2-(3-pyridin-2-yl-4-quinolin-4-yl-pyrazol-1-yl)-acetamide derivatives as transforming growth factor-beta receptor i / alk5 inhibitors

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-beta receptor I (also known as activin receptor-like kinase 5) (TGFβRI) / ALK5. Other objects of the present invention are to provide processes for preparing these compounds; pharmaceutical compositions comprising an effective amount of these compounds; the use of said compounds for the preparation of a medicament for the treatment of pathological conditions or diseases which can be ameliorated by the inhibition of transforming growth factor-beta receptor I (TGFβRI) / ALK5, such as respiratory diseases, including idiopathic pulmonary fibrosis, asthma, COPD and lung cancer and skin and ocular fibrotic disorders.

Description

Invention Field

[0001] This invention relates to a novel 2-(3-pyridin-2-yl-4-quinoline-4-yl-pyrazol-1-yl)-acetamide derivative, which is a potent inhibitor of transforming growth factor-β receptor I (also known as activin receptor-like kinase 5) (TGFβRI) / ALK5.

[0002] Other objects of the present invention are to provide methods for preparing these compounds; pharmaceutical compositions comprising effective amounts of these compounds; and use of the compounds in the preparation of medicaments for treating pathological conditions or diseases that can be improved by inhibiting transforming growth factor-β receptor I (TGFβRI) / ALK5, such as respiratory diseases including idiopathic pulmonary fibrosis, asthma, COPD, and lung cancer, as well as skin and ocular fibrosis. Existing technology

[0003] Transforming growth factor-β (TGF-β) belongs to the TGF-β superfamily and is composed of TGF-β1, TGF-β2, TGF-β3, and other proteins. TGF-β is involved in many cellular processes, including cell proliferation, cell migration, invasion, epithelial-mesenchymal transition, extracellular matrix production, and immunosuppression. TGF-β and its receptors are often overexpressed long-term in a variety of human diseases, including cancer, inflammation, tissue fibrosis, and autoimmunity. Therefore, blocking the TGF-β signaling pathway is considered an attractive target for drug development (Heldin CH et al., Signalling Receptors for TGF-β Family Members, ColdSpring Harb Perspect Biol, 2016).

[0004] TGF-β signals via two associated transmembrane type I and type II serine / threonine kinase receptors. Upon binding to the constitutively active type II receptor, the type I receptor (also known as activin receptor-like kinase 5 (ALK5)) is phosphorylated, creating binding sites for the Smad2 and Smad3 proteins, which are further phosphorylated. The phosphorylated Smad2 / Smad3 proteins form a heteropolymer complex with Smad4, which translocates to the nucleus, assembles with specific DNA-binding cofactors and coregulators, and binds to promoters of TGF-β target genes involved in cell differentiation, proliferation, apoptosis, migration, and extracellular matrix production. (Akhurst RJ et al., Targeting the TGFβ signalalling 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 major TGFβ receptor I, which is activated by TGF-β via TGFβ receptor II. This interaction requires extracellular and intracellular domains for signal transduction. ALK5 and TGFβ receptor II proteins can also form active heterooligomeric complexes in the absence of ligands. When both receptors are co-expressed, these complexes are able to transduce basal signals because they have an intrinsic affinity for each other. (Bierie B et al., TGF-β: the molecular Jekyll and Hyde of cancer, Nature Reviews, Cancer, Vol. 6, July 2006).

[0006] The functional TGFβRII-TGFβRI (ALK5) heteropolymer signaling complex is commonly associated with human cancers, and it regulates the activation of downstream Smad-dependent and Smad-independent pathways. Indeed, numerous studies have identified mutations in components associated with the TGF-β pathway, and these mutations are associated with cancer development and prognosis in many human tissues. Overexpression of TGF-β1 is associated with breast cancer, colon cancer, esophageal cancer, gastric cancer, hepatocellular carcinoma, lung cancer, and pancreatic cancer. Importantly, overexpression of TGF-β in human cancers is associated with tumor progression, metastasis, angiogenesis, and poor prognosis.

[0007] Transforming growth factor-β (TGF-β) cytokines play a crucial role in the development and progression of chronic respiratory diseases. In the most prevalent chronic respiratory diseases, including pulmonary fibrosis, asthma, COPD, and lung cancer, TGF-β is overexpressed in chronic inflammation, remodeling, fibrotic processes, and susceptibility to viral infections.

[0008] Idiopathic pulmonary fibrosis

[0009] Pulmonary fibrosis is a chronic and progressive lung disease in which repeated trauma and repair processes lead to irreversible structural changes and tissue hardening. The pathophysiological steps include alveolar epithelial damage induced by external stimuli, fibroblast activation, and a persistent fibrotic response. Differentiation of pulmonary fibroblasts into myofibroblasts is a key step in the development of tissue fibrosis. TGF-β is the most potent factor inducing myofibroblast differentiation, and its increased expression has been reported in fibrotic lung. The primary cellular sources of TGF-β in pulmonary fibrosis have been shown to be alveolar macrophages and metaplastic type II alveolar epithelial cells. TGF-β induces molecular regulators of small GTPases and promotes pulmonary fibrosis by inhibiting the production of anti-fibrotic molecules such as hepatocyte growth factor and prostaglandin E2. In addition, TGF-β inhibits the growth and repair of alveolar epithelial cells, thus it is a key player in the fibrosis process, acting on fibroblasts and alveolar epithelial cells (Saito A. et al., TGF-β Signaling in Lung Health and Disease, Int. J. Mol. Sci. 2018, 19, 2460).

[0010] Extensive evidence suggests that the classic ALK5 / Smad3 pathway plays a crucial role in the pathogenesis of fibrosis in many tissues. In a rat model of progressive TGF-β1-induced pulmonary fibrosis, oral administration of a low-molecular-weight selective inhibitor of ALK5 kinase activity suppressed fibrosis. Furthermore, Smad3-free mice showed reduced fibrosis in a wide range of experimental models and were resistant to bleomycin-induced pulmonary fibrosis. (Biernacka, A et al., TGF-β signalling in fibrosis, Growth Factors. Oct 2011; 29(5):196-202).

[0011] Asthma and COPD

[0012] Asthma and COPD exacerbations are often associated with viral infections. Subsequent airway inflammation leads to resistance to the anti-inflammatory effects of glucocorticoids (GCs). Viral infection induces transforming growth factor-β (TGF-β) activity, a growth factor that attenuates GC activity in human airway epithelial cells through activation of activin-like kinase 5 (ALK5). This study examined the contribution of TGF-β activity to viral infection-induced GC resistance, demonstrating that the selective ALK5 / TGFβ inhibitor SB431542 attenuated GC damage, while the therapeutic agent tranilast prevented GC damage by reducing TGF-β activity associated with viral infection. This study suggests that virus-induced glucocorticoid insensitivity is partly mediated by the activation of endogenous TGF-β. (Xia YC et al., Glucocorticoid Insensitivity in Virally Infected Airway Epithelial Cells IsDependent on Transforming Growth Factor-βActivity, PLoS Pathog, January 3, 2017, 13(1), doi:10.1371 / journal.ppat.1006138).

[0013] Specifically, asthma is characterized by chronic airway inflammation and hyperresponsiveness mediated by T-helper type 2 (Th2) cells and several cytokines and interleukins. These cytokines induce chronic inflammation, eosinophilia in the lungs, mucocytosis, smooth muscle contraction, and airway remodeling. In addition to Th2 cells, Th17 cells, which secrete IL-17A and IL-17F, are also involved in the development of allergic airway inflammation. The importance of TGF-β signaling in the pathogenesis of asthma has been elucidated through genome-wide association studies. Increased TGF-β concentrations in bronchoalveolar lavage fluid have been demonstrated in atopic asthma, and increased TGF-β expression has been observed in bronchial samples from asthmatic patients. The pathological role of TGF-β in asthma is not limited to airway remodeling, and its role in the immune response is considered more important than previously thought (Saito A. et al., TGF-β Signaling in Lung Health and Disease, Int. J. Mol. Sci. 2018, 19, 2460).

[0014] Immunohistochemical localization using TGF-β1 or pan-specific antibodies in asthmatic airways revealed increased TGF-β expression, primarily associated with the submucosa and inflammatory cells, including fibroblasts, smooth muscle cells, eosinophils, macrophages, and connective tissue of the airways, with variable expression in epithelial cells. The increased TGF-β expression in asthmatic airways was mainly attributed to an increase in the number of eosinophils and macrophages.

[0015] Consistent with studies showing increased TGF-β expression in the airways of asthma, there is also evidence of increased TGF-β signaling, increased phosphorylation of Smad2, and decreased Smad7 immunoreactivity. Furthermore, studies in animal models of airway remodeling have demonstrated increased levels of TGF-β1 in bronchoalveolar lavage and evidence of TGF-β / Smad signaling activation.

[0016] Furthermore, evidence from animal models suggests that the use of active agents targeting TGF-β can prevent or reverse airway remodeling. Therefore, TGF-β or the regulation of its activity represents a potential therapeutic target for asthma. (Howell, JE et al., TGF-β: Its Role in Asthma and Therapeutic Potential, Current Drug Targets, 2006, 7, 547-565).

[0017] On the other hand, chronic obstructive pulmonary disease (COPD) is characterized by irreversible airflow obstruction, minor airway inflammation, and the destruction of alveolar structure as air volume expands. Several studies have confirmed impaired TGF-β1 signaling in patients with COPD. Researchers have identified increased TGF-β1 and decreased expression of inhibitory Smad in the airway epithelium of smokers and those with COPD. Similar to the role of TGF-β in pulmonary fibrosis, in COPD patients, TGF-β promotes fibrotic airway remodeling, which may further contribute to impaired lung function. Some of the increase in TGF-β1 in the airway epithelium of COPD patients may be a direct response to cigarette smoke, which is the most significant 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).

[0018] lung cancer

[0019] Lung cancer is a leading cause of cancer-related death worldwide. Non-small cell lung cancer (NSCLC) accounts for the majority of lung cancers, including histological subtypes of adenocarcinoma and squamous cell carcinoma. Higher 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. TGF-β is widely believed to play a dual role during tumor progression, inhibiting epithelial cell proliferation and acting as a tumor inhibitor in the early stages of tumorigenesis; loss-of-function mutations in TGF-β signaling components have been identified in several cancer types.

[0020] In addition to its direct effects on cancer cells, TGF-β promotes invasion and metastasis through interactions between cancer cells and the tumor stromal microenvironment. TGF-β coordinates tumor stromal development and promotes angiogenesis, immune evasion, and remodeling. It is hypothesized that TGF-β-mediated stromal responses are associated with poor prognosis in resected lung adenocarcinoma (Saito A et al., TGF-β Signalling in Lung Health and Disease, Int. J. Mol. Sci. 2018, 19, 2460).

[0021] Viral infection

[0022] Other studies have shown that concomitant viral infection in the context of pre-existing bleomycin-induced fibrosis in mice leads to significant and widespread inflammatory changes, suggestive of ground-glass opacities and consolidation reported in individuals with AE-IPF. Blocking TGFβ-ALK5 signaling by therapeutic administration of the potent and selective ALK5 antagonist SB525334 was highly effective in halting the progression of fibrosis in a mouse model of bleomycin-only injury, but the antifibrotic effect of this active agent was significantly reduced in the presence of concomitant viral infection. Conversely, this inhibitor was highly effective in alleviating the widespread inflammatory cellular infiltration associated with concomitant viral infection, and it enhanced the antiviral cytokine response.

