Benzylamide derivatives as inhibitors of transforming growth factor-β receptor I / ALK5

Abstract

The present invention relates to novel benzylamide derivatives of formula (I), processes for the preparation of said compounds; pharmaceutical compositions comprising said compounds, and said compounds for use in the treatment of pathological conditions or diseases that may be ameliorated by inhibition of transforming growth factor-β receptor I (TGFβRI) / ALK5, such as diseases and disorders associated with fibrotic conditions of the gastrointestinal system, skin, and eye, methods for the treatment and / or prevention of said diseases or pathological conditions, and combinations comprising said compounds and further comprising a therapeutically effective amount of another therapeutic agent useful in the treatment of said diseases or pathological conditions. [Formula 1] TIFF2023504795000066.tif53170

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to novel advantageously substituted benzylamide derivatives as potent inhibitors of transforming growth factor-β receptor I kinase, also known as activin receptor-like kinase 5 (TGFβRI) / ALK5.

[0002] The invention also relates to processes for preparing these compounds; pharmaceutical compositions containing effective amounts of these compounds; and the use of the compounds for the manufacture of medicaments for the treatment of pathological conditions or disorders that may be ameliorated 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 eye. [Background technology]

[0003] (Technical level) Transforming growth factor-β (TGF-β) belongs to the TGF-β superfamily, which consists of TGF-β1, TGF-β2, TGF-β3, and other proteins. TGF-β is involved in many cellular processes, including cell proliferation, cell migration, invasion, epithelial-mesenchymal transition, extracellular matrix production, and immunosuppression. 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 discovery. (Heldin CH et al., "Signaling Receptors for TGF-β Family Members," Cold Spring Harbor Perspective Biol, 2016, doi: 10.1101 / cshperspect.a022053)

[0004] 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 to create binding sites for the Smad2 and Smad3 proteins, which are further phosphorylated. The phosphorylated Smad2 / Smad3 proteins form a heteromeric complex with Smad4, which translocates to 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, Vol. 11)

[0005] In most cell types, activin receptor-like kinase 5-ALK5 (also known as TGFβR1) is the primary TGFβ receptor I activated by TGFβ via TGFβ receptor II. This interaction requires both the extracellular and intracellular domains for signal transduction. ALK5 and TGFβ receptor II proteins can also form active hetero-oligomeric complexes in the absence of ligand. These complexes can transmit basal signals when both receptors are co-expressed due to their inherent affinity for interaction. (Bierie B. et al., "TGF-β: the molecular Jekyll and Hyde of cancer," Nature Reviews, Cancer, Vol. 6, July 2006).

[0006] Functional TGFβRII-TGFβRI (ALK5) heteromeric signaling complexes are commonly associated with human cancers, where they regulate the activation of downstream Smad-dependent and Smad-independent pathways. Indeed, numerous studies have identified mutations in components related to the TGF-β pathway, which correlate with the development and prognosis of cancer in many human tissues. Overexpression of TGF-β1 has been associated with breast, colon, esophageal, gastric, hepatocellular, lung, and pancreatic cancers. Importantly, overexpression of TGF-β in human cancers correlates with tumor progression, metastasis, angiogenesis, and poor prognosis.

[0007] (cancer) Currently, the TGF-β pathway is being targeted using strategies including immune component modification or small molecule inhibitors and delivery of soluble protein or antisense compound inhibitors. Immunotherapeutic strategies have been used to target the TGF-β pathway in animals.

[0008] The immunotherapeutic strategies typically reduce TGF-β signaling of immune components prior to reconstitution in tumor-bearing recipients, thereby allowing productive interactions 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 evasion, angiogenesis, stromal-epithelial crosstalk, and tumor-cell-autonomous signaling. Due to the immune-mediated disease and lethality associated with genetic loss or inhibition of TGF-β signaling in mice, it was unclear whether inhibiting this pathway to treat cancer would be compatible with patient survival when delivered long-term in vivo. However, it has recently been shown that lifelong exposure to systemic soluble TGF-β inhibitors in mouse models did not result in significant adverse effects. These studies indicate that TGF-β-specific inhibition should be compatible with long-term survival when administered to humans long-term 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, pp. 235-257 (2003)).

[0009] In the tumor microenvironment, TGF-β signaling influences several cell types, including immune cells, cancer-initiating cells, endothelial cells, and fibroblasts. The combined effects of these microenvironmental changes lead to tumor progression and metastasis. TGF-β signaling is present in most malignant tumors, including hepatocellular carcinoma, pancreatic cancer, and myelodysplastic syndromes. Due to 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-in-Human Dose Study of the Novel Transforming Growth Factor-β Receptor I Kinase Inhibitor LY2157299 Monohydrate in Patients with Advanced Cancer and Glioma," Association for Cancer Research, November 25, 2014; doi: 10.1158 / 1078-0432.CCR-14-1380).

[0010] Hepatocellular carcinoma (HCC) is a highly malignant cancer that is the third most common cause of tumor-related deaths in the United States and Europe. Current treatment options are invasive and aim to physically remove or destroy the tumor mass. However, subsequent recurrence and / or metastatic spread are common, negatively impacting survival. Overall prognosis remains unsatisfactory, and little progress has been made in discovering new treatment options. It has been reported that TGF-β is overexpressed in both blood and urine in HCC patients, correlates with poor prognosis and survival, and thus serves as a marker for this cancer. TGF-β has been shown to play an important role in regulating the malignant potential of HCC by triggering cellular epithelial-mesenchymal transition (EMT). This study suggests that inhibiting the TGF-β pathway with small molecule inhibitors may be a promising therapy for HCC patients. (Fransvea, E. et al., "Blocking Transforming Growth Factor-β Up-Regulates E-Cadherin and Reduces Migration and Invasion of Hepatocellular Carcinoma Cells," Wiley InterScience, 2008, doi 10.1002 / hep.22201).

[0011] Pancreatic adenocarcinoma is one of the leading causes of cancer deaths in adults worldwide. The 5-year survival rate for all stages combined is 5%, with a median survival time after diagnosis of <6 months. At the time of diagnosis, two-thirds of patients present with locally advanced or metastatic disease. Even when pancreatic cancer is apparently localized to the pancreas and surgically removed, 70% of patients develop liver metastases. Therefore, pancreatic cancer poses one of the greatest challenges in cancer research. In particular, human pancreatic cancers exhibiting increased levels of TGF-β have been found to be significantly associated with venous invasion, advanced tumor stage, aggressive disease, shorter patient survival, and liver metastasis. TGF-β production by pancreatic tumors impedes effective antitumor immune responses by affecting the phenotype and function of dendritic cells in the tumor microenvironment. Studies have shown that inhibition of the TGF-β signaling cascade by systemic administration of the novel small molecule, selective TGFRI / II kinase inhibitor LY2109761, suppresses metastasis to the liver and other abdominal sites 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 suppress pancreatic cancer metastasis," Mol Cancer Ther 2008;7(4). April 2008.)

[0012] Colorectal cancer, also known as colon cancer, has specific tumor microenvironment characteristics, such as a lack of T cell infiltration, low type 1 T helper cell (TH1) activity, and reduced immune cytotoxicity or elevated TGF-β levels. Recent studies have demonstrated that elevated TGF-β in the tumor microenvironment is a major mechanism of immune evasion, promoting T cell elimination and preventing the acquisition of a TH1 effector phenotype. Therefore, immunotherapy targeting TGF-β signaling may have broad application in the treatment of patients with advanced colorectal cancer. (Tauriello DVF et al., "TGF-β drives immune evasion in genetically reconstituted colon cancer metastasis," Nature, published online February 14, 2018, doi:10.1038 / nature25492).

[0013] Meningiomas account for approximately 36 percent of primary brain tumors. The lack of promising chemotherapy has led to a search for novel therapies targeting growth-regulatory cytokines. Among these, members of the transforming growth factor-β (TGF-β) superfamily may be particularly relevant. Higher-grade, especially anaplastic, meningiomas have the highest recurrence rates and show very poor response to all current therapies for all grades of meningiomas. Restoring TGF-β inhibitory signaling pathways may be a key element in developing effective chemotherapy for meningiomas. To date, direct treatment options are limited, in part due to the toxicity associated with restoring baseline TGF-β inhibition. Nevertheless, in malignancies where TGF-β switches from an inhibitory effect to promoting tumor progression, TGF-β signaling can be blocked by small-molecule inhibitors of the TGF-β type I receptor. Preliminary studies suggest that LY 2157229 (galunisertib) is effective in blocking the action 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).

