: Rt 8.608 m / z 244.0-246.0 [MH]-. Intermediate 11: 2-bromo-N-(4-chlorobenzyl)acetamide HPLC-MS: Rt 9.273 m / z 262.2 [MH]-. Intermediate 12: 2-bromo-N-(4-bromobenzyl)acetamide This intermediate was used in the next step without additional purification. Intermediate 13: 2-bromo-N-(4-methoxybenzyl)acetamide HPLC-MS: Rt 6.125 m / z 258.1-259.9 [M+H]+. Intermediate 14: 2-bromo-N-(4-methylbenzyl)acetamide 1H-NMR (300 MHz, DMSO-d6): δ =7.14 (s, 4H), 4.24 (d, J = 5.9 Hz, 2H), 3.94 (s, 2H), 2.27 (s, 3H). HPLC-MS: Rt 9.098 m / z 242.1-244.0 [M+H]+. Intermediate 15: 2-bromo-N-(4-(tert-butyl)benzyl)acetamide HPLC-MS: Rt 10.406 m / z 282.0-284.2 [MH]-. Intermediate 16: 2-bromo-N-(3-methylbenzyl)acetamide1H-NMR (300 MHz, DMSO-d6): δ = 7.24-7.19 (m, 1H), 7.08-7.03 (m, 3H), 4.25 (d, J = 5.9), ( Hz, 3.9, Hz 2H), 2.29 (s, 3H). Intermediat 17: 2-bromo-N-(3-fluorobenzil)asetamida1H-NMR (300 MHz, DMSO-d6): δ = 8,83 (br s, 1H), 7,41-7,33 (m, 1H), 7,12-7,03 (m, 3H), 4,31 (d, J = 6,0 Hz, 2H), 3,92 (s, 2H). HPLC-MS: Rt 8,642 m / z 244,0-246,1 [M-H]-. Intermediat 18: 2-bromo-N-(3-klorobenzil)asetamida 1H-NMR (300 MHz, DMSO-d6): δ = 8,83 (br s, 1H), 7,51 — 7,08 (m, 4H), 4,30 (d, J = 6,0 Hz, 2H), 3,92 (s, 2H). HPLC-MS: Rt 9,266 m / z 260,0-262,1 [M-H]-. Intermediat 19: 2-bromo-N - (3-sianobenzil)asetamida 1H-NMR (300 MHz, DMSO-d6): δ= 7,78 — 7, 66 (m, 2H), 7,66 — 7,45 (m, 2H), 4,35 (d, J = 6,0 Hz, 2H), 3,94 (s,2H). HPLC-MS: Rt 8,018 m / z 251,0-253,1 [M-H]-. Intermediat 20: 2-bromo-N-(2-metilbenzil)asetamida 1H-NMR (300 MHz, CDCl3): δ = 7,26-7,15 (m, 4H), 4,48 (d, J = 5,5 Hz, 2H), 3,93 (s, 2H), 2,34 (s,3H). HPLC-MS: Rt 9,004 m / z 240,0 [M-H]-. Intermediat 21: 2-bromo-N-(2-fluorobenzil)acetamida 1H-NMR (300 MHz, CDCl3): δ =7.39-7.30(m, 2H), 7.20-7.01(m, (2H), 6.87 (s, 1H), 4.55 (d, J = 6.0 Hz, 2H), 3.94 (s, 2H). HPLC-MS: Rt 8,532 m / z 244.0-246.1 [MH]-. Intermediat 22: 2-bromo-N-(2-klorobenzil)acetamida 1H-NMR (300 MHz, DMSO-d6): δ =8.44(br s, 1H), 7.25 — 6.79(m, 4H), 3.98 (d, J=5.8 Hz, 2H), 3.56 (s,1H). HPLC-MS: Rt 9,097 m / z 264,0 [MH]-. Intermediat 23: 2-bromo-N-(2,6-difluorobenzil)acetamida 1H-NMR (300 MHz, DMSO-d6): δ = 8.70 (br s, 1H), 7.55-7.29 (m, 1H), 7.16-7.07 (m, 2H), 4.34 (d, J = 5.3 Hz, 2H), 3.84(s, 2H). Intermediat 24: 2-bromo-N-(2-klorobenzil)acetamida 1H-NMR (300 MHz, DMSO-d6): δ = 8.34 (br s, 1H), 7.13-7.02 (m, 3H), 4.29 (d, J = 4.8 Hz, 2H), 3.84 (s, 2H), 2.30 (s,6H). HPLC-MS: Rt 9,542 m / z 256.0 [MH]-. Intermediat 25: 2-bromo-N-(2-etilbenzil)asetamida HPLC-MS: Rt 9,526 m / z 253,9-256,0 [M-H]-. Intermediat 166: 2-bromo-N-(2,6-diklorobenzil)asetamida HPLC-MS: Rt 9,466 m / z 294,0 [M-H]-. Intermediat 27: 2-bromo-N-(4-sianobenzil)asetamida To a suspension of 4-(aminomethyl)benzonitrile hydrochloride (0.150 g, 0.890 mmol) in dichloromethane (4 mL), cooled to 5°C