2-(3-Pyridin-2-yl-4-quinolin-4-yl-pyrazol-1-yl)-acetamide derivatives as inhibitors of transforming growth factor-β receptor I / ALK5

Abstract

The present invention relates to novel 2-(3-pyridin-2-yl-4-quinolin-4-yl-pyrazol-1-yl)-acetamide derivatives as potent inhibitors of transforming growth factor-β receptor I (also known as activin receptor-like kinase 5) (TGFβRI) / ALK5. Another object of the present invention is to provide processes for preparing these compounds; pharmaceutical compositions containing effective amounts of these compounds; and the use of the compounds for producing medicaments for the treatment of pathological conditions or diseases that may be ameliorated by the inhibition of transforming growth factor-β receptor I (TGFβRI) / ALK5, such as respiratory diseases including idiopathic pulmonary fibrosis, asthma, COPD, and lung cancer, as well as fibrotic conditions of the skin and eye.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to novel 2-(3-pyridin-2-yl-4-quinolin-4-yl-pyrazol-1-yl)-acetamide derivatives as potent inhibitors of transforming growth factor-β receptor I (also known as activin receptor-like kinase 5) (TGFβRI) / ALK5.

[0002] Another object of the present invention is to provide processes for preparing these compounds; pharmaceutical compositions containing effective amounts of these compounds; and the use of the compounds to produce medicaments for the treatment of pathological conditions or diseases that may be ameliorated by inhibition of transforming growth factor-β receptor I (TGFβRI) / ALK5, such as respiratory diseases including idiopathic pulmonary fibrosis, asthma, COPD, and lung cancer, and fibrotic conditions of the 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, such as 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).

[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] Transforming growth factor (TGF-β) cytokines play a central role in the development and exacerbation of chronic respiratory diseases. TGF-β overexpression in chronic inflammation, remodeling, fibrotic processes, and susceptibility to viral infections has been established in the most prevalent chronic respiratory diseases, such as pulmonary fibrosis, asthma, COPD, and lung cancer.

[0008] (idiopathic pulmonary fibrosis) Pulmonary fibrosis is a chronic and progressive lung disease in which repeated injury and repair processes lead to irreversible structural changes and tissue hardening. The pathophysiological steps include alveolar epithelial injury by exogenous stimuli, fibroblast activation, and a persistent fibrotic response. Differentiation of pulmonary fibroblasts into myofibroblasts is a key step in the development of tissue fibrosis. Transforming growth factor-β (TGF-β) is the most potent factor for inducing myofibroblast differentiation, and increased expression of this factor has been reported in fibrotic lungs. It has been shown that the primary cellular source of TGF-β in pulmonary fibrosis is alveolar macrophages and dysplastic type II alveolar epithelial cells. TGF-β promotes pulmonary fibrosis by inducing molecular regulators of small GTPases and suppressing the production of antifibrotic molecules such as hepatocyte growth factor and prostaglandin E2. Furthermore, TGF-β inhibits the proliferation and repair of alveolar epithelial cells, and thus it is a key player in the fibrotic process, acting on both fibroblasts and alveolar epithelial cells (Saito A. et al., "TGF-β Signaling in Lung Health and Disease," Int. J. Mol. Sci. 2018, 19, 2460).

[0009] 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 the kinase activity of ALK5 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. (Biernacka, A. et al., "TGF-β signaling in fibrosis," Growth Factors. 2011 Oct;29(5):196-202).

[0010] (Asthma and COPD) Asthma and chronic obstructive pulmonary disease (COPD) exacerbations are commonly associated with viral infections. The ensuing airway inflammation is resistant to the anti-inflammatory effects of glucocorticoids (GCs). Viral infection induces the activity of transforming growth factor-β (TGF-β), a growth factor that impairs GC function in human airway epithelial cells through activation of activin-like kinase 5 (ALK5). One study investigated the contribution of TGF-β activity to GC resistance caused by viral infection and showed that GC impairment was attenuated by SB431542, a selective ALK5 / TGFβRI inhibitor, and prevented by tranilast, a therapeutic agent that reduced TGF-β activity associated with viral infection. This study showed that virus-induced glucocorticoid insensitivity is mediated in part by activation of endogenous TGF-β (Xia YC et al., "Glucocorticoid Insensitivity in Virally Infected Airway Epithelial Cells Is Dependent on Transforming Growth Factor-β Activity," PLoS Pathog, 3 January 2017, 13(1), doi:10.1371 / journal.ppat.1006138).

[0011] In particular, asthma is characterized by chronic airway inflammation and hyperresponsiveness mediated by type 2 helper T (Th2) cells and several cytokines and interleukins. These cytokines cause chronic inflammation, pulmonary eosinophilia, mucus cell hyperplasia, smooth muscle contraction, and airway remodeling. In addition to Th2 cells, Th17 cells, which secrete IL-17A and IL-17F, also contribute to the development of allergic airway inflammation. The importance of TGF-β signaling in the pathogenesis of asthma has been demonstrated by genome-wide association studies. TGF-β concentrations in bronchoalveolar lavage fluid have been shown to be elevated in atopic asthma, and TGF-β expression has been shown to be increased in bronchial specimens from asthmatic patients. The pathological role of TGF-β in asthma is not limited to airway remodeling, and its effects on the immune response are thought to be more important than previously recognized. (Saito A. et al., "TGF-β Signaling in Lung Health and Disease," Int. J. Mol. Sci. 2018, 19, 2460).

[0012] In the airways of asthmatic patients, immunohistochemical localization using TGF-β1-specific or panspecific antibodies shows that TGF-β is increased and primarily associated with submucosal and inflammatory cells, such as fibroblasts, smooth muscle cells, eosinophils, and macrophages, as well as connective tissue in the airways, and also shows variable expression in epithelial cells. The increased expression of TGF-β in the airways of asthmatic patients has been attributed primarily to increased numbers of eosinophils and macrophages.

[0013] Consistent with studies showing increased expression of TGF-β in the airways of asthmatic patients, there is also evidence of increased TGF-β signaling, accompanied by increased phosphorylated Smad2 and decreased Smad7 immunoreactivity. Furthermore, studies in animal models of airway remodeling have shown increased bronchoalveolar lavage levels of TGF-β1, with evidence of activated TGF-β / Smad signaling.

[0014] In addition, evidence from animal models suggests that airway remodeling can be prevented or reversed using drugs that target TGF-β. Therefore, modulation of TGF-β or their activity represents a promising therapeutic target for asthma. (Howell, JE et al., "TGF-β: Its Role in Asthma and Therapeutic Potential," Current Drug Targets, 2006, 7, 547-565).

[0015] On the other hand, chronic obstructive pulmonary disease (COPD) is characterized by irreversible airflow obstruction, small airway inflammation, and destruction of alveolar structure accompanied by airspace enlargement. Several studies have demonstrated impaired TGF-β1 signaling in COPD patients. Researchers have confirmed increased TGF-β1 and decreased expression of inhibitory Smads in the airway epithelium of smokers and COPD patients. Similar to the role of TGF-β in pulmonary fibrosis, TGF-β promotes fibrotic airway remodeling in COPD patients, which may further contribute to the decline in lung function. Part of the increased TGF-β1 in the airway epithelium of COPD patients may be a direct response to cigarette smoke, the most important risk factor for the development of this disease state. (Aschner, Y. et al., "Transforming Growth Factor-β: Master Regulator of the Respiratory System in Health and Disease," American Journal of Respiratory Cell and Molecular Biology, 2016. 54(5), 647-655).

[0016] (lung cancer) Lung cancer is the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) comprises the majority of lung cancers, including the histological subtypes adenocarcinoma and squamous cell carcinoma. Elevated TGF-β expression levels are associated with lymph node metastasis and tumor angiogenesis in NSCLC, and tumor cells established from NSCLC express TGF-β ligands. It is widely believed that TGF-β plays a dual role during tumor progression, suppressing epithelial cell proliferation and acting as a tumor suppressor in the early stages of tumorigenesis; loss-of-function mutations in TGF-β signaling components have been identified in several cancer types.

[0017] In addition to its direct effects on cancer cells, TGF-β promotes invasion and metastatic spread through reciprocal interactions between cancer cells and the tumor stromal microenvironment. TGF-β orchestrates tumor stromal development and promotes angiogenesis, immune evasion, and remodeling. Stromal responses, likely mediated by TGF-β, are associated with poor prognosis in resected lung adenocarcinoma (Saito A et al., "TGF-β Signaling in Lung Health and Disease," Int. J. Mol. Sci. 2018, 19, 2460).

[0018] (Viral infection) Another study showed that concurrent viral infection in mice with pre-existing bleomycin-induced fibrosis resulted in significant and widespread inflammatory changes resembling the ground-glass opacities and consolidation reported in individuals with AE-IPF. Blockade of TGFβ-ALK5 signaling with the potent and selective ALK5 antagonist SB525334 was highly effective in preventing the progression of fibrosis in a single-hit bleomycin-induced mouse model, but the antifibrotic effects of this agent were dramatically reduced in the presence of concurrent viral infection. In contrast, this inhibitor was highly effective in attenuating the widespread inflammatory cell infiltration associated with concurrent viral infection, which enhanced the antiviral cytokine response.