[0023] These studies highlight the pleiotropic nature of the TGFβ-ALK5 signaling axis in pulmonary fibrosis, with responses to ALK5 inhibition yielding different outcomes depending on the presence of viral infection. Therefore, these findings raise important considerations for future targeting of TGFβ signaling in pulmonary fibrosis, anticipating different outcomes in stable IPF and viral-associated acute exacerbation-IPF. (Smoktunowicz, N et al., The anti-fibrotic effect of inhibition of TGFβ-ALK5signalling 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).

[0024] It has been demonstrated that both innate and adaptive TGF-β immune signaling lead to increased HSV-1 latency and reactivation. The synergistic activity of TGF-β signaling in these two immune compartments appears to be crucial in regulating the latency of viral infection. If these results are extrapolated to clinical HSV-1 infection, then blocking TGF-β signaling in immune cells could represent an important new approach to treating virus-related diseases. (Allen, SJ et al., Adaptive and Innate Transforming Growth Factor β Signaling Impact Herpes Simplex Virus 1 Latency and Reactivation, Journal of Virology, November 2011, pp. 11448-11456).

[0025] In 2003, Severe Acute Respiratory Syndrome (SARS)-associated coronavirus (SARS-CoV) was the pathogen of the SARS outbreak. SARS-CoV infection induces severe respiratory illness, such as bronchial epithelial desquamation, ciliary loss, multinucleated syncytiocytoid cells, squamous metaplasia, and transendothelial migration of monocytes / macrophages and neutrophils into the lung tissue. SARS-CoV triggers a pro-inflammatory cytokine storm associated with pulmonary fibrosis in SARS patients. Nearly 20% of recovered SARS patients still have pulmonary fibrosis nine months after infection.

[0026] The SARS coronavirus (SARS-CoV) papain-like protease (PLpro) has been identified in human premonocytes with upregulation of TGF-β1. SARS-CoV PLpro induces TGF-β1-mediated prefibrotic responses in human lung epithelial cells and mouse lung tissue, consistent with previous reports of PLpro upregulating TGF-β1 and its related genes such as glial fibrillary acidic protein (GFAP) and vimentin. In addition to the SARS-CoV nucleocapsid, PLpro has been identified as generating TGF-β1, which is associated with 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 TGF-β1-mediated pulmonary fibrosis in the pathogenesis of SARS. (Li SW et al., SARScoronavirus papin-like protease induces Egr-1-dependent up-regulation of TGF-β1via ROS / p38 MAPK / STAT3 pathway, Sci Rep. 2016 May 13;6:25754).

[0027] Available or developing antifibrotic therapies may be valuable in preventing severe other coronavirus infections such as COVID-19 in patients with IPF and may play a role in preventing fibrosis following SARS-CoV-2 infection. Therefore, developing antifibrotic therapies for chronic fibrotic lung disease using bleomycin models may actually be beneficial for COVID-19, both in the acute phase of the disease and in preventing long-term complications. (George, PM, et al., Pulmonary fibrosis and COVID-19: the potential role for antifibrotic therapy, www.thelancet.com / respiratory, published online, May 15, 2020).

[0028] The primary target of antifibrotic therapy is the TGF-β pathway. Many drugs are under development targeting various molecules within this pathway, including those targeting αvβ6 integrin (BG00011 [Biogen, Cambridge, MA, USA]; PLN-74809 [Pliant Therapeutics, San Francisco, CA, USA]) and galactagogue (TD139 [GalectoBiotech, Copenhagen, Denmark]). Some experimental data support the use of these three drugs in virus-induced lung injury.

[0029] Eye diseases

[0030] Transforming growth factor-β (TGF-β) may play a role in the pathogenesis of primary open-angle glaucoma (POAG). TGF-β has been implicated in the pathogenesis of POAG, and potential targets of TGF-β include production, activation, downstream signaling, and local modulation. Elevated TGF-β levels have been found in the aqueous humor and reactive optic nerve astrocytes of glaucoma patients. Although recent studies have revealed many unknowns, a deeper understanding of the cellular signaling pathways of TGF-β is essential for designing potential TGF-β intervention strategies. (Wang, J et al., Targeting Transforming Growth Factor-β Signalling in Primary Open-Angle Glaucoma, J Glaucoma 2017; 26:390-395).

[0031] Eye diseases associated with fibroproliferative conditions include retinal reattachment surgery with proliferative vitreoretinopathy, cataract extraction with intraocular lens implantation, and posterior glaucoma drainage surgery associated with excessive TGF-β1 production.

[0032] The authors of this invention have developed new, appropriately substituted ester derivatives that act as potent and selective inhibitors of the TGF-β signaling pathway, particularly as inhibitors of transforming growth factor-β receptor I / activin-like kinase 5 (TGFβRI / ALK5). Invention Overview

[0034] In one aspect (Aspect 1) of the invention, the invention relates to a suitably substituted ester derivative of formula (I):

[0035]

[0036] in:

[0037] -R 1It indicates that the group is selected from the following:

[0038] a) A phenyl ring, which is either unsubstituted or substituted with one or two groups selected from the following: halogen atom, straight-chain or branched C1-C3 haloalkyl, straight-chain or branched C1-C3 alkyl, straight-chain or branched C1-C3 alkoxy, cyano, and hydroxyl.

[0039] b) A 5- or 6-membered heteroaryl ring, which is unsubstituted or substituted by one or two groups selected from the following: halogen atom, straight-chain or branched C1-C3 haloalkyl, straight-chain or branched C1-C3 alkyl, straight-chain or branched C1-C3 alkoxy, cyano, and hydroxyl.

[0040] -R 2 It is selected from the following groups:

[0041] a) Hydrogen atom,

[0042] b) Straight-chain or branched C1-C3 alkyl groups optionally substituted with 1, 2, or 3 halogen atoms.

[0043] -R 3 It indicates that the group is selected from the following:

[0044] a) Hydrogen atom,

[0045] b) Straight-chain or branched C1-C3 alkyl groups optionally substituted with 1, 2, or 3 halogen atoms.

[0046] c) Halogen atoms,

[0047] -R 4 and R 5 Indicates that the group is independently selected from the following:

[0048] a) Hydrogen atom,

[0049] b) Straight-chain or branched C1-C3 alkyl groups optionally substituted with 1, 2, or 3 halogen atoms.

[0050] c) Halogen atoms,

[0051] -n is an integer from 0 to 3.

[0052] -R 6 It indicates that the group is selected from the following:

[0053] a)-N(R 7 (R) 8 ), where R 7 and R 8 Independently representing straight-chain or branched C1-C6 alkyl or hydrogen atoms, and

[0054] b) A saturated 4- to 10-membered monocyclic or bicyclic nitrogen-containing heterocyclic group, optionally comprising another heteroatom selected from oxygen and nitrogen, wherein the heterocyclic group is optionally substituted with a group selected from C1-C3 alkyl groups.

[0055] And its pharmaceutically acceptable salts.

[0056] In a second aspect, the present invention relates to a method for preparing the compound of aspect 1.

[0057] In a third aspect, the present invention relates to pharmaceutical compositions comprising the compound of aspect 1 and a pharmaceutically acceptable diluent or carrier.

[0058] In a fourth aspect, the present invention relates to a pharmaceutical composition according to the third aspect above, further comprising a therapeutically effective amount of a therapeutic agent selected from those used to treat respiratory diseases such as pulmonary fibrosis, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, interstitial pulmonary fibrosis, pulmonary hypertension, and lung cancer; fibrotic skin diseases such as scleroderma, nephrotic fibrotic skin disease, mixed connective tissue disease, sclerosing myxedema, and eosinophilic fasciitis; and fibrotic eye diseases such as dry eye, age-related macular degeneration, corneal and conjunctival scarring, postcataract fibrosis, proliferative vitreoretinopathy, and proliferative diabetic retinopathy.

[0059] Fifthly, the present invention relates to the use of the compound of aspect 1 in the preparation of a medicament for treating diseases or pathological conditions that can be improved by inhibiting 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 hypertension, and lung cancer; fibrotic skin diseases, such as scleroderma, nephrotic fibrotic skin diseases, mixed connective tissue diseases, sclerosing myxedema, and eosinophilic fasciitis; fibrotic eye diseases, such as dry eye, age-related macular degeneration, corneal and conjunctival scarring, postcataract fibrosis, proliferative vitreoretinopathy, and proliferative diabetic retinopathy.

[0060] In a sixth aspect, the present invention relates to a method for treating diseases that can be improved by inhibiting transforming growth factor-β receptor I (TGFβRI) / ALK5, such as respiratory diseases, including pulmonary fibrosis, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, interstitial pulmonary fibrosis, pulmonary hypertension, and lung cancer; fibrotic skin diseases, including scleroderma, nephrotic fibrotic skin diseases, mixed connective tissue diseases, sclerosing myxedema, and eosinophilic fasciitis; and fibrotic eye diseases, including dry eye, age-related macular degeneration, corneal and conjunctival scarring, postcataract fibrosis, proliferative vitreoretinopathy, and proliferative diabetic retinopathy.

[0061] In a seventh aspect, the present invention relates to combination products of the compounds of the first aspect above with one or more therapeutic agents, said therapeutic agents being known for treating respiratory diseases such as pulmonary fibrosis, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, interstitial pulmonary fibrosis, pulmonary hypertension and lung cancer; fibrotic skin diseases such as scleroderma, nephrotic fibrotic skin diseases, mixed connective tissue diseases, sclerosing myxedema and eosinophilic fasciitis; fibrotic eye diseases such as dry eye, age-related macular degeneration, corneal and conjunctival scarring, postcataract fibrosis, proliferative vitreoretinopathy and proliferative diabetic retinopathy.

[0062] In the eighth aspect, the present invention relates to the compounds of aspect 1, which are used as pharmaceuticals.

[0063] In a ninth aspect, the present invention relates to compounds of aspect 1 for treating diseases or pathological conditions that can be improved by inhibiting transforming growth factor-β receptor I (TGFβRI) / ALK5, such as respiratory diseases, pulmonary fibrosis, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, interstitial pulmonary fibrosis, pulmonary hypertension, and lung cancer; fibrotic skin diseases, such as scleroderma, nephrotic fibrotic skin diseases, mixed connective tissue diseases, sclerosing myxedema, and eosinophilic fasciitis; and fibrotic eye diseases, such as dry eye, age-related macular degeneration, corneal and conjunctival scarring, postcataract fibrosis, proliferative vitreoretinopathy, and proliferative diabetic retinopathy.

[0064] As described above, the ester derivatives of the present invention can be used to treat or prevent diseases known to be readily improved by treatment with transforming growth factor-β receptor I (TGFβRI) / ALK5 inhibitors, such as respiratory diseases, such as pulmonary fibrosis, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, interstitial pulmonary fibrosis, pulmonary hypertension, and lung cancer; fibrotic skin diseases, such as scleroderma, nephrotic fibrotic skin diseases, mixed connective tissue diseases, sclerosing myxedema, and eosinophilic fasciitis; and fibrotic eye diseases, such as dry eye, age-related macular degeneration, corneal and conjunctival scarring, postcataract fibrosis, proliferative vitreoretinopathy, and proliferative diabetic retinopathy.