with the aid of an external ice / water bath, Et3N (0.150 mL, 1.067 mmol) and bromoacetyl bromide (0.082 mL, 0.934 mmol) were added. The reaction mixture was stirred for minutes, allowed to reach room temperature, diluted with dichloromethane (10 mL) and washed with H2O (15 mL). The aqueous layer was extracted with dichloromethane (10 mL) and the combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (50% EtOAc / Hexane) to give a creamy solid (0.118 g, 52%). 1H-NMR (300 MHz, DMSO-d6): δ = 8.89 (br s, 1H), 7.97-7.64 (m, 2H), 7.59-7.26 (m, 2H), 4.36 (d, J = 6.0 Hz, 2H), 3.91(s, 2H). The following Intermediate 28 is prepared by following the procedure described for Intermediate 27. Intermediat 28: tert-butil 4-((2-bromoacetamido)metil)benzoate 1H-NMR (300 MHz, DMSO-d6): δ =8.87 (m, 1H), 7.85 (d, J =8.5) (Hz, 2H), 7.36 (d, J = 8.5 Hz, 2H), 4.35 (d, J = 6.1 Hz, 2H), 3.92 (s, 2H), 1.53 (s, 9H). Intermediat 29: tert-butil 4-((2-(3-(piridin-2-il)-4-(kuinolin4-il)-1H -pirazol-1-il)acetamido)metil)benzoat Intermediat ini dibuat dengan mengikuti prosedur yang dijelaskan untuk 1. HPLC: Rt 18,982, 99,36%. Example Contoh 1: N-benzil-2-(3-(piridin-2-il)-4-(quinolin-4-il)-1Hpirazol-1-il)asetamida To a solution of N -benzyl-2-bromoacetamide (0.100 g, 0.441 mmol) in acetonitrile (2 mL), K2CO3 (0.076 g, 0.550 mmol) and 4-(3-(pyridine-2-yl)-1H-pyrazol-4-yl)quinoline (0.100 g, 0.367 mmol) were added and the reaction mixture was refluxed for 6 h. N-benzyl-2-bromoacetamide (0.017 g, 0.073 mmol) was added and the mixture was refluxed for another 1 h and allowed to reach room temperature. H2O (10 mL) was added and extracted with EtOAc (3x5 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by C18 chromatography with a Combiflash system (5^100% H2O / MeOH:MeCN 1:1) and by flash chromatography on silica gel (3% MeOH / CH2Cl2) to give a white solid (0.080 g, 52%). 1H-NMR (500 MHz, CDCl3): δ = 8.89 (d, J = 4.4 Hz, 1H),8.42 (d, J = 4.4, Hz, 1H), 8.16 (d, J = 8.4 Hz, 1H), 7.74 (s,1H), 7.72-7.66 (m, 2H), 7.45 (td, J = 7.8, 1.8 Hz, 1H), 7.37-7.34(m, 1H), 7.32-7.21 (m, 7H), 7.10 (ddd, J = 7.8, 4.4, 1.8 Hz, 1H), 6.87 (br suatu, 1H), 5.05 (s, 2H), 4.52 (d, J = 5.8 Hz, 2H). HPLC-MS: Rt 16,753 m / z 420.2 [M+H]+. Contoh-contoh 2-4 berikut disintesis dengan menggunakankan prosedur yang dijelaskan untuk contoh 1 dari turunan-turunan 4(3-(piridin-2-il)-1H-pirazol-4-il)kuinolin yang sesuai. Example 2: N-(4-fluorobenzil)-2-(3-(piridin-2-il)-4-(kuinolin-4-il)-1H-pirazol-1-il)asetamida1H-NMR (300 MHz, DMSO-d6): 8.98-8.65 (m, 2H), 8.19-7.95 (m, 3H), 7.87-7.58 (m, 4H), 7.51-7.25 (m, 4H), 7.26-7.05 (m, 3H), 5.06 (s, 2H), 4.36 (d, J = 5.8 Hz, 2H). HPLC-MS: Rt 16,989 m / z 438.2 [M+H]+. Example 3: N-(4-klorobenzil)-2-(3-(piridin-2-il)-4-(kuinolin-4il)-1H-pirazol-1-il)asetamida1H-NMR (300 MHz, DMSO-d6): δ = 8.99-8.62 (m, 2H), 8.22-7.89 (m, 3H), 7.88-7.50 (m, 4H), 7.53-7.22 (m, 6H), 7.17-7.13 (m, 1H), 5.06 (s, 2H), 4.36 (d, J = 5.8 Hz, 2H). HPLC-MS: Rt 17,839 m / z 454.2 [M+H]+. Example 4: N-(4-bromobenzil)-2-(3-(piridin-2-il)-4-(kuinolin-4-il)-1H-pirazol-1-il)asetamida1H-NMR (300 MHz, DMSO-d6): δ = 8.84-8.80 (m, 2H), 8.18-7.93 (m, 3H), 7.88-7.60 (m, 4H), 7.60-7.20 (m, 6H), 7.18-7.14 (m, 1H), 5.06 (s, 2H), 4.34 (d, J = 5.9 Hz, 2H). HPLC-MS: Rt 18,057 m / z 498.0-500.0 [M+H]+. Contoh 5: N-(4-cyanobenzil)-2-(3-(piridin-2-il)-4-(kuinolin-4il)-1H-pirazol-1-il)acetamida To a suspension of 4-(3-(pyridine-2-yl)-1H-pyrazol-4yl)quinoline (0.060 g, 0.220 mmol) in tetrahydrofuran (3 mL), cooled to 5°C with the aid of an external ice / water bath, 60% sodium hydride (0.012 g, 0.308 mmol) was added and the mixture was stirred at the same temperature for 30 min. A solution of N-(4-cyanobenzyl)-2-bromoacetamide (0.078 g, 0.308 mmol) in a mixture of tetrahydrofuran (1 mL) and dimethylformamide (0.3 mL) was added dropwise and the mixture was stirred for 40 min. A portion of N-(4-cyanobenzyl)-2-bromoacetamide (0.011 g, Another 0.048 mmol was added with stirring for another 1.5 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3x10 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (2-4.5¾ MeOH / CH2Cl2) and by C18 chromatography with a Combiflash system (5-100% H2O / MeCN) to give a white solid (0.016 g, 16%). 1H-NMR (500 MHz, DMSO-d6): δ =8.89 (t, J = 6.0 Hz, 1H), 8.83 (dd, J = 4.4, 1.1 Hz, 1H), 8.16 — 8.07 (m, 2H), 8.03 (d, J = 8.4 Hz, 1H), 7.85—7.61 (m, 5H), 7.53 (d, J = 7.9 Hz, 2H), 7.44—7.36 (m, 1H), 7.32 (dd, J = 4.4, 1.0 Hz, 1H), 7.20—7.12 (m, 1H), 5.10 (s, 2H), 4.47 (d, J = 6.0 Hz, 2H). HPLC-MS: Rt 16.091 m / z 445.1 [M+H]+. The following examples 6-29 were synthesized using the procedure described for example 5. Example 6: N-(4-metoksibenzil)-2-(3-(piridin-2-il)-4-(kuinolin-4il)-1H-pirazol-1-il)asetamida1H-NMR (500 MHz, DMSO-d6): δ = 8.84 (d, J = 4.5 Hz, 1H), 8.73 (t, J = 5.9 Hz, 1H), 8.15 — 8.06 (m, 2H), 8.03 (d, J =8.6 Hz, 1H), 7.82-7, 65 (m, 4H), 7.41-7.12 (m, 5H), 6, 93 — 6.87(m, (2H), 5.04 (s, 2H), 4.30 (d, J = 5.8 Hz, 2H), 3.73 (s, 3H). HPLC-MS: Rt 17,709 m / z 450.1[M+H]+. Example 7: N-(4-methylbenzil)-2-(3-(piridin-2-il)-4-(kuinolin-4il)-1H-pirazol-1-il)asetamida1H-NMR (500 MHz, DMSO-d6): δ = 8.84 (d, J = 4.4 Hz, 1H), 8.74 (t, J = 5.9 Hz, 1H), 8.13-8.07 (m, 2H), 8.03 (d, J =9.1 Hz, 1H), 7.83-7.65 (m, 4H), 7.41 (ddd, J = 8.2, 6.8, 1.3 Hz, 1H), 7.33 (d, J = 4.4 Hz, 1H), 7.24-7.10 (m, 5H), 5.05 (s,2H), 4.33 (d, J = 5.8 Hz, 2H), 2.28 (s, 3H). HPLC-MS: Rt 17,574 m / z 434.1 [M+H]+. Example 8: N-(4-(tert-butyl)benzyl)-2-(3-(pyridine-2-yl)-4(quinoline-4-yl)-1H-pyrazol-1-yl)acetamide 1H-NMR (500 MHz, DMSO-d6): δ = 8.83 (d, J = 4.4 Hz, 1H), 8.74 (t, J = 5.8 