[0014] Galunisertib is a TGFβRI kinase inhibitor currently in 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 has an IC of 0.172 μM. 50 inhibits the TGFβRI / Alk5 kinase domain with an IC of 0.77 μM 50 It also inhibits ALK4 at submicromolar IC 50 It also inhibits a variety of other kinases, including MINK, TGFβRII, ALK6, and ACVR2B. Previous reports have shown that high doses of these compounds were associated with adverse effects in rats and dogs. Therefore, high rigor was recommended in selecting dosing regimens in human subjects to achieve the desired effect with minimal toxicity. This compound is orally bioavailable. (Yingling, JM et al., "Preclinical assessment of galunisertib (LY2157299 monohydrate), a first-in-class transforming growth factor-β receptor type I inhibitor," Oncotarget. 2018 Jan 23;9(6):6659-6677.)

[0015] Other inhibitors of TGF-β type I receptor kinase in clinical development have IC of 0.013 μM in the kinase assay. 50The first drug, EW-7197, inhibits ALK5 at a potent agonist level. It is a highly selective ALK5 / ALK4 inhibitor that exhibits 51% oral bioavailability with high systemic exposure in pharmacokinetic studies in rats. (Jin, CH et al., "Discovery of N-((4-([1,2,4]Triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-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 J. Med. Chem. 2014, 57, 4213-4238).

[0016] (fibrotic state) Extensive evidence suggests that the canonical ALK5 / Smad3 pathway is critically involved in the pathogenesis of fibrosis in many tissues. Oral administration of a low-molecular-weight selective inhibitor of ALK5 kinase activity inhibited fibrosis in a rat model of progressive TGF-β1-induced pulmonary fibrosis. Furthermore, Smad3-deficient mice exhibit attenuated fibrosis in a wide range of experimental models and are resistant to bleomycin-induced pulmonary fibrosis. Similarly, skin fibrosis after irradiation, renal interstitial fibrosis caused 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. 2011 Oct;29(5):196-202. doi:10.3109 / 08977194.2011.595714).

[0017] Inhibitors of the TGF-β intracellular signaling pathway are useful treatments for fibroproliferative diseases. Specifically, fibroproliferative diseases include kidney disorders associated with unregulated TGF-β activity and excessive types of fibrosis, including glomerulonephritis (GN), such as mesangial proliferative GN, immune-mediated GN, and crescentic GN. Other kidney 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 features include systemic lupus erythematosus and rheumatoid arthritis.

[0018] Myelofibrosis (MF) is a bone marrow disorder characterized by clonal myeloproliferation, abnormal cytokine production, extramedullary hematopoiesis, and myelofibrosis. Although somatic mutations in Janus kinase 2 (JAK2), myeloproliferative leukemia virus (MPL), and calreticulin gene (CALR) have been identified in the pathogenesis of these diseases, inhibitors of the JAK2 pathway have not shown efficacy in improving MF in patients. TGF-β family members are profibrotic cytokines, and significant TGF-β1 isoform overexpression has been observed in large cohorts of primary MF patient samples. It has been demonstrated that TGF-β1 stimulates excessive collagen deposition by mesenchymal stromal cells (MSCs) by activating the TGF-β receptor I kinase (ALK5) / Smad3 pathway. The use of galunisertib, a clinically active ALK5 inhibitor, significantly improved MF in a mouse model. Data indicate a role for the malignant hematopoietic stem cell (HSC) / TGF-β / MSC axis in the pathogenesis of MF and provide a preclinical rationale for ALK5 blockade 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)

[0019] Additionally, studies have investigated the therapeutic potential of TGF-β inhibitors in preventing postoperative peritoneal adhesive band formation, and results have shown that these compounds significantly attenuate adhesive band formation by inhibiting inflammation, oxidative stress, downregulating pro-inflammatory genes, and suppressing fibrosis and pro-fibrotic 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)

[0020] Several small molecules that inhibit ALK5 have been developed and have shown promising results in animal models of renal fibrosis. However, questions remain regarding the homeostatic role of ALK5 signaling and, therefore, the safety implications of targeting this enzyme. Studies have shown that immunohistochemical analysis revealed that ALK5 expression in the heart was specific to the valves. Two compounds (AZ12601011 and AZ12799734) were tested in rats. Microscopic evaluation revealed cardiac valvular lesions in response to treatment with either compound. Both compounds induced histopathological cardiac valvular lesions characterized by hemorrhage, inflammation, degeneration, and proliferation of valvular interstitial cells. Pathology was observed in all animals at all doses tested and occurred in all four heart valves. Analysis of ALK5 in rat 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 an important role in maintaining the integrity of heart valves. (Anderton MJ et al., "Induction of Heart Valve Lesions by Small-Molecule ALK5 Inhibitors," Toxicologic Pathology, 39: 916-924, 2011).

[0021] Additionally, another ALK-5 inhibitor, galunisertib, was tested in both rats and dogs. In both cases, the heart and large vessels were identified as the primary target organs of toxicity. Cardiovascular findings in F344 rats treated with LY2157299 included degenerative and inflammatory valve lesions (valvular disease), 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.)

[0022] (Irritable bowel disease (IBD)) In the gastrointestinal tract, many immune and non-immune cells produce transforming growth factor-β1, and nearly all mucosal cells are targeted by this cytokine. TGF-β1 is secreted as part of a latent complex containing latency-associated peptide (LAP) and latent TGF-β binding protein. Data from recent studies clearly indicate that transforming growth factor-β1 is one of the key molecules involved in regulating epithelial cell biology and immunity in the gastrointestinal tract.

[0023] These studies clearly demonstrate the crucial role of TGF-β1 in maintaining intestinal homeostasis and suggest that defects in the function of this cytokine may contribute to triggering and / or amplifying harmful signals in the gastrointestinal tract. (Troncone E. et al., "Transforming Growth Factor-β1 / Smad7 in intestinal immunity, inflammation, and cancer," Front. Immunol. 9:1407, 2018)

[0024] So far, researchers have been studying the mechanisms of inflammation to reduce and inhibit intestinal fibrosis. However, anti-inflammatory drugs have various problems and limitations in alleviating or treating fibrosis in inflammatory bowel disease (IBD). Therefore, new approaches to anti-fibrotic mechanisms should be explored to treat fibrotic diseases. Numerous publications have shown that molecules related to TGF-β signaling are involved in fibrosis, and therefore, they are important targets for the progression of intestinal fibrosis in IBD because they are correlated with the complex and diverse signaling pathways that regulate the mechanism of intestinal fibrosis progression. Therefore, TGF-β signaling is a promising strategy for treating and reducing fibrosis in several fibrotic diseases, including IBD (Yun SM et al., "The Molecular Mechanism of Transforming Growth Factor-β Signaling for Intestinal Fibrosis: A Mini-Review," Frontiers in Pharmacology, Mini-Review, published February 27, 2019; Binabaj MM et al., "EW-7197 prevents ulcerative colitis-associated fibrosis and inflammation," J Cell Physiol. 2018;1-8).

[0025] (eye disease) 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 promising areas for targeting TGF-β include production, activation, downstream signaling, and local regulation. Elevated levels of TGF-β are found in the aqueous humor and reactive optic nerve astrocytes of patients with glaucoma. Although recent studies have revealed many unknowns, a deeper understanding of the intracellular signaling pathways of TGF-β is necessary to design promising TGF-β therapeutic intervention strategies (Wang, J. et al., "Targeting Transforming Growth Factor-β Signaling in Primary Open-Angle Glaucoma," J Glaucoma 2017;26:390-395).

[0026] Ocular diseases associated with fibroproliferative conditions, including retinal reattachment surgery associated with proliferative vitreoretinopathy, cataract extraction with intraocular lens implantation, and post-glaucoma drainage surgery, are associated with TGF-β1 overproduction.

[0027] The inventors of the present invention have developed novel, advantageously substituted benzylamide derivatives as potent inhibitors of the TGF-β signaling pathway, in particular as inhibitors of transforming growth factor-β receptor I / activin-like kinase 5 (TGFβRI / ALK5), that exhibit low systemic exposure, which facilitates avoiding known significant side effects. Thus, the present invention discloses ALK5 inhibitors that exhibit low systemic exposure, resulting in a good therapeutic window. Summary of the Invention

[0028] (Summary of the Invention) In one embodiment (embodiment 1) of the present invention, the present invention provides novel advantageously substituted benzylamide derivatives of formula (I): [ka] (In the formula: R 1 are independently: a) a halogen atom, b) linear or branched C1-C6 alkyl optionally substituted with 1, 2, or 3 halogen atoms; c) a cyano group, d) C1-C3 alkoxy, e) -COOH represents one or two groups selected from R 2 teeth: a) a hydrogen atom, b) C1-C3 alkyl, c) C3-C4 cycloalkyl represents a group selected from R 3 teeth: a) C1-C3 alkyl optionally substituted with 1, 2, or 3 halogen atoms; b) a hydrogen atom, c) Halogen atoms represents a group selected from R 4 and R 5 are independently: a) a hydrogen atom, b) C1-C3 alkyl optionally substituted with 1, 2, or 3 halogen atoms; c) Halogen atoms represents a group selected from (n can take the value 0, 1, or 2) and pharmaceutically acceptable salts thereof.

