4-(2-(4((2,4-dioxothiazolidin-5-yl)methyl)phenoxy) derivatives and their (biological) equivalents as PPARγ agonists and autotaxin inhibitors

Abstract

The present invention relates to a pharmaceutical compound or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of the following conditions, wherein the pharmaceutical compound or a pharmaceutically acceptable salt thereof is characterized in that it simultaneously inhibits autotaxin (ATX) and agonizes PPARγ, and has a chemical formula selected from the group consisting of formulas (A), (B), (C), (D), (E), (F), (G), and (H): a) fibroproliferative diseases, in particular interstitial lung diseases (ILD) and / or liver diseases such as all types of hepatitis and / or non-alcoholic fatty liver disease (NAFLD) and / or non-alcoholic steatohepatitis (NASH) and / or cirrhosis, where the ILD is a primary disease, preferably idiopathic pulmonary fibrosis and / or sarcoidosis and / or interstitial pneumonia, or where the ILD is associated with an autoimmune and / or inflammatory and / or metabolic disease, preferably rheumatoid arthritis-ILD ​​and / or scleroderma-ILD and / or myositis-ILD ​​and / or diabetes-ILD ​​and / or cardiovascular disease-ILD combination, and / or b) an inflammatory and / or autoimmune disease, preferably rheumatoid arthritis and / or scleroderma, and / or c) cancer, in particular lung cancer and / or hepatocellular carcinoma and / or pancreatic cancer and / or glioblastoma and / or neuroblastoma, and / or d) metabolic diseases, in particular type 1 diabetes and / or type 2 diabetes and / or obesity [Formula 1] TIFF2026503883000014.tif94126

Description

Summary of the Invention

[0001] The present invention provides a pharmaceutical compound or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of the following: a) fibroproliferative diseases, in particular interstitial lung diseases (ILD) and / or liver diseases such as all types of hepatitis and / or non-alcoholic fatty liver disease (NAFLD) and / or non-alcoholic steatohepatitis (NASH) and / or cirrhosis, where the ILD is a primary disease, preferably idiopathic pulmonary fibrosis and / or sarcoidosis and / or interstitial pneumonia, or where the ILD is associated with an autoimmune and / or inflammatory and / or metabolic disease, preferably rheumatoid arthritis-ILD ​​and / or scleroderma-ILD and / or myositis-ILD ​​and / or diabetes-ILD ​​and / or cardiovascular disease-ILD combination, and / or b) an inflammatory and / or autoimmune disease, preferably rheumatoid arthritis and / or scleroderma, and / or c) cancer, in particular lung cancer and / or hepatocellular carcinoma and / or pancreatic cancer and / or glioblastoma and / or neuroblastoma, and / or d) metabolic diseases, in particular type 1 diabetes and / or type 2 diabetes and / or obesity, The present invention relates to the pharmaceutical compound or a pharmaceutically acceptable salt thereof, characterized in that the pharmaceutical compound exhibits autotaxin (ATX) inhibition and PPARγ agonism simultaneously, and comprises a chemical formula selected from the group consisting of formulas (A), (B), (C), (D), (E), (F), (G), and (H). [ka]

[0002] Fibrosis is the excessive deposition of collagen and other extracellular matrix components, altering tissue architecture and resulting in impaired functional properties and partial or complete failure of the corresponding organ (lung, liver, skin, kidney, heart, pancreas). In developed countries, fibrosis and related fibroproliferative disorders, including but not limited to pulmonary fibrosis and hepatic fibrosis, are estimated to account for up to 50% of deaths. Furthermore, fibrosis is a frequent side effect of radiation therapy and COVID-19, while its presence has been shown to critically influence cancer metastasis and accelerate chronic transplant rejection, demonstrating the profound impact of fibrosis on human health [Rockey, DC, P.D.Bell, and J.A.Hill (2015). “Fibrosis—A Common Pathway to Organ Injury and Failure.” N Engl J Med 372(12):1138-1149].

[0003] Interstitial lung diseases (ILDs) comprise a complex group of pulmonary fibroproliferative disorders that primarily affect the lung parenchyma and have diverse prognoses and clinical behaviors. It is estimated that more than 200 distinct diseases can cause ILD, including systemic autoimmune diseases such as scleroderma (SSc-ILD) and rheumatoid arthritis (RA-ILD) [Wijsenbeek, MA Suzuki, and TM Maher (2022). “Interstitial lung diseases.” The Lancet 400(10354):769-786]. Idiopathic pulmonary fibrosis (IPF), the most common and most fatal ILD, is a chronic, progressive, and usually fatal lung disease. It primarily affects patients over the age of 60, with a median survival time from diagnosis of 3–5 years, regardless of treatment, and a prognosis worse than many types of cancer.

[0004] Pulmonary fibrosis shares many characteristics with the aging lung, including genomic instability, loss of proteostasis, telomere shortening, cellular senescence, and dysregulated mitochondrial homeostasis. As a result, patients with IPF exhibit significant age-related comorbidities, such as emphysema, lung cancer, pulmonary hypertension, and gastroesophageal reflux disease, as well as endocrine / metabolic disorders, such as diabetes, hypothyroidism, and dyslipidemia, which significantly impact survival and quality of life [Oldham, JM, and HR Collard (2017). “Comorbid Conditions in Idiopathic Pulmonary Fibrosis Recognition and Management” Front Med (Lausanne) 4:123]. Focusing more specifically on metabolic disorders, hypothyroidism, diabetes, and dyslipidemia are prevalent (10–39%) and have been suggested to be associated with poor prognosis in IPF patients [Oldham, J.M. and H.R. Collard (2017). “Comorbid Conditions in Idiopathic Pulmonary Fibrosis Recognition and Management” Front Med (Lausanne) 4:123]. IPF-associated metabolic reprogramming, a hallmark of cancer, includes increased glycolysis, glutaminolysis, and fatty acid oxidation, leading to dysregulation of mitochondrial homeostasis and function [Selvarajah, B., I. Azuelos, D. Anastasiou and R.C. Chambers (2021). “Fibrometabolism—An emerging therapeutic frontier in pulmonary fibrosis.” Sci. Signal 14(697)]. Adipokines are not only cell signaling molecules produced by adipose tissue (e.g., adiponectin, leptin, autotaxin) but also nuclear receptors, such as PPARγ, that transduce signals from nutritional, hormonal, metabolic, and reductive stimuli and play a central role in regulating metabolic reprogramming.Nuclear receptors also regulate the expression of genes involved in cellular processes related to energy production, such as mitochondrial biogenesis and autophagy [S.F.Choltes, C. and V.Giguere(2022). “Transcriptional control of energy metabolism by nuclear receptors.” Nature reviews Molecular Cell Biology 23(11):750-770].