[0019] These studies, along with the variable outcome of the response to ALK5 inhibition depending on the presence of viral infection, highlight the multifaceted nature of the TGFβ-ALK5 signaling axis in pulmonary fibrosis. Thus, these findings raise important considerations for future targeting of TGFβ signaling in the context of pulmonary fibrosis: differential outcomes for fibrosis exacerbation are expected in stable versus acutely exacerbated IPF associated with viral infection (Smoktunowicz, N et al., "The anti-fibrotic effect of inhibition of TGFβ-ALK5 signaling in experimental pulmonary fibrosis in mice is attenuated in the presence of concurrent γ-herpesvirus infection," Dis Model Mech. 2015 Sep 1;8(9):1129-1139).

[0020] Both innate and adaptive TGF-β immune signaling have been shown to lead to increased HSV-1 latency and reactivation. The coordinated activity of TGF-β signaling in these two immune compartments appears to be essential for regulating the latency of viral infection. These results suggest that blocking TGF-β signaling in immune cells in cases of presumed clinical HSV-1 infection may represent an important novel therapeutic approach for virus-associated diseases (Allen, SJ et al., "Adaptive and Innate Transforming Growth Factor β Signaling Impact Herpes Simplex Virus 1 Latency and Reactivation," Journal of Virology, Nov. 2011, pp. 11448-11456).

[0021] Severe acute respiratory syndrome (SARS)-associated coronavirus (SARS-CoV) was the cause of the SARS epidemic in 2003. SARS-CoV infection induces severe respiratory disease, including bronchial epithelial desquamation, loss of cilia, multinucleated syncytial cells, squamous epithelial metaplasia, and transendothelial migration of monocytes / macrophages and neutrophils into lung tissue. SARS-CoV induces a pro-inflammatory cytokine storm associated with pulmonary fibrosis in SARS patients. Nearly 20% of recovered SARS patients still have pulmonary fibrosis 9 months after infection.

[0022] SARS-CoV papain-like protease (PLpro) has been confirmed to upregulate TGF-β1 in human promonocytes, inducing TGF-β1-mediated profibrotic responses in human lung epithelial cells and mouse lung tissue. Consistent with previous reports, PLpro upregulated TGF-β1 and its related genes, such as glial fibrillary acidic protein (GFAP) and vimentin. Except for SARS-CoV nucleocapsid, PLpro was confirmed to induce TGF-β1 production, which is linked to the activation of profibrotic responses. Among SARS-CoV-induced cytokines, TGF-β1 may be involved in the induction of pulmonary fibrosis. Therefore, SARS-CoV PLpro plays an important role in SARS pathogenesis and TGF-β1-mediated pulmonary fibrosis. (Li SW et al., "SARS coronavirus papain-like protease induces Egr-1-dependent up-regulation of TGF-β1 via ROS / p38 MAPK / STAT3 pathway," Sci Rep. 2016 May 13;6:25754).

[0023] Available or in development antifibrotic therapies may be valuable in preventing severe infections with other coronaviruses, such as COVID-19, in patients with IPF and may have a role in preventing fibrosis after SARS-CoV-2 infection. Thus, it is possible that antifibrotic therapies developed for chronic fibrotic lung disease using the bleomycin model may actually be beneficial for COVID-19, both in the acute phase of the disease and in preventing long-term complications. (George, P.M. et al., "Pulmonary fibrosis and COVID-19: the potential role for antifibrotic therapy," www.thelancet.com / respiratory, published online May 15, 2020.)

[0024] A major target for antifibrotic therapy is the TGF-β pathway. Several drugs are under development that target different molecules in this pathway, including those directed against αvβ6 integrin (BG00011 [Biogen, Cambridge, MA, USA]; PLN-74809 [Pliant Therapeutics, San Francisco, CA, USA]) and galectin (TD139 [Galecto Biotech, Copenhagen, Denmark]). Several experimental data support the use of these three drugs in virus-induced lung injury.

[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 ester derivatives as potent and selective inhibitors of the TGF-β signaling pathway, in particular as inhibitors of transforming growth factor-β receptor I / activin-like kinase 5 (TGFβRI / ALK5). Summary of the Invention

[0028] (Summary of the Invention) In one of its embodiments (embodiment 1), the present invention provides a compound of formula (I): [ka] (In the formula: R 1is the following: a) a phenyl ring which is unsubstituted or substituted by one or two groups selected from a halogen atom, a linear or branched C1-C3 haloalkyl, a linear or branched C1-C3 alkyl, a linear or branched C1-C3 alkoxy, a cyano group, and a hydroxy group; b) a 5- or 6-membered heteroaryl ring that is unsubstituted or substituted with one or two groups selected from a halogen atom, a linear or branched C1-C3 haloalkyl, a linear or branched C1-C3 alkyl, a linear or branched C1-C3 alkoxy, a cyano group, and a hydroxy group; represents a group selected from R 2 is the following: a) a hydrogen atom, b) linear or branched C1-C3 alkyl optionally substituted with one, two, or three halogen atoms; is a group selected from R 3 is the following: a) a hydrogen atom, b) linear or branched C1-C3 alkyl optionally substituted with one, two, or three halogen atoms; c) Halogen atoms represents a group selected from R 4 and R 5 are independently: a) a hydrogen atom, b) linear or branched C1-C3 alkyl optionally substituted with one, two, or three halogen atoms; c) Halogen atoms represents a group selected from n is an integer from 0 to 3, R 6 is the following: a)-N(R 7 )(R 8 )(wherein, R 7 and R 8 independently represent a linear or branched C1-C6 alkyl group or a hydrogen atom), and b) a saturated 4-10 membered monocyclic or bicyclic nitrogen-containing heterocyclyl optionally containing another heteroatom selected from the group consisting of oxygen and nitrogen, and optionally substituted with a group selected from a C1-C3 alkyl group; represents a group selected from the group consisting of 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 provides a therapeutically effective amount of a steroid hormone receptor antagonist (SRG) for use in the treatment of respiratory diseases such as pulmonary fibrosis, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, interstitial pulmonary fibrosis, pulmonary arterial hypertension, and lung cancer; scleroderma, nephrogenic fibrosing dermatosis, mixed connective tissue disease, scleromyxedema, and scleromyxedema. , good The present invention relates to a pharmaceutical composition according to the third aspect described above, further comprising a therapeutic agent selected from agents useful in the treatment of fibrotic skin diseases such as 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.

[0032] In a fifth aspect, the present invention provides a method for treating respiratory diseases such as pulmonary fibrosis, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, interstitial pulmonary fibrosis, pulmonary arterial hypertension, and lung cancer; scleroderma, nephrogenic fibrosing dermatosis, mixed connective tissue disease, scleromyxedema, and scleromyxedema. , good Use of a compound of embodiment 1 in the manufacture of a medicament for the treatment of a disease or pathological condition that can be ameliorated by inhibition of transforming growth factor-β receptor I (TGFβRI) / ALK5, such as fibrotic skin diseases such as 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.

[0033] In a sixth aspect, the present invention provides a method for treating respiratory diseases such as pulmonary fibrosis, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, interstitial pulmonary fibrosis, pulmonary arterial hypertension, and lung cancer; scleroderma, nephrogenic fibrosing dermatosis, mixed connective tissue disease, scleromyxedema, and scleromyxedema. , good The present invention relates to methods for the treatment of diseases that can be ameliorated by the inhibition of transforming growth factor-β receptor I (TGFβRI) / ALK5, such as fibrotic skin diseases such as 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.

[0034] In a seventh aspect, the present invention provides a compound of the first aspect above, which is used in combination with a compound of the first aspect above, to treat respiratory diseases such as pulmonary fibrosis, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, interstitial pulmonary fibrosis, pulmonary arterial hypertension, and lung cancer; scleroderma, nephrogenic fibrosing dermatosis, mixed connective tissue disease, scleromyxedema, and rheumatoid arthritis. , good The present invention relates to combination products with another therapeutic agent known to be useful in the treatment of fibrotic skin diseases such as 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.

[0035] In an eighth aspect, the present invention relates to a compound of aspect 1 for use as a medicament.

[0036] In a ninth aspect, the present invention provides a method for treating respiratory diseases such as pulmonary fibrosis, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, interstitial pulmonary fibrosis, pulmonary arterial hypertension, and lung cancer; scleroderma, nephrogenic fibrosing dermatosis, mixed connective tissue disease, scleromyxedema, and scleromyxedema. , good and a compound of embodiment 1 for use in the treatment of a disease or pathological condition that can be ameliorated by inhibition of transforming growth factor-β receptor I (TGFβRI) / ALK5, such as fibrotic skin diseases such as 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.

[0037] As already mentioned, the ester derivatives of the present invention are useful in the treatment of respiratory diseases such as pulmonary fibrosis, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, interstitial pulmonary fibrosis, pulmonary arterial hypertension, and lung cancer; scleroderma, nephrogenic fibrosing dermatosis, mixed connective tissue disease, scleromyxedema; , good These compositions 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 fibrotic skin diseases such as 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.

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

[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 contain 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 straight or branched C alkyl group linked to an oxygen atom. a -C b Radicals containing alkyl radicals (C x H 2x+1-O-). Preferred alkoxy radicals include, for example, methoxy, ethoxy, n-propoxy, and i-propoxy.