[0029] In a second aspect, the present invention relates to a process for the preparation of a compound of aspect 1.

[0030] In a third aspect, the present invention relates to a pharmaceutical composition comprising a compound of aspect 1 and a pharmaceutically acceptable diluent or carrier.

[0031] In a fourth aspect, the present invention relates to a pharmaceutical composition according to the third aspect above, further comprising a therapeutically effective amount of a therapeutic agent selected from agents useful for the treatment of gastrointestinal diseases such as inflammatory bowel diseases, including Crohn's disease and ulcerative colitis, liver fibrosis, and cancer, in particular gastric, esophageal, and colorectal cancer; fibrotic skin diseases such as scleroderma, nephrogenic fibrosing dermatosis, mixed connective tissue disease, scleromyxedema, edematous sclerosis, and eosinophilic fasciitis; and fibrotic ocular diseases such as dry eye, age-related macular degeneration, scarring in the cornea and conjunctiva, post-cataract fibrosis, proliferative vitreoretinopathy, and proliferative diabetic retinopathy.

[0032] In a fifth aspect, the invention relates to the use of a compound of aspect 1 in the manufacture of a medicament for the treatment and / or prevention of diseases or pathological conditions that may be ameliorated by inhibition of transforming growth factor-β receptor I (TGFβRI) / ALK5, such as gastrointestinal diseases, such as inflammatory bowel diseases, including Crohn's disease and ulcerative colitis, liver fibrosis, and cancer, in particular gastric, esophageal, and colorectal cancer; fibrotic skin diseases, such as scleroderma, nephrogenic fibrosing dermatosis, mixed connective tissue disease, scleromyxedema, edematous sclerosis, and eosinophilic fasciitis; and fibrotic ocular diseases, such as dry eye, age-related macular degeneration, scarring in the cornea and conjunctiva, post-cataract fibrosis, proliferative vitreoretinopathy, and proliferative diabetic retinopathy.

[0033] In a sixth aspect, the present invention relates to a method for the treatment and / or prevention of diseases or pathological conditions that may be ameliorated by the inhibition of transforming growth factor-β receptor I (TGFβRI) / ALK5, such as gastrointestinal diseases, such as inflammatory bowel diseases, including Crohn's disease and ulcerative colitis, liver fibrosis, and cancer, in particular gastric, esophageal, and colorectal cancer; fibrotic skin diseases, such as scleroderma, nephrogenic fibrosing dermatosis, mixed connective tissue disease, scleromyxedema, edematous sclerosis, and eosinophilic fasciitis; and fibrotic eye diseases, such as dry eye, age-related macular degeneration, scarring in the cornea and conjunctiva, post-cataract fibrosis, proliferative vitreoretinopathy, and proliferative diabetic retinopathy.

[0034] In a seventh aspect, the present invention relates to a combination of a compound product of the first aspect above with another therapeutic agent known to be useful in the treatment of a disease selected from gastrointestinal diseases such as inflammatory bowel diseases, including Crohn's disease and ulcerative colitis, liver fibrosis, and cancer, particularly gastric, esophageal, and colorectal cancer; fibrotic skin diseases such as scleroderma, nephrogenic fibrosing dermatosis, mixed connective tissue disease, scleromyxedema, edematous sclerosis, and eosinophilic fasciitis; fibrotic eye diseases such as dry eye, age-related macular degeneration, scarring in the cornea and conjunctiva, post-cataract fibrosis, proliferative vitreoretinopathy, and proliferative diabetic retinopathy.

[0035] In an eighth aspect, the present invention relates to a compound of aspect 1 for use in the treatment and / or prevention of a disease or pathological condition that may be ameliorated by inhibition of transforming growth factor-β receptor I (TGFβRI) / ALK5, such as gastrointestinal diseases, such as inflammatory bowel diseases, including Crohn's disease and ulcerative colitis, liver fibrosis, and cancer, in particular gastric, esophageal, and colorectal cancer; fibrotic skin diseases, such as scleroderma, nephrogenic fibrosing dermatosis, mixed connective tissue disease, scleromyxedema, edematous sclerosis, and eosinophilic fasciitis; fibrotic ocular diseases, such as dry eye, age-related macular degeneration, scarring in the cornea and conjunctiva, post-cataract fibrosis, proliferative vitreoretinopathy, and proliferative diabetic retinopathy. DETAILED DESCRIPTION OF THE INVENTION

[0036] In certain embodiments, the compound of formula (I) exhibits low systemic exposure after oral, topical or ophthalmic administration due to its very low metabolic stability, which leads to the formation of inactive metabolites.Therefore, they are suitable for treating diseases such as gastrointestinal diseases, including inflammatory bowel diseases, including Crohn's disease and ulcerative colitis, liver fibrosis, and cancer, especially gastric cancer, esophageal cancer, and colorectal cancer; fibrotic skin diseases, such as scleroderma, nephrogenic fibrosing dermatosis, mixed connective tissue disease, scleromyxedema, edematous sclerosis, 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.

[0037] As mentioned above, the benzylamide derivatives of the present invention are useful for the treatment or prevention of diseases known to be susceptible to improvement by treatment with inhibitors of transforming growth factor-β receptor I (TGFβRI) / ALK5, such as gastrointestinal diseases such as inflammatory bowel diseases including Crohn's disease and ulcerative colitis, liver fibrosis, and cancer, particularly gastric cancer, esophageal cancer, and colorectal cancer; fibrotic skin diseases such as scleroderma, nephrogenic fibrosing dermatosis, mixed connective tissue disease, scleromyxedema, edematous sclerosis, and eosinophilic fasciitis; and fibrotic ocular diseases such as dry eye, age-related macular degeneration, scarring in the cornea and conjunctiva, post-cataract fibrosis, proliferative vitreoretinopathy, and proliferative diabetic retinopathy.

[0038] Accordingly, the derivatives of the present invention and their pharmaceutically acceptable salts, as well as pharmaceutical compositions containing such compounds and / or their salts, may be used in methods for the treatment of pathological conditions or diseases in the human body, comprising administering to a subject in need of such treatment an effective amount of a benzylamide derivative of the present invention or a pharmaceutically acceptable salt thereof.

[0039] As used herein, C a -C b The term alkyl includes straight-chain or branched radicals having a to b carbon atoms. Preferred radicals have 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. Examples of straight-chain or branched alkyl groups are methyl, ethyl, n-propyl, iso-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, pentyl, and hexyl.

[0040] As used herein, linear or branched C a -C b The term alkoxy refers to a C linked to an oxygen atom. a -C b Radicals with alkyl radicals (C x H 2x+1-O-). Preferred radicals have 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. Preferred alkoxy radicals include, for example, methoxy, ethoxy, n-propoxy, and i-propoxy.

[0041] As used herein, the term halogen atom includes chlorine, fluorine, bromine, and iodine atoms, preferably fluorine, chlorine, and bromine atoms. The term halo has the same meaning when used as a prefix. By way of example only, haloalkyl means alkyl substituted with one or more halogen atoms.

[0042] As used herein, some atoms, radicals, chains, or rings present within the general structures of the present invention are "optionally substituted." This means that these atoms, radicals, chains, or rings may be unsubstituted or substituted at any position with one or more, e.g., 1, 2, 3, or 4, substituents, whereby a hydrogen atom attached to the unsubstituted atom, radical, chain, or ring is replaced by a chemically permissible atom, radical, chain, or ring. When two or more substituents are present, each substituent may be the same or different.

[0043] As used herein, the term "pharmaceutically acceptable salt" refers to a salt with a pharmaceutically acceptable acid or base. Pharmaceutically acceptable acids include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, diphosphoric acid, hydrobromic acid, hydroiodic acid, and nitric acid, as well as organic acids such as citric acid, fumaric acid, maleic acid, malic acid, mandelic acid, ascorbic acid, oxalic acid, succinic acid, tartaric acid, benzoic acid, acetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, or p-toluenesulfonic acid. Pharmaceutically acceptable bases include hydroxides of alkali metals (e.g., sodium or potassium), alkaline earth metals (e.g., calcium or magnesium), and organic bases such as alkylamines, arylalkylamines, and heterocyclic amines.

[0044] Other preferred salts according to the invention are those containing an equivalent amount of anion (X -n ) is associated with a positive charge on the N atom, making it a quaternary ammonium compound. -n X can be, for example, the anions of various mineral acids, such as chloride, bromide, iodide, sulfate, nitrate, and phosphate, or the anions of organic acids, such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, methanesulfonate, and p-toluenesulfonate. -n is preferably an anion selected from chloride, bromide, iodide, sulfate, nitrate, acetate, maleate, oxalate, succinate, or trifluoroacetate. - is chloride, bromide, trifluoroacetate, or methanesulfonate.

[0045] According to one embodiment of the present invention, in the compound of formula (I), each R 1 In a preferred embodiment, n is 0, or n is 1 or 2, and each R 1 represents a halogen atom. In a more preferred embodiment, n is 1 or 2 and each R 1 represents a fluorine or chlorine atom.

[0046] According to one embodiment of the present invention, in the compound of formula (I), R 2 represents a hydrogen atom.

[0047] According to one embodiment of the present invention, in the compound of formula (I), R 3 represents a group selected from C1-C3 alkyl optionally substituted with 1, 2, or 3 halogen atoms, and a hydrogen atom. 3 represents hydrogen or C1-C3 alkyl. In a more preferred embodiment, R 3represents hydrogen, a methyl group, or an ethyl group, and preferably represents hydrogen or a methyl group.

[0048] According to one embodiment of the present invention, in the compound of formula (I), R 4 represents a hydrogen atom.

[0049] According to one embodiment of the present invention, in the compound of formula (I), R 2 , R 4 , and R 5 represents a hydrogen atom.

[0050] According to one embodiment of the present invention, in the compound of formula (I), n is 0, or n is 1 or 2, and each R 1 each independently represents a halogen atom; R 2 , R 4 , and R 5 each independently represents a hydrogen atom, and R 3 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 R 1 represents a halogen atom, and R 3 represents a methyl group. In a more preferred embodiment, n is 1 or 2 and each R 1 independently represent a fluorine or chlorine atom.

[0051] Specific individual compounds of the present invention include: N-Benzyl-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide N-(4-Fluorobenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide N-(4-chlorobenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide N-(4-Bromobenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide N-(4-cyanobenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide N-(4-Methoxybenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide N-(4-methylbenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide N-(4-(tert-butyl)benzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide N-benzyl-2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide N-(3-methylbenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide N-(3-Fluorobenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide N-(3-chlorobenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide N-(3-cyanobenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide N-(2-methylbenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide N-(2-methylbenzyl)-2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide N-(2-Fluorobenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide N-(2-Fluorobenzyl)-2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide N-benzyl-2-(3-(6-ethylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide 2-(3-(6-ethylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)-N-(2-methylbenzyl)acetamide N-(4-methylbenzyl)-2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide N-(2-chlorobenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide N-(2-chlorobenzyl)-2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide N-(2,6-Difluorobenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide N-(2,6-Difluorobenzyl)-2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide N-(2,6-dimethylbenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide N-(2,6-dimethylbenzyl)-2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide N-(2-ethylbenzyl)-2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide N-(2,6-Dichlorobenzyl)-2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide 4-((2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)methyl)benzoic acid hydrochloride Examples include:

[0052] The compounds of the present invention can be prepared by using the following procedures. Specific examples are used to facilitate the illustration of the procedures, but they do not in any way limit the scope of the invention.

[0053] The synthesis of compounds of formula (I) is outlined in Scheme 1. (Scheme 1) [ka]

[0054] (Reagents and conditions:) Step a) NaH, THF, DMF, 0°C to room temperature, or Na2CO3, DMF, room temperature. The compounds of general formula (I) are prepared in several steps from 4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)quinoline derivatives (II) by reaction with the corresponding bromoacetamides (III) (WO 2009123316 A1; Chem. Eur. J., 2013, 19(32), 10506-10510). Some 4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)quinoline derivatives (II) are commercially available, while others can be prepared in several steps as shown in Scheme 2 (J. Med. Chem. 2004, 47, 4494-4506; WO 2004026302 A1). (Scheme 2) [ka]

[0055] (Reagents and conditions:) Step b) LiHMDS, THF, -60°C to -10°C. Stage c) R 4=H. Step 1. DMF·DMA, AcOH, DMF, room temperature; Step 2. N2H4·H2O, room temperature.

[0056] R 2 = C3-C4 cycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen atoms: Step d) R according to the following scheme (Scheme 2-1): 2 -CO-N2H3, HCl, THF, 40℃.

[0057] Condensation of the 4-methylquinoline derivative (IV) with 2-ethylpyridinecarboxylate (V) in the presence of lithium bis(trimethylsilyl)amide gives the compound of formula (VI). Reaction of the derivative (VI) with dimethylformamide dimethyl acetal gives the unisolated enamine intermediate, which is directly cyclized by reaction with hydrazine in the presence of acetic acid to give the pyrazole of formula (II).

[0058] Another route to obtain compounds of formula (II) is as follows: (Scheme 2-1) [ka]

[0059] formula( II The pyrazole derivatives of formula (IIa) can be halogenated to give the corresponding halogenated compounds. These compounds, after protection of the nitrogen of the pyrazole ring, can be prepared using standard halogenation reagents as succinimide derivatives to give compounds of formula (IIa). CC coupling and subsequent deprotection of the pyrazole nitrogen give derivatives of formula (II). PG = protecting group. Protecting groups include tetrahydropyran (THP), tert-butoxycarbonyl, Lu( Boc), and tritium aryl group (Tr).

[0060] Bromoacetamides of formula (III) are readily synthesized in one step from commercially available amines (VII) by reaction with bromoacetyl bromides of formula (VIII), as shown in Scheme 3 (J. Med. Chem. 2009, 52, 6851-6859). (Scheme 3) [ka]

[0061] (Reagents and conditions:) Step f) THF, 0° C. to room temperature; or CH 2 Cl 2 , DIPEA, 0° C. to room temperature.

[0062] Other amines of formula (VII) are not commercially available and can be prepared in several steps as shown in Scheme 4.

[0063] The compound of formula (VII) can be synthesized from the compound of formula (IX) in which X is a halogen atom according to the following scheme 4. (Scheme 4) [ka]

[0064] (Reagents and conditions:) X: halogen atom Step g) Phthalimide, K2CO3, DMF 50°C, Step h) N2H4·H2O, EtOH, reflux.

[0065] Amines of formula (VII) are prepared using the classical conditions of the Gabriel synthesis, which involves the reaction of the conjugate base of a phthalimide and an alkyl halide (IX), followed by subsequent removal of the phthaloyl group using hydrazine to give the primary amine (VII).

[0066] (abbreviation) In this application, the following abbreviations with corresponding definitions are used: AcOH: acetic acid ACVR2B: Activin A receptor, type II B ALKn: activin receptor-like kinase n ATP: adenosine triphosphate Boc2O: t-butyl dicarbonate Clint: Inherent Clearance 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 serum 1 H-NMR: proton nuclear magnetic resonance K2EDTA: Dipotassium ethylenediaminetetraacetic acid KOtBu: potassium tert-butoxide LC: liquid chromatography LiHMDS: Lithium bis(trimethylsilyl)amide LLOQ: Lower limit of quantification MeCN: acetonitrile MeOH: Methanol MS: mass spectrometry N2H4·H2O: Hydrazine monohydrate NaCMC: sodium carboxymethylcellulose 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 TGFβ: Transforming growth factor-β THF: tetrahydrofuran THF:EtOH: tetrahydrofuran:ethanol UPLC: Ultra-high performance liquid chromatography UV: Ultraviolet

[0067] (Pharmacological activity) (In vitro enzyme assay: inhibition of TGFβR-1 kinase activity) Human TGFβR-1 inhibition experiments were performed in white, low flange 384 microplates (Corning 3572) using the ADP-Glo ​​Kinase Assay Kit (Promega V9101) and the TGFβR-1 Kinase Enzyme System (Promega V4092). Test compounds and standard galunisertib (Cayman 15312), 50 ng / well of TGFβR-1 kinase, and 50 μM ATP were added in a final volume of 10 μL / well, using the reaction buffer provided with the kit as the assay buffer. The reaction mixture was incubated for 120 minutes at room temperature with gentle shaking. After incubation, 10 μL of ADP-Glo ​​reagent was added and incubated for 40 minutes at room temperature with gentle shaking. 20 μL of kinase detection reagent was added, and the plate was incubated for 30 minutes at room temperature with gentle shaking. Luminescence (1000 ms) was measured on a Perkin Elmer EnSpire multimode plate reader.

[0068] (result) Table 1 shows the results of the following assays for some compounds of the invention. (Table 1) [Table 1] TIFF0007808032000008.tif236170TIFF0007808032000009.tif214170Range: A: IC 50 =<100nM B: 100nM <IC 50 <800nM

[0069] (Determination of intracellular TGF-β kinase activity (ALK-5)) This experiment was performed on the A549 cell line. 30,000 cells were seeded onto a 96-well microplate (Becton Dickinson 353072) in 200 μL of culture medium (Sigma D6046) supplemented with L-glutamine (Sigma G7513), penicillin / streptomycin (Invitrogen 11058), and FBS (Sigma F9665). After 16 hours, the medium was replaced with serum-free medium. Galunisertib (Cayman CAY-15312) as an inhibitor ligand and recombinant human TGF-β2 (R&D Systems 302-B2-002) as an activator of ALK-5 were added to their corresponding wells and incubated according to the instructions of the Alphascreen AlphaLISA® SureFire® Ultra™ p-SMAD3 (Ser423 / 425) kit (Perkin Elmer ALSU-PSM3-A500).