[0005] Autotaxin (ATX) is a secreted lysophospholipase D enzyme widely present in body fluids. It catalyzes the extracellular conversion of lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA), a growth factor-like signaling phospholipid [Barbayianni, E., E. Kaffe, V. Aidinis, and G. Kokotos (2015). “Autotaxin, a secreted lysophospholipase D, as a promising therapeutic target in chronic inflammation and cancer.” Prog Lipid Res 58:76-96; Magkrioti, C., A. Galaris, P. Kanellopoulou, E. A. Stylianaki, E. A. Kaffe, and V. Aidinis (2019). “Autotaxin and chronic inflammatory diseases.” J. Autoimmun 104:102327]. Elevated ATX / LPA levels have been reported in different types of cancer in different organs, including the lung [Magkrioti, C., N. Oikonomou, E. Kaffe, M.-A. Mouratis, N. Xylourgidis, I. Barbayianni, P. Megadoukas, V. Harokopos, C. Valavanis, J. Chun, A. Kosma, G.T. Stathopoulos, E. Bouros, D. Bouros, K. Syrigos and V. Aidinis (2018). “The Autotaxin-Lysophosphatidic Acid Axis Promotes Lung Carcinogenesis” Cancer Research 78(13):3634-3644], liver [Kaffe, E., A. Katsifa, N. V. Aidinis (2017).“Development of smooth muscle cells in the presence of smooth muscle cells.” Hepatology 65(4):1369-1383;Kaffe,E.,C.Magkrioti and V.Aidinis(2019). Cancers (Basel) 11(11)]and [Auciello,FR,V.Bulusu,C.Oon,J.Tait-Mulder,M.Berry,S.Bhattacharyya,S.Tumanov,BLAllen-Petersen,J.Link ,NDKendsersky,E.Vringer,M.Schug,D.Novo,RFHwang,RMEvans,C.Nixon,C.Dorrell,JPMorton,JCNorman,RCSears,JJKamphorst and MHSherman(2019).“A Stromal Lysolipid-Autotaxin Signaling Axis Promotes Pancreatic Tumor Progression.” Cancer Discov 9(5):617-627] and the effects of intraproteinogenic factors (IPF). [Oikonomou,N.,MAMouratis,A.Tzouvelekis,E.Kaffe,C.Valavanis,G.Vilaras,A.Karameris,GDPrestwich,D.BourosandV.Aidinis(2012). Am J Respir Cell Mol Biol 47(5):566-574]; E.,A.Katsifa,N.Xylourgidis,I.Ninou,M.Zannikou,V.Harokopos,P.Foka,A.Dimitriadis,K.Evangelou,ANMoulas,U.Georgopoulou,VGGorgoulis,GNDalekos and V. Aidinis(2017). “Hepatology 65(4):1369-1383” and rheumatoid arthritis [Nikitopoulou, I., N. Oikonomou, E. Karouzakis, I. Sevastou, N. Nikolaidou-Katsaridou, Z. Zhao, V. Mersinias, M. Armaka, Y. Xu, M. Masu, G.B. Mills, S. Gay, G. Kollias and V. Aidinis(2012). “Autotaxin expression from synovial fibroblasts is essential for the development of arthritis models.” (Autotaxin expression from synovial fibroblasts is essential for the pathogenesis of modeled arthritis. J Exp Med 209(5):925-933). Genetic or pharmacological targeting of ATX attenuates bleomycin (BLM)-induced pulmonary fibrosis, collagen-induced arthritis (CIA), and CCl4-induced hepatitis, establishing ATX as a potential therapeutic target for fibroproliferative and interstitial lung diseases. (Magkrioti, C., A. Galaris, P. Kanellopoulou, E. A. Stylianaki, E. A. Kaffe, and V. Aidinis (2019). “Autotaxin and chronic inflammatory diseases.” J Autoimmun 104:102327).