[0041] As used herein, the term 5- or 6-membered heteroaryl ring refers to an unsaturated aromatic ring system having 5 or 6 ring members selected from the group consisting of C, N, O, and S, wherein at least one of the ring members is one of N, O, and S. The radical may be optionally substituted with one or two groups selected from a halogen atom, a linear or branched C1-C3 haloalkyl, a linear or branched C1-C3 alkyl, a linear or branched C1-C3 alkoxy, a cyano group, and a hydroxy group. Preferred radicals are optionally substituted pyridinyl, pyrazolyl, and thiazolyl rings. When a heteroaryl radical has two or more substituents, the substituents may be the same or different.

[0042] As used herein, the term "saturated 4-10 membered monocyclic or bicyclic nitrogen-containing heterocyclyl" is used to refer to a ring system that may contain one or two rings, wherein the one or two rings have a total of 4 to 10 ring members, and at least one of the ring members is a nitrogen atom. When the ring system has two rings, each ring may have 3 to 6 ring members, and the two rings may share one or more bonds. An example of two rings that share one bond is 1-aza. B An example of two rings sharing two bonds is cyclo[2.2.0]hexane. B An example of two rings sharing three bonds is cyclo[2.2.1]heptane, 1-aza B Cyclo[2.2.2]octane. Examples of monocyclic nitrogen-containing heterocyclyl groups are piperidinyl, morpholinyl, piperazinyl, 4-methyl-piperazinyl, pyrrolidinyl, azetidinyl, and aziridinyl. Examples of bicyclic nitrogen-containing heterocyclyl groups are 1-aza. B Cyclo[2.2.0]hexanyl, 1-aza Bcyclo[2.2.1]heptanyl, and decahydroquinolinyl. The radicals may be optionally substituted with one, two, or three groups selected from linear or branched C1-C3 alkyl and hydroxy groups. Preferred radicals are optionally substituted piperazinyl, piperidinyl, morpholinyl, and 1-aza. B It is a cyclo[2.2.2]octanyl (quinuclidinyl) group.

[0043] 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.

[0044] 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.

[0045] 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.

[0046] 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. More preferably, X -n is chloride, bromide, trifluoroacetate, or methanesulfonate.

[0047] According to one embodiment of the present invention, in the compound of formula (I), R 1 represents a phenyl ring that is unsubstituted or substituted by one or two halogen atoms. In a preferred embodiment, R1は、 In a more preferred embodiment, R represents a phenyl ring substituted by one or two halogen atoms. 1 represents a phenyl ring substituted with one halogen atom.

[0048] According to one embodiment of the present invention, in the compound of formula (I), R 2 represents a hydrogen atom.

[0049] According to one embodiment of the present invention, in the compound of formula (I), R 3 represents a group selected from a hydrogen atom and an unsubstituted linear or branched C1-C3 alkyl. 3 represents a methyl group.

[0050] According to one embodiment of the present invention, in the compound of formula (I), R 4 represents a hydrogen atom.

[0051] According to one embodiment of the present invention, in the compound of formula (I), R 5 represents a hydrogen atom.

[0052] According to one embodiment of the present invention, in the compound of formula (I), n is an integer from 0 to 2. In a preferred embodiment, n is an integer from 1 to 2.

[0053] According to one embodiment of the present invention, in the compound of formula (I), R 6 is -N(R 7 )(R 8 ) group (wherein, R 7 and R 8 represent independently a group selected from a linear C1-C3 alkyl group and a hydrogen atom.

[0054] According to one embodiment of the present invention, in the compound of formula (I), R 6 represents a saturated 4-6 membered monocyclic nitrogen-containing heterocyclyl containing a nitrogen atom attached to a -(CH)- group and, optionally, one further nitrogen atom optionally substituted by a methyl group. In a preferred embodiment, R6 represents a saturated 6-membered heterocyclic group containing one or two nitrogen atoms, optionally substituted by a methyl group.

[0055] In a more preferred embodiment, R 6 represents a group selected from piperazinyl and piperidinyl groups.

[0056] According to one embodiment of the present invention, in the compound of formula (I), R 6 represents a 1-aza-bicyclo[2.2.2]octanyl group.

[0057] 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.

[0058] According to one embodiment of the present invention, in the compound of formula (I), n is an integer from 1 to 2, and R 6 is -N(R 7 )(R 8 ) group, preferably in the formula 7 and R 8 independently represent a group selected from a linear C1-C3 alkyl group and a hydrogen atom.

[0059] 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, and R 3 represents a straight chain C1-C3 alkyl, and R 1 represents a phenyl ring substituted by one or two halogen atoms, n is an integer of 0 to 2, and R 6 is the following: a)-N(R 7 )(R 8 )(wherein, R 7 and R 8 is selected from a linear C1-C3 alkyl group and a hydrogen atom, b) a saturated 6-membered heterocyclic group containing one or two nitrogen atoms, optionally substituted by a methyl group; c) 1-Aza-bicyclo[2.2.2]octanyl represents a group selected from the group consisting of:

[0060] Specific individual compounds of the present invention include: 2-(Dimethylamino)ethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate 2-(Dimethylamino)ethyl 5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)nicotinate 2-(Dimethylamino)ethyl 6-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)nicotinate 2-Morpholinoethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate 2-(Dimethylamino)ethyl 5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)picolinate 2-(4-Methylpiperazin-1-yl)ethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate 2-(Diethylamino)ethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate 1-Methylpiperidin-4-yl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate (1-Methylpiperidin-4-yl)methyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate (R)-Quinuclidin-3-yl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate (S)-Quinuclidin-3-yl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate Quinuclidin-4-yl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate 2-(Azetidin-1-yl)ethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate 2-(Aziridin-1-yl)ethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate 2-(Methylamino)ethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate 2-Aminoethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate 2-(Ethylamino)ethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate 2-(Isopropylamino)ethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate 2-(Piperazin-1-yl)ethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate Piperidin-4-ylmethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate Piperidin-4-yl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate and pharmaceutically acceptable salts thereof.

[0061] 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 in no way limit the scope of the invention. The synthesis of compounds of formula (I) is outlined in Scheme 1. (Scheme 1) [ka]

[0062] The amide-forming reaction a) can be carried out under the following selective conditions: Option 1: Step 1. SOCl2, CH2Cl2, reflux Step 2. HO-(CH2) n -R 6 , CH2Cl2, DIPEA, room temperature Option 2: Step 1. SOCl2, CH2Cl2, reflux Step 2. HO-(CH2) n -R 6 , CH2Cl2, room temperature Option 3: Process 1. HO-(CH2) n -R 6 , HATU, DIPEA, DMF, room temperature Option 4: Process 1. HO-(CH2) n -R 6 , HOBT, EDCI, DIPEA, DMF, room temperature This can be done in one or two steps according to one of the following:

[0063] base R 6 but ,a amine group (-N(R 7 )(R 8 )) and R 7 and R 8 If at least one of the is a hydrogen atom , applicable The amine group is protected with BOC (see Scheme 7) before the above-mentioned reaction, and the protecting Boc group is cleaved after the above-mentioned reaction with HCl dioxane, dioxane, 0° C. to room temperature.

[0064] The carboxylic acid esters of general formula (I) are prepared from 2-(2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)acetic acid derivatives (II) by esterification with the appropriate alcohol (III) under acidic conditions (Lee, J.-J. et al., "Fluorescent Chemosensor for Chloroalkanes", Organic Letters, 10(9), 1735-1738; 2008) or in the presence of a coupling reagent system (Wang, X. et al., "Metal-Free Etherification of Aryl Methyl Ether Derivatives by C-OMe Bond Cleavage", Organic Letters, 20(14), 4267-4272; 2018).

[0065] R 7 or R 8 In compounds where N represents a hydrogen group, deprotection of the N-Boc protected precursor is carried out under acid conditions.

[0066] Compounds of general formula (II) are prepared in several steps from 4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)quinoline derivatives (IV) by deprotonation and subsequent reaction with the corresponding bromoacetamide (V), as shown in Scheme 2 and described in WO2009123316A1, which is incorporated by reference.

[0067] (Scheme 2) [ka] R 9 =H or tBu (Reagents and conditions:) Reaction b) Step 1. NaH, THF, DMF, 0°C to room temperature. R 9 = t-butyl group compound: Step 2. HCl·dioxane, dioxane, reflux or room temperature. 4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)quinoline derivatives (IV) are either commercially available or can be prepared in several steps as shown in Scheme 3 and described in WO2004026302A1, which is incorporated by reference (R 2 However, there are also some that are H.

[0068] (Scheme 3) [ka] (Reagents and conditions:) Reaction c) LiHMDS, THF, -30°C to room temperature. Reaction d) R 2 Compounds where =H Step 1. DMF·DMA, AcOH, DMF, 0℃ to room temperature; Step 2. N2H4·H2O, 0℃ to room temperature. The 4-methylquinoline derivative (VI) is condensed with ethyl 2-pyridinecarboxylate (VII) in the presence of lithium bis(trimethylsilyl)amide to give the compound of formula (VIII). Reaction of the derivative (VIII) 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 derivative of formula (IVa).

[0069] R 2 Compound (IVb), in which is a straight or branched C1-C3 alkyl optionally substituted with one, two or three halogen atoms, can be prepared according to the following Scheme 4: (Scheme 4) [ka] (Reagents and conditions:) Reaction e): Step 1. NBS, CH2Cl2, 0°C Step 2. SemCl, Cs2CO3, DMF, 0°C. Reaction f): Step 1. R 2 B(OH)2, DMF, NaHCO3, PdCl2(PPh3)2 Step 2. BCl3, SMe2, CH2Cl2, 0℃.