Hz, 1H), 8.10–8.07 (m, 2H), 8.03 (d, J =8.4 Hz, 1H), 7.84–7.61 (m, 4H), 7.40 (t, J = 7.6 Hz, 1H), 7.38–7.29 (m, 3H), 7.25 (d, J = 8.2 Hz, 2H), 7.20–7.10(s), 1,5, 1H 2H), 4.32 (d, J = 5.8 Hz, 2H), 1.26 (s.9H). HPLC-MS: Rt 19.625 m / z 476.2 [M+H]+. Example 9: N -benzyl-2-(3-(6-methylpyridine-2-yl)-4-(quinoline-4-yl)1H-pyrazol-1-yl)acetamide1H-NMR (300 MHz, DMSO-d6): δ = 8.84 (d, J = 1.5 Hz), 8.81–8.75 (m, 1H), 8.11 (d, J = 1.2 Hz, 1H), 8.03 (d, J =8.1 Hz, 1H), 7.79–7.45 (m, 4H), 7.45–7.21 (m, 7H), 6.98 (d, J =7.5 Hz, 1H), 5.06 (s, 2H), 4.39 (d, J = 5.7 Hz, 2H), 1.83 (s,3H). HPLC-MS: Rt 17,541 m / z 434.1 [M+H]+. Example 10: N-(3-methylbenzil)-2-(3-(piridin-2-il)-4-(kuinolin-4il)-1H-pirazol-1-il)asetamida1H-NMR (300 MHz, DMSO-d6): δ = 8.90-8.62 (m, 2H), 8.19-7.89 (m, 3H), 7.88-7.53 (m, 4H), 7.51-6.90 (m, 7H), 5.06 (s, 2H), 4.34 (d, J = 5.7 Hz, 2H), 2.27 (s, 3H). HPLC-MS: Rt 17,625 m / z 433.9 [M+H]+. Example 11: N-(3-fluorobenzil)-2-(3-(piridin-2-il)-4-(kuinolin-4il)-1H-pirazol-1-il)asetamida1H-NMR (300 MHz, DMSO-d6): δ = 8.83 (d, J = 4.3 Hz, 2H), 8,13 (s, 1H), 8,10 (d, J = 5,2 Hz, 1H), 8,03 (d, J = 8,4 Hz, 1H), 7.84-7.65 (m, 4H), 7.48-7.27 (m, 3H), 7.22-7.02 (m, 4H), 5.08 (s, 2H), 4.40 (d, J = 5.9 Hz, 2H). HPLC-MS: Rt 16,970 m / z 438.0 [M+H]+. Example 12: N-(3-klorobenzil)-2-(3-(piridin-2-il)-4-(kuinolin-4-il)-1H-pirazol-1-il)asetamida1H-NMR (300 MHz, DMSO-d6): δ = 8.86-8.82 (m, 2H), 8.12 (s, 1H), 8.09 (d, J = 5.1 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7,887.61 (m, 4H), 7.48–7.23 (m, 6H), 7.18–7.12 (s, 5, 1H), 2H), 4.39 (d, J = 5.8 Hz, 2H). HPLC-MS: Rt 17.747 m / z 454.1 [M+H]+. Example 13: N-(3-cyanobenzyl)-2-(3-(pyridine-2-yl)-4-(quinoline-4yl)-1H-pyrazol-1-yl)acetamide 1H-NMR (300 MHz, DMSO-d6): δ = 9, 03 — 8.70 (m, 2H), 8.14 (d, J = 1.7 Hz, 1H), 8.09 (d, J = 4.9 Hz, 1H), 8.04 (d, J = 8, 8 1H), 7.86–7.63 (m, 7H), 7.56 (t, J = 7.6 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.35 (dd, J = 4.9, 1.7 Hz, 1H), 7.16 (dd, J = 6.9, 5.0 Hz, 1H), 5.10 (s, 2H), 4.44 (d, J = 5.9 Hz, 2H). HPLC-MS: Rt 16.152 m / z 445.1 [M+H]+. Example 14: N -(2-methylbenzyl)-2-(3-(pyridine-2-yl)-4-(quinolin-4yl)-1H-pyrazol-1-yl)acetamide1H-NMR (300 MHz, DMSO-d6): δ = 8.85-8.82 (Hr, 1, s 8.18–7.95 (m, 3H), 7.88–7.60 (m, 4H), 7.49–7.08 (m,7H), 5.06 (s, 2H), 4.35 (d, J = 5.4 Hz, 2H), 2.30 (s, 3H). HPLC-MS: Rt 17,417 m / z 434.1 [M+H]+. Example 15: N-(2-methylbenzil)-2-(3-(6-methylpiridin-2-il)-4(kuinolin-4-il)-1H-pirazol-1-il)asetamida1H-NMR (300 MHz, DMSO-d6): δ = 8.84 (d, J = 4.5 Hz, 1H), 8.68 (br s, 1H), 8.12 (s, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.78-7.23 (m, 7H), 7.19 (br s, 3H), 6.98 (d, J = 7.5 Hz, 1H), 5.06 (s, (2H), 4.35 (d, J = 5.6 Hz, 2H), 2.31 (s, 3H), 1.82 (s, 3H). HPLC-MS: Rt 18,202 m / z 448.1 [M+H]+. Example 16: N-(2-fluorobenzil)-2-(3-(piridin-2-il)-4-(kuinolin-4il)-1H-pirazol-1-il)asetamida1H-NMR (300 MHz, DMSO-d6): δ = 8.93-8.70 (m, 2H), 8.24-7.91 (m, 3H), 7.91-7.60 (m, 4H), 7.55-7.02 (m, 7H), 5.07 (s, 2H), 4.41 (d, J = 5.5 Hz, 2H). HPLC-MS: Rt 16,941 m / z 438.1 [M+H]+. Example 17: N-(2-fluorobenzil)-2-(3-(6-methylpiridin-2-il)-4(kuinolin-4-il)-1H-pirazol-1-il)asetamida1H-NMR (300 MHz, DMSO-d6): δ = 8.85-8.80 (m, 2H), 8.11 (s, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.78–7.11 (m, 10H), 6.98 (d, J = 7.5 Hz, 1H), 5.07 (s, 2H), 4.42 (d, J = 5.6 Hz, 2H), 1.83 (s, 3H). HPLC-MS: Rt 17.628 m / z 452.0 [M+H]+. Example 18: N -benzyl-2-(3-(6-ethylpyridine-2-yl)-4-(quinoline-4-yl)1H-pyrazol-1-yl)acetamide 1H-NMR (300 MHz, DMSO-d6): δ = 8.85 (d, J = 4.4 Hz, 1H), 8.78 (t, J = 5.9 Hz, 1H), 8.09 (s, 1H), 8.02 (d, J = 9.3 Hz, 1H), 7.72–7, 62 (m, 4H), 7.42–7.16 (m, 7H), 6.95 (dd, J = 6.7, 2.0 Hz, 1H), 5.07 (s, 2H), 4.39 (d, J = 5.8 Hz, 2H), 2.10 (q, J = 7.5 Hz, 2H), 0.28 (t, J = 7.5 Hz, 3H). HPLC-MS: Rt 18.386 m / z 448.1 [M+H]+. Example 19: 2-(3-(6-ethylpyridine-2-yl)-4-(quinoline-4-yl)-1Hpyrazol-1-yl)-N-(2-methylbenzyl)acetamide1H-NMR (300 MHz, DMSO-d6): δ = 9.04 (H, 4), J = 8.86 (t, J = 5.7 Hz, 1H), 8.28 (s, 1H), 8.21 (d, J = 8.4 Hz, 1H), 7,92-7,77 (m, 4H), 7,62 - 7,45 (m, 3H), 7,38 (m, 3H), 7,14 (dd, J = 6,4, 2,4 Hz, 1H), 5,25 (s, 2H), 4,55 (d, J = 5,6 Hz, 2H), 2,50 (s, 3H), 2,29 (q, J = 7,5 Hz, 2H), 0,46 (t, J = 7,5 Hz, 3H). HPLC-MS: Rt 19,102 m / z 462,1 [M+H]+. Contoh 20: N-(4-metilbenzil)-2-(3-(6-metilpiridin-2-il)-4(kuinolin-4-il)-1H-pirazol-1-il)asetamida1H-NMR (300 MHz, DMSO-d6): δ = 8,84 (d, J = 4,4 Hz, 1H), 8,75 (t, J = 5,9 Hz, 1H), 8,11 (s, 1H), 8,03 (d, J = 8,3 Hz, 1H), 7,75-7,47 (m, 4H), 7,44-7,31 (m, 2H), 7,26-7,10 (m, 4H), 6,98 (d, J = 7,5 Hz, 1H), 5,05 (s, 2H), 4,33 (d, J = 5,8 Hz, 2H), 2,28 (s, 3H), 1,83 (s, 3H). HPLC-MS: Rt 16,848 m / z 448,1 [M+H]+. Example 21: N-(2-klorobenzil)-2-(3-(piridin-2-il)-4-(kuinolin-4il)-1H-pirazol-1-il)asetamida1H-NMR (300 MHz, DMSO-d6): δ = 8.85-8.79 (m, 1H), 8.18-8.06 (m, 2H), 8.03 (d, J = 8.5 Hz, 1H), 7.88-7.62 (m, 4H), 7.57-7.23 (m, 6H), 7.24-7.06 (m, 1H), 5.10 (s, 2H), 4.44 (d, J = 5.7 Hz) 2H). HPLC-MS: Rt 17,627 m / z 454.0 [M+H]+. Contoh 22: N-(2-klorobenzil)-2-(3-(6-metilpiridin-2-il)-4(quinolin-4-il)-1H-pirazol-1-il)asetamida 1H-NMR (300 MHz, DMSO-dg): δ = 8.89 — 8.73 (m, 2H), 8.13 (s, 1H), 8.03 (d, J = 8.3 Hz, 1H), 7.77-7.26 (m, 10H), 6.98 (d, J = 7.4 Hz, 1H), 5.11 (s, 2H), 4.45 (d, J = 5.7 Hz, 2H), 1.83 (s, 3H). HPLC-MS: Rt 18,273 m / z 468.0 [M+H]+. Contoh 23: N-(2,6-difluorobenzil)-2-(3-(piridin-2-il)-4(kuinolin-4-il)-1H-pirazol-1-il)asetamida1H-NMR (300 MHz, DMSO-d6): δ = 8.83 (d, J = 4.5 Hz, 1H), 8.77 (t, J = 5.4 Hz, 1H), 8.15-7.96 (m, 3H), 7.82-7.63 (m, 4H), 7.50–7.34 (m, 2H), 7.31 (d, J = 4.5 Hz, 1H), 7.22–7.04 (m, 