[0006] PPARγ is one of 48 known nuclear receptors that plays a central role in regulating metabolic reprogramming by integrating signals from key metabolic sensing systems, such as AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin (mTOR), and synchronizing their activity with the biological clock. Consequently, nuclear receptors are well-known targets for multidrug therapies for various diseases [Scholtes, C. and V. Giguere (2022). “Transcriptional control of energy metabolism by nuclear receptors.” Nature reviews Molecular Cell Biology 23(11):750-770]. The nuclear receptor and transcription factor PPARγ (peroxisome proliferator-activated receptor γ) regulates the expression of genes involved in lipid and glucose metabolism, thereby playing a crucial role in maintaining metabolic homeostasis [Ahmadian, M., JM Suh, N. Hah, C. Liddle, A.R. Atkins, M. Downes, and R.M. Vans (2013). “PPARγ signaling and metabolism: the good, the bad, and the future.” Nat Med 19(5):557-566]. PPARγ activators (agonists) include thiazolidinediones (TZDs) or glitazones (tropiolides, piroctones, and rosizones). Diabetes and dyslipidemia are common complications of IPF and are associated with poor prognosis [Oldham, JM and HR Collard (2017). “Comorbid Conditions in Idiopathic Pulmonary Fibrosis Recognition and Management.” Front Med (Lausanne) 4:123], while previous studies have suggested an association between PPARγ-regulated metabolic abnormalities and pulmonary fibrosis.TGFβ, a major profibrotic factor, has been shown to suppress PPARγ, whereas PPARγ activation suppressed TGFβ-induced mitochondrial activation [Calvier, L., P. Chouvarine, E. Legchenko, N. Hoffmann, J. Geldner, P. Borchert, D. Jonigk, M. M. Mozes and G. Hansmann (2017). “PPARγ Links BMP2 and TGFβ1 Pathways in Vascular Smooth Muscle Cells, Regulating Cell Proliferation and Glucose Metabolism” Cell Metab 25(5):1118-1134.e1117]. More recently, it has been suggested that the pathogenesis of pulmonary fibrosis involves TGFβ-induced differentiation of lipofibroblasts, a novel subset of lung fibroblasts, into myofibroblasts, and that activation of PPARγ inhibits this differentiation and suppresses the formation of pulmonary fibrosis [El Agha, E., A. Moiseenko, V. Kheirollahi, S. DeLanghe, S. Crnkovic, G. Kwapiszewska, M. Szibor, D. Kosanovic, F. Schwind, R.T. Schermuly, I. Henneke, B. MacKenzie, J. Quantius, S. Herold, A. Ntokou, K. Ahlbrecht, T. Braun, R.E. Morty, A. Guenther, W. Seeger and S. Bellusci (2017). “Two-Way Conversion between Lipogenic and Myogenic Fibroblastic Phenotypes Marks the Progression and Resolution of Lung Fibrosis.” Cell Stem Cell 20(2):261-273,e263].Genetic deletion of PPARγ exacerbates pulmonary fibrosis in animal models [Malur, A., A. Mohan, R.A. Barrington, N. Leffler, A. Malur, B. Muller-Borer, G. Murray, K. Kew, C. Zhou, J. Russell, J.L. Jones, C.J. Wingard, B.P. Barna and M.J. Thomassen (2019). “Peroxisome Proliferator-Activated Receptor-γ Deficiency Exacerbates Fibrotic Response to Mycobacterial Peptide in a Murine Sarcoidosis Model.” American Journal of Respiratory Cell and Molecular Biology 61(2):198-208], whereas pharmacological activation with PPARγ agonists has been shown to attenuate BLM-induced pulmonary fibrosis [Kheirollahi, V., R.M. Wasnick, V. Biasin, A.I. Vazquez-Armendariz, X. Chu, A. Moiseenko, A. Weiss, J.Wilhelm, J.S. Zhang, G. Kwapiszewska, S. Herold, R.T. Schermuly, B. Mari, X. Li, W. Seeger, A. Guenther, S. Bellusci and E. ElAgha (2019). “Metformin induces lipogenic differentiation in myofibroblasts to reverse lung fibrosis.” Nat Commun 10(1):2987], suggesting that PPARγ activation plays a beneficial role in disease pathogenesis.

[0007] Interestingly, LPA, the enzymatic product of ATX, has been suggested to inactivate PPARγ [D'Souza, K., GV Paramel and PC Kienesberger (2018). "Lysophosphatidic Acid Signaling in Obesity and Insulin Resistance." Nutrients 10(4)] and / or reduce PPARγ transcription [Li, L., L. Tam, L. Liu, T. Jin and DSNg (2011). "Wnt-signaling mediates the anti-adipogenic action of lysophosphatidic acid through cross-talking with the Rho / Rho associated kinase (ROCK) pathway." Biochem Cell Biol 89(6):515-521], although the mechanism may involve activation of Wnt signaling [Burkhalter, RJ, SD Westfall, Y. Liu and MS Stack (2015). "Lysophosphatidic Acid “Initiates Epithelial to Mesenchymal Transition and Induces β-Catenin-mediated Transcription in Epithelial Ovarian Carcinoma.” Journal of Biological Chemistry 290(36):22143-22154]. Negative regulation of the ATX / LPA axis by PPARγ may also be involved, but remains poorly understood.

[0008] The document US Patent 9051320B1 relates to a method for preventing or delaying the onset of metabolic diseases by combining an autotaxin inhibitor with a hypoglycemic agent. The documents EP Patent 3302490B1, US Patent 10183949B2, US Patent 20170037030A1 and US Patent 10125132B2 refer to compounds with autotaxin inhibitory activity. Greek Patent 1010268B (N-[2-(4-bromophenyl)-2,5-dihydro-4H-thieno[3,4-c]pyrazol-3-ylacetamides with autotaxin inhibitory activity), Greek Patent 1010099B (Thieno[3,4-c]pyrazol-3-ylacetamides with autotaxin inhibitory activity), and PCT International Application 2022003377A1 (Thieno[3,4-c]pyrazol-3-ylacetamides as autotaxin inhibitors) are also cited as compounds with autotaxin inhibitory activity.

[0009] However, there is no prior art document that describes the prevention or treatment of the following through the simultaneous action of autotaxin (ATX) inhibition and PPARγ agonism: a) fibroproliferative diseases, in particular interstitial lung diseases (ILD) and / or liver diseases such as all types of hepatitis and / or non-alcoholic fatty liver disease (NAFLD) and / or non-alcoholic steatohepatitis (NASH) and / or cirrhosis, where the ILD is a primary disease, preferably idiopathic pulmonary fibrosis and / or sarcoidosis and / or interstitial pneumonia, or where the ILD is associated with an autoimmune and / or inflammatory and / or metabolic disease, preferably rheumatoid arthritis-ILD ​​and / or scleroderma-ILD and / or myositis-ILD ​​and / or diabetes-ILD ​​and / or cardiovascular disease-ILD combination, and / or b) an inflammatory and / or autoimmune disease, preferably rheumatoid arthritis and / or scleroderma, and / or c) cancer, in particular lung cancer and / or hepatocellular carcinoma and / or pancreatic cancer and / or glioblastoma and / or neuroblastoma, and / or d) Metabolic diseases, in particular type 1 diabetes and / or type 2 diabetes and / or obesity.

[0010] Novel pharmaceutical compounds were synthesized that incorporate both the functional group of a thiazolidinedione with PPARγ agonistic activity and the functional groups of the potent ATX inhibitors PF8380, GLPG1690, and HA-155 into their structures. Among the newly synthesized compounds, only the pharmaceutical compounds with chemical formulas selected from the chemical formulas (A), (B), (C), (D), (E), (F), (G), and (H) described in this invention, in which the R group is a structural analog of the functional group of PF8380 or GLPG1690, exhibited potent autotaxin inhibitory activity at the nanomolecular scale (IC50). 50 = 0.19 μM and IC 50 =0.47 μM), whereas structural analogs of HA-155 had IC 50 =20.67 μM.