[0070] The pyrazole derivative of formula (IVa), after protection of the nitrogen of the pyrazole ring, can be halogenated with a standard halogenating reagent as a succinimide derivative to give the corresponding compound of formula (IX). CC coupling and subsequent deprotection of the pyrazole nitrogen give the derivative of formula (IVb).

[0071] Bromoacetamides of formula (V) are readily synthesized in one step from commercially available amines (X) by reaction with bromoacetyl bromides of formula (XI), as shown in Scheme 5 (Shaw, SJ et al., "Structure-Activity Relationships of 9-Substituted-9-Dihydroerythromycin-Based Motilin Agonists: Optimizing for Potency and Safety," J. Med. Chem., 52, 6851-6859, 2009). (Scheme 5) [ka] (Reagents and conditions:) Reaction g) THF, 0°C to room temperature or CH2Cl2, Et3N, 0°C to room temperature.

[0072] Amines (X) are either commercially available or can be prepared in several steps as shown in Scheme 6. (Scheme 6) [ka] R 9 = t Bu R 1 is the following: a) is unsubstituted, or a phenyl ring substituted with one or two groups selected from a halogen atom, a linear or branched C1-C3 haloalkyl, a linear or branched C1-C3 alkyl, a linear or branched C1-C4 alkoxy, a cyano group, and a hydroxy group; b) is unsubstituted, or a 5- or 6-membered heteroaryl ring substituted by one or two groups selected from a halogen atom, a linear or branched C1-C3 haloalkyl, a linear or branched C1-C3 alkyl, a linear or branched C1-C4 alkoxy, a cyano group, and a hydroxy group; represents a group selected from Reaction h) Boc2O, DMAP, THF, room temperature. Reaction j) trans-4-hydroxy-L-proline, CuI, NH4OH, DMSO, 80°C.

[0073] Esterification of the corresponding acid (XII) by reaction with BocO and a catalytic amount of DMAP (Wright, SW et al., "Preparation of 2-, 4-, 5-, and 6-aminonicotinic acid tert-butyl esters," J. Heterocyclic Chem, 2, 49, 442-445, 2012), followed by treatment of the resulting ester with ammonium hydroxide in the presence of CuI (Substituted tetrahydroisoquinoline compounds as factor XIa inhibitors," WO 2013056034), gave the amine derivative of formula (X).

[0074] R 7 and / or R 8 The protected amines of formula (IIIb), in which at least one of represents a hydrogen atom, are readily synthesized in one step from commercially available unprotected amines (IIIa) by treatment with BocO, as shown in Scheme 7. (Scheme 7) [ka] R 7 =H or linear or branched C 1- C6 alkyl group. Reaction k) Boc2O, CH2Cl2, 0℃ to room temperature.

[0075] (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: bicarbonate ter t -butyl Boc: tert-butoxycarbonyl Clint: Inherent Clearance DIPEA: N,N-diisopropylethylamine DMA: Dimethylacetamide DMAP: 4-dimethylaminopyridine DMF: N,N-dimethylformamide DMSO: dimethyl sulfoxide EDCI: N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide Et3N: Triethylamine EtOAc: ethyl acetate EtOH: Ethanol FBS: fetal bovine serum H: Time HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HOBT: Hydroxybenzotriazole HPLC: High-performance liquid chromatography 1 H-NMR: proton nuclear magnetic resonance K2EDTA: Dipotassium ethylenediaminetetraacetic acid LC: liquid chromatography LiHMDS: Lithium bis(trimethylsilyl)amide LLOQ: Lower limit of quantification MeCN: acetonitrile MeOH: Methanol Min: minutes MS: mass spectrometry MTBE: Methyl tert-butyl ether NBS: N-bromosuccinimide NaCMC: sodium carboxymethylcellulose Rt: retention time RT: room temperature Sem: 2-(trimethylsilyl)ethoxymethyl TGFβ: Transforming growth factor-β THF: tetrahydrofuran THF:EtOH: tetrahydrofuran:ethanol UPLC: Ultra-high performance liquid chromatography UV: Ultraviolet

[0076] (Pharmacological activity) (In vitro enzyme assay: inhibition of TGFβR-1) 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.

[0077] (result) Table 1 shows the results of the following assays for some compounds of the invention. (Table 1) [Table 1] TIFF0007752684000010.tif240170TIFF0007752684000011.tif187170Range: A: IC50≦100nM B: 100nM <IC50<250nM

[0078] (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).

[0079] (result) Table 2 shows the results of the following assays for some compounds of the invention. (Table 2) [Table 2] range: A: IC50≦1μM B: IC50>1μM

[0080] As can be seen from the results set forth in Table 2, the compounds of the present invention are potent inhibitors of transforming growth factor-beta receptor I ((TGFβRI) / ALK5).

[0081] (Determining plasma stability of some compounds) Human plasma collected in pooled citrate tubes from healthy donors was used in the assay. Briefly, plates containing 10 μM compound in plasma (total volume: 50 μL) were incubated at 37°C for various times (0, 30, 120, and 360 min). 100 μL of acetonitrile was then added to precipitate plasma proteins, and the plates were centrifuged at 46,000 g for 60 min at 5°C. The supernatant was collected and analyzed by UPLC / MS / MS for sample quantification. Stationary phase: Reverse-phase Acquity UPLC® BEH C18 1.7 μm (2.1 mm × 50 mm) (Waters). Mobile phase: 0.1% formic acid in water / acetonitrile. (Gradient:) [Table 3] Flow rate: 0.6 ml / min. The chromatography equipment used was UPLC QSM Waters Acquity. Compound concentrations were calculated from MS peak areas.

[0082] (result) Table 3 shows the results of the following assays for some compounds, showing the percentage remaining for each of the tested compounds in human plasma at various times the test was conducted. (Table 3) [Table 4]

[0083] Unlike the compounds of Comparative Examples 1, 2, and 3, which retained up to 60% of their initial amount after 6 hours, all tested examples of the present invention showed poor stability in human plasma.

[0084] The derivatives of the present invention are useful for the treatment or prevention of diseases known to be susceptible to treatment with inhibitors of transforming growth factor-β receptor I (TGFβRI) / ALK5, such as respiratory diseases such as pulmonary fibrosis, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, interstitial pulmonary fibrosis, pulmonary arterial hypertension, and lung cancer; scleroderma, nephrogenic fibrosing dermatosis, mixed connective tissue disease, and scleromyxedema. , good fibrotic skin diseases such as 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.

[0085] Accordingly, the derivatives of the present invention and their pharmaceutically acceptable salts, as well as pharmaceutical compositions comprising 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 an ester derivative of the present invention or a pharmaceutically acceptable salt thereof to a subject in need of such treatment.

[0086] The present invention also provides pharmaceutical compositions comprising at least the ester derivative of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient, together with pharmaceutically acceptable excipients such as other therapeutic agents, carriers, or diluents. The active ingredient may comprise 0.001% to 99% by weight of the composition, preferably 0.01% to 90% by weight, depending on the nature of the formulation and whether further dilution is performed before application.

[0087] Preferably, the compounds of formula (I), pharmaceutically acceptable salts, and compositions thereof are prepared in a form suitable for inhalation, nasal administration, oral administration, topical administration, or ophthalmic administration. More preferably, the compounds of formula (I), pharmaceutically acceptable salts, and compositions thereof are prepared in a form suitable for inhalation administration.

[0088] 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.

[0089] The compound of formula (I) of the present invention, its pharmaceutically acceptable salts, and compositions are preferably adapted for oral administration.In this case, the composition for oral administration can take the form of an inhalation aerosol, an inhalation solution, a dry powder inhalant, a tablet, a retard tablet, a sublingual tablet, a capsule, or a liquid preparation, such as a mixture, an elixir, a syrup, or a suspension, all of which contain the compound of the present invention; such preparations can be prepared by methods well known in the art.

[0090] Respiratory diseases such as pulmonary fibrosis, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, interstitial pulmonary fibrosis, pulmonary arterial hypertension, and lung cancer; scleroderma, nephrogenic fibrosing dermatosis, mixed connective tissue disease, and scleromyxedema , good The administration of the compound of formula (I) to mammals in the treatment of fibrotic skin diseases such as 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 is a particular aspect of the present invention, and can be carried out in any feasible manner.Preferably, the administration is oral administration.Preferably, the oral administration is inhalation administration.

[0091] 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.

[0092] 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.

[0093] 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.

[0094] 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]

[0095] (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 or using a Vertex CombiFlash system. Spectroscopic data were determined on a Varian Mercury 300 spectrometer. Melting points were determined on a Buchi 535 instrument. HPLC-MS was performed on a Gilson instrument equipped with a Gilson 321 piston pump, a Gilson 864 vacuum degasser, a Gilson 189 injection module, a 1 / 1000 Gilson splitter, a Gilson 307 pump, a Gilson 170 detector, and a Thermoquest Fenigan aQa detector. UPLC-MS was performed on an Acquity H-Class (Waters) equipped with an Acquity sample manager, Acquity 4 solvent manager, Acquity PDA detector, Acquity QDA detector, and a Vaccubrand vacuum pump.