[0065] Therefore, the derivatives of the present invention and their pharmaceutically acceptable salts, as well as pharmaceutical compositions comprising the compounds and / or their salts, can be used in methods for treating pathological conditions or diseases in humans, the methods comprising administering an effective amount of the ester derivatives of the present invention or their pharmaceutically acceptable salts to an individual requiring the treatment.

[0066] The term C used in this article a -C bAlkyl groups include straight-chain or branched groups having a to b carbon atoms. Preferred groups include 1 to 4 carbon atoms. Examples of straight-chain or branched alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.

[0067] The terms straight chain or branch chain used in this article are C a -C b Alkyl groups are used to indicate straight-chain or branched carbon atoms connected to oxygen atoms. a -C b alkyl group (C x H 2x+1 Preferred alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, and isopropoxy.

[0068] As used herein, the term 5- or 6-membered heteroaryl ring refers to an unsaturated aromatic ring system having 5 or 6 members selected from C, N, O, and S, wherein at least one member is one of N, O, and S, and said group may optionally be substituted with one or two groups selected from halogen atoms, straight-chain or branched C1-C3 haloalkyl, straight-chain or branched C1-C3 alkyl, straight-chain or branched C1-C3 alkoxy, cyano, and hydroxyl groups. Preferred groups are optionally substituted pyridyl, pyrazolyl, and thiazolyl rings. When the heteroaryl group has two or more substituents, the substituents may be the same or different.

[0069] As used herein, the term "saturated 4-10 membered monocyclic or bicyclic nitrogen-containing heterocyclic group" is used to denote a ring system that may contain one or two rings, wherein the one or two rings have a total of 4 to 10 members, at least one of which is a nitrogen atom. When the ring system has two rings, each ring may have 3 to 6 members, and the two rings may share one or more bonds. An example of a bicyclic ring sharing one bond is 1-azabicyclo[2.2.0]hexane, an example of a bicyclic ring sharing two bonds is 1-azabicyclo[2.2.1]heptane, and an example of a bicyclic ring sharing three bonds is 1-azabicyclo[2.2.2]octane. Examples of monocyclic nitrogen-containing heterocyclic groups are piperidinyl, morpholinyl, piperazine, 4-methyl-piperazine, pyrrolidinyl, azabicyclobutyl, and acridineyl. Examples of bicyclic nitrogen-containing heterocyclic groups are 1-azabicyclo[2.2.0]hexyl, 1-azabicyclo[2.2.1]heptyl, and decahydroquinolinyl. These groups may optionally be substituted with one, two, or three groups selected from straight-chain or branched C1-C3 alkyl and hydroxyl groups. Preferred groups are optionally substituted piperazine, piperidinylmorpholinyl, and 1-azabicyclo[2.2.2]octyl (quininecycloyl).

[0070] As used herein, the term halogen atom includes chlorine, fluorine, bromine, and iodine atoms, preferably fluorine, chlorine, and bromine atoms. The term "halogenated" has the same meaning when used as a prefix. As an example, haloalkyl refers to an alkyl group substituted with one or more halogen atoms.

[0071] As used herein, some atoms, groups, chains, or rings present in the general formula of this invention are "optionally substituted." This means that these atoms, groups, chains, or rings may be unsubstituted or substituted at any position by one or more, for example, 1, 2, 3, or 4 substituents, whereby the hydrogen atoms to which the unsubstituted atoms, groups, chains, or rings are attached are replaced by chemically acceptable atoms, groups, chains, or rings. When two or more substituents are present, each substituent may be the same or different.

[0072] As used herein, the term pharmaceutically acceptable salt is used to refer to a salt formed with a pharmaceutically acceptable acid or base. Pharmaceutically acceptable acids include inorganic acids and organic acids, such as hydrochloric acid, sulfuric acid, phosphoric acid, diphosphoric acid, hydrobromic acid, hydroiodic acid, and nitric acid, and 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 alkali metal (e.g., sodium or potassium), alkaline earth metal (e.g., calcium or magnesium) hydroxides, and organic bases such as alkylamines, aralkylamines, and heterocyclic amines.

[0073] Other preferred salts of the present invention are quaternary ammonium compounds, wherein a considerable amount of anion (X) is present. -n It combines with the positive charge of the N atom. X -n It can be anion of various inorganic acids, such as chloride, bromide, iodide, sulfate, nitrate, and phosphate, or anion of organic acids, such as acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelic acid, trifluoroacetate, methanesulfonate, and p-toluenesulfonate. -n Preferably, the anion is selected from chloride, bromide, iodide, sulfate, nitrate, acetate, maleate, oxalate, succinate, or trifluoroacetate. More preferably, X -n It is chloride, bromine, trifluoroacetate or methanesulfonate.

[0074] According to one embodiment of the present invention, in the compound of formula (I), R 1 This indicates an unsubstituted benzene ring or a benzene ring substituted with one or two halogen atoms. In a preferred embodiment, R 1 This indicates a benzene ring substituted with one or two halogen atoms. In a more preferred embodiment, R 1 This indicates a benzene ring that has been replaced by a halogen atom.

[0075] According to one embodiment of the present invention, in the compound of formula (I), R 2 It represents a hydrogen atom.

[0076] According to one embodiment of the present invention, in the compound of formula (I), R 3 The group represents a group selected from hydrogen atoms and unsubstituted straight-chain or branched C1-C3 alkyl groups. In a preferred embodiment, R 3 It indicates a methyl group.

[0077] According to one embodiment of the present invention, in the compound of formula (I), R 4 It represents a hydrogen atom.

[0078] According to one embodiment of the present invention, in the compound of formula (I), R 5 It represents a hydrogen atom.

[0079] According to one embodiment of the 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.

[0080] According to one embodiment of the present invention, in the compound of formula (I), R 6 Represents -N(R) 7 (R) 8 ) group, wherein R 7 and R 8 Independently represents a group selected from straight-chain C1-C3 alkyl groups and hydrogen atoms.

[0081] According to one embodiment of the present invention, in the compound of formula (I), R 6 This indicates a saturated 4- to 6-membered monocyclic nitrogen-containing heterocyclic group, comprising a nitrogen atom attached to a -(CH2)n- group and optionally another nitrogen atom that may be substituted with a methyl group. In a preferred embodiment, R 6 This indicates a saturated 6-membered heterocyclic group containing one or two nitrogen atoms, which may optionally be substituted with a methyl group.

[0082] In a more preferred embodiment, R 6 This indicates a group selected from piperazinyl and piperidinyl.

[0083] According to one embodiment of the present invention, in the compound of formula (I), R 6 It represents 1-aza-bicyclo[2.2.2]octyl.

[0084] According to one embodiment of the present invention, in the compound of formula (I), R 2 R 4 and R 5 It represents a hydrogen atom.

[0085] 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 Represents -N(R) 7 (R) 8 ) group, preferably wherein R 7 and R 8 Independently represents a group selected from straight-chain C1-C3 alkyl groups and hydrogen atoms.

[0086] According to one embodiment of the present invention, in the compound of formula (I), R 2 R 4 and R 5 R represents a hydrogen atom. 3 Indicates a straight-chain C1-C3 alkyl group, R 1 This represents a benzene ring substituted with one or two halogen atoms, where n is an integer from 0 to 2, and R 6 It indicates that the group is selected from the following:

[0087] a)-N(R 7 (R) 8 ), where R 7 and R 8 Selected from straight-chain C1-C3 alkyl groups and hydrogen atoms,

[0088] b) A saturated 6-membered heterocyclic group containing one or two nitrogen atoms, optionally substituted with a methyl group.

[0089] c) 1-aza-bicyclo[2.2.2]octyl.

[0090] The specific individual compounds of this invention include:

[0091] 2-(dimethylamino)ethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoic acid

[0092] 5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)nicotinic acid 2-(dimethylamino)ethyl ester

[0093] 6-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)nicotinic acid 2-(dimethylamino)ethyl ester

[0094] 2-morpholinoethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoic acid

[0095] 2-(dimethylamino)ethyl 5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)pyridinecarboxylic acid

[0096] 2-(4-methylpiperazin-1-yl)ethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoic acid

[0097] 2-(diethylamino)ethyl benzoate of 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoic acid

[0098] 1-Methylpiperidin-4-yl ester of 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoic acid

[0099] 3-Fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoic acid (1-methylpiperidin-4-yl)methyl ester

[0100] (R)-3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)quininecyclo-3-yl ester of benzoate

[0101] (S)-3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)quininecyclo-3-yl ester of benzoate

[0102] 3-Fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoic acid quinine ring-4-yl ester

[0103] 2-(azacyclobutane-1-yl)ethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoic acid

[0104] 2-(aziridin-1-yl)ethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoic acid

[0105] 2-(methylamino)ethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoic acid

[0106] 2-Aminoethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoic acid

[0107] 2-(ethylamino)ethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoic acid

[0108] 2-(isopropylamino)ethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoic acid

[0109] 2-(piperazin-1-yl)ethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoic acid

[0110] 3-Fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)piperidin-4-ylmethyl benzoate

[0111] 3-Fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)piperidin-4-yl ester of benzoate and its pharmaceutically acceptable salts.

[0112] The compounds of the present invention can be prepared using the methods described below. Specific examples are used for ease of description of these steps, but they do not limit the scope of the invention in any way. The synthesis of compounds of formula (I) is summarized in process 1.

[0113] Process 1

[0114]

[0115] The amide formation reaction a) can be carried out in one or two steps under the following alternative conditions:

[0116] Alternative 1: Step 1. SOCl2, CH2Cl2, reflux; Step 2. HO-(CH2) n -R 6 ,CH2Cl2,DIPEA, room temperature

[0117] Alternative 2: Step 1. SOCl2, CH2Cl2, reflux; Step 2. HO-(CH2) n -R 6 CH2Cl2, room temperature

[0118] Option 3: Step 1. HO-(CH2)n -R 6 HATU, DIPEA, DMF, room temperature

[0119] Alternative 4: Step 1. HO-(CH2) n -R 6 ,HOBT,EDCI,DIPEA,DMF, room temperature.

[0120] In group R 6 It represents the amino group (-N(R) 7 (R) 8 )), where R 7 and R 8 In the case where at least one hydrogen atom is present, the amino group is protected with BOC before the above reaction (see process 7), and the protected Boc group is cleaved with HCl·dioxane, or dioxane at 0°C to room temperature after the above reaction.

[0121] The carboxylic acid ester of general formula (I) is prepared by esterification of 2-(2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)acetic acid derivative (II) with a suitable 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 agent system (Wang, X. et al., Metal-Free Etherification of Aryl Methyl EtherDerivatives by C-OMe Bond Cleavage, Organic Letters, 20(14), 4267-4272; 2018).

[0122] In which R 7 or R 8 In compounds representing hydrogen groups, the deprotection of precursors protected by N-Boc under acidic conditions.

[0123] As described in Procedure 2 and WO2009123316 A1 (which is incorporated herein by reference), compounds of general formula (II) are prepared in several stages from 4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)quinoline derivatives (IV) by deprotonation followed by reaction with the corresponding bromoacetamide (V).

[0124] Process 2

[0125]

[0126] R9 =H or tBu

[0127] Reagents and conditions:

[0128] Reaction b) Step 1. NaH, THF, DMF, 0℃ to room temperature.

[0129] Compound, wherein R 9 =tert-butyl: Step 2. HCl·dioxane, dioxane, reflux or room temperature.