[0011] It is surprising that pharmaceutical compounds having a chemical formula selected from chemical formulas (A), (B), (C), (D), (E), (F), (G), and (H) of the present invention exhibit both PPARγ agonism and autotaxin inhibition properties.

[0012] It is surprising that the novel pharmaceutical compounds having chemical formulas selected from the chemical formulas (A), (B), (C), (D), (E), (F), (G), and (H) of the present invention have shown impressive results in each of the above-mentioned therapeutic methods due to the simultaneous action of PPARγ agonism and autotaxin inhibition.

[0013] It is surprising that the novel pharmaceutical compounds of the present invention having a chemical formula selected from the group consisting of formulas (A), (B), (C), (D), (E), (F), (G), and (H) show impressive results in the anti-fibrotic treatment of interstitial lung diseases (ILDs) caused by or complicated with autoimmune and / or inflammatory and / or metabolic diseases through the simultaneous action of PPARγ agonism and autotaxin inhibition.

[0014] It is surprising that the pharmaceutical compounds having a chemical formula selected from chemical formulas (A), (B), (C), (D), (E), (F), (G), and (H) of the present invention show impressive results in the treatment of bleomycin-induced pulmonary fibrosis and idiopathic pulmonary fibrosis through the simultaneous action of PPARγ agonism and autotaxin inhibition.

[0015] It is surprising that the pharmaceutical compounds having a chemical formula selected from the chemical formulas (A), (B), (C), (D), (E), (F), (G), and (H) of the present invention lower blood glucose levels and show excellent results in the treatment of diabetes through the simultaneous action of PPARγ agonism and autotaxin inhibition.

[0016] It is surprising that the novel pharmaceutical compounds of the present invention having a chemical formula selected from chemical formulas (A), (B), (C), (D), (E), (F), (G), and (H) show impressive effects against scleroderma through the simultaneous action of PPARγ agonism and autotaxin inhibition.

[0017] It is surprising that the novel pharmaceutical compounds of the present invention having a chemical formula selected from the group consisting of formulas (A), (B), (C), (D), (E), (F), (G), and (H) show impressive effects against rheumatoid arthritis through the simultaneous action of PPARγ agonism and autotaxin inhibition.

[0018] It is surprising that the novel pharmaceutical compounds having a chemical formula selected from chemical formulas (A), (B), (C), (D), (E), (F), (G), and (H) of the present invention show impressive results in the simultaneous treatment of pulmonary fibrosis and rheumatoid arthritis through the simultaneous action of PPARγ agonism and autotaxin inhibition.

[0019] It is surprising that the novel pharmaceutical compounds having a chemical formula selected from the chemical formulas (A), (B), (C), (D), (E), (F), (G), and (H) of the present invention show impressive results in the simultaneous treatment of pulmonary fibrosis and scleroderma through the simultaneous action of PPARγ agonism and autotaxin inhibition.

[0020] It is surprising that the novel pharmaceutical compounds having a chemical formula selected from the chemical formulas (A), (B), (C), (D), (E), (F), (G), and (H) of the present invention show impressive results in the simultaneous treatment of pulmonary fibrosis and diabetes through the simultaneous action of PPARγ agonism and autotaxin inhibition.

[0021] It is surprising that, in contrast to other thiazolidinedione derivatives used in the treatment of diabetes, the novel pharmaceutical compounds of the present invention having a formula selected from formulas (A), (B), (C), (D), (E), (F), (G), and (H) do not exhibit cardiotoxicity.

[0022] It is surprising that the novel pharmaceutical compounds of the present invention having a formula selected from formulas (A), (B), (C), (D), (E), (F), (G), and (H) do not exhibit hepatotoxicity.

[0023] The present invention is defined by the following definitions.

[0024] [Definition 1] A pharmaceutical compound or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of: a) fibroproliferative diseases, in particular interstitial lung diseases (ILD) and / or liver diseases such as all types of hepatitis and / or non-alcoholic fatty liver disease (NAFLD) and / or non-alcoholic steatohepatitis (NASH) and / or cirrhosis, where the ILD is a primary disease, preferably idiopathic pulmonary fibrosis and / or sarcoidosis and / or interstitial pneumonia, or where the ILD is associated with an autoimmune and / or inflammatory and / or metabolic disease, preferably rheumatoid arthritis-ILD ​​and / or scleroderma-ILD and / or myositis-ILD ​​and / or diabetes-ILD ​​and / or cardiovascular disease-ILD combination, and / or b) an inflammatory and / or autoimmune disease, preferably rheumatoid arthritis and / or scleroderma, and / or c) cancer, in particular lung cancer and / or hepatocellular carcinoma and / or pancreatic cancer and / or glioblastoma and / or neuroblastoma, and / or d) metabolic diseases, in particular type 1 diabetes and / or type 2 diabetes and / or obesity, The pharmaceutical compound or a pharmaceutically acceptable salt thereof is characterized in that it simultaneously inhibits autotaxin (ATX) and agonizes PPARγ, and comprises a chemical formula selected from the group consisting of formulas (A), (B), (C), (D), (E), (F), (G), and (H). [ka] (wherein n=1 to 5. The R group is a group selected from groups (i), (ii), and (iii). [ka] where X groups are O, N, and (CH) m and m=0 to 5. Ar is an aromatic or heteroaromatic ring, and the ring is substituted with hydrogen, halogen, (C 1-6 ) has one or more substituents selected from an alkyl group, a nitro group, a methoxy group, and a trifluoromethoxy group. R1 and R2 are selected from a cyano group, a fluoro group, a chloro group, a bromo group, and a methyl group.

[0025] [Definition 2] A pharmaceutical compound according to definition 1, wherein preferably n=1 or 2, more preferably n=1.

[0026] [Definition 3] A pharmaceutical compound according to any of definitions 1 to 2, wherein X is preferably selected from oxygen and nitrogen, more preferably oxygen.

[0027] [Definition 4] A pharmaceutical compound according to any of Definitions 1 to 3, wherein Ar is preferably an aromatic or heteroaromatic ring, said ring bearing one or more halogens, more preferably a 3,5-dichlorophenyl group.