[0096] (Intermediate 1: 1-(6-methylpyridin-2-yl)-2-(quinolin-4-yl)ethan-1-one) To a solution of 4-methylquinoline (5.0 g, 34.91 mmol) in THF (50 mL) cooled to -30 °C using an external CO2 / acetone bath, LiHMDS (105 mL, 104.73 mmol) was added dropwise over 1 h, and the reaction mixture was stirred at low temperature for 1 h. 、- After cooling to 30° C., ethyl 6-methylpyridine-2-carboxylate (6.3 g, 41.90 mmol) was added dropwise over 5 min, and the mixture was stirred for 18 h at room temperature. The resulting suspension was filtered and washed with THF (40 mL) to give a yellow solid (7.04 g, 76%). [ka] HPLC-MS: Rt 10.077 m / z 262.7 [M+H] + .

[0097] (Intermediate 2: 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 (7.04 g, 26.58 mmol) in DMF (35 mL) cooled using an ice / HO bath at 9 °C, DMF-DMA (10.6 mL, 79.75 mmol) was added over 8 min. AcOH (5.5 mL, 95.68 mmol) was added dropwise, and the reaction mixture was stirred for 17 h at room temperature. The reaction mixture was cooled to 7 °C using an ice / HO bath, and N2H4·HO (6.45 mL, 50.06 mmol, 64-65%) was added dropwise and stirred at low temperature for 3 h. HO (70 mL) was added dropwise, and the resulting suspension was stirred at room temperature overnight. The resulting suspension was filtered and washed with HO (60 mL) to give a beige solid (3.45 g, 45%). [ka] HPLC-MS: Rt 9.100 m / z 286.9 [M+H] + .

[0098] (Intermediate 3: tert-butyl 2-hydroxyethyl isopropylcarbamate) To a solution of 2-(isopropylamino)ethanol (1.4 g, 9.69 mmol) in dichloromethane (10 mL) cooled to 5 °C using an ice / water bath was added a solution of tert-butyl dicarbonate (2.5 g, 11.63 mmol) in dichloromethane (5 mL). The reaction mixture was allowed to reach room temperature, stirred for 22 h, diluted with dichloromethane (10 mL), and washed with ammonium chloride (2 × 15 mL, saturated aqueous solution) and citric acid (15 mL, 1 M aqueous solution). The organic layer was dried over sodium sulfate and concentrated to give a yellow oil (2.1 g). The product was used in the next step without further purification. [ka]

[0099] The following intermediates 4-10 were prepared following the procedure described for intermediate 3.

[0100] (Intermediate 4: tert-butyl 2-hydroxyethylcarbamate) [ka] (Intermediate 5: tert-butyl 2-hydroxyethylmethylcarbamate) [ka] (Intermediate 6: tert-butyl ethyl 2-hydroxyethylcarbamate) [ka] (Intermediate 7: tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate) [ka] (Intermediate 8: tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate) [ka] (Intermediate 9: tert-butyl 4-hydroxypiperidine-1-carboxylate) [ka]

[0101] (Intermediate 10: tert-butyl 6-bromopyridine-3-carboxylate) THF(15 mL To a suspension of 6-bromopyridine-3-carboxylic acid (1 g, 4.95 mmol) and (4-dimethylamino)pyridine (50 mg, 0.08 mmol) in HCl (2 mL) was added dropwise a solution of di-tert-butyl dicarbonate (2.7 g, 12.38 mmol) in THF (2 mL), and the reaction mixture was refluxed for 5 h. The reaction was allowed to reach room temperature and stirred for 17 h. The solvent was evaporated under reduced pressure, and the residue was dissolved in MTBE (10 mL) and washed with HO (×10 mL), citric acid (10 mL, 0.5 M aqueous solution), HO (10 mL), and NaHCO (10 mL, saturated aqueous solution). The organic layer was dried over sodium sulfate and concentrated to dryness to give a yellow solid (0.890 g, 70%). The product was used in the next step without further purification. HPLC-MS: Rt 3.791 m / z 258.1 [M+H] + .

[0102] (Intermediate 11: tert-butyl 5-aminopicolinate) Cuprous iodide (0.510 g, 2.68 mmol), trans-4-hydroxy-L-proline (0.703 g, 5.36 mmol), and tert-butyl 5-bromopicolinate (3.46 g, 13.40 mmol) were stirred in a sealed tube with dimethyl sulfoxide (20 mL). Concentrated ammonium hydroxide (15 mL) was added, the tube was closed, and the homogeneous blue solution was heated at 80° C. for 17 hours. The reaction mixture was allowed to reach room temperature and filtered. The resulting solid was dissolved in dichloromethane (30 mL) and washed with saturated ammonium chloride solution (50 mL). The aqueous layer was extracted with dichloromethane (2×30 mL), and the combined organic extracts were dried over sodium sulfate and concentrated to give a white solid (2.16 g, 83%). [ka] HPLC-MS: Rt 8.607 m / z 195.2 [M+H] + .

[0103] The following intermediate 12 was prepared following the procedure described for intermediate 11. (Intermediate 12: tert-butyl 6-aminopyridine-3-carboxylate) HPLC-MS: Rt 3.262 m / z 195.3 [M+H] + .

[0104] (Intermediate 13: tert-butyl 5-(2-bromoacetamido)picolinate) tert-Butyl 5-aminopicolinate (1.07 g, 5.51 mmol) was suspended in dichloromethane (15 mL) and cooled to 0 °C. Triethylamine (0.84 mL, 6.06 mmol) was added, followed by the dropwise addition of a solution of bromoacetyl bromide (0.67 mL, 7.71 mmol) in dichloromethane (2 mL). The reaction mixture was stirred at 0 °C for 40 minutes and then allowed to warm to room temperature. The resulting suspension was filtered and washed with dichloromethane (5 mL). The solid was purified by flash chromatography on silica gel (2→3% MeOH / CH2Cl2) to give an orange solid (1.11 g, 64%). [ka] HPLC-MS: Rt 9.514 m / z 313.0-315.0 [MH] - .

[0105] (Intermediate 14: 3-(2-bromoacetamido)-5-fluorobenzoic acid) To a solution of 3-amino-5-fluorobenzoic acid (6.0 g, 38.67 mmol) in THF (60 mL) cooled in an HO / ice bath was added 2-bromoacetyl bromide (3.7 mL, 42.54 mmol), and the reaction mixture was stirred at low temperature for 10 min, then allowed to warm to room temperature and stirred for 22 h. The resulting suspension was filtered, washed with EtOAc (30 mL), and the mother liquor was concentrated to dryness. The solid was slurried with a 1:1 mixture (25 mL) of EtO:hexane (isomeric mixture) to give a white solid (7.4 g, 70%). [ka] HPLC-MS: Rt 1.89 m / z 276.2 [M+H] + .

[0106] The following intermediates 15 and 16 were prepared following the procedure described for intermediate 14. (Intermediate 15: tert-butyl 6-(2-bromoacetamido)pyridine-3-carboxylate) [ka] HPLC-MS: Rt 3.658 m / z 317.1 [M+H] + . (Intermediate 16: 5-(2-bromoacetamido)pyridine-3-carboxylic acid) [ka] HPLC-MS: Rt 1.205 m / z 257.1 - 259.2 [M+H] + .

[0107] Intermediate 17: 3-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)-5-fluorobenzoic acid To a suspension of 4-(3-(6-methylpyridin-2-yl)-1H-pyrazol-4-yl)quinoline (3.5 g, 12.26 mmol) in THF (100 mL) cooled to −11 °C using an EtOH / ice bath was added NaH (1.5 g, 36.78 mmol, 60% dispersion in mineral oil) in one portion, and the reaction mixture was stirred at low temperature for 30 min. A solution of 3-(2-bromoacetamido)-5-fluorobenzoic acid (4.4 g, 15.94 mmol) in THF (100 mL) was added dropwise over 45 min, and the mixture was stirred for 3 h and allowed to reach room temperature overnight. Silica was added, and the solvent was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (8→15% MeOH / CHCl+1% AcOH) to give a beige solid (4.71 g, 80%). [ka] HPLC-MS: Rt 3.018 m / z 482.1 [M+H] + .

[0108] The following intermediates 18 and 19 were prepared following the procedure described for intermediate 17. (Intermediate 18: tert-butyl 5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)picolinate) The residue was purified by flash chromatography on silica gel (2.5→4% MeOH / CH 2 Cl 2 ) to give a yellow solid (0.950 g, 69%). [ka] HPLC-MS: Rt 10.376 m / z 521.1 [M+H] + .

[0109] (Intermediate 19: tert-butyl 6-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)pyridine-3-carboxylate) [ka] HPLC-MS: Rt 4.011 m / z 521.3 - 522.2 [M+H] + .

[0110] (Intermediate 20: 5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)picolinic acid) A solution of tert-butyl 5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)picolinate (0.170 mg, 0.518 mmol) in hydrochloric acid solution (8 ml, 4 M solution in dioxane) was refluxed for 2 h and allowed to reach room temperature. EtOAc (2×15 mL) was added and the solvent was removed in vacuo. The crude residue was purified by C18 chromatography using a Combiflash system (5→100% HO / MeCN) to give a beige solid (0.063 g, 26%). [ka] HPLC-MS: Rt 12.726 m / z 465.0 [M+H] + .