[0130] Some 4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)quinoline derivatives (IV) are commercially available, while others (of which R) 2 H) can be prepared by several steps as shown in process 3 and described in WO2004026302 A1, which is incorporated herein by reference.

[0131] Process 3

[0132]

[0133] Reagents and conditions:

[0134] Reaction c) LiHMDS, THF, -30℃ to room temperature.

[0135] Reaction d) where R 2 =H compounds, step 1. DMF·DMA, AcOH, DMF, 0℃ to room temperature; step 2. N2H4·H2O, 0℃ to room temperature.

[0136] In the presence of lithium bis(trimethylsilyl)amino, the condensation of a 4-methylquinoline derivative (VI) with ethyl 2-pyridinecarboxylate (VII) yields a compound of formula (VIII). The reaction of derivative (VIII) with dimethylformamide dimethyl acetal gives an unseparated enamine intermediate, which is directly cyclized by reaction with hydrazine in the presence of acetic acid to give a pyrazole derivative of formula (IVa).

[0137] Where R 2 Compounds (IVb) consisting of straight-chain or branched C1-C3 alkyl groups optionally substituted with 1, 2, or 3 halogen atoms can be prepared according to the following procedure 4:

[0138] Process 4

[0139]

[0140] Reagents and conditions:

[0141] Reaction e): Step 1. NBS, CH2Cl2, 0℃ Step 2. SemCl, Cs2CO3, DMF, 0℃.

[0142] Reaction f): Step 1. R 2 Step 2: B(OH)2, DMF, NaHCO3, PdCl2(PPh3)2, BCl3, SMe2, CH2Cl2, 0℃.

[0143] After the nitrogen atom of the pyrazole ring is protected, the pyrazole derivative of formula (IVa) can be halogenated with a standard halogenating agent to give the corresponding compound of formula (IX), which, after the nitrogen atom of the pyrazole ring is protected, is used as a succinimide derivative. CC coupling is then performed, followed by deprotection of the nitrogen atom of the pyrazole to give the derivative of formula (IVb).

[0144] As shown in process 5, bromoacetamide of formula (V) can be readily synthesized in one step from a commercially available amine (X) by reacting with bromoacetyl bromide (XI) (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).

[0145] Process 5

[0146]

[0147] Reagents and conditions:

[0148] The reaction is carried out at 0°C to room temperature (g) with THF or CH2Cl2 and Et3N, and at 0°C to room temperature (g).

[0149] Some amines (X) are commercially available, while others can be prepared in several steps as shown in process 6.

[0150] Process 6

[0151]

[0152] R 9 = t Bu

[0153] R 1 It indicates that the group is selected from the following:

[0154] a) A phenyl ring, which is either unsubstituted or substituted with one or two groups selected from the following: halogen atom, straight-chain or branched C1-C3 haloalkyl, straight-chain or branched C1-C3 alkyl, straight-chain or branched C1-C4 alkoxy, cyano, and hydroxyl.

[0155] b) A 5- or 6-membered heteroaryl ring, which is unsubstituted or substituted by one or two groups selected from the following: halogen atom, straight or branched C1-C3 haloalkyl, straight or branched C1-C3 alkyl, straight or branched C1-C4 alkoxy, cyano and hydroxyl.

[0156] The reaction was carried out with Boc2O, DMAP, and THF at room temperature.

[0157] Reaction j) trans-4-hydroxy-L-proline, CuI, NH4OH, DMSO, 80℃.

[0158] The corresponding acid (XII) was esterified by reaction with Boc2O 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), and then the resulting ester was treated with ammonium hydroxide in the presence of CuI (as a substituted tetrahydroisoquinoline compound as an inhibitor of factor XIa, WO 2013056034) to give an amine derivative of formula (X).

[0159] Protected amines of formula (IIIb) (where R) 7 and / or R 8 (At least one of which represents a hydrogen atom) can be readily synthesized in one step from a commercially available unprotected amine (IIIa) by treating it with Boc2O, as shown in process 7.

[0160] Process 7

[0161]

[0162] R 7 =H or straight-chain or branched C1-C6 alkyl.

[0163] The reaction is k)Boc2O,CH2Cl2, 0℃ to room temperature.

[0164] abbreviation

[0165] The following abbreviations are used in this application and have their respective definitions:

[0166] AcOH: Acetic acid

[0167] ACVR2B: activin A receptor, type IIB

[0168] ALKn: activin receptor-like kinase n

[0169] ATP: adenosine triphosphate

[0170] Boc2O: tert-butyl dicarbonate

[0171] Boc: tert-Butyloxycarbonyl

[0172] Clint: Inherent clearance rate

[0173] DIPEA: N,N-Diisopropylethylamine

[0174] DMA: Dimethylacetamide

[0175] DMAP: 4-Dimethylaminopyridine

[0176] DMF: N,N-Dimethylformamide

[0177] DMSO: Dimethyl sulfoxide

[0178] EDCI: N-(3-Dimethylaminopropyl)-N′-(Ethylcarbonyldiamine)

[0179] Et3N: Triethylamine

[0180] EtOAc: Ethyl acetate

[0181] EtOH: Ethanol

[0182] FBS: Fetal bovine serum

[0183] H: Hour

[0184] HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate

[0185] HOBT: Hydroxybenzotriazole

[0186] HPLC: High Performance Liquid Chromatography

[0187] 1 H-NMR: Proton Nuclear Magnetic Resonance

[0188] K2EDTA: Dipotassium salt of ethylenediaminetetraacetate

[0189] LC: Liquid Chromatography

[0190] LiHMDS: Bis(trimethylsilyl)aminolithium

[0191] LLOQ: Lower limit of quantitation

[0192] MeCN: Acetonitrile

[0193] MeOH: Methanol

[0194] Min: minutes

[0195] MS: Mass spectrometry

[0196] MTBE: Methyl tert-butyl ether

[0197] NBS: N-bromosuccinimide

[0198] NaCMC: Sodium carboxymethyl cellulose

[0199] Rt: Retention time

[0200] RT: Room temperature

[0201] Sem:2-(trimethylsilyl)ethoxymethyl

[0202] TGFβ: Transforming growth factor-β

[0203] THF: Tetrahydrofuran

[0204] THF:EtOH:Tetrahydrofuran:Ethanol

[0205] UPLC: Ultra-high performance liquid chromatography

[0206] UV: Ultraviolet

[0207] Pharmacological activity

[0208] In vitro enzyme assay: Inhibition of TGFβR-1

[0209] Human TGFβR-1 inhibition assays were performed in white 384-well microplates with low-friction (Corning 3572) using an ADP-Glo ​​kinase assay kit (Promega V9101) and a TGFβR-1 kinase system (Promega V4092). Using the reaction buffer provided in the kit as the assay buffer, the test compound, standard Galunisertib (Cayman 15312), 50 ng / well TGFβR-1 kinase, and 50 μM ATP were added in a final volume of 10 μL / well. The reaction mixture was incubated for 120 min with gentle shaking at room temperature. After incubation, 10 μL of ADP-glo reagent was added and the plate was incubated for 40 min with gentle shaking at room temperature. 20 μL of the kinase assay reagent was added, and the plate was incubated for 30 min with gentle shaking at room temperature. Luminescence was measured (1000 ms) using a Perkin Elmer EnSpire multimode plate reader.

[0210] result

[0211] Table 1 shows the determination results of some of the compounds of the present invention described below.

[0212] Table 1

[0213]

[0214]

[0215] scope :

[0216] A:IC 50 =<100nM

[0217] B:100nM <IC 50 <250nM

[0218] Measurement of intracellular TGF-β kinase activity (ALK-5)

[0219] The experiment was conducted on the A549 cell line. 30,000 cells were seeded in 200 μL of medium (Sigma D6046) supplemented with L-glutamine (Sigma G7513), penicillin / streptomycin (Invitrogen 11058), and FBS (Sigma F9665) in 96-well microplates (Becton Dickinson 353072). 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 ALK-5 activator were added to their respective wells, and the cells were cultured according to Alphascreen instructions. Ultra TM Incubate according to the instructions of the p-SMAD3 (Ser423 / 425) kit (Perkin Elmer ALSU-PSM3-A500).

[0220] result

[0221] Table 2 shows the determination results of some of the compounds of the present invention described below.

[0222] Table 2

[0223]

[0224]

[0225] scope:

[0226] A:IC 50 =<1μM

[0227] B:IC 50 >1μM

[0228] As can be seen from the results described in Table 2, the compounds of the present invention are potent inhibitors of transforming growth factor-β receptor I ((TGFβRI) / ALK5).

[0229] Determination of plasma stability of some compounds

[0230] Human plasma collected from healthy donors and extracted from citric acid tubes was used in this assay. Briefly, plates (total volume: 50 μL) containing 10 μM of the compound in plasma were incubated at 37 °C for different times (0, 30, 120, and 360 min). Then, 100 μL of acetonitrile was added to precipitate plasma proteins, and the plates were centrifuged at 46000 g for 60 min at 5 °C. The supernatant was collected and analyzed by UPLC / MS / MS for sample quantification. Stationary phase: reversed-phase Acquity BEH C18 1.7μm (2.1mm x 50mm) (Waters). Mobile phase: 0.1% formic acid in water / 0.1% formic acid in acetonitrile.

[0231] gradient:

[0232] Time (min) water Acetonitrile 0 95％ 5％ 0.1 95％ 5％ 1 0％ 100％ 2 0％ 100％ 2.2 95％ 5％ 2.5 95％ 5％

[0233] Flow rate: 0.6 ml / min. The chromatographic equipment used was a UPLC QSM Waters Acquity. Compound concentrations were calculated from the MS peak areas.

[0234] result

[0235] Table 3 shows the assay results for some of the compounds described below. It shows the percentage of each compound remaining in human plasma at different test times.

[0236] Table 3

[0237]

[0238] All the embodiments of the invention studied showed low stability in human plasma, unlike the compounds in Comparative Examples 1, 2 and 3, which maintained up to 60% of their initial amount after 6 hours.

[0239] The derivatives of this invention can be used to treat or prevent diseases known to be readily improved by treatment with transforming growth factor-β receptor I (TGFβRI) / ALK5 inhibitors. These diseases include respiratory diseases such as pulmonary fibrosis, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, interstitial pulmonary fibrosis, pulmonary hypertension, and lung cancer; fibrotic skin diseases such as scleroderma, nephrotic fibrotic dermatitis, mixed connective tissue disease, sclerosing myxedema, and eosinophilic fasciitis; and fibrotic eye diseases such as dry eye, age-related macular degeneration, corneal and conjunctival scarring, postcataract fibrosis, proliferative vitreoretinopathy, and proliferative diabetic retinopathy.

[0240] Therefore, the derivatives of the present invention and their pharmaceutically acceptable salts, as well as pharmaceutical compositions comprising these compounds and / or their salts, can be used in methods of treating human diseases, the methods comprising administering an effective amount of the ester derivatives of the present invention or their pharmaceutically acceptable salts to an individual in need of such treatment.

[0241] The present invention also provides pharmaceutical compositions comprising at least one ester derivative of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient, and other therapeutic agents, pharmaceutically acceptable excipients, such as carriers or diluents. The active ingredient may comprise from 0.001% to 99% by weight of the composition, preferably from 0.01% to 90% by weight, depending on the nature of the formulation and whether further dilution is performed prior to application.

[0242] Preferably, the compound of formula (I), its pharmaceutically acceptable salts, and the composition are formulated into a form suitable for inhalation, nasal, oral, topical, or ocular application. More preferably, the compound of formula (I), its pharmaceutically acceptable salts, and the composition are formulated into a form suitable for inhalation.