[0028] [Definition 5] A pharmaceutical compound according to any of definitions 1 to 4, wherein n=1, said X is oxygen and said Ar is a 3,5-dichlorophenyl group (A-1). [ka]

[0029] [Definition 6] A pharmaceutical compound according to any of Definitions 1 to 2, wherein R1 is preferably selected from cyano, fluoro and chloro groups, more preferably cyano, and R2 is preferably selected from fluoro, chloro, bromo and methyl groups, more preferably fluoro.

[0030] [Definition 7] The pharmaceutical compound (A-2) according to definition 6, wherein n=1, R1 is a cyano group, and R2 is a fluoro group at the 4-position of the phenol ring. [ka]

[0031] [Definition 8] A pharmaceutical compound according to any of Definitions 1 to 2, having a group R having the structure (iii), wherein said X is oxygen and said Ar is a 3,5-dichlorophenyl group (A-3). [ka]

[0032] [Definition 9] A pharmaceutical composition comprising a compound according to any one of Definitions 1 to 8, and further comprising one or more pharmaceutically acceptable excipients, for use in the prevention or treatment of: a) fibroproliferative diseases, in particular interstitial lung diseases (ILD) and / or liver diseases such as all types of hepatitis and / or non-alcoholic fatty liver disease (NAFLD) and / or non-alcoholic steatohepatitis (NASH) and / or cirrhosis, where the ILD is a primary disease, preferably idiopathic pulmonary fibrosis and / or sarcoidosis and / or interstitial pneumonia, or where the ILD is associated with an autoimmune and / or inflammatory and / or metabolic disease, preferably rheumatoid arthritis-ILD ​​and / or scleroderma-ILD and / or myositis-ILD ​​and / or diabetes-ILD ​​and / or cardiovascular disease-ILD combination, and / or b) an inflammatory and / or autoimmune disease, preferably rheumatoid arthritis and / or scleroderma, and / or c) cancer, in particular lung cancer and / or hepatocellular carcinoma and / or pancreatic cancer and / or glioblastoma and / or neuroblastoma, and / or d) Metabolic diseases, in particular type 1 diabetes and / or type 2 diabetes and / or obesity.

[0033] [Definition 10] 10. A pharmaceutical composition according to definition 9, formulated with one or more excipients and suitable for inhaled, or intraperitoneal, or oral, or nasal, or subcutaneous, or intravenous, or topical administration, preferably suitable for inhaled administration.

[0034] Chemical formulae (B), (C), (D), (E), (F), (G), and (H) are (biological) equivalents of chemical formula (A) (4-(2-(4-((2,4-dioxothiazolidin-5-yl)methyl)phenoxy) derivatives).

[0035] In accordance with the present invention, a pharmaceutical compound having a formula selected from formulas (A), (B), (C), (D), (E), (F), (G), and (H) has an R group, wherein the R group is a substituted piperazine derivative.

[0036] In accordance with the present invention, a pharmaceutical compound having a formula selected from formulas (A), (B), (C), (D), (E), (F), (G), and (H) has an R group of structure (i), wherein the X groups are oxygen, nitrogen, or 0 to 5 methylene ((CH) m , m=0 to 5).

[0037] In accordance with the present invention, a pharmaceutical compound having a formula selected from formulas (A), (B), (C), (D), (E), (F), (G), and (H) has an R group of structure (i), wherein the X group is selected from oxygen and nitrogen.

[0038] In accordance with the present invention, a pharmaceutical compound having a formula selected from formulas (A), (B), (C), (D), (E), (F), (G), and (H) has an R group of structure (i) and is selected from hydrogen, halogen, (C 1-6 ) an aromatic ring or heteroaromatic ring having one or more substituents selected from an alkyl group, a nitro group, a methoxy group, and a trifluoromethoxy group.

[0039] In accordance with the present invention, a pharmaceutical compound having a formula selected from formulas (A), (B), (C), (D), (E), (F), (G), and (H) has an R group of structure (i), wherein the Ar group is selected from an aromatic or heteroaromatic ring containing one or more halogen atoms.

[0040] In a preferred embodiment, the pharmaceutical compound having a formula selected from formulas (A), (B), (C), (D), (E), (F), (G), and (H) is (A-1), where n=1 and has an R group of structure (i), where X group is oxygen and Ar group is 3,5-dichloro-phenyl group.

[0041] In accordance with the present invention, a pharmaceutical compound having a formula selected from formulas (A), (B), (C), (D), (E), (F), (G), and (H) has a substituted aminothiazole derivative as the R group.

[0042] In accordance with the present invention, a pharmaceutical compound having a formula selected from formulas (A), (B), (C), (D), (E), (F), (G), and (H) has an R group of structure (ii), wherein the R and R groups are selected from cyano, fluoro, chloro, bromo, or methyl groups.

[0043] In accordance with the present invention, a pharmaceutical compound having a formula selected from formulas (A), (B), (C), (D), (E), (F), (G), and (H) has an R group of structure (ii), wherein the R group is selected from a cyano group, a fluoro group, and a chloro group.

[0044] In accordance with the present invention, a pharmaceutical compound having a formula selected from formulas (A), (B), (C), (D), (E), (F), (G), and H) has an R group of structure (ii), wherein the R group is preferably selected from fluoro, chloro, bromo, and methyl.

[0045] In a preferred embodiment, the pharmaceutical compound having a formula selected from formulas (A), (B), (C), (D), (E), (F), (G), and (H) has n=1 and an R group of structure (ii), wherein the R group is a cyano group and the R group is a fluoro group at the 4-position of the phenol ring (A-2).

[0046] According to the present invention, a pharmaceutical compound having a formula selected from formulas (A), (B), (C), (D), (E), (F), (G), and (H) has a substituted piperine derivative as the R group.

[0047] In accordance with the present invention, a pharmaceutical compound having a formula selected from formulas (A), (B), (C), (D), (E), (F), (G), and (H) has an R group of structure (iii), wherein X is oxygen and Ar is a 3,5-dichlorophenyl group (A-3). [ka]

[0048] Surprisingly, pharmaceutical compound A-1 exhibited IC 50 showed inhibitory activity against ATX at 0.19 μM, demonstrating superior performance to existing non-toxic inhibitors.