[0111] The following intermediate 21 was prepared following the procedure described for intermediate 20. (Intermediate 21: 6-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide)pyridine-3-carboxylic acid) HPLC-MS: Rt 3.158 m / z 465.1 [M+H] + .

[0112] (Intermediate 22: tert-butyl 2-(3-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)-5-fluorobenzoyloxy)ethyl ethylcarbamate) To a suspension of 3-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)-5-fluorobenzoic acid (0.20 g, 0.415 mmol) in DMF (4 mL) was added N,N-diisopropylethylamine (0.21 mL, 1.24 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (0.26 g, 0.622 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. A solution of tert-butyl ethyl 2-hydroxyethylcarbamate (0.15 g, 0.830 mmol) in DMF (1 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with EtOAc (15 mL) and washed with brine (3×10 mL). The organic layer was dried over sodium sulfate and concentrated to give a brown oil (0.3 g) which was used in the next step without further purification. HPLC-MS: Rt 4.021 m / z 653.3 [M+H] + .

[0113] The following intermediates 23-28 were prepared following the procedure described for intermediate 22. (Intermediate 23: tert-butyl 2-(3-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)-5-fluorobenzoyloxy)ethyl isopropylcarbamate) HPLC-MS: Rt 4.112 m / z 667.3 [M+H] + . (Intermediate 24: tert-butyl 2-(3-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)-5-fluorobenzoyloxy)ethylcarbamate) HPLC-MS: Rt 3.878 m / z 625.3 [M+H] + . (Intermediate 25: tert-butyl 2-(3-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)-5-fluorobenzoyloxy)ethylmethylcarbamate) HPLC-MS: Rt 3.954 m / z 639.3 [M+H] + . (Intermediate 26: tert-butyl 4-(2-(3-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)-5-fluorobenzoyloxy)ethyl)piperazine-1-carboxylate) HPLC-MS: Rt 3.981 m / z 694.2 [M+H] + . (Intermediate 27: tert-butyl 4-((3-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)-5-fluorobenzoyloxy)methyl)piperidine-1-carboxylate) HPLC-MS: Rt 4.091 m / z 679.3 [M+H] + . (Intermediate 28: tert-butyl 4-(3-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)-5-fluorobenzoyloxy)piperidine-1-carboxylate) HPLC-MS: Rt 4.060 m / z 665.3 [M+H] + .

[0114] Intermediate 29: Methyl 3-(2-bromoacetamido)-5-chlorobenzoate HPLC-MS: Rt 9.991 m / z 306.0 [MH] - . This intermediate was prepared following the procedure described for Intermediate 17.

[0115] (Example) Example 1: 2-(Dimethylamino)ethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate To a suspension of 3-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)-5-fluorobenzoic acid (2.0 g, 4.150 mmol) in dichloromethane (50 mL) was added thionyl chloride (1.5 mL, 20.75 mmol) and the reaction mixture was heated under reflux overnight. The reaction was allowed to reach room temperature and the solvent was evaporated under reduced pressure. The residue was suspended in dichloromethane (50 mL) and 2-(dimethylamino)ethanol (0.59 mL, 6.22 mmol) and N,N-diisopropylethylamine (3 mL, 17.48 mmol) were added and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured onto water (50 mL), the phases were separated and the organic phase was washed with water (50 mL) and brine (50 mL). Aqueous citric acid was added to the organic layer to pH 1.7, the layers were separated, and the final organic layer was dried over sodium sulfate and concentrated to dryness. Acetonitrile (25 mL) was added to the residue, and the mixture was stirred at room temperature for 20 minutes, heated to 55°C for 15 minutes, and allowed to reach room temperature overnight. The resulting suspension was filtered and washed with acetonitrile (15 mL) to give a beige solid (1.24 g, 54%). [ka] UPLC-MS: Rt 3.562 m / z 553.4 - 554.4 [M+H] + .

[0116] The following Examples 2 and 3 were prepared according to the procedure described for Example 1. Example 2: 2-(Dimethylamino)ethyl 5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)nicotinate [ka] UPLC-MS: Rt 2.853 m / z 536.4 - 537.4 [M+H] + . Example 3: 2-(Dimethylamino)ethyl 6-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)nicotinate [ka] UPLC-MS: Rt 2.911 m / z 536.4 - 537.4 [M+H] + .

[0117] Example 4: 2-Morpholinoethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate To a suspension of 3-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)-5-fluorobenzoic acid (0.200 g, 0.397 mmol) in dichloromethane (8 mL) was added thionyl chloride (0.290 mL, 3.97 mmol) and the reaction mixture was heated under reflux for 3 h, brought to room temperature and the solvent was evaporated under reduced pressure. The residue was suspended in dichloromethane (8 mL) and 2-morpholinoethanol (0.145 mL, 1.19 mmol) was added and the mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was dissolved in EtOAc (20 mL) and washed with sodium bicarbonate (2×20 mL, saturated aqueous solution). The organic phase was dried over sodium sulfate and concentrated. The reaction product was suspended in MeCN (10 mL) and stirred at room temperature for 4 h, and the resulting suspension was filtered and washed with MeCN (2×5 mL) to give a white solid (0.130 g, 55%). [ka] UPLC-MS: Rt 3.449 m / z 595.4 - 596.4 [M+H]+ .

[0118] The following Examples 5-8 were synthesized using the procedure described for Example 4. Example 5: 2-(Dimethylamino)ethyl 5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)picolinate [ka] UPLC-MS: Rt 2.682 m / z 536.5 [M+H] + .

[0119] Example 6: 2-(4-methylpiperazin-1-yl)ethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate [ka] UPLC-MS: Rt 3.083 m / z 608.3 - 609.3 [M+H] + .

[0120] Example 7: 2-(Diethylamino)ethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate [ka] UPLC-MS: Rt 3.393 m / z 581.4 - 582.4 [M+H] + .

[0121] Example 8: 1-Methylpiperidin-4-yl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate [ka] UPLC-MS: Rt 3.248 m / z 579.4 - 580.4 [M+H] + .

[0122] Example 9: (1-Methylpiperidin-4-yl)methyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate To a solution of 3-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)-5-fluorobenzoic acid (0.20 g, 0.415 mmol) in N,N-dimethylformamide (4 mL), N,N-diisopropylethylamine (0.21 mL, 1.24 mmol), hydroxybenzotriazole (0.125 g, 0.623 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.120 g, 0.623 mmol) were added, and the reaction mixture was stirred at room temperature for 40 minutes. A solution of (1-methylpiperidin-4-yl)methanol (0.11 g, 0.830 mmol) in N,N-dimethylformamide (1 mL) was added, and the mixture was continued to stir at room temperature for 3 hours. The reaction mixture was diluted with EtOAc (20 mL) and washed with brine (3 × 15 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by C18 chromatography (5→80% HO / MeCN + 0.1% formic acid) using a Combiflash system to give an off-white solid (0.015 g, 6%). [ka] UPLC-MS: Rt 3.141 m / z 593.4 - 594.4 [M+H] + .

[0123] Example 10: (R)-Quinuclidin-3-yl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate To a suspension of 3-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)-5-fluorobenzoic acid (0.20 g, 0.415 mmol) in N,N-dimethylformamide (4 mL) was added N,N-diisopropylethylamine (0.21 mL, 1.24 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (0.23 g, 0.623 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. To this reaction mixture was added (R)-quinuclidin-3-ol (0.105 g, 0.830 mmol), and stirring was continued at room temperature overnight. The reaction mixture was diluted with EtOAc (30 mL) and washed with brine (2 × 20 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by C18 chromatography (5→80% HO / MeCN + 0.1% formic acid) using a Combiflash system to give an off-white solid (0.057 g, 23%). [ka] UPLC-MS: Rt 3.144 m / z 591.4 - 592.4 [M+H] + .

[0124] The following Examples 11-14 were synthesized using the procedure described for Example 10. Example 11: (S)-Quinuclidin-3-yl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate [ka] UPLC-MS: Rt 3.045 m / z 591.4 - 592.4 [M+H] + . Example 12: Quinuclidin-4-yl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate [ka] UPLC-MS: Rt 6.744 m / z 591.5 - 592.5 [M+H] + . Example 13: 2-(Azetidin-1-yl)ethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate [ka] UPLC-MS: Rt 3.887 m / z 565.5 - 566.5 [M+H] + . Example 14: 2-(Aziridin-1-yl)ethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate [ka] UPLC-MS: Rt 3.439 m / z 551.4 - 552.4 [M+H] + .

[0125] Example 15: 2-(Methylamino)ethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate To a solution of tert-butyl 2-(3-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)-5-fluorobenzoyloxy)ethylmethylcarbamate (0.30 g, 0.469 mmol) in dioxane (3 mL) was added HCl (0.58 mL, 2.34 mmol, 4 M solution in dioxane) and the reaction mixture was stirred at room temperature for 4 h. The solvent was concentrated under reduced pressure and the residue was dissolved in a mixture of EtOAc (15 mL) and NaHCO3 (10 mL, saturated aqueous solution). The phases were separated and the organic layer was washed with sodium bicarbonate (10 mL, saturated aqueous solution), ammonium chloride (10 mL, saturated aqueous solution), dried over sodium sulfate and concentrated. The reaction product was purified by C18 chromatography using a Combiflash system (5->80% MeCN:H2O+0.1 formic acid) to give a white solid (0.043 g, 17%). [ka] UPLC-MS: Rt 3.010 m / z 539.4 - 540.4 [M+H] + .