[0243] Pharmaceutically acceptable excipients that are mixed with an active compound or a salt thereof to form the compositions of the present invention are known in themselves, and the actual excipients used depend particularly on the method of application of the composition.

[0244] The compounds of formula (I) of the present invention, their pharmaceutically acceptable salts, and compositions are preferably suitable for oral administration. In this case, the compositions for oral administration may be in the form of inhaled aerosols, inhaled solutions, dry powder inhalers, tablets, sustained-release tablets, sublingual tablets, capsules, or liquid formulations, such as mixtures, elixirs, syrups, or suspensions, all of which contain the compounds of the present invention; such formulations may be prepared by methods known in the art.

[0245] In the treatment of respiratory diseases such as pulmonary fibrosis, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, interstitial pulmonary fibrosis, pulmonary hypertension, and lung cancer; fibrotic skin diseases such as scleroderma, nephrotic fibrotic dermatitis, mixed connective tissue disease, sclerosing myxedema, 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, administration of a compound of formula (I) to mammals is a specific aspect of the invention and can be carried out in any feasible manner. Preferably, the administration is oral. Preferably, the oral administration is inhalation.

[0246] Diluents that can be used to prepare the composition include liquid and solid diluents compatible with the active ingredient, and, if desired, colorants or flavorings. Tablets or capsules may conveniently contain 2 to 500 mg of the active ingredient or an equivalent amount of salt.

[0247] Liquid compositions suitable for oral administration may be in the form of solutions or suspensions. Solutions may be aqueous solutions of soluble salts or other derivatives of the active compound, which are combined with, for example, sucrose to form a syrup. Suspensions may contain the insoluble active compound of the present invention or a pharmaceutically acceptable salt thereof, as well as water, and suspending agents or flavoring agents.

[0248] The effective dose is typically 2-2000 mg of the active ingredient daily. The daily dose can be administered in one or more treatments, preferably 1 to 4 times daily.

[0249] The present invention will be further illustrated by the following examples. The following description is given by way of example only and does not limit the scope of the invention in any way. The synthesis of the compounds of the present invention is illustrated by the following examples, including the preparation of intermediates, which does not limit the scope of the invention in any way. Example

[0250] General Notes. Reagents, solvents, and starting products were obtained from commercial sources. The term "concentration" refers to vacuum evaporation using a Büchi rotary evaporator. When necessary, reaction products were purified by silica gel (40-63 μm) "fast" chromatography using a specified solvent system or using a Vertex CombiFlash system. Spectral data were measured in a Varian Mercury 300 spectrometer. Melting points were measured in a Büchi 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 Fennigan aQa detector. UPLC-MS was performed on an Acquity H-class (Waters) instrument equipped with an Acquity sample manager, an Acquity quaternary solvent manager, an Acquity PDA detector, an Acquity QDA detector, and a Vaccubrand vacuum pump.

[0251] Intermediate 1: 1-(6-methylpyridin-2-yl)-2-(quinolin-4-yl)ethyl-1-one

[0252] LiHMDS (105 mL, 104.73 mmol) was added dropwise to 4-methylquinoline (5.0 g, 34.91 mmol) in THF (50 mL) and cooled to -30 °C using an external CO2 / acetone bath for 1 hour. The reaction mixture was stirred at low temperature for 1 hour. The reaction was then cooled to -30 °C, and ethyl 6-methylpyridine-2-carboxylate (6.3 g, 41.90 mmol) was added dropwise over 5 minutes. The mixture was stirred for 18 hours until it reached room temperature. The resulting suspension was filtered and washed with THF (40 mL) to give a yellow solid (7.04 g, 76%).

[0253] 1 H-NMR (300MHz, CDCl3): δ = 8.84 (d, J = 4.4Hz, 1H), 8.138-8.045 (m, 2H), 7.85 (d, J = 7.6Hz, 1H), 7.74-7.66 (m,2H),7.56-7.51(m,1H),7.41(d,J=4.4Hz,1H),7.36(dd,J=7.6,0.5Hz,1H),5.02(s,2H),2.67(s,3H).

[0254] HPLC-MS:Rt 10.077m / z 262.7[M+H] + .

[0255] Intermediate 2: 4-(3-(6-methylpyridin-2-yl)-1H-pyrazol-4-yl)quinoline

[0256] DMF-DMA (10.6 mL, 79.75 mmol) was added to a solution of 1-(6-methylpyridin-2-yl)-2-(quinolin-4-yl)ethyl-1-one (7.04 g, 26.58 mmol) in DMF (35 mL) cooled at 9 °C with an external ice / H2O bath for 8 minutes. AcOH (5.5 mL, 95.68 mmol) was added dropwise, and the reaction mixture was stirred for 17 hours to reach room temperature. The reaction mixture was cooled at 7 °C with an external ice / H2O bath, and N2H4·H2O (6.45 mL, 50.06 mmol, 64-65%) was added dropwise, and the mixture was stirred at low temperature for 3 hours. H2O (70 mL) was added dropwise, and the resulting suspension was stirred overnight at room temperature. The resulting suspension was filtered and washed with H2O (60 mL) to give a pale yellow solid (3.45 g, 45%).

[0257] 1H-NMR (300MHz, DMSO-d6): δ = 13.63 (br s, 1H), 8.81 (br s, 1H), 8.04 (d, J = 9.6Hz, 1H), 7.73-7.40 (m, 7H), 7.02 (m, 1H), 2.50 (s, 3H).

[0258] HPLC-MS:Rt 9.100m / z 286.9[M+H] + .

[0259] Intermediate 3: 2-Hydroxyethyl isopropyl carbamate tert-butyl ester

[0260] A solution of tert-butyl dicarbonate (2.5 g, 11.63 mmol) in dichloromethane (5 mL) was added to a solution of 1.4 g (9.69 mmol) of 2-(isopropylamino)ethanol in dichloromethane (10 mL) cooled to 5 °C using an external ice / water bath. The reaction mixture was allowed to reach room temperature and stirred for 22 hours. It was then diluted with dichloromethane (10 mL) and washed with ammonium chloride (2 x 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 for the next step without further purification.

[0261] 1 H NMR (300MHz, CDCl3) δ = 4.17 (s, 1H), 3.69 (t, J = 5.6Hz, 2H), 3.30-3.25 (m, 2H), 1.46 (s, 9H), 1.11 (dd, J = 6.8, 1.2Hz, 6H).

[0262] The following intermediates 4 to 10 are prepared according to the method described for intermediate 3.

[0263] Intermediate 4: 2-Hydroxyethylcarbamate tert-butyl ester

[0264] 1 H NMR (300 MHz, CDCl3) δ = 3.71 (t, J = 5.0 Hz, 2H), 3.30 (t, J = 5.0 Hz, 2H), 1.46 (s, 9H).

[0265] Intermediate 5: 2-hydroxyethyl methyl carbamate tert-butyl ester

[0266] 1 H NMR (300MHz, CDCl3) δ3.76 (t, J = 5.3 Hz, 2H), 3.41 (t, J = 5.3 Hz, 2H), 2.93 (s, 3H), 1.48 (s, 9H).

[0267] Intermediate 6: tert-butylethyl 2-hydroxyethyl carbamate

[0268] 1 H NMR (300MHz, CDCl3) δ = 3.72 (t, J = 5.2Hz, 2H), 3.35 (t, J = 5.2Hz, 2H), 3.26 (q, J = 7.0Hz, 2H), 2.58 (s, 1H), 1.46 (s, 9H), 1.10 (t, J = 7.0Hz, 3H).

[0269] Intermediate 7: 4-(2-hydroxyethyl)piperazine-1-carboxylic acid tert-butyl ester

[0270] 1 H NMR (300MHz, CDCl3) δ = 3.62 (t, J = 5.4Hz, 2H), 3.43 (t, J = 5.1Hz, 4H), 2.55 (t, J = 5.4Hz, 2H), 2.45 (t, J = 5.1Hz, 4H), 1.44 (s, 9H).

[0271] Intermediate 8: 4-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester

[0272] 1 H NMR (300MHz, CDCl3) δ = 4.12 (d, J = 13.4Hz, 2H), 3.56-3.42 (m, 2H), 2.70 (t, J = 12.9Hz, 2H), 1.71 (d, J = 13.9Hz, 2H), 1.60-1.45 (m, 11H), 1.19-1.08 (m, 1H).

[0273] Intermediate 9: 4-Hydroxypiperidine-1-carboxylic acid tert-butyl ester

[0274] 1 H NMR (300MHz, CDCl3) δ = 4.00-3.70 (m, 3H), 3.02 (ddd, J = 13.4, 9.8, 3.3Hz, 2H), 1.63 (sa, 2H), 1.95-1.77 (m, 2H), 1.45 (s, 9H).

[0275] Intermediate 10: tert-butyl 6-bromopyridine-3-carboxylate

[0276] A solution of di-tert-butyl dicarbonate (2.7 g, 12.38 mmol) in THF (2 mL) was added dropwise to a suspension of 6-bromopyridine-3-carboxylic acid (1 g, 4.95 mmol) and (4-dimethylamino)pyridine (50 mg, 0.08 mmol) in THF (15 mL), and the reaction mixture was refluxed for 5 hours. The reaction was allowed to reach room temperature and stirred for 17 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in MTBE (10 mL) and washed with H2O (10 mL x 10 mL), citric acid (10 mL, 0.5 M aqueous solution), H2O (10 mL), and NaHCO3 (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 for the next step without further purification.

[0277] HPLC-MS:Rt 3.791m / z 258.1[M+H] + .

[0278] Intermediate 11: tert-butyl 5-aminopyridinecarboxylate

[0279] Cuprous iodide (0.510 g, 2.68 mmol), trans-4-hydroxy-L-proline (0.703 g, 5.36 mmol), and tert-butyl 5-bromopyridinecarboxylate (3.46 g, 13.40 mmol) were stirred with dimethyl sulfoxide (20 mL) in a sealed tube. Concentrated ammonium hydroxide (15 mL) was added, the tube was sealed, 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), the combined organic extracts were dried over sodium sulfate, and concentrated to give a white solid (2.16 g, 83%).

[0280] 1 H-NMR (300MHz, CDCl3): δ = 8.13 (br.s, 1H), 7.86 (d, J = 8.8Hz, 1H), 6.95 (dd, J = 8.8, 2.3Hz, 1H), 1.61 (s, 9H).

[0281] HPLC-MS:Rt 8.607m / z 195.2[M+H] + .

[0282] The following intermediate 12 is prepared according to the method described for intermediate 11.

[0283] Intermediate 12: 6-Aminopyridine-3-carboxylic acid tert-butyl ester

[0284] HPLC-MS:Rt 3.262m / z 195.3[M+H] + .

[0285] Intermediate 13: tert-butyl 5-(2-bromoacetamido)pyridinecarboxylate

[0286] 1.07 g (5.51 mmol) of tert-butyl 5-aminopyridinecarboxylate was suspended in 15 mL of dichloromethane and cooled to 0 °C. Triethylamine (0.84 mL, 6.06 mmol) was added, followed by dropwise addition of a solution of 0.67 mL (7.71 mmol) in 2 mL of dichloromethane. The reaction mixture was stirred at 0 °C for 40 min. The mixture was then allowed to warm to room temperature. The resulting suspension was filtered and washed with 5 mL of dichloromethane. The solid was purified by rapid silica gel chromatography (2→3% MeOH / CH2Cl2) to give an orange solid (1.11 g, 64%).