[0049] Surprisingly, pharmaceutical compound A-1 has been found to show impressive results in each of the above treatment modalities.

[0050] Surprisingly, it has been found that the pharmaceutical compound A-1 has a clear indication in the antifibrotic treatment of interstitial lung diseases (ILDs) that are primary or complicated by autoimmune and / or inflammatory and / or metabolic disorders.

[0051] Surprisingly, pharmaceutical compound A-1 was found to have impressive efficacy in the treatment of pulmonary fibrosis and associated interstitial lung disease and / or lung transplant fibrosis through the simultaneous action of autotaxin inhibition and PPARγ agonism.

[0052] Surprisingly, pharmaceutical compound A-1 has been found to have clear indications for the treatment of type 2 diabetes.

[0053] Surprisingly, it has been found that the pharmaceutical compound A-1 shows impressive results in the treatment of pulmonary or cardiac fibrosis following type 2 diabetes.

[0054] Surprisingly, it has been found that pharmaceutical compound A-1 shows impressive results in the treatment of pulmonary fibrosis associated with rheumatoid arthritis.

[0055] Surprisingly, pharmaceutical compound A-1 was found to show impressive results in treating the complications of skin and pulmonary fibrosis.

[0056] Surprisingly, it was found that pharmaceutical compound A-1 does not exhibit cardiotoxicity.

[0057] Surprisingly, it was found that pharmaceutical compound A-1 does not exhibit hepatotoxicity.

[0058] Surprisingly, compound A-1 was found to exhibit a very favorable pharmacokinetic profile.

[0059] Surprisingly, pharmaceutical compound A-2 exhibited IC 50 showed inhibitory activity against ATX at 0.47 μM, demonstrating superior performance to existing non-toxic inhibitors.

[0060] Surprisingly, pharmaceutical compound A-2 has been found to show impressive results in each of the above treatment modalities.

[0061] Surprisingly, it has been found that pharmaceutical compound A-2 has a clear indication in the antifibrotic treatment of interstitial lung diseases (ILDs) that are primary or complicated by autoimmune and / or inflammatory and / or metabolic disorders.

[0062] Surprisingly, pharmaceutical compound A-2 was found to have impressive efficacy in the treatment of pulmonary fibrosis and associated interstitial lung disease and / or lung transplant fibrosis through the simultaneous action of autotaxin inhibition and PPARγ agonism.

[0063] Surprisingly, pharmaceutical compound A-2 has been found to have clear indications for the treatment of type 2 diabetes.

[0064] Surprisingly, it has been found that pharmaceutical compound A-2 shows impressive results in the treatment of pulmonary or cardiac fibrosis following type 2 diabetes.

[0065] Surprisingly, pharmaceutical compound A-2 has been found to show impressive results in the treatment of pulmonary fibrosis associated with rheumatoid arthritis.

[0066] Surprisingly, pharmaceutical compound A-2 has been found to show impressive results in the treatment of combined cutaneous and pulmonary fibrosis.

[0067] Surprisingly, pharmaceutical compound A-2 was found to exhibit no cardiotoxicity.

[0068] Surprisingly, it was found that pharmaceutical compound A-2 does not exhibit hepatotoxicity.

[0069] Surprisingly, compound A-2 was found to exhibit a very favorable pharmacokinetic profile.

[0070] Surprisingly, pharmaceutical compound A-3 exhibited inhibitory activity against ATX in well-established in vitro experimental protocols, with IC 50 The inhibitory activity was 0.03 μM, demonstrating superior performance to existing non-toxic inhibitors.

[0071] Surprisingly, pharmaceutical compound A-3 was found to show impressive results in each of the above treatment modalities.

[0072] Surprisingly, it has been found that the pharmaceutical compound A-3 has a clear indication in the antifibrotic treatment of interstitial lung diseases (ILDs) that are primary or complicated by autoimmune and / or inflammatory and / or metabolic disorders.

[0073] Surprisingly, pharmaceutical compound A-3 was found to have impressive efficacy in the treatment of pulmonary fibrosis and associated interstitial lung disease and / or lung transplant fibrosis through the simultaneous action of autotaxin inhibition and PPARγ agonism.

[0074] Surprisingly, pharmaceutical compound A-3 has been found to have clear indications for the treatment of type 2 diabetes.

[0075] Surprisingly, it has been found that the pharmaceutical compound A-3 shows impressive results in the treatment of pulmonary or cardiac fibrosis following type 2 diabetes.

[0076] Surprisingly, pharmaceutical compound A-3 has been found to show impressive results in the treatment of pulmonary fibrosis associated with rheumatoid arthritis.

[0077] Surprisingly, pharmaceutical compound A-3 has been found to show impressive results in the treatment of combined cutaneous and pulmonary fibrosis.

[0078] Surprisingly, pharmaceutical compound A-3 was found to be non-cardiotoxic.

[0079] Surprisingly, it was found that pharmaceutical compound A-3 does not exhibit hepatotoxicity.

[0080] Surprisingly, compound A-3 was found to exhibit a very favorable pharmacokinetic profile.

[0081] According to the present invention, pharmaceutical compounds having a chemical formula selected from chemical formulas (A), (B), (C), (D), (E), (F), (G), and (H) can be mixed with suitable pharmaceutically acceptable excipients and formulated in various pharmaceutical forms and in suitable amounts to exert the intended therapeutic effect.

[0082] The present invention will now be illustrated by the following representative but non-limiting examples. [Example]

[0083] [Example 1] Synthesis and activity evaluation of pharmaceutical compound A-1 In the synthesis of pharmaceutical compound A-1, synthetic route 1 is followed.

[0084] The synthesis of pharmaceutical compound A-1 is as follows.