3H), 4.99 (s, 2H), 4.42 (d, J = 5.1 Hz, 2H). HPLC-MS: Rt 16,731 m / z 455.9 [M+H]+. Example 24: N-(2,6-difluorobenzyl)-2-(3-(6-methylpyridine-2-yl)-4(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide1H-NMR (300 MHz, DMSO-d6): δ = J = 8,84 (H, d 8.76 (t, J = 5.3 Hz, 1H), 8.11–7.97 (m, 2H), 7.75–7.28 (m,7H), 7.13 (t, J = 7.8 Hz, 2H), 6.97 (d, J = 7.5 Hz, 1H), 4.99(s, 2H), 4.43 (d, J = 5.3 Hz, 2H), 1.83 (s,3H). HPLC-MS: Rt 17.513 m / z 470.0 [M+H]+. Example 25: N-(2,6-dimethylbenzyl)-2-(3-(pyridine-2-yl)-4(quinoline-4-yl)-1H-pyrazol-1-yl)acetamide1H-NMR (300 MHz, DMSO-d6): δ = 8.83 (d, JHz, = 4.1 8.43–8.39 (m, 2H), 8.16–8.06 (m, 2H), 8.03 (d, J = 8.4 Hz,1H), 7.81–7.63 (m, 4H), 7.48–7.35 (m, 1H), 7.32 (d, J = 4.5 Hz,1H), 7.21–6.97 (m, 4H), 4.99 (s, 2H), 4.37 (d, J = 4.8 Hz, 2H),2.35 (s,6H). HPLC-MS: Rt 18.188 m / z 448.1 [M+H]+. Example 26: N-(2,6-dimethylbenzyl)-2-(3-(6-methylpyridine-2-yl)-4(quinoline-4-yl)-1H-pyrazol-1-yl)acetamide1H-NMR (300 MHz, DMSO-d6): δ = 8,83 (H,4), J 8.40 (t, J = 4.9 Hz, 1H), 8.08 (s, 1H), 8.02 (dd, J = 8.9.1.3 Hz, 1H), 7.77–7.27 (m, 6H), 7.18–6.92 (m, 4H), 4.98 (s,2H), 4.37 (d, J = 4.8 Hz, 2H), 2.35 (s, 6H), 1.82 (s,3H). HPLC-MS: Rt 18.911 m / z 462.1 [M+H]+. Example 27: N-(2-ethylbenzyl)-2-(3-(6-methylpyridine-2-yl)-4(quinoline-4-yl)-1H-pyrazol-1-yl)acetamide 1H-NMR (300 MHz, DMSO-d6): δ = 8.84 (d, J = 4.5 Hz, 1H), 8.69 (t, J = 5.6 Hz, 1H), 8.11 (s, 1H), 8.03 (d, J = 8.3 Hz, 1H), 7.77–7.13 (m, 10H), 6.98 (d, J = 7.5 Hz, 1H), 5.05 (s, 2H), 4.39 (d, J = 5.6 Hz, 2H), 2.66 (q, J = 7.5 Hz, 2H), 1.17 (t, J = 7.5 Hz, 3H). HPLC-MS: Rt 18,940 m / z 462.1 [M+H]+. Example 28: N -(2,6-dichlorobenzyl)-2-(3-(6-methylpyridine-2-yl)-4(quinoline-4-yl)-1H-pyrazole-1-yl)acetamide1H-NMR (300 MHz, DMSO-d6): δ = 8.84 (d, J = 4.5 Hz, 1H), 8.61 (m, 1H), 8.09 (s, 1H), 8.03 (d, J = 8.6 Hz, 1H), 7.75-7.28 (m, 9H), 6.98 (d, J = 7.5 Hz, 1H), 5.01 (s, 2H), 4.61 (d, J = 4.6 Hz, 2H), 1.83 (s, 3H). HPLC-MS: Rt 18.877 m / z 502.1 [M+H]+. Example 29: Hydrochloride of 4-((2-(3-(pyridine-2-yl)-4(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)methyl)benzoic acid A suspension of tert-butyl 4-((2-(3-(pyridine-2-yl)-4(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)methyl)benzoate (0.106 g, 0.204 mmol) in hydrochloroic acid (9 mL. 4M dissolution in dioxane) was heated at 80°C for 1 h. The reaction was cooled and concentrated in vacuo. The residue was purified by C18 chromatography with a Combiflash system (5^100% H2O:MeCN) to yield a white solid (0.033 g, 33%). 1H-NMR (300 MHz, DMSO-d6): δ =9,04 (d, J = 5,3 Hz, 1H), 8,95 (m, 1H), 8,27 (s, 1H), 8,21 (d, J = 8,2 Hz, 1H), 8,09 (d, J = 4,1 Hz, 1H), 7,92-7,79 (m, 5 H), 7,63-7,57 (m, 2H), 7,45 (d, J = 7,6 Hz, 2H), 7,21 (m, 1H), 5,13 (s, 2H), 4,45 (d, J = 5,3 Hz, 2H). HPLC-MS: Rt 13,067 m / z 464,2 [M+H]+.