[0126] The following Examples 16-21 were synthesized from the corresponding ester derivatives using the procedure described for Example 15. Example 16: 2-Aminoethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate [ka] UPLC-MS: Rt 2.880 m / z 525.3 - 526.3 [M+H] + . Example 17: 2-(Ethylamino)ethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate [ka] UPLC-MS: Rt 3.016 m / z 553.3 - 554.3 [M+H] + . Example 18: 2-(Isopropylamino)ethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate [ka] UPLC-MS: Rt 3.113 m / z 567.4 - 568.4 [M+H] + . Example 19: 2-(Piperazin-1-yl)ethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate [ka] UPLC-MS: Rt 3.070 m / z 594.4 - 595.4 [M+H] + . Example 20: Piperidin-4-ylmethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate [ka] UPLC-MS: Rt 3.068 m / z 579.4 - 580.4 [M+H] + . Example 21: Piperidin-4-yl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate [ka] UPLC-MS: Rt 3.012 m / z 565.4 - 566.4 [M+H]+ .

[0127] (Comparative Example 1: Cyclopropylmethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate) This compound was prepared according to the procedure described in Example 1. [ka] UPLC-MS: Rt 4.16 m / z 536.5 - 537.5 [M+H] + .

[0128] (Comparative Example 2: Methyl 3-chloro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate) [ka] To a suspension of 4-(3-(6-methylpyridin-2-yl)-1H-pyrazol-4-yl)quinoline (0.3 g, 1.06 mmol) in DMF (8 mL) cooled using an EtOH / ice bath was added NaH (50 mg, 1.27 mmol, 60% dispersion in mineral oil) in one portion, and the reaction mixture was stirred at low temperature for 20 min. A solution of methyl 3-(2-bromoacetamido)-5-chlorobenzoate (0.36 g, 1.17 mmol) in DMF (2 mL) was added dropwise, and the mixture was stirred for 16 h and allowed to reach room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the crude residue was dissolved in NH4Cl (15 mL, saturated aqueous solution), extracted with dichloromethane (2 × 10 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (0→3% MeOH / CH2Cl2) and by C18 chromatography using a Combiflash system (5→90% HO / MeOH), and the resulting solid was slurried with diethyl ether (2×3 mL) to give a beige solid (0.257 g, 47%). [ka] HPLC-MS: Rt 19.792 m / z 512.1 [M+H] + .

[0129] (Comparative Example 3: 2-hydroxyethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate) [ka] This compound was prepared according to the procedure described for Example 1, except that Et3N was used instead of DIPEA. [ka] UPLC-MS: Rt 3.135 m / z 526.4 - 527.4 [M+H] + . The present application provides the following aspects of the invention. (Aspect 1) Compounds of formula (I): (chemical 1) TIFF0007752684000059.tif66170 (In the formula: R 1 is the following: a) unsubstituted or halogen atom, straight-chain or branched C 1 -C 3 Haloalkyl, linear or branched C 1 -C 3 Alkyl, linear or branched C 1 -C 3 a phenyl ring substituted with one or two groups selected from alkoxy, cyano, and hydroxy; b) unsubstituted or halogen atoms, straight-chain or branched C 1 -C 3 Haloalkyl, linear or branched C 1 -C 3 Alkyl, linear or branched C 1 -C 3 a 5- or 6-membered heteroaryl ring substituted with one or two groups selected from alkoxy, cyano, and hydroxy groups; represents a group selected from R 2 is the following: a) a hydrogen atom, b) Linear or branched C optionally substituted by one, two, or three halogen atoms 1 -C 3 Alkyl is a group selected from R 3 is the following: a) a hydrogen atom, b) Linear or branched C optionally substituted by one, two, or three 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) Linear or branched C optionally substituted by one, two, or three halogen atoms 1 -C 3 Alkyl, c) Halogen atoms represents a group selected from n is an integer from 0 to 3, R 6 is the following: a)-N(R 7 )(R 8 )(wherein, R 7 and R 8 are independently linear or branched C 1 -C 6 represents an alkyl group or a hydrogen atom), and b) saturated 4-10 membered monocyclic or bicyclic nitrogen-containing heterocyclyl optionally containing another heteroatom selected from the group consisting of oxygen and nitrogen, wherein C 1 -C 3 the heterocyclyl optionally substituted with a group selected from alkyl groups; represents a group selected from the group consisting of and pharmaceutically acceptable salts thereof. (Aspect 2) R 2 、R 4 and R 5 represents a hydrogen atom. (Aspect 3) R 3 A compound according to any one of the preceding aspects, wherein represents a methyl group. (Aspect 4) R 1 A compound according to any one of embodiments 1 to 3, wherein represents a phenyl ring substituted by one or two halogen atoms. (Aspect 5) n is an integer of 1 to 2, and R 6 But -N(R 7 )(R 8 5. The compound according to any one of embodiments 1 to 4, wherein the compound represents a ) group. (Aspect 6) R 7 and R 8 are independently linear C 1 -C 3 6. The compound according to embodiment 5, wherein R represents a group selected from an alkyl group and a hydrogen atom. (Aspect 7) R 6 A compound according to any one of embodiments 1 to 4, wherein represents a saturated 6-membered heterocyclic group containing one or two nitrogen atoms, optionally substituted by a methyl group. (Aspect 8) R 6 8. The compound according to embodiment 7, wherein represents a group selected from piperazinyl and piperidinyl groups. (Aspect 9) R 2 、R 4 and R 5 represents a hydrogen atom, and R 3 But linear C 1 -C 3 represents alkyl, and R 1 represents a phenyl ring substituted by one or two halogen atoms, n is an integer of 0 to 2, and R 6 But the following: a)-N(R 7 )(R 8 )(wherein, R 7 and R 8 is a linear C 1 -C 3 alkyl groups and hydrogen atoms), b) a saturated 6-membered heterocyclic group containing one or two nitrogen atoms, optionally substituted by a methyl group; c) 1-Aza-bicyclo[2.2.2]octanyl The compound according to embodiment 1, wherein R represents a group selected from the group consisting of: (Aspect 10) below: 2-(Dimethylamino)ethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate 2-(Dimethylamino)ethyl 5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)nicotinate 2-(Dimethylamino)ethyl 6-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)nicotinate 2-Morpholinoethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate 2-(Dimethylamino)ethyl 5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)picolinate 2-(4-Methylpiperazin-1-yl)ethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate 2-(Diethylamino)ethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate 1-Methylpiperidin-4-yl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate (1-Methylpiperidin-4-yl)methyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate (R)-Quinuclidin-3-yl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate (S)-Quinuclidin-3-yl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate Quinuclidin-4-yl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate 2-(Azetidin-1-yl)ethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate 2-(Aziridin-1-yl)ethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate 2-(Methylamino)ethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate 2-Aminoethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate 2-(Ethylamino)ethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate 2-(Isopropylamino)ethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate 2-(Piperazin-1-yl)ethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate Piperidin-4-ylmethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate Piperidin-4-yl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate or a pharmaceutically acceptable salt thereof. (Aspect 11) Use of a compound according to any one of aspects 1 to 10 in the manufacture of a medicament for the treatment of a disease or pathological condition that can be ameliorated by inhibition of transforming growth factor-β receptor I (TGFβRI) / ALK5, such as respiratory diseases, such as pulmonary fibrosis, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, interstitial pulmonary fibrosis, pulmonary arterial hypertension, and lung cancer; fibrotic skin diseases, such as scleroderma, nephrogenic fibrosing dermatosis, mixed connective tissue disease, scleromyxedema, scleroderma, 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. (Aspect 12) 11. Use of a compound according to any one of aspects 1 to 10 in the manufacture of a medicament for administration to a mammal in the treatment of a respiratory disease selected from lung cancer, adult respiratory distress syndrome, idiopathic pulmonary fibrosis, interstitial pulmonary fibrosis, asthma, chronic obstructive pulmonary disease (COPD), and pulmonary arterial hypertension, comprising: The above use, wherein the administration is oral administration. (Aspect 13) 13. The use of a compound according to embodiment 12, wherein oral administration is inhaled administration. (Aspect 14) A compound of formula (I) according to any one of embodiments 1 to 10 for use as a medicament. (Aspect 15) 11. A compound of formula (I) according to any one of aspects 1 to 10 for use in the treatment of a disease or pathological condition that can be ameliorated by inhibition of transforming growth factor-β receptor I (TGFβRI) / ALK5, such as respiratory diseases such as pulmonary fibrosis, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, interstitial pulmonary fibrosis, pulmonary arterial hypertension, and lung cancer; fibrotic skin diseases such as scleroderma, nephrogenic fibrosing dermatosis, mixed connective tissue disease, scleromyxedema, scleroderma, eosinophilic fasciitis; and fibrotic eye diseases such as dry eye, age-related macular degeneration, corneal and conjunctival scarring, post-cataract fibrosis, proliferative vitreoretinopathy, and proliferative diabetic retinopathy. (Aspect 16) the disease is selected from the group consisting of respiratory diseases selected from lung cancer, adult respiratory distress syndrome, idiopathic pulmonary fibrosis, interstitial pulmonary fibrosis, asthma, chronic obstructive pulmonary disease (COPD), and pulmonary arterial hypertension; and 16. The compound for use according to embodiment 15, wherein said administration is oral administration. (Aspect 17) 17. The compound for use according to embodiment 16, wherein oral administration is inhaled administration. (Aspect 18) A pharmaceutical composition comprising a compound according to any one of aspects 1 to 10 and a pharmaceutically acceptable diluent or carrier. (Aspect 19) 17. The pharmaceutical composition of embodiment 16, further comprising a therapeutically effective amount of a therapeutic agent selected from the group consisting of agents useful for the treatment of diseases or pathological conditions that can be ameliorated by inhibition of transforming growth factor-β receptor I (TGFβRI) / ALK5, such as respiratory diseases, such as pulmonary fibrosis, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, interstitial pulmonary fibrosis, pulmonary arterial hypertension, and lung cancer; fibrotic skin diseases, such as scleroderma, nephrogenic fibrosing dermatosis, mixed connective tissue disease, scleromyxedema, scleroderma, and eosinophilic fasciitis; and fibrotic ocular diseases, such as dry eye, age-related macular degeneration, corneal and conjunctival scarring, post-cataract fibrosis, proliferative vitreoretinopathy, and proliferative diabetic retinopathy. (Aspect 20) A compound according to any one of aspects 1 to 10, and The therapeutic agent is selected from agents useful for treating diseases or pathological conditions that can be ameliorated by inhibition of transforming growth factor-β receptor I (TGFβRI) / ALK5, such as at least respiratory diseases, including pulmonary fibrosis, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, interstitial pulmonary fibrosis, pulmonary arterial hypertension, and lung cancer; fibrotic skin diseases, including scleroderma, nephrogenic fibrosing dermatosis, mixed connective tissue disease, scleromyxedema, scleroderma, and eosinophilic fasciitis; and fibrotic eye diseases, including dry eye, age-related macular degeneration, scarring in the cornea and conjunctiva, post-cataract fibrosis, proliferative vitreoretinopathy, and proliferative diabetic retinopathy. Combination products including: (Aspect 21) 19. A method for the treatment of diseases that can be ameliorated by inhibition of transforming growth factor-β receptor I (TGFβRI) / ALK5, such as respiratory diseases, such as pulmonary fibrosis, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, interstitial pulmonary fibrosis, pulmonary arterial hypertension, and lung cancer; fibrotic skin diseases, such as scleroderma, nephrogenic fibrosing dermatosis, mixed connective tissue disease, scleromyxedema, scleroderma, and eosinophilic fasciitis; and fibrotic eye diseases, such as dry eye, age-related macular degeneration, corneal and conjunctival scarring, post-cataract fibrosis, proliferative vitreoretinopathy, and proliferative diabetic retinopathy, comprising administration of a therapeutically effective compound according to any one of aspects 1 to 10 to a patient in need thereof. (Aspect 22) the disease is selected from the group consisting of respiratory diseases selected from lung cancer, adult respiratory distress syndrome, idiopathic pulmonary fibrosis, interstitial pulmonary fibrosis, asthma, chronic obstructive pulmonary disease (COPD), and pulmonary arterial hypertension; and the administration of the compound is by oral administration; 22. The method of embodiment 21. (Aspect 23) The method of embodiment 22, wherein the oral administration is an inhaled administration.