[0085] [Synthesis of 4-(2-bromoethoxy)benzaldehyde (i)] 4-Hydroxybenzaldehyde (0.75 g, 6.14 mmol) was dissolved in anhydrous CH3CN (45 mL) and 1,2-dibromoethane (5.29 mL, 61.4 mmol) and K2CO3 (1.55 g, 11.2 mmol) were added. The mixture was stirred under reflux for 20 h, cooled to room temperature, water (45 mL) was added, and the mixture was extracted with Et2O (2 x 30 mL). The combined organic phases were washed with brine (25 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The residue was recrystallized from Et2O:hexane to give the product as a white solid. Yield = 0.92 g (65%). 1 H-NMR(CDCl3,400MHz)δ3.69(td,J1=1.7Hz,J2=6.2Hz,2H),4.40(td,J2=1.7Hz,J2=6.2Hz ,2H),7.04(dd,J1=1.7Hz,J2=8.7Hz,2H),7.87(dd,J1=1.9Hz,J2=8.7Hz,2H),9.92(s,1H). MS [ESI+] m / z 229.9 [M + H] + .

[0086] [Synthesis of 3,5-dichlorobenzylpiperazine-1-carboxylate hydrochloride (ii)] 4N HCl in dioxane (16 ml, 63 mmol) is added to 1-(tert-butyl) 4-(3,5-dichlorobenzyl)piperazine-1,4-dicarboxylate (iii, 2.44 g, 6.27 mmol) at 0° C., the synthesis of which is described below. The reaction mixture is stirred at room temperature for 3 hours. The solvent is evaporated under reduced pressure, and the remaining white solid is used in the next step without further purification. Yield = 2 g (quantitative). 1 H-NMR (CDCl3, 400MHz) δ3.09 (m, 4H), 3.65 (m, 4H), 5.10 (s, 2H), 7.47 (s, 2H), 7.57 (s, 1H), 9.49 (brs, 2H). MS [ESI+] m / z 326.1 [M + H] + .

[0087] [Synthesis of 1-(tert-butyl)4-(3,5-dichlorobenzyl)piperazine-1,4-dicarboxylate (iii)] To a solution of (3,5-dichlorobenzyl)methanol (1.50 g, 8.47 mmol) in dry DMF, CDI (1.92 g, 11.86 mmol) is added and the reaction is stirred at 45° C. for 2 hours. Next, 1-boc-piperazine (1.97 g, 10.59 mmol) is added and the reaction mixture is stirred at room temperature overnight. Water (30 mL) is added to the mixture, and the precipitate is filtered, washed with water (2×10 mL) and hexane (10 mL), and dried. The crude product (white solid) is used immediately in the next step without further purification. Yield = 3.30 g (74%). MS [ESI+] m / z 390.1 [M + H] + .

[0088] [Synthesis of 3,5-dichlorobenzyl 4-(2-(4-formylphenoxy)ethyl)piperazine-1-carboxylate (iv)] A mixture of compound i (0.92 g, 4.02 mmol), ii (0.44 g, 4.42 mmol), and NaHCO3 (1.35 g, 16.08 mmol) in anhydrous DMF (20 mL) was stirred at 80 °C for 24 h and at 55 °C for 12 h. Water (50 mL) was then added, and the mixture was extracted with ethyl acetate (3 × 25 mL). The combined organic phases were washed with water (25 mL) and brine (25 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash column chromatography eluting with hexane:ethyl acetate (7:3 to 100% ethyl acetate) to give a pale yellow oil that solidified upon standing in the refrigerator. Yield = 1.76 g (71%). 1 H-NMR(dmso-d6,400MHz)δ2.50-2.52(m,3H),2.78(t,J=5.6Hz,2H),2.97(t,J=5.6Hz,1H),3.46(m,4H),4.27(t, J=5.6Hz,2H),5.11(s,2H),7.12(d,J=8.4Hz,2H),7.42(s,2H),7.66(d,J=8.1Hz,2H),7.70(s,1H),9.90(s,1H). MS [ESI+] m / z 424.2 [M + H] + .

[0089] [Synthesis of 3,5-dichlorobenzyl (E)-4-(2-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)ethyl)piperazine-1-carboxylate (2)] In an oven-dried round-bottom flask, compound iv (1.681 g, 3.85 mmol) and 2,4-thiazolidinedione (0.54 g, 4.62 mmol) were dispersed in anhydrous toluene (16 mL). Then, piperidine (0.20 mL, 1.92 mmol) was added, followed by acetic acid (0.11 mL, 1.92 mmol), and the mixture was refluxed overnight. The reaction mixture was allowed to cool at room temperature, and a brownish solid precipitated. The mixture was filtered, washed with toluene (20 mL) and hexane (20 mL), and dried overnight at 50 °C. A pale yellow powder was obtained. Yield = 2 g (quantitative). 1 H-NMR(dmso-d6,400MHz)δ2.50-2.52(m,3H),2.76(t,J=5.6Hz,2H),2.99(t,J=5.6Hz,1H),3.42(m,4H),4.17(t, J=5.6Hz,2H),5.08(s,2H),7.10(d,J=8.4Hz,2H),7.42(s,2H),7.53(s,1H),7.56(d,J=8.1Hz,2H),7.70(s,1H). MS [ESI+] m / z 537.3 [M + H] + .

[0090] [Synthesis of 3,5-dichlorobenzyl 4-(2-(4-((2,4-dioxothiazolidin-5-yl)methyl)phenoxy)ethyl)piperazine-1-carboxylate (A-1)] Thiazolidinone derivative 2 (0.45 g, 0.84 mmol) was mixed with water (25 mL) and five drops of 0.5 M NaOH aqueous solution were added until the pH reached 11. A mixture of 20 mL of THF:DMF (2:1) was then added, followed by CoCl₂·6H₂O (0.128 g, 0.537 mmol), dimethylglyoxime (0.129 g, 1.107 mmol), and sodium borohydride (0.374 g, 9.88 mmol). The reaction mixture was stirred at room temperature for 24 h, after which TLC and MS showed partial conversion of the starting material to the desired product. Subsequently, additional CoCl₂ / 6H₂O (0.128 g, 0.537 mmol), dimethylglyoxime (0.129 g, 1.107 mmol), and sodium borohydride (0.374 g, 9.88 mmol) were added, and the mixture was stirred overnight. The pH of the reaction was adjusted to 3 with 6N HCl, and then 1N NaOH was added to adjust the pH to 10. Extraction with ethyl acetate (2 x 50 mL) was performed, and the combined organic phases were washed with water (30 mL) and brine (30 mL), dried (NaSO), filtered, and concentrated in vacuo. The residue was purified by flash column chromatography eluting with ethyl acetate to give the desired product (A-1) as a slightly yellow semi-solid. Yield = 0.226 g (50%). 1 H-NMR(dmso-d6,400MHz)δ2.45-2.49(m,5H),2.72(q,J=5.0Hz,2H),3.00-3.09(m,1H),3.37-3.48(m,4H),4.06(q,J=5.0Hz,2H),4.86(dt,J1= 3.8Hz,J2=8.5Hz,1H),5.09(s,2H),6.89(dd,J1=3.2Hz,J2=8.5Hz),7.15(dd,J1=3.1Hz,J2=8.4Hz),7.43(s,2H),7.57(s,1H),11.96(brs,1H). MS [ESI+] m / z 539.1 [M + H] + .