[0287] 1 H-NMR (300MHz, DMSO-d6): δ = 10.97 (s, 1H), 8.79 (d, J = 2.6Hz, 1H), 8.24 (dd, J = 8.5, 2.6Hz, 1H), 8.01 (d, J = 8.5Hz, 1H), 4.11 (s, 2H), 1.54 (s, 9H).

[0288] HPLC-MS:Rt 9.514m / z 313.0-315.0[MH] - .

[0289] Intermediate 14: 3-(2-bromoacetamido)-5-fluorobenzoic acid

[0290] 2-Bromoacetyl bromide (3.7 mL, 42.54 mmol) was added to a solution of 3-amino-5-fluorobenzoic acid (6.0 g, 38.67 mmol) in THF (60 mL) cooled in an external H2O / ice bath. The reaction mixture was stirred at low temperature for 10 min, allowed to reach room temperature, and then 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 of Et2O and hexane (25 mL) to give a white solid (7.4 g, 70%).

[0291] 1 H NMR (300MHz, DMSO-d6) δ10.79(s,1H),7.95(t,J=1.4Hz,1H),7.79(dt,J=10.9,2.2Hz,1H),7.38(ddd,J=8.9,2.2,1.4Hz,1H), 4.06(s,2H).

[0292] HPLC-MS: Rt 1.89 m / z 276.2 [M+H] + .

[0293] The following intermediates 15 to 16 are prepared according to the method described for intermediate 14.

[0294] Intermediate 15: tert-butyl 6-(2-bromoacetamido)pyridine-3-carboxylic acid ester

[0295] 1 H NMR (60MHz, DMSO-d6) δ8.80 (dd, J=2.1, 1.1Hz, 1H), 8.19 (t, J=1.8Hz, 2H), 4.17 (s, 2H), 1.55 (s, 9H).

[0296] HPLC-MS:Rt 3.658m / z 317.1[M+H] + .

[0297] Intermediate 16: 5-(2-bromoacetamido)pyridine-3-carboxylic acid

[0298] 1 H NMR (60MHz, DMSO-d6) δ10.98(s,1H),9.17-8.49(m,2H),8.57-7.81(m,1H),4.08(s,2H).

[0299] HPLC-MS:Rt 1.205m / z 257.1-259.2[M+H] + .

[0300] Intermediate 17: 3-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)-5-fluorobenzoic acid

[0301] 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 by an external EtOH / ice bath, NaH (1.5 g, 36.78 mmol, 60% mineral oil dispersion) was added in a single addition, 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 to reach room temperature overnight. Silica was added, and the solvent was concentrated under vacuum. The residue was purified by rapid silica gel chromatography (8 → 15% MeOH / CH2Cl2 + 1% AcOH) to give a beige solid (4.71 g, 80%).

[0302] 1 H NMR (300MHz, DMSO-d6) δ = 10.90 (s, 1H), 8.88 (d, J = 4.5Hz, 1H), 8.18 (s, 1H), 8.10-7.96 (m, 2 H),7.85-7.69(m,3H),7.64-7.31(m,5H),6.98(d,J=7.5Hz,1H),5.27(s,2H),1.82(s,3H).

[0303] HPLC-MS:Rt 3.018m / z 482.1[M+H] + .

[0304] The following intermediates 18 to 19 are prepared according to the method described for intermediate 17.

[0305] Intermediate 18: 5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)tert-butyl pyridinecarboxylate

[0306] The residue was purified by rapid silica gel chromatography (2.5→4% MeOH / CH2Cl2) to give a yellow solid (0.950 g, 69%).

[0307] 1H-NMR (300MHz, CDCl3): δ = 10.83 (s, 1H), 8.92 (dd, J = 4.7, 1.4Hz, 1H), 8.54 (m, 1H), 8.30-8.26 (m, 1H), 8.18 (d, J = 8.5Hz, 1H), 7.95 (d, J = 8.2Hz,1H),7.80-7.69(m,3H),7.49-7.31(m,3H),7.00(d,J=7.9Hz,1H),6.90(d,J=7.9Hz,1H),5.29(s,2H),2.37(s,3H),1.62(s,9H).

[0308] HPLC-MS:Rt 10.376m / z 521.1[M+H] + .

[0309] Intermediate 19: 6-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)pyridine-3-carboxylic acid tert-butyl ester

[0310] 1 H NMR(300MHz,DMSO-d6)δ11.20(s,1H),8.68(m,1H),8.26-7.64(m,4H),7.72 -7.02(m,7H),6.81(d,J=7.4Hz,1H),5.19(s,2H),1.67(s,3H),1.39(s,9H).

[0311] HPLC-MS:Rt 4.011m / z 521.3-522.2[M+H] + .

[0312] Intermediate 20: 5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)pyridinecarboxylic acid.

[0313] A solution of tert-butyl 5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)pyridinecarboxylate (0.170 mg, 0.518 mmol) in hydrochloric acid solution (8 mL, 4 M in dioxane) was refluxed for 2 hours and allowed to reach room temperature. EtOAc (2 x 15 mL) was added, and the solvent was removed under vacuum. The remaining crude product was purified by C18 chromatography using a Combiflash system (5 → 100% H2O / MeCN) to give a pale yellow solid (0.063 g, 26%).

[0314] 1H-NMR (300MHz, DMSO-d6): δ = 11.06 (s, 1H), 8.91 (s, 1H), 8.85 (d, J = 4.4Hz, 1H), 8.26 (d, J = 8.1Hz, 1H), 8 .18(s,1H),8.05(t,J=9.3Hz,2H),7.72-7.37(m,6H),6.98(d,J=7.5Hz,1H),5.33(s,2H),1.83(s,3H).

[0315] HPLC-MS:Rt 12.726m / z 465.0[M+H] + .

[0316] The following intermediate 21 is prepared according to the method described for intermediate 20.

[0317] Intermediate 21: 6-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)pyridine-3-carboxylic acid

[0318] HPLC-MS:Rt 3.158m / z 465.1[M+H] + .

[0319] Intermediate 22: 2-(3-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)-5-fluorobenzoyloxy)ethyl ethyl carbamate tert-butyl ester

[0320] 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), N,N-diisopropylethylamine (0.21 mL, 1.24 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium hexafluorophosphate (0.26 g, 0.622 mmol) were added, and the 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 x 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.

[0321] HPLC-MS:Rt 4.021m / z 653.3[M+H] + .

[0322] The following intermediates 23 to 28 are prepared according to the method described for intermediate 22.

[0323] Intermediate 23: 2-(3-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)-5-fluorobenzoyloxy)ethyl isopropyl carbamate tert-butyl ester

[0324] HPLC-MS:Rt 4.112m / z 667.3[M+H] + .

[0325] Intermediate 24: 2-(3-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)-5-fluorobenzoyloxy) tert-butyl ethylcarbamate

[0326] HPLC-MS:Rt 3.878m / z 625.3[M+H] + .

[0327] Intermediate 25: 2-(3-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)-5-fluorobenzoyloxy)ethyl methyl carbamate tert-butyl ester

[0328] HPLC-MS:Rt 3.954m / z 639.3[M+H] + .

[0329] Intermediate 26: 4-(2-(3-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)-5-fluorobenzoyloxy)ethyl)piperazine-1-carboxylic acid tert-butyl ester

[0330] HPLC-MS:Rt 3.981m / z 694.2[M+H] + .

[0331] Intermediate 27: 4-((3-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)-5-fluorobenzoyloxy)methyl)piperidine-1-carboxylic acid tert-butyl ester

[0332] HPLC-MS:Rt 4.091m / z 679.3[M+H] + .

[0333] Intermediate 28: 4-(3-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)-5-fluorobenzoyloxy)piperidine-1-carboxylic acid tert-butyl ester

[0334] HPLC-MS:Rt 4.060m / z 665.3[M+H] + .

[0335] Intermediate 29 methyl 3-(2-bromoacetamido)-5-chlorobenzoate

[0336] HPLC-MS: Rt 9.991 m / z 306.0 [MH] - .

[0337] The intermediate was prepared according to the method described for intermediate 17.

[0338] Example

[0339] Example 1 2-(dimethylamino)ethyl benzoate of 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoic acid

[0340] Add thionyl chloride (1.5 mL, 20.75 mmol) 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), and heat the mixture under reflux overnight. Allow the reaction to reach room temperature, and evaporate the solvent under reduced pressure. Resuspend the residue in dichloromethane (50 mL), add 2-(dimethylamino)ethanol (0.59 mL, 6.22 mmol) and N,N-diisopropylethylamine (3 mL, 17.48 mmol), and stir the mixture at room temperature for 30 minutes. Pour the mixture onto water (50 mL), separate the phases, and wash the organic phase with water (50 mL) and brine (50 mL). Citric acid aqueous solution was added to the organic layer to achieve 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 cool to room temperature overnight. The resulting suspension was filtered and washed with acetonitrile (15 mL) to give a pale yellow solid (1.24 g, 54%).

[0341] 1H NMR (300MHz, DMSO-d6) δ = 10.95 (s, 1H), 8.84 (d, J = 4.4Hz, 1H), 8.32-7.10 (m, 11H), 6.96 (d, J = 7 .4Hz,1H),5.22(s,2H),4.36(t,J=5.6Hz,2H),2.60(t,J=5.6Hz,2H),2.19(s,6H),1.82(s,3H).

[0342] UPLC-MS:Rt 3.562m / z 553.4-554.4[M+H] + .

[0343] The following Examples 2 and 3 were prepared according to the method described in Example 1.

[0344] Example 2: 5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)nicotinic acid 2-(dimethylamino)ethyl ester

[0345] 1 H NMR (300MHz, DMSO-d6) δ10.99(s,1H),9.01(d,J=2.5Hz,1H),8.84(dd,J=10.2,3.2Hz,2H),8.65(t,J=2.2Hz,1H),8.19(s,1H),8.04(d,J= 8.3Hz,1H),7.81-7.27(m,7H),6.98(d,J=7.4Hz,1H),5.32(s,2H),4.40(t,J=5.7Hz,2H),2.63(t,J=5.7Hz,2H),2.21(s,6H),1.84(s,3H).

[0346] UPLC-MS:Rt 2.853m / z 536.4-537.4[M+H] + .

[0347] Example 3: 6-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)nicotinic acid 2-(dimethylamino)ethyl ester

[0348] 1H NMR(300MHz,DMSO-d6)δ11.43(s,1H),9.07-8.66(m,2H),8.46-7.88(m,4H),7.81-7.23(m,6H),6.98( d,J=7.4Hz,1H),5.37(s,2H),4.37(t,J=5.7Hz,2H),2.62(t,J=5.7Hz,2H),2.22(s,6H),1.84(s,3H).

[0349] UPLC-MS:Rt 2.911m / z 536.4-537.4[M+H] + .

[0350] Example 4 2-morpholinoethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoic acid

[0351] 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), thionyl chloride (0.290 mL, 3.97 mmol) was added, and the reaction mixture was heated under reflux for 3 hours to reach 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. The mixture was stirred overnight at room temperature. The solvent was removed under vacuum, and the residue was dissolved in EtOAc (20 mL) and washed with sodium bicarbonate (2 x 20 mL, saturated aqueous solution). The organic phase was dried over sodium sulfate and concentrated. The reaction product was suspended in MeCN (10 mL), stirred at room temperature for 4 hours, and the resulting suspension was filtered and washed with MeCN (2 x 5 mL) to give a white solid (0.130 g, 55%).