[0070] (result) Table 2 shows the results of the following assays for some compounds of the invention. (Table 2) [Table 2] range: A: IC 50 =<100nM B: 100nM <IC 50 <500nM As can be seen from the results set forth in the table above, the compounds of the present invention are potent inhibitors of transforming growth factor-beta receptor I (TGFβRI / ALK5).

[0071] (Plasma Pharmacokinetic Assay) The purpose of this study was to investigate the plasma pharmacokinetics of selected compounds of the present invention in male Sprague-Dawley rats after a single oral dose. Three rats per compound were used in this study. Animals received a suspension formulation of each compound in 0.5% Tween-80 and 99.5% NaCMC (0.5% w / v in RO water) at 5 mg / kg by the oral route. Blood samples were collected (orally) from sets of three rats per 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. Plasma samples were separated by centrifugation of whole blood and stored below -70 ± 10°C until bioanalysis. All samples were processed for analysis by protein precipitation using acetonitrile and analyzed by a purpose-built LC-MS / MS method (LLOQ = 1.01 ng / mL). Pharmacokinetic parameters were calculated using the non-compartmental analysis tool in Phoenix WinNonlin® (version 7.0). The main pharmacokinetic parameters from several examples are shown in Table 3 below. (Table 3) [Table 3] 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 the last observation above the limit of quantitation. AUCinf: represents the total exposure to the drug. Tmax: The time from administration of a compound or drug when the maximum plasma concentration is reached.

[0072] From the PK data presented above, it can be concluded that the compounds of the present invention exhibit low systemic exposure after oral administration.

[0073] (Metabolic Stability Assay) Human and rat recombinant microsomes from Tebu-Xenotech were used in this assay. They contained 0.5 mg / mL of protein. The following amounts were added to each well of a 96-well microplate: [Table 4]

[0074] The plate was incubated at 37°C, and 75 μL samples were taken at 0, 10, 20, 40, and 60 minutes. The samples were transferred to a microplate, 75 μL of acetonitrile was added to inactivate the microsomes, and 30 μL of HO was added to improve the chromatographic conditions, and the plate was kept at 4°C. Once all samples were taken, the plate was centrifuged at 46000 g for 30 minutes at 15°C. The supernatant was collected and injected into the UPLC-MS / MS. Stationary phase: Reverse-phase Acquity UPLC® BEH C18 1.7 μm (2.1 mm × 50 mm) (Waters). Mobile phase: A: 0.1% formic acid; B: acetonitrile + 0.1% formic acid. Flow rate: 0.6 ml / min. The chromatography system used was a UPLC QSM Waters Acquity. Compound concentrations were calculated from UV peak areas. 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 remaining compound at each time point evaluated.

[0075] (Data Analysis) The data were fit to a one phase exponential decay equation using GraphPad Prism® software. The half-life (t 1 / 2 ) shall be reported. The intrinsic clearance is calculated by the following formula: where k = decay rate constant (min -1 )) shall be calculated.

number

[0076] The examples analyzed above were unstable in liver microsomal assays and showed high clearance in both species evaluated.

[0077] In the metabolite identification test, Compound A was identified, which is 2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetic acid, having the following formula: [ka] [ka] HPLC-MS: Rt 13.025 m / z 345.1 (MH + ).

[0078] Compound A was identified as the major metabolite in Examples 9, 15, 20, 22, 24, and 26, among others.

[0079] The activity of Compound A against TGFβR-1 was measured under the conditions described above, and the IC 50 Intracellular TGF-β kinase activity (ALK-5) was also determined, with an IC of over 5000 nM. 50 was shown.

[0080] Due to their low metabolic stability, the compounds of the present invention exhibit low systemic exposure after oral, topical, or ophthalmic administration, and are therefore particularly suitable for the treatment of diseases such as gastrointestinal diseases, such as inflammatory bowel diseases, including Crohn's disease and ulcerative colitis, liver fibrosis, and cancer, in particular gastric, esophageal, and colorectal cancer; fibrotic skin diseases, such as scleroderma, nephrogenic fibrosing dermatosis, mixed connective tissue disease, scleromyxedema, edematous sclerosis, and eosinophilic fasciitis; and fibrotic eye diseases, such as dry eye, age-related macular degeneration, scarring in the cornea and conjunctiva, post-cataract fibrosis, proliferative vitreoretinopathy, and proliferative diabetic retinopathy.

[0081] Accordingly, the derivatives of the present invention and their pharmaceutically acceptable salts, as well as pharmaceutical compositions containing such compounds and / or their salts, may be used in methods for the treatment of disorders of the human body, comprising administering an effective amount of a benzylamide derivative of the present invention or a pharmaceutically acceptable salt thereof to a subject in need of such treatment.

[0082] The present invention also provides other therapeutic agents, and A pharmaceutical composition is provided which comprises, as an active ingredient, at least a benzylamide derivative of formula (I) or a pharmaceutically acceptable salt thereof, together with 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% by weight, of the composition, depending on the nature of the formulation and whether further dilution is performed prior to administration.

[0083] Preferably, the compounds of formula (I), pharmaceutically acceptable salts, and compositions thereof are made in a form suitable for oral, topical, ophthalmic, rectal, or transdermal administration.

[0084] Pharmaceutically acceptable excipients which can be mixed with the active compounds or salts of such compounds to form compositions of the present invention are well known per se, and the actual excipient used will depend, inter alia, on the intended method of administering the composition.

[0085] The compound of formula (I) of the present invention, as a medicine Acceptable The salts and compositions are preferably adapted for injection and oral administration. In this case, the compositions for oral administration can be taken in the form of tablets, retard tablets, sublingual tablets, capsules, or liquid preparations such as mixtures, elixirs, syrups, or suspensions, all containing the compounds of the present invention; such preparations can be prepared by methods well known in the art.

[0086] Diluents that may be used in preparing the compositions include liquid and solid diluents that are compatible with the active ingredient, together with coloring or flavoring agents, if desired. A tablet or capsule may conveniently contain 2 to 500 mg of the active ingredient or an equivalent amount of its salt.

[0087] Liquid compositions adapted for oral use may be in the form of solutions or suspensions. Solutions may be, for example, aqueous solutions of soluble salts or other derivatives of the active compound with sucrose to form a syrup. Suspensions may contain an insoluble active compound of the present invention or its pharmaceutically acceptable salt together with water, a suspending agent, or a flavoring agent.

[0088] Compositions for parenteral injection may be prepared from soluble salts, which may be lyophilized or not, and which may be dissolved in pyrogen-free aqueous media or other suitable parenteral injection fluids.

[0089] Effective doses typically range from 2 to 2000 mg of active ingredient per day. The daily dosage may be administered in one or more treatments, preferably 1 to 4 treatments, per day.

[0090] The present invention is further illustrated by the following examples, which are given by way of illustration and in no way limit the scope of the invention. The synthesis of compounds of the present invention is illustrated by the following examples, including the preparation of intermediates, which in no way limit the scope of the invention. [Example]

[0091] (Example) (General) Reagents, solvents, and starting products were obtained from commercial suppliers. The term "concentrated" refers to vacuum evaporation using a Buchi rotary evaporator. Where indicated, reaction products were purified by "flash" chromatography on silica gel (40-63 μm) using the indicated solvent system. 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 UV-Vis W 2996 detector, and a Micromass ZQ 200.

[0092] (Intermediate 1: ethyl 6-methylpicolinate) To a solution of 6-methylpicolinic acid (2.0 g, 14.58 mmol) in ethanol (50 mL) was added sulfuric acid (1.2 mL), and the mixture was heated at reflux for 22 h and then concentrated to dryness. The residue was dissolved in water (50 mL), sodium bicarbonate was added until pH 8-9, and it was extracted with ethyl acetate (3 x 40 mL). The combined organic layers were dried over sodium sulfate and concentrated to give a yellow oil (1.88 g, 78%). [ka] HPLC-MS: Rt 8.258 m / z 166.5 [M+H] + .

[0093] (Intermediate 2: 1-(6-methylpyridin-2-yl)-2-(quinolin-4-yl)ethan-1-one) 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, 1 M tetrahydrofuran solution) was added, and the reaction mixture was stirred at low temperature for 30 minutes. 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 (saturated aqueous solution), and the solvent was removed under vacuum. The residue was dissolved in ethyl acetate (60 mL) and washed with ammonium chloride (2×50 mL, saturated aqueous solution). The organic layer was dried over sodium sulfate and concentrated. The reaction product was purified by flash chromatography on silica gel (40% EtOAc / hexanes) to give an orange oil (0.423 g, 46%). [ka] HPLC-MS: Rt 10.077 m / z 262.7 [M+H] + .