Claims

1. (I) where: - R1 independently represents 1 or 2 groups chosen from: a) halogen atoms, b) linear or branched C1-C6 alkyl optionally substituted by 1, 2 or 3 halogen atoms, c) cyano group, d) C1-C3 alkoxy, e) -COOH, - R2 represents a group chosen from: a) hydrogen atoms, b) C1-C3 alkyl, - R3 represents a group chosen from: a) hydrogen atoms, b) C1-C3 alkyl optionally substituted by 1, 2 or 3 halogen atoms, c) halogen atoms, - R4 and R5 independently represent a group chosen from: a) hydrogen atoms, b) C1-C3 alkyl optionally substituted by 1, 2 or 3 halogen atoms, c) halogen atoms, - n has a value of 0, 1 or 2 or its salts pharmaceutically acceptable.

2. A pharmaceutically acceptable compound or salt thereof according to claim 1 wherein R2, R4 and R5 represent hydrogen atoms.

3. A pharmaceutically acceptable compound or salt thereof according to claim 1 or claim 2 wherein n is 0 or n is 1 or 2 and each R1 independently represents a halogen atom.

4. A pharmaceutically acceptable compound or salt thereof according to claim 3 wherein n is 1 or 2 and each R1 represents a halogen atom.

5. A pharmaceutically acceptable compound or salt thereof according to claim 4 wherein each R1 is selected from the group consisting of fluorine and chlorine atoms.

6. A compound or a pharmaceutically acceptable salt thereof according to any of claims 1 to 5 wherein R3 represents a group selected from a hydrogen atom, an ethyl group and a methyl group.

7. The compound or its pharmaceutically acceptable salt according to claim 6 wherein R3 represents a methyl group.

8. The pharmaceutically acceptable compound or salt thereof according to claim 1 wherein R2, R4 and R5 independently represent hydrogen atoms, n is 0 or n is 1 or 2, each R1 independently represents a halogen atom, and R3 represents a group selected from hydrogen atoms, an ethyl group and a methyl group.

9. A pharmaceutically acceptable compound or salt thereof according to claim 8 wherein n is 1 or 2, each R1 is selected from the group consisting of a fluorine atom and a chlorine atom and R3 represents a methyl group.