Claims

1. Compounds of formula (I): 【Chemical 1】 or a pharmaceutically acceptable salt thereof (In the formula: R 1 is the following: a) unsubstituted or halogen atom, straight-chain or branched C 1 -C 3 Haloalkyl, linear or branched C 1 -C 3 Alkyl, linear or branched C 1 -C 3 a phenyl ring substituted with one or two groups selected from alkoxy, cyano, and hydroxy; b) unsubstituted or halogen atoms, straight-chain or branched C 1 -C 3 Haloalkyl, linear or branched C 1 -C 3 Alkyl, linear or branched C 1 -C 3 a 5- or 6-membered heteroaryl ring substituted with one or two groups selected from alkoxy, cyano, and hydroxy groups; represents a group selected from R 2 is the following: a) a hydrogen atom, b) Linear or branched C optionally substituted by one, two, or three halogen atoms 1 -C 3 Alkyl is a group selected from R 3 is the following: a) a hydrogen atom, b) Linear or branched C optionally substituted by one, two, or three halogen atoms 1 -C 3 Alkyl, c) Halogen atoms represents a group selected from R 4 and R 5 are, independently, the following: a) a hydrogen atom, b) Linear or branched C optionally substituted by one, two, or three halogen atoms 1 -C 3 Alkyl, c) Halogen atoms represents a group selected from n is an integer from 0 to 3, R 6 is the following: a)-N(R 7 )(R 8 )(wherein, R 7 and R 8 are independently linear or branched C 1 -C 6 represents an alkyl group or a hydrogen atom), and b) saturated 4- to 10-membered monocyclic or bicyclic nitrogen-containing heterocyclyl, optionally containing one more heteroatom selected from the group consisting of oxygen and nitrogen, and C 1 -C 3 the heterocyclyl optionally substituted with a group selected from alkyl groups; represents a group selected from the group consisting of:

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. R 3 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein represents a methyl group.

4. R 1 4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein represents a phenyl ring substituted by one or two halogen atoms.

5. 5. The compound according to any one of claims 1 to 4, wherein n is an integer of 1 to 2, or a pharmaceutically acceptable salt thereof.

6. R 6 6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein represents a saturated 6-membered heterocyclic group containing one or two nitrogen atoms, optionally substituted by a methyl group.

7. R 6 7. The compound according to claim 6, or a pharmaceutically acceptable salt thereof, wherein represents a group selected from piperazinyl and piperidinyl groups.

8. below: 2-(Dimethylamino)ethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate 2-(Dimethylamino)ethyl 5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)nicotinate 2-(Dimethylamino)ethyl 6-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)nicotinate 2-Morpholinoethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate 2-(Dimethylamino)ethyl 5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)picolinate 2-(4-Methylpiperazin-1-yl)ethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate 2-(Diethylamino)ethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate 1-Methylpiperidin-4-yl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate (1-Methylpiperidin-4-yl)methyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate (R)-Quinuclidin-3-yl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate (S)-Quinuclidin-3-yl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate Quinuclidin-4-yl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate 2-(Azetidin-1-yl)ethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate 2-(Aziridin-1-yl)ethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate 2-(Methylamino)ethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate 2-Aminoethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate 2-(Ethylamino)ethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate 2-(Isopropylamino)ethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate 2-(Piperazin-1-yl)ethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate Piperidin-4-ylmethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate and Piperidin-4-yl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate 2. The compound of claim 1, selected from the group consisting of:

9. 10. Use of a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease or pathological condition that can be ameliorated by inhibition of transforming growth factor-beta receptor I (TGFβRI) / ALK5, such as respiratory diseases; fibrotic skin diseases; and fibrotic eye diseases.

10. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8 for use as a medicament.

11. 11. The composition for use according to claim 10, for use in the treatment of a disease or pathological condition that can be ameliorated by inhibition of transforming growth factor-β receptor I (TGFβRI) / ALK5, such as a disease selected from respiratory diseases; fibrotic skin diseases; and fibrotic eye diseases.

12. 12. The composition for use according to claim 11, wherein the respiratory disease is selected from the group consisting of pulmonary fibrosis, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, idiopathic pulmonary fibrosis, interstitial pulmonary fibrosis, pulmonary arterial hypertension, and lung cancer; the fibrotic skin disease is selected from the group consisting of scleroderma, nephrogenic fibrosing dermatosis, mixed connective tissue disease, scleromyxedema, and eosinophilic fasciitis; and the fibrotic eye disease is selected from the group consisting of dry eye, age-related macular degeneration, scarring in the cornea and conjunctiva, post-cataract fibrosis, proliferative vitreoretinopathy, and proliferative diabetic retinopathy.

13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

14. A compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, and The therapeutic agent is selected from agents useful for treating diseases or pathological conditions that can be ameliorated by inhibition of transforming growth factor-β receptor I (TGFβRI) / ALK5, such as at least respiratory diseases, including pulmonary fibrosis, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, interstitial pulmonary fibrosis, pulmonary arterial hypertension, and lung cancer; fibrotic skin diseases, including scleroderma, nephrogenic fibrosing dermatosis, mixed connective tissue disease, scleromyxedema, scleroderma, and eosinophilic fasciitis; and fibrotic eye diseases, including dry eye, age-related macular degeneration, scarring in the cornea and conjunctiva, post-cataract fibrosis, proliferative vitreoretinopathy, and proliferative diabetic retinopathy. Combination products including:

15. Compounds of formula (II): 【Chemistry 2】 or its salt (In the formula, R 1 , R 2 , R 3 , R 4 and R 5 is as defined in any one of claims 1 to 8).

16. 3-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)-5-fluorobenzoic acid; 5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)picolinic acid; and 16. The compound of claim 15, or any one of its salts, selected from the group consisting of 6-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)pyridine-3-carboxylic acid.

17. A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, comprising: Compounds of formula (II): 【Chemistry 3】 or a salt thereof, with a compound of formula (III): 【Chemistry 4】 or a salt thereof. (where n, R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 is as defined in any one of claims 1 to 8).

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