[0094] (Intermediate 3: 1-(6-ethylpyridin-2-yl)-2-(quinolin-4-yl)ethan-1-one) HPLC-MS: Rt 10.643 m / z 276.7[M+H] + .

[0095] (Intermediate 4: 4-(3-(6-methylpyridin-2-yl)-1H-pyrazol-4-yl)quinoline) To a solution of 1-(6-methylpyridin-2-yl)-2-(quinolin-4-yl)ethan-1-one (0.420 g, 1.60 mmol) in dimethylformamide (5 mL) were added acetic acid (0.330 mL, 5.76 mmol) and N,N-dimethylformamide dimethyl acetal (0.640 mL, 4.80 mmol), and the reaction mixture was stirred at room temperature for 1 hour. Hydrazine monohydrate (1.75 mL, 35.84 mmol) was added, and the solution was heated at 50° C. for 1 hour. 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 brine (2×20 mL), dried over sodium sulfate, and concentrated. The solid crude product was recrystallized from acetonitrile to give a yellow solid (0.335 g, 73%). [ka] HPLC-MS: Rt 9.100 m / z 286.9 [M+H] + .

[0096] (Intermediate 5: 4-(3-(6-ethylpyridin-2-yl)-1H-pyrazol-4-yl)quinoline) [ka] HPLC-MS: Rt 9.616 m / z 301.2 [M+H] + .

[0097] (Intermediate 6: (2-ethylphenyl)methanamine) External ice / water BathTo a solution of 2-ethylbenzonitrile (0.20 g, 1.52 mmol) in THF (8 mL) cooled to 5 °C was added LiAlH (0.28 mg, 7.62 mmol) in portions. The reaction mixture was allowed to reach room temperature and stirred for 21 h. HO (3 mL) and NaOH (1 mL, 36% aqueous solution) were added to the mixture and stirred for 5 min. The suspension was filtered through Celite and washed with EtOAc (15 mL). The mother liquor was concentrated to dryness to give a pink oil (140 mg). The product was used in the next step without further purification.

[0098] (Intermediate 7: tert-butyl 4-((1,3-dioxoisoindolin-2-yl)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 (2×15 mL). The combined organic extracts were dried over sodium sulfate and concentrated to give a white solid (0.42 g, 95%). [ka]

[0099] (Intermediate 8: tert-butyl 4-(aminomethyl)benzoate) To a suspension of tert-butyl 4-((1,3-dioxoisoindolin-2-yl)methyl)benzoate (0.41 g, 1.23 mmol) in ethanol (5 mL) was added hydrazine monohydrate (0.12 g, 2.46 mmol), and the mixture was refluxed with vigorous stirring for 2 h. The reaction mixture was cooled to room temperature, 6 M (22%) hydrochloric acid solution was added, and the solution was heated for an additional 5 min. Water (10 mL), ethyl acetate (10 mL), and an aqueous solution of 10% hydrochloric acid to reach pH 1 were added. The layers were separated, and the organic layer was extracted with an aqueous solution of 10% hydrochloric acid (2 × 5 mL). The combined aqueous extracts were made basic with 24% aqueous sodium hydroxide solution and extracted with ethyl acetate (2 × 10 mL). The combined organic extracts were dried over sodium sulfate and concentrated to give a pale yellow oil (0.12 g, 48%). [ka]

[0100] (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 liquor was concentrated to dryness. The crude residue was purified by flash chromatography on silica gel (30% to 50% EtOAc / hexanes) to give a white solid (1.33 g, 42%). HPLC-MS: Rt 8.327 m / z 226.0-228.1 [MH] - .

[0101] The following intermediates, Intermediate 10 to Intermediate 26, were prepared following the procedure described for Intermediate 9.

[0102] (Intermediate 10: 2-bromo-N-(4-fluorobenzyl)acetamide) HPLC-MS: Rt 8.608 m / z 244.0-246.0 [MH]- .

[0103] (Intermediate 11: 2-bromo-N-(4-chlorobenzyl)acetamide) HPLC-MS: Rt 9.273 m / z 262.2 [MH] - .

[0104] (Intermediate 12: 2-bromo-N-(4-bromobenzyl)acetamide) This intermediate was used in the next step without further purification.

[0105] (Intermediate 13: 2-bromo-N-(4-methoxybenzyl)acetamide) HPLC-MS: Rt 6.125 m / z 258.1-259.9 [M+H] + .

[0106] (Intermediate 14: 2-bromo-N-(4-methylbenzyl)acetamide) [ka] HPLC-MS: Rt 9.098 m / z 242.1-244.0 [M+H] + .

[0107] Intermediate 15: 2-bromo-N-(4-(tert-butyl)benzyl)acetamide HPLC-MS: Rt 10.406 m / z 282.0-284.2 [MH] - .

[0108] (Intermediate 16: 2-bromo-N-(3-methylbenzyl)acetamide) [ka]

[0109] (Intermediate 17: 2-bromo-N-(3-fluorobenzyl)acetamide) [ka] HPLC-MS: Rt 8.642 m / z 244.0-246.1 [MH] - .

[0110] (Intermediate 18: 2-bromo-N-(3-chlorobenzyl)acetamide) [ka] HPLC-MS: Rt 9.266 m / z 260.0-262.1 [MH] - .

[0111] (Intermediate 19: 2-bromo-N-(3-cyanobenzyl)acetamide) [ka] HPLC-MS: Rt 8.018 m / z 251.0-253.1 [MH] - .

[0112] (Intermediate 20: 2-bromo-N-(2-methylbenzyl)acetamide) [ka] HPLC-MS: Rt 9.004 m / z 240.0 [MH] - .

[0113] (Intermediate 21: 2-bromo-N-(2-fluorobenzyl)acetamide) [ka] HPLC-MS: Rt 8.532 m / z 244.0-246.1 [MH] - .

[0114] (Intermediate 22: 2-bromo-N-(2-chlorobenzyl)acetamide) [ka] HPLC-MS: Rt 9.097 m / z 264.0 [MH] - .

[0115] (Intermediate 23: 2-bromo-N-(2,6-difluorobenzyl)acetamide) [ka]

[0116] (Intermediate 24: 2-bromo-N-(2-chlorobenzyl)acetamide) [ka] HPLC-MS: Rt 9.542 m / z 256.0 [MH] - .

[0117] (Intermediate 25: 2-bromo-N-(2-ethylbenzyl)acetamide) HPLC-MS: Rt 9.526 m / z 253.9-256.0 [MH] - .

[0118] (Intermediate 166: 2-Bromo-N-(2,6-dichlorobenzyl)acetamide) HPLC-MS: Rt 9.466 m / z 294.0 [MH] - .

[0119] (Intermediate 27: 2-bromo-N-(4-cyanobenzyl)acetamide) 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, EtN (0.150 mL, 1.067 mmol) and bromoacetyl bromide (0.082 mL, 0.934 mmol) were added. The reaction mixture was stirred for 30 min, allowed to reach room temperature, diluted with dichloromethane (10 mL), and washed with HO (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 / hexanes) to give a beige solid (0.118 g, 52%). [ka]

[0120] The following intermediate 28 was prepared following the procedure described for intermediate 27.

[0121] (Intermediate 28: tert-butyl 4-((2-bromoacetamido)methyl)benzoate) [ka]

[0122] (Intermediate 29: tert-butyl 4-((2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)methyl)benzoate) This intermediate was prepared according to the procedure described for Example 1. HPLC: Rt 18.982, 99.36%.

[0123] (Example) Example 1: N-benzyl-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide To a solution of N-benzyl-2-bromoacetamide (0.100 g, 0.441 mmol) in acetonitrile (2 mL) was added K2CO3 (0.076 g, 0.550 mmol) and 4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)quinoline (0.100 g, 0.367 mmol), 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 an additional 1 h and allowed to reach room temperature. HO (10 mL) was added, and extraction with EtOAc (3 × 5 mL) was performed. The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by C18 chromatography using 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%). [ka] HPLC-MS: Rt 16.753 m / z 420.2 [M+H] + .

[0124] The following Examples 2-4 were synthesized from the corresponding 4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)quinoline derivatives using the procedure described for Example 1.

[0125] Example 2: N-(4-fluorobenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide [ka] HPLC-MS: Rt 16.989 m / z 438.2 [M+H] + .

[0126] Example 3: N-(4-chlorobenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide [ka] HPLC-MS: Rt 17.839 m / z 454.2 [M+H] + .

[0127] Example 4: N-(4-Bromobenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide [ka] HPLC-MS: Rt 18.057 m / z 498.0-500.0 [M+H] + .

[0128] Example 5: N-(4-cyanobenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide To a suspension of 4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)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 minutes. 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 minutes. Additional N-(4-cyanobenzyl)-2-bromoacetamide (0.011 g, 0.048 mmol) was added, and the mixture was stirred for an additional 1.5 hours. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure, and the residue was purified by flash chromatography on silica gel (2→4→5% MeOH / CH2Cl2) and by C18 chromatography using a Combiflash system (5→100% HO / MeCN) to give a white solid (0.016 g, 16%). [ka] HPLC-MS: Rt 16.091 m / z 445.1 [M+H] + .