10. A pharmaceutically acceptable compound or salt thereof according to claim 1 selected from the group consisting of: N-benzyl-2-(3-(pyridine-2-yl)-4-(quinoline-4-yl)-1H-pyrazol1-yl)acetamide; N-(4-fluorobenzyl)-2-(3-(pyridine-2-yl)-4-(quinoline-4-yl)1H-pyrazol-1-yl)acetamide; N-(4-chlorobenzyl)-2-(3-(pyridine-2-yl)-4-(quinoline-4-yl)-1Hpyrazol-1-yl)acetamide; N-(4-bromobenzyl)-2-(3-(pyridine-2-yl)-4-(quinoline-4-yl)-1Hpyrazol-1-yl)acetamide; N-(4-cyanobenzyl)-2-(3-(pyridine-2-yl)-4-(quinoline-4-yl)-1Hpyrazole-1-yl)acetamide; N-(4-methoxybenzyl)-2-(3-(pyridine-2-yl)-4-(quinoline-4-yl)1H-pyrazole-1-yl)acetamide; N-(4-methylbenzyl)-2-(3-(pyridine-2-yl)-4-(quinoline-4-yl)-1Hpyrazole-1-yl)acetamide; N-(4-(tert-butyl)benzyl)-2-(3-(pyridine-2-yl)-4-(quinoline-4yl)-1H-pyrazole-1-yl)acetamide; N-benzyl-2-(3-(6-methylpyridine-2-yl)-4-(quinoline-4-yl)-1Hpyrazol-1-yl)acetamide; N- (3-methylbenzyl)-2-(3-(pyridine-2-yl)-4-(quinoline-4-yl)-1Hpyrazol-1-yl)acetamide;N- (3-fluorobenzyl)-2-(3-(pyridine-2-yl)-4-(quinoline-4-yl)1H-pyrazol-1-yl)acetamide; N- (3-chlorobenzyl)-2-(3-(pyridin-2-yl)-4-(quinoline-4-yl)-1Hpyrazol-1-yl)acetamide; N- (3-cyanobenzyl)-2-(3-(pyridin-2-yl)-4-(quinoline-4-yl)-1Hpyrazol-1-yl)acetamide; N- (2-methylbenzyl)-2-(3-(pyridine-2-yl)-4-(quinoline-4-yl)-1Hpyrazol-1-yl)acetamide; N- (2-methylbenzyl)-2-(3-(6-methylpyridine-2-yl)-4-(quinoline-4yl)-1H-pyrazol-1-yl)acetamide; N- (2-fluorobenzyl)-2-(3-(pyridine-2-yl)-4-(quinoline-4-yl)1H-pyrazol-1-yl)acetamide; N- (2-fluorobenzyl)-2-(3-(6-methylpyridine-2-yl)-4-(quinoline4-yl)-1H-pyrazol-1-yl)acetamide; N-benzyl-2-(3-(6-ethylpyridine-2-yl)-4-(quinoline-4-yl)-1Hpyrazol-1-yl)acetamide; 2- (3- (6-ethylpyridine-2-yl)-4-(quinoline-4-yl)-1H-pyrazol-1yl)-N-(2-methylbenzyl)acetamide; N- (4-methylbenzyl)-2-(3-(6-methylpyridine-2-yl)-4-(quinoline-4yl)-1H-pyrazol-1-yl)acetamide; N-(2-chlorobenzyl)-2-(3-(pyridin-2-yl)-4-(quinoline-4-yl)-1Hpyrazol-1-yl)acetamide;N-(2-chlorobenzyl)-2-(3-(6-methylpyridine-2-yl)-4-(quinoline-4yl)-1H-pyrazole-1-yl)acetamide; N-(2,6-difluorobenzyl)-2-(3-(pyridine-2-yl)-4-(quinoline-4yl)-1H-pyrazole-1-yl)acetamide; N-(2,6-difluorobenzyl)-2-(3-(6-methylpyridine-2-yl)-4(quinoline-4-yl)-1H-pyrazole-1-yl)acetamide; N-(2,6-dimethylbenzyl)-2-(3-(pyridine-2-yl)-4-(quinoline-4yl)-1H-pyrazole-1-yl)acetamide; N-(2,6-dimethylbenzyl)-2-(3-(6-methylpyridine-2-yl)-4(quinoline-4-yl)-1H-pyrazole-1-yl)acetamide; N-(2-ethylbenzyl)-2-(3-(6-methylpyridine-2-yl)-4-(quinoline-4yl)-1H-pyrazole-1-yl)acetamide; N-(2,6-dichlorobenzyl)-2-(3-(6-methylpyridine-2-yl)-4(quinoline-4-yl)-1H-pyrazole-1-yl)acetamide; and 4-((2-(3-(pyridine-2-yl)-4-(quinoline-4yl)-1H-pyrazole-1-yl)acetamido)methyl)benzoic acid hydrochloride; or pharmaceutically acceptable salts thereof.; 11. A pharmaceutical composition comprising a pharmaceutically acceptable compound or salt thereof as defined in any one of claims 1 to 10 and a pharmaceutically acceptable diluent or vehicle.

12. A pharmaceutically acceptable compound or salt thereof as defined in any one of claims 1 to 10 for use as a treatment.

13. A compound or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 10 for use in the treatment and / or prevention of a disease or pathological condition susceptible to improvement by inhibition of transforming growth factorβ receptor I (TGF3RI / ALK5).

14. A compound for use according to claim 13 wherein the disease or pathological condition is selected from the group consisting of gastrointestinal diseases, such as inflammatory bowel diseases among which there are Crohn's disease and ulcerative colitis, liver fibrosis and cancer, in particular gastric cancer, esophageal cancer and colorectal cancer; fibrotic skin diseases, such as scleroderma, nephrogenic scarring dermopathy, mixed connective tissue disease, scleromyxedema, scleredema and eosinophilic fasciitis; fibrotic eye diseases such as dry eye, age-related macular degeneration, corneal and conjunctival scarring, post-cataract fibrosis, proliferative vitreoretinopathy and proliferative diabetic retinopathy.

15. A combination product comprising a compound or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 10 and a therapeutic agent used for the treatment and / or prevention of a disease selected from the group consisting of gastrointestinal diseases, such as inflammatory bowel diseases among which there are Crohn's disease and ulcerative colitis, liver fibrosis and cancer, in particular gastric cancer, esophageal cancer and colorectal cancer; fibrotic skin diseases, such as scleroderma, nephrogenic scarring dermopathy, mixed connective tissue disease, scleromyxedema, scleredema and eosinophilic fasciitis; fibrotic eye diseases such as dry eye, age-related macular degeneration, corneal and conjunctival scarring, post-cataract fibrosis, proliferative vitreoretinopathy and proliferative diabetic retinopathy.

16. A compound, pharmaceutical composition, compound for use, or combination product according to any one of claims 1 to 15, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is the compound of formula (I).

17. A compound, pharmaceutical composition, compound for use, or combination product according to any one of claims 1 to 15, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is a pharmaceutically acceptable salt of the compound of formula (I).