[0352] 1 H NMR (300MHz, DMSO-d6) δ=10.93(s,1H),8.83(d,J=4.5Hz,1H),8.15(s,1H),8.02(d,J=8.0Hz,2H),7.85(d,J=11.1Hz,1H),7.74-7.25(m ,7H),6.96(d,J=7.5Hz,1H),5.25(s,2H),4.39(t,J=5.8Hz,2H),3.53(t,J=4.6Hz,4H),2.67(t,J=5.8Hz,2H),2.44(m,4H),1.81(s,3H).

[0353] UPLC-MS:Rt 3.449m / z 595.4-596.4[M+H] + .

[0354] The following Examples 5 to 8 were synthesized using the method described in Example 4.

[0355] Example 5 5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)pyridinecarboxylic acid 2-(dimethylamino)ethyl ester

[0356] 1 H NMR (300MHz, DMSO-d6) δ=11.07(s,1H),8.93-8.81(m,2H),8.30(d,J=8.8Hz,1H),8.17(s,1H),8.06(dd,J=13.5,8.4Hz,2H),7 .76-7.34(m,6H),6.98(d,J=7.7Hz,1H),5.33(s,2H),4.37(t,J=6.1Hz,2H),2.61(t,J=6.1Hz,2H),2.21(s,6H),1.84(s,3H).

[0357] UPLC-MS:Rt 2.682m / z 536.5[M+H] + .

[0358] 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)benzoic acid

[0359] 1 H NMR (300MHz, DMSO-d6) δ = 10.94 (s, 1H), 8.83 (d, J = 4.4Hz, 1H), 8.29-7.23 (m, 11H), 6.96 (d, J = 7.6Hz, 1H), 5.26 (s, 2H), 4.36 (br s, 2H), 2.66 (br s,2H),2.48(br s,4H),2.27(br s,4H),2.09(s,3H),1.82(s,3H).

[0360] UPLC-MS:Rt 3.083m / z 608.3-609.3[M+H] + .

[0361] Example 72-(diethylamino)ethyl benzoate of 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoic acid

[0362] 1 H NMR (300MHz, DMSO-d6) δ = 10.94 (s, 1H), 8.84 (d, J = 4.4Hz, 1H), 8.25-7.23 (m, 11H), 6.96 (d, J = 7.5Hz, 1H), 5.26 ( s, 2H), 4.34 (t, J = 5.8Hz, 2H), 2.82 (t, J = 5.8Hz, 2H), 2.59 (q, J = 7.1Hz, 4H), 1.82 (s, 3H), 0.97 (t, J = 7.1Hz, 6H).

[0363] UPLC-MS:Rt 3.393m / z 581.4-582.4[M+H] + .

[0364] Example 8 3-Fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoic acid 1-methylpiperidin-4-yl ester

[0365] 1 H NMR (300MHz, DMSO-d6) δ = 10.93 (s, 1H), 8.84 (d, J = 4.5Hz, 1H), 8.29-7.76 (m, 5H), 7.79-7.24 (m, 7H), 6.96 (d, J = 7.5Hz, 1H), 5.26 (s, 2H), 4.97 (br s,1H),2.70(br s,2H),2.28(br s,2H),1.94(br s,2H),1.82(m,5H).

[0366] UPLC-MS:Rt 3.248m / z 579.4-580.4[M+H] + .

[0367] Example 9 3-Fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoic acid (1-methylpiperidin-4-yl)methyl ester

[0368] 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) and 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. Then, 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 stirred at room temperature for another 3 hours. The reaction mixture was diluted with EtOAc (20 mL) and washed with brine (3 x 15 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by C18 chromatography using a Combiflash system (5 → 80% H2O / MeCN + 0.1% formic acid) to give a white solid (0.015 g, 6%).

[0369] 1 H NMR (300MHz, DMSO-d6) δ = 11.02 (s, 1H), 8.86 (d, J = 4.5Hz, 1H), 8.24-7.84 (m, 5H), 7.78-7.28 (m, 6H), 6.98 (d, J = 7.5Hz, 1H), 5.28 (s, 2H), 4.1 8(d,J=5.8Hz,2H),2.88(d,J=11.2Hz,2H),2.24(s,3H),2.04(t,J=11.2Hz,2H),1.84(s,3H),1.73(d,J=11.9Hz,3H),1.39(t,J=11.9Hz,2H).

[0370] UPLC-MS:Rt 3.141m / z 593.4-594.4[M+H] + .

[0371] Example 10 :(R)-3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)quinine cyclo-3-yl ester

[0372] 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), N,N-diisopropylaminosilane (0.21 mL, 1.24 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium hexafluorophosphate (0.23 g, 0.623 mmol) were added, and the reaction mixture was stirred at room temperature for 30 minutes. (R)-quininecyclo-3-ol (0.105 g, 0.830 mmol) was continuously added to the reaction mixture, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc (30 mL) and washed with brine (2 x 20 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by C18 chromatography using a Combiflash system (5 → 80% H2O / MeCN + 0.1% formic acid) to give an off-white solid (0.057 g, 23%).

[0373] 1 H NMR (400MHz, DMSO-d6) δ = 10.95 (s, 1H), 8.83 (d, J = 4.4Hz, 1H), 8.16 (d, J = 11.7Hz, 2H), 8.02 (tt, J = 3.7, 1. 0Hz,2H),7.91(dt,J=10.9,2.3Hz,1H),7.77-7.61(m,2H),7.56(t,J=7.7Hz,1H),7.52-7.43(m,2H),7.43- 7.33(m,2H),6.96(dt,J=7.5,0.8Hz,1H),5.26(s,2H),4.99(ddd,J=8.2,4.9,2.1Hz,1H),3.34-3.21(m,2 H),2.98-2.66(m,4H),2.10(m,1H),2.00-1.86(m,1H),1.82(s,3H),1.76-1.52(m,2H),1.53-1.39(m,1H).

[0374] UPLC-MS:Rt 3.144m / z 591.4-592.4[M+H] + .

[0375] Examples 11 to 14 were synthesized using the method described in Example 10.

[0376] Example 11:(S)-3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)quinine cyclo-3-yl ester

[0377] 1 H NMR (300MHz, DMSO-d6) δ10.92(s,1H),8.84(d,J=4.5Hz,1H),8.20-7.81(m,4H),7.76-7.28(m,8H),6.96(d,J=7.4Hz,1H),5.26(s, 2H),5.13-4.78(m,1H),3.38-3.18(m,2H),22.84-2.66(m,4H),2.06(s,1H),1.88-1.80(m,1H),1.82(s,3H),1.73-1.29(m,3H).

[0378] UPLC-MS:Rt 3.045m / z 591.4-592.4[M+H] + .

[0379] Example 12 3-Fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)quinoline cyclo-4-yl ester

[0380] 1 H NMR (300MHz, DMSO-d6) δ10.81(d,J=9.3Hz,1H),8.86(d,J=4.4Hz,1H),8.17(d,J=2.1Hz,1H),8.04(d,J=8.2Hz, 1H),7.90-7.63(m,4H),7.64-7.30(m,6H),6.99(d,J=7.5Hz,1H),5.26(s,2H),1.84(s,3H),1.44-1.12(m,12H).

[0381] UPLC-MS:Rt 6.744m / z 591.5-592.5[M+H] + .

[0382] Example 13 2-(azacyclobutane-1-yl)ethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoic acid

[0383] 1H NMR (300MHz, DMSO-d6) δ10.97(s,1H),8.86(d,J=4.4Hz,1H),8.17(s,1H),8.10-8.00(m,2H),7.90(dt,J=10.9,2.3Hz,1H),7.81-7.29(m,7H) ,6.98(d,J=7.5Hz,1H),5.28(s,2H),4.24(t,J=5.4Hz,2H),3.18(t,J=6.9Hz,4H),2.69(t,J=5.4Hz,2H),1.96(p,J=6.9Hz,2H),1.84(s,3H).

[0384] UPLC-MS:Rt 3.887m / z 565.5-566.5[M+H] + .

[0385] Example 14 2-(aziridin-1-yl)ethyl benzoate of 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate

[0386] 1 H NMR(300MHz,DMSO-d6)δ10.98(s,1H),8.97-8.59(m,1H),8.24-7.80(m,4H),7.82-7.28(m,8H),6.99(d ,J=7.5Hz,1H),5.29(s,2H),4.41(t,J=5.3Hz,2H),1.84(s,3H),1.72-1.44(m,2H),1.41-1.02(m,2H).

[0387] UPLC-MS:Rt 3.439m / z 551.4-552.4[M+H] + .

[0388] Example 15 2-(methylamino)ethyl benzoate of 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate

[0389] To a solution of 0.30 g (0.469 mmol) of tert-butyl 2-(3-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)-5-fluorobenzoyloxy)ethyl methylcarbamate in dioxane (3 mL), HCl (0.58 mL, 2.34 mmol, 4 M in dioxane) was added, and the reaction mixture was stirred at room temperature for 4 hours. 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) and ammonium chloride (10 mL, saturated aqueous solution), dried over sodium sulfate, and concentrated. The reaction product was purified by C18 chromatography using the Combiflash system (5→80% MeCN:H2O+0.1 formic acid) to give a white solid (0.043 g, 17%).

[0390] 1 H NMR (300MHz, DMSO-d6) δ=11.10(s,1H),8.86(d,J=4.4Hz,1H),8.30(s,1H),8.17(s,1H),8.12-7.97(m,2H),7.92(dt,J=11.0,2.3Hz ,1H),7.80-7.29(m,6H),6.98(d,J=7.4Hz,1H),5.28(s,2H),4.39(t,J=5.3Hz,2H),2.99(t,J=5.3Hz,2H),2.43(s,3H),1.84(s,3H).

[0391] UPLC-MS:Rt 3.010m / z 539.4-540.4[M+H] + .

[0392] Using the method described in Example 15, the following Examples 16 to 21 were synthesized from the corresponding ester derivatives.

[0393] Example 16 2-Aminoethyl benzoate of 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoic acid

[0394] 1H NMR (300MHz, DMSO-d6) δ = 11.19 (s, 1H), 8.83 (d, J = 4.5Hz, 1H), 8.31 (s, 1H), 8.14 (br s,2H),8.02(d,J=8.3Hz,1H),7.91(d,J=10.8Hz,1H),7.78-7.24(m,8H),6.96(d,J=7.5Hz,1H),5.27(s,2H),4.34(br s,2H),3.07(br s,2H),1.82(s,3H).

[0395] UPLC-MS:Rt 2.880m / z 525.3-526.3[M+H] + .

[0396] Example 17 2-(ethylamino)ethyl benzoate of 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate

[0397] 1 H NMR (300MHz, DMSO-d6) δ11.11(s,1H),8.85(d,J=4.5Hz,1H),8.30(br s,1H),8.17(s,1H),8.11(br s,1H),8.04(d,J=8.2Hz,1H),7.91-7.89(m,1H),7.80-7.29(m,7H),6.98(d,J=7.5Hz,1H),5.28(s,2H),4.38(t,J=5.5Hz,2H),3.01(br s,2H),2.84-2.64(m,2H),1.84(s,3H),1.08(t,J=7.1Hz,3H).