[0129] The following Examples 6-29 were synthesized using the procedure described for Example 5.

[0130] Example 6: N-(4-Methoxybenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide [ka] HPLC-MS: Rt 17.709 m / z 450.1[M+H] + .

[0131] Example 7: N-(4-methylbenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide [ka] HPLC-MS: Rt 17.574 m / z 434.1 [M+H] + .

[0132] Example 8: N-(4-(tert-butyl)benzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide [ka] HPLC-MS: Rt 19.625 m / z 476.2 [M+H] + .

[0133] Example 9: N-benzyl-2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide [ka] HPLC-MS: Rt 17.541 m / z 434.1 [M+H] + .

[0134] Example 10: N-(3-methylbenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide [ka] HPLC-MS: Rt 17.625 m / z 433.9 [M+H] + .

[0135] Example 11: N-(3-fluorobenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide [ka] HPLC-MS: Rt 16.970 m / z 438.0 [M+H] + .

[0136] Example 12: N-(3-chlorobenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide [ka] HPLC-MS: Rt 17.747 m / z 454.1 [M+H] + .

[0137] Example 13: N-(3-cyanobenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide [ka] HPLC-MS: Rt 16.152 m / z 445.1 [M+H] + .

[0138] Example 14: N-(2-methylbenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide [ka] HPLC-MS: Rt 17.417 m / z 434.1 [M+H] + .

[0139] Example 15: N-(2-methylbenzyl)-2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide [ka] HPLC-MS: Rt 18.202 m / z 448.1 [M+H] + .

[0140] Example 16: N-(2-fluorobenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide [ka] HPLC-MS: Rt 16.941 m / z 438.1 [M+H] + .

[0141] Example 17: N-(2-fluorobenzyl)-2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide [ka] HPLC-MS: Rt 17.628 m / z 452.0 [M+H] + .

[0142] Example 18: N-benzyl-2-(3-(6-ethylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide [ka] HPLC-MS: Rt 18.386 m / z 448.1 [M+H] + .

[0143] Example 19: 2-(3-(6-ethylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)-N-(2-methylbenzyl)acetamide [ka] HPLC-MS: Rt 19.102 m / z 462.1 [M+H] + .

[0144] Example 20: N-(4-methylbenzyl)-2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide [ka] HPLC-MS: Rt 16.848 m / z 448.1 [M+H] + .

[0145] Example 21: N-(2-chlorobenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide [ka] HPLC-MS: Rt 17.627 m / z 454.0 [M+H] + .

[0146] Example 22: N-(2-chlorobenzyl)-2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide [ka] HPLC-MS: Rt 18.273 m / z 468.0 [M+H] + .

[0147] Example 23: N-(2,6-difluorobenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide [ka] HPLC-MS: Rt 16.731 m / z 455.9 [M+H] + .

[0148] Example 24: N-(2,6-difluorobenzyl)-2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide [ka] HPLC-MS: Rt 17.513 m / z 470.0 [M+H] + .

[0149] Example 25: N-(2,6-dimethylbenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide [ka] HPLC-MS: Rt 18.188 m / z 448.1 [M+H] + .

[0150] Example 26: N-(2,6-dimethylbenzyl)-2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide [ka] HPLC-MS: Rt 18.911 m / z 462.1 [M+H] + .

[0151] Example 27: N-(2-ethylbenzyl)-2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide [ka] HPLC-MS: Rt 18.940 m / z 462.1 [M+H] + .

[0152] Example 28: N-(2,6-dichlorobenzyl)-2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide [ka] HPLC-MS: Rt 18.877 m / z 502.1 [M+H] + .

[0153] Example 29: 4-((2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)methyl)benzoic acid hydrochloride A suspension of tert-butyl 4-((2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)methyl)benzoate (0.106 g, 0.204 mmol) in hydrochloroic acid (9 mL, 4 M 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 using a Combiflash system (5→100% HO:MeCN) to give a white solid (0.033 g, 33%). [ka] HPLC-MS: Rt 13.067 m / z 464.2 [M+H] + . The present application provides the following aspects of the invention. (Aspect 1) Compounds of formula (I): (chemical 1) TIFF0007808032000064.tif71170 (In the formula: R 1 are independently: a) a halogen atom, b) a straight-chain or branched C optionally substituted with 1, 2, or 3 halogen atoms 1 -C 6 Alkyl, c) a cyano group, d) C 1 -C 3 Alkoxy, e) -COOH represents one or two groups selected from R 2 teeth: a) a hydrogen atom, b) C 1 -C 3 Alkyl represents a group selected from R 3 teeth: a) a hydrogen atom, b) C optionally substituted with 1, 2, or 3 halogen atoms 1 -C 3 Alkyl, c) Halogen atoms represents a group selected from R 4 and R 5 are independently: a) a hydrogen atom, b) C optionally substituted with 1, 2, or 3 halogen atoms 1 -C 3 Alkyl, c) Halogen atoms represents a group selected from (n can take the value 0, 1, or 2) and pharmaceutically acceptable salts thereof. (Aspect 2) R 2 、R 4 , and R 5 represents a hydrogen atom. (Aspect 3) n is 0, or n is 1 or 2, and each R 1 A compound according to any one of the preceding aspects, wherein independently represent a halogen atom. (Aspect 4) n is 1 or 2, and each R 1 represents a halogen atom. (Aspect 5) n is 1 or 2, and each R 1 is selected from the group consisting of fluorine atoms and chlorine atoms. (Aspect 6) R 3 A compound according to any one of the preceding aspects, wherein represents a group selected from a hydrogen atom, an ethyl group, and a methyl group. (Aspect 7) R 3 7. The compound of embodiment 6, wherein represents a methyl group. (Aspect 8) R 2 、R 4 , and R 5 independently represent a hydrogen atom, n is 0, or n is 1 or 2, and each R 1 each independently represents a halogen atom, and R 3 represents a group selected from a hydrogen atom, an ethyl group, and a methyl group. (Aspect 9) n is 1 or 2, and each R 1 is selected from the group consisting of fluorine atoms and chlorine atoms, and R 3 represents a methyl group. (Aspect 10) N-Benzyl-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide N-(4-Fluorobenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide N-(4-chlorobenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide N-(4-Bromobenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide N-(4-cyanobenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide N-(4-Methoxybenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide N-(4-methylbenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide N-(4-(tert-butyl)benzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide N-benzyl-2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide N-(3-methylbenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide N-(3-Fluorobenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide N-(3-chlorobenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide N-(3-cyanobenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide N-(2-methylbenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide N-(2-methylbenzyl)-2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide N-(2-Fluorobenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide N-(2-Fluorobenzyl)-2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide N-benzyl-2-(3-(6-ethylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide 2-(3-(6-ethylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)-N-(2-methylbenzyl)acetamide N-(4-methylbenzyl)-2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide N-(2-chlorobenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide N-(2-chlorobenzyl)-2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide N-(2,6-Difluorobenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide N-(2,6-Difluorobenzyl)-2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide N-(2,6-dimethylbenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide N-(2,6-dimethylbenzyl)-2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide N-(2-ethylbenzyl)-2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide N-(2,6-Dichlorobenzyl)-2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide 4-((2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)methyl)benzoic acid hydrochloride 2. The compound of embodiment 1, wherein (Aspect 11) A pharmaceutical composition comprising a compound according to any one of Aspects 1 to 10, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier. (Aspect 12) A compound according to any one of aspects 1 to 10 for use in the treatment and / or prophylaxis of a disease or pathological condition amenable to amelioration by inhibition of transforming growth factor-beta receptor I (TGFβRI / ALK5). (Aspect 13) 13. The compound for use according to aspect 12, wherein the disease or pathological condition is selected from the group consisting of gastrointestinal diseases, such as inflammatory bowel diseases, including Crohn's disease and ulcerative colitis, liver fibrosis, and cancer, in particular gastric, esophageal, and colorectal cancer; fibrotic skin diseases, such as scleroderma, nephrogenic fibrosing dermatosis, mixed connective tissue disease, scleromyxedema, edematous sclerosis, and eosinophilic fasciitis; fibrotic eye diseases, such as dry eye, age-related macular degeneration, scarring in the cornea and conjunctiva, post-cataract fibrosis, proliferative vitreoretinopathy, and proliferative diabetic retinopathy. (Aspect 14) A compound according to any one of aspects 1 to 10, and Therapeutic agents used for the treatment and / or prevention of diseases selected from the group consisting of gastrointestinal diseases such as inflammatory bowel diseases, including Crohn's disease and ulcerative colitis, liver fibrosis, and cancer, particularly gastric cancer, esophageal cancer, and colorectal cancer; fibrotic skin diseases such as scleroderma, nephrogenic fibrosing dermatosis, mixed connective tissue disease, scleromyxedema, edematous sclerosis, and eosinophilic fasciitis; fibrotic eye diseases such as dry eye, age-related macular degeneration, scarring in the cornea and conjunctiva, post-cataract fibrosis, proliferative vitreoretinopathy, and proliferative diabetic retinopathy. A combination including: (Aspect 15) 11. Use of a compound according to any one of aspects 1 to 10 for the production of a medicament for the treatment and / or prevention of a disease or pathological condition amenable to amelioration by inhibition of transforming growth factor-beta receptor I (TGFβRI / ALK5). (Aspect 16) 16. The use according to aspect 15, wherein the disease or pathological condition is selected from the group consisting of gastrointestinal diseases, such as inflammatory bowel diseases, including Crohn's disease and ulcerative colitis, liver fibrosis, and cancer, in particular gastric, esophageal, and colorectal cancer; fibrotic skin diseases, such as scleroderma, nephrogenic fibrosing dermatosis, mixed connective tissue disease, scleromyxedema, edematous sclerosis, and eosinophilic fasciitis; fibrotic eye diseases, such as dry eye, age-related macular degeneration, scarring in the cornea and conjunctiva, post-cataract fibrosis, proliferative vitreoretinopathy, and proliferative diabetic retinopathy. (Aspect 17) 11. A method for the treatment and / or prophylaxis of a disease or pathological condition amenable to amelioration by inhibition of transforming growth factor-beta receptor I (TGFβRI / ALK5), said method comprising administration to a subject in need thereof a compound according to any one of aspects 1 to 10. (Aspect 18) The disease or pathological condition may be gastrointestinal disease, such as inflammatory bowel disease, including Crohn's disease and ulcerative colitis, liver fibrosis, and cancer, particularly gastric, esophageal, and colorectal cancer; fibrotic skin diseases, such as scleroderma, nephrogenic fibrosing dermatosis, mixed connective tissue disease, scleromyxedema, edematous sclerosis, and eosinophilic fasciitis; fibrotic eye diseases, such as dry eye, age-related macular degeneration, scarring in the cornea and conjunctiva, post-cataract fibrosis, proliferative vitreoretinopathy, and proliferative diabetic retinopathy. 20. The method of embodiment 17, wherein the compound is selected from the group consisting of:

Claims

1. Compounds of formula (I): 【Chemistry 1】 (In the formula: R 1 represents a halogen atom, R 2 teeth: a) a hydrogen atom, b) C 1 -C 3 Alkyl represents a group selected from R 3 teeth: a) a hydrogen atom, b) C optionally substituted with 1, 2, or 3 halogen atoms 1 -C 3 Alkyl, c) Halogen atoms represents a group selected from R 4 and R 5 are independently: a) a hydrogen atom, b) C optionally substituted with 1, 2, or 3 halogen atoms 1 -C 3 Alkyl, c) Halogen atoms represents a group selected from (n takes the value 1 or 2) or a pharmaceutically acceptable salt thereof.

2. R 2 , R 4 , and R 5 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein represents a hydrogen atom.

3. 3. The compound according to claim 1 or 2, wherein n is 1, or a pharmaceutically acceptable salt thereof.

4. 3. The compound according to claim 1 or 2, wherein n is 2, or a pharmaceutically acceptable salt thereof.

5. Each R 1 5. The compound according to claim 3 or 4, or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of a fluorine atom and a chlorine atom.

6. R 3 6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein represents a group selected from a hydrogen atom, an ethyl group, and a methyl group.

7. R 3 7. The compound according to claim 6, or a pharmaceutically acceptable salt thereof, wherein represents a methyl group.

8. R 2 , R 4 , and R 5 independently represent a hydrogen atom, and R 3 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein represents a group selected from a hydrogen atom, an ethyl group, and a methyl group.

9. Each R 1 is selected from the group consisting of fluorine atoms and chlorine atoms, and R 3 9. The compound according to claim 8, or a pharmaceutically acceptable salt thereof, wherein represents a methyl group.

10. N-(4-fluorobenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide N-(4-chlorobenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide N-(4-Bromobenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide N-(3-Fluorobenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide N-(3-chlorobenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide N-(2-Fluorobenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide N-(2-Fluorobenzyl)-2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide N-(2-chlorobenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide N-(2-chlorobenzyl)-2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide N-(2,6-Difluorobenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide N-(2,6-difluorobenzyl)-2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide, and N-(2,6-Dichlorobenzyl)-2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide or a pharmaceutically acceptable salt thereof 2. The compound of claim 1, selected from the group consisting of:

11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

12. 11. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.

13. 11. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prophylaxis of a disease or pathological condition amenable to amelioration by inhibition of transforming growth factor-beta receptor I (TGFβRI / ALK5).

14. 14. The compound for use according to claim 13, wherein the disease or pathological condition is selected from the group consisting of gastrointestinal diseases, liver fibrosis, cancer, fibrotic skin diseases, and fibrotic eye diseases.

15. 14. The compound for use according to claim 13, wherein the disease or pathological condition is selected from the group consisting of inflammatory bowel disease, gastric cancer, esophageal cancer, colorectal cancer, scleroderma, nephrogenic fibrosing dermatosis, mixed connective tissue disease, scleromyxedema, edematous sclerosis, eosinophilic fasciitis, dry eye, age-related macular degeneration, scarring in the cornea and conjunctiva, post-cataract fibrosis, proliferative vitreoretinopathy, and proliferative diabetic retinopathy.

16. 16. The compound for use according to claim 15, wherein the inflammatory bowel disease is selected from the group consisting of Crohn's disease and ulcerative colitis.

17. A compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, and Therapeutic agents used for the treatment and / or prevention of diseases selected from the group consisting of gastrointestinal diseases, liver fibrosis, cancer, fibrotic skin diseases, and fibrotic eye diseases. Combination products, including:

18. 18. The combination product of claim 17, wherein the disease or pathological condition is selected from the group consisting of inflammatory bowel disease, gastric cancer, esophageal cancer, colorectal cancer, scleroderma, nephrogenic fibrosing dermatosis, mixed connective tissue disease, scleromyxedema, edematous sclerosis, eosinophilic fasciitis, dry eye, age-related macular degeneration, scarring in the cornea and conjunctiva, post-cataract fibrosis, proliferative vitreoretinopathy, and proliferative diabetic retinopathy.

19. 19. The combination product of claim 18, wherein the inflammatory bowel disease is selected from the group consisting of Crohn's disease and ulcerative colitis.

20. 11. Use of a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament.

21. 11. Use of a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment and / or prevention of a disease or pathological condition amenable to amelioration by inhibition of transforming growth factor-beta receptor I (TGFβRI / ALK5).

22. 22. The use of claim 21, wherein the disease or pathological condition is selected from the group consisting of gastrointestinal diseases, liver fibrosis, cancer, fibrotic skin diseases, and fibrotic eye diseases.

23. 22. The use of claim 21, wherein the disease or pathological condition is selected from the group consisting of inflammatory bowel disease, gastric cancer, esophageal cancer, colorectal cancer, scleroderma, nephrogenic fibrosing dermatosis, mixed connective tissue disease, scleromyxedema, edematous sclerosis, eosinophilic fasciitis, dry eye, age-related macular degeneration, scarring in the cornea and conjunctiva, post-cataract fibrosis, proliferative vitreoretinopathy, and proliferative diabetic retinopathy.

24. 24. The use according to claim 23, wherein the inflammatory bowel disease is selected from the group consisting of Crohn's disease and ulcerative colitis.

25. 12. The pharmaceutical composition according to claim 11, for use in the prevention or treatment of a disease or pathological condition selected from the group consisting of gastrointestinal diseases, liver fibrosis, cancer, fibrotic skin diseases, and fibrotic eye diseases.

26. 12. The pharmaceutical composition according to claim 11, for use in the prevention or treatment of a disease or pathological condition selected from the group consisting of inflammatory bowel disease, gastric cancer, esophageal cancer, colorectal cancer, scleroderma, nephrogenic fibrosing dermatosis, mixed connective tissue disease, scleromyxedema, edematous sclerosis, eosinophilic fasciitis, dry eye, age-related macular degeneration, scarring in the cornea and conjunctiva, post-cataract fibrosis, proliferative vitreoretinopathy, and proliferative diabetic retinopathy.

27. 27. The pharmaceutical composition according to claim 26, for use in the prevention or treatment of a disease or pathological condition selected from the group consisting of Crohn's disease and ulcerative colitis.

28. The compound according to any one of claims 1 to 10, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (I):

29. The compound according to any one of claims 1 to 10, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is a pharmaceutically acceptable salt of a compound of formula (I).

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