[0398] UPLC-MS:Rt 3.016m / z 553.3-554.3[M+H] + .

[0399] Example 18 2-(isopropylamino)ethyl benzoate of 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoic acid

[0400] 1H NMR (300MHz, DMSO-d6) δ = 11.14 (s, 1H), 8.85 (d, J = 4.4Hz, 1H), 8.29 (s, 1H), 8.17 (s, 1H), 8.12 (br s,1H),8.04(d,J=8.3Hz,1H),7.91(dt,J=11.1,2.3Hz,1H),7.78-7.33(m,7H),6.98(d,J=7.5Hz,1H),5.29( s, 2H), 4.38 (t, J = 5.6Hz, 2H), 3.03 (t, J = 5.6Hz, 2H), 3.01-2.93 (m, 1H), 1.84 (s, 3H), 1.08 (d, J = 6.2Hz, 6H).

[0401] UPLC-MS:Rt 3.113m / z 567.4-568.4[M+H] + .

[0402] Example 19 2-(piperazin-1-yl)ethyl benzoate of 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate

[0403] 1 H NMR (300MHz, DMSO-d6) δ = 11.13 (s, 1H), 8.85 (d, J = 4.4Hz, 1H), 8.35 (s, 1H), 8.17 (s, 1H) ,8.12-7.30(m,10H),6.98(d,J=7.6Hz,1H),5.29(s,2H),4.40(t,J=5.5Hz,2H),2.84(br s,4H),2.79-2.63(m,2H),1.84(s,3H).

[0404] UPLC-MS:Rt 3.070m / z 594.4-595.4[M+H] + .

[0405] Example 20 3-Fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)piperidin-4-ylmethyl benzoate

[0406] 1H NMR (300MHz, DMSO-d6) δ = 10.38 (s, 1H), 7.90 (br s,1H),7.42(s,1H),7.21(s,1H),7.17-6.90(m,3H),6.87-6.32(m,7H),6.02(d,J=7.6Hz,1H),4.34 (s,2H),3.24(d,J=3.8Hz,2H),2.28(d,J=12.2Hz,2H),1.85(t,J=12.6Hz,2H),1.06(m,1H),0.86(br s, 5H), 0.55 (q, J = 12.4Hz, 2H).

[0407] UPLC-MS:Rt 3.068m / z 579.4-580.4[M+H] + .

[0408] Example 21 3-Fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)piperidin-4-yl benzoate

[0409] 1 H NMR (300MHz, DMSO-d6) δ=11.11(s,1H),8.85(dd,J=4.6,1.8Hz,1H),8.49-7.80(m,5H),7.80-7.26(m,7H),6.98(d,J=7.5Hz,1H),5.29(s,2H),5.14(br s,1H),3.17(br s,2H),2.95(s,2H),2.11-1.93(m,2H),1.84(m,J=1.8Hz,5H).

[0410] UPLC-MS:Rt 3.012m / z 565.4-566.4[M+H] + .

[0411] Comparative Example 1: 3-Fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)cyclopropyl methyl benzoate

[0412] The compound was prepared according to the method described in Example 1.

[0413]

[0414] 1H NMR(300MHz,DMSO-d6)δ10.96(s,1H),8.86(m,1H),8.25-7.80(m,4H),7.79-7 .28(m,7H),6.98(d,J=7.6Hz,1H),5.28(s,2H),4.15(d,J=8.0Hz,2H),1.84(br s, 3H), 1.24 (br s, 1H), 0.58 (d, J = 7.5Hz, 2H), 0.37 (br s, 2H).

[0415] UPLC-MS:Rt 4.16m / z 536.5-537.5[M+H] + .

[0416] Comparative Example 2: methyl 3-chloro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate

[0417]

[0418] 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 with an external EtOH / ice bath, NaH (50 mg, 1.27 mmol, 60% mineral oil dispersion) was added in a single addition, and the reaction mixture was stirred at low temperature for 20 minutes. 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 hours until it reached 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 x 10 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (0→3% MeOH / CH2Cl2) and then by C18 chromatography using a Combiflash system (5→90% H2O / MeOH). The obtained solid was adjusted into a slurry with diethyl ether (2×3mL) to obtain a light yellow solid (0.257g, 47%).

[0419] 1 H NMR (300MHz, DMSO-d6) δ = 10.93 (s, 1H), 8.86 (d, J = 4.4Hz, 1H), 8.44-7.84 (m, 4H), 7.81-7.23(m,7H),6.98(d,J=7.5Hz,1H),5.28(s,2H),3.88(s,3H),1.83(s,3H).

[0420] HPLC-MS:Rt 19.792m / z 512.1[M+H] + .

[0421] Comparative Example 3: 2-Hydroxyethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoic acid

[0422]

[0423] The compound was prepared according to the method described in Example 1, but Et3N was used instead of DIPEA.

[0424] 1 H NMR (300MHz, DMSO-d6) δ = 10.99 (s, 1H), 8.85 (d, J = 4.5Hz, 1H), 8.25-7.83 (m, 4H), 7.78-7.34 (m, 7H), 6.98 (d, J = 7.5Hz, 1H), 5.28 (s, 2H), 4.98 (br s, 1H), 4.31 (t, J = 4.9Hz, 2H), 3.71 (br s, 2H), 1.84 (s, 3H).

[0425] UPLC-MS:Rt 3.135m / z 526.4-527.4[M+H] + .

Claims

1. Compounds of formula (I): in: -R 1 It indicates that the group is selected from the following: a) A phenyl ring, which is either unsubstituted or substituted with one or two groups selected from the following: halogen atom, straight-chain or branched C1-C3 haloalkyl, straight-chain or branched C1-C3 alkyl, straight-chain or branched C1-C3 alkoxy, cyano, and hydroxyl. b) A 5- or 6-membered heteroaryl ring, which is unsubstituted or substituted by one or two groups selected from the following: halogen atom, straight-chain or branched C1-C3 haloalkyl, straight-chain or branched C1-C3 alkyl, straight-chain or branched C1-C3 alkoxy, cyano, and hydroxyl. -R 2 It is selected from the following groups: a) Hydrogen atom, b) Straight-chain or branched C1-C3 alkyl groups optionally substituted with 1, 2, or 3 halogen atoms. -R 3 It indicates that the group is selected from the following: a) Hydrogen atom, b) Straight-chain or branched C1-C3 alkyl groups optionally substituted with 1, 2, or 3 halogen atoms. c) Halogen atoms, -R 4 and R 5 Indicates that the group is independently selected from the following: a) Hydrogen atom, b) Straight-chain or branched C1-C3 alkyl groups optionally substituted with 1, 2, or 3 halogen atoms. c) Halogen atoms, -n is an integer from 0 to 3. -R 6 It indicates that the group is selected from the following: a)-N(R 7 (R) 8 ), where R 7 and R 8 Independently representing straight-chain or branched C1-C6 alkyl or hydrogen atoms, and b) A saturated 4- to 10-membered monocyclic or bicyclic nitrogen-containing heterocyclic group, optionally comprising another heteroatom selected from oxygen and nitrogen, wherein the heterocyclic group is optionally substituted with a group selected from C1-C3 alkyl groups. Or its pharmaceutically acceptable salt.

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

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 It indicates a methyl group.

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 This indicates a benzene ring that has been replaced by one or two halogen atoms.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein n is an integer from 1 to 2, and R 6 Represents -N(R) 7 (R) 8 ) group.

6. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein R 7 and R 8 Independently represents a group selected from straight-chain C1-C3 alkyl groups and hydrogen atoms.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 6 This indicates a saturated 6-membered heterocyclic group containing one or two nitrogen atoms, which may optionally be substituted with a methyl group.

8. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein R 6 This indicates a group selected from piperazinyl and piperidinyl.

9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 R 4 and R 5 R represents a hydrogen atom. 3 Indicates a straight-chain C1-C3 alkyl group, R 1 This represents a benzene ring substituted with one or two halogen atoms, where n is an integer from 0 to 2, and R 6 It indicates that the group is selected from the following: a)-N(R 7 (R) 8 ), where R 7 and R 8 Selected from straight-chain C1-C3 alkyl groups and hydrogen atoms, b) A saturated 6-membered heterocyclic group containing one or two nitrogen atoms, optionally substituted with a methyl group, and c) 1-aza-bicyclo[2.2.2]octyl.

10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, selected from: 2-(dimethylamino)ethyl benzoate of 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate; 5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)nicotinic acid 2-(dimethylamino)ethyl ester; 6-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)nicotinic acid 2-(dimethylamino)ethyl ester; 2-morpholinoethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoic acid; 5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)pyridinecarboxylic acid 2-(dimethylamino)ethyl ester; 2-(4-methylpiperazin-1-yl)ethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoic acid; 2-(diethylamino)ethyl benzoate of 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate; 1-Methylpiperidin-4-yl ester of 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoic acid; 3-Fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoic acid (1-methylpiperidin-4-yl)methyl ester; (R)-3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoic acid quinine ring-3-yl ester; (S)-3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoic acid quinine ring-3-yl ester; 3-Fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoic acid quinine ring-4-yl ester; 2-(azacyclobutane-1-yl)ethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoic acid; 2-(aziridin-1-yl)ethyl benzoate of 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate; 2-(methylamino)ethyl benzoate of 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate; 2-Aminoethyl benzoate of 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate; 2-(ethylamino)ethyl benzoate of 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate; 2-(isopropylamino)ethyl benzoate of 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)benzoic acid; 3-Fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)piperidin-4-ylmethyl benzoate; and 3-Fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)piperidin-4-yl benzoate; Or any of these pharmaceutically acceptable salts.

11. Use of a compound of any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disease or pathological condition selected from respiratory diseases, fibrotic skin diseases, and fibrotic eye diseases.

12. Use of the compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein the respiratory disease is selected from pulmonary fibrosis, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, idiopathic pulmonary fibrosis, interstitial pulmonary fibrosis, pulmonary hypertension, and lung cancer.

13. Use of the compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein the fibrotic dermatitis is selected from scleroderma, nephrotic fibrotic dermatitis, mixed connective tissue disease, sclerosing myxedema, and eosinophilic fasciitis.

14. Use of the compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein the fibrotic eye disease is selected from dry eye, age-related macular degeneration, corneal and conjunctival scarring, postcataract fibrosis, proliferative vitreoretinopathy, and proliferative diabetic retinopathy.

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

16. The pharmaceutical composition of claim 15, further comprising a therapeutically effective amount of a therapeutic agent for treating a disease or pathological condition selected from respiratory diseases, fibrotic skin diseases, and fibrotic eye diseases.

17. A combination product comprising a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10 and at least one therapeutic agent for treating a disease or pathological condition selected from respiratory diseases, fibrotic skin diseases, and fibrotic eye diseases.

18. Compounds of formula (II): or its salt; Where R 1 R 2 R 3 R 4 and R 5 As defined in any one of claims 1 to 10.

19. The compound of claim 18 or a salt thereof, wherein the compound is selected from: 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)pyridinecarboxylic acid; and 6-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)pyridine-3-carboxylic acid; Or any of these salts.

20. A method for preparing a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, comprising: a compound of formula (II) or a salt thereof: Reacts with compounds of formula (III) or their salts: OH-(CH2) n -R 6 (III) Where n and R 1 R 2 R 3 R 4 R 5 and R 6 As defined in any one of claims 1 to 10.

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