[0091] [ATX inhibitory activity evaluation] The inhibition of ATX enzyme activity by pharmaceutical compound A-1 was measured in vitro using the Amplex Red assay. Briefly, 2 μL of derivative (A4) at concentrations of 0.001–5 μmol / L in DMSO was incubated with 50 μL of 8 nM ATX (final concentration 2 nM and 1 nM for human ATX) and 48 μL of buffer (50 mM Tris-Cl and 5 mM CaCl at pH 8.0) at 37 °C for 15 min. Subsequently, 50 μL of buffer containing 200 μM LPC 16:0 (final concentration 50 μM) was added to the reaction mixture, which was further incubated at 37 °C for 30 min. Finally, the reaction was initiated by adding 50 μL of a working solution of 50 mM Tris-HCl (pH 8.0) and 5 mM CaCl2 containing 200 μM Amplex Red reagent, choline oxidase (0.2 U / mL), and και HRP (2 U / mL). The reaction was monitored every 5 minutes for 30 minutes at 37°C using a fluorescence plate reader (Tecan Infinite 200) with excitation at 530 nm and reading at 590 nm. IC 50 Values ​​were calculated from two independent experiments using a sigmoidal dose-response curve (PrismH software) based on the equation f = y0 + a / 1 + exp(-(x-x0) / b) given in SigmaPlot 110.

[0092] A modified Ampex assay was used to determine the mode of inhibition of ATX by each inhibitor. Briefly, various concentrations of inhibitor (1, 2.5, 5, and 7.5 μM) were tested against various substrate concentrations (25, 50, and 100 μM LPC). Mouse ATX (Sino Biological) was used for all inhibition assay modes. The reaction velocity (V) was then calculated, and the reciprocal of the velocity (1 / V) was plotted against the reciprocal of the substrate concentration (1 / S) on a Lineweaver-Burk graph using GraphPad software (GraphPad Software, San Diego, CA, USA).

[0093] Figure 2 shows the IC of drug compound A-1. 50The results show that the activity of compound A-1 (0.19 μM) was lower than that of TGL (0.61 μM). Figure 3 also demonstrates the non-competitive inhibition of ATX by compound A-1. Furthermore, as shown in Figure 4, A-1 did not inhibit choline oxidase or HRP peroxidase. Therefore, it is a specific inhibitor of ATX.

[0094] [In vitro ADMET (absorption, distribution, metabolism, excretion, and toxicity) analysis] The physicochemical properties evaluated were in vitro membrane permeability, as well as in vitro metabolism and cardiotoxicity.

[0095] In vitro absorption analysis was performed in a renal MDCKII cell line to evaluate the permeability from A to B when A and B are separated by the MDCKII cell membrane. Ideally, a compound must have high permeability from A to B and low permeability from B to A for adequate absorption. Calculations showed that the permeability from A to B of compound A-1 was 3.7 x 10 -6 cm / s, whereas the transmission from B to A was 0.8x10 -6 The permeability from A to B is much higher than that from B to A, so both compounds are well absorbed in vitro.

[0096] In vitro metabolism analysis was performed using liver microsomes. Compound A-1 had a half-life (t 1 / 2 ) was calculated. Because this half-life is longer than that of known drugs such as imipramine, A-1 is not rapidly eliminated from the circulation and therefore appears to remain available in the circulation for a sufficient period of time. This conclusion is further supported by the low Clint value, a parameter indicating intrinsic clearance (328.6 μL / min / mg for compound A-1, lower than the Clint values ​​of many other drugs).

[0097] Cardiotoxicity studies were performed in CHO cells expressing the human ether-a-go-go-related gene (hERG), which encodes an inwardly rectifying voltage-gated potassium channel in the heart involved in cardiac repolarization. Inhibition of hERG can cause potentially fatal ventricular tachycardia. The IC value of pharmaceutical compound A-1 for hERG inhibition was 1.25. 50 The relative value of IC for ATX was estimated to be 12 μM (Fig. 5). This value was quite high (IC for ATX). 50 higher), therefore, pharmaceutical compound A-1 is not cardiotoxic.

[0098] In vitro evaluation of pharmaceutical compound A-1 in pulmonary fibrosis in mice Ten-week-old male wild-type C57B16 / J animals were administered bleomycin (BLM) in saline via the oral tracheal route directly into the lungs. The dose of bleomycin was 0.8 U / kg. Pharmaceutical compound A-1 was administered at a dose of 30 mg / kg twice daily to each animal, starting one day before BLM injection. All animals were monitored daily and sacrificed 14 days after BLM injection. No adverse side effects occurred in the groups administered pharmaceutical compound A-1 compared with the untreated group during the model experiment. At the end of the experiment, serum, bronchoalveolar fluid, and lung tissue samples were collected and used to evaluate the severity of fibrosis in each animal.

[0099] Serum was collected from each animal, and the levels of ALT and AST transaminases, which are markers of liver damage, were evaluated using an automated biochemical analyzer. As shown in Figure 6, the ALT and AST levels were within the normal range in all five groups (ALT: 28-132 U / L, AST: 59-247 U / L, respectively). These results demonstrated that pharmaceutical compound A-1 did not cause adverse liver toxicity in the animals.

[0100] Next, the cell count and total protein concentration in the collected bronchoalveolar fluid were evaluated as indicators of inflammation and endothelial infiltration, respectively. As shown in Figure 7, the group administered novel pharmaceutical compound A-1 (B+A-1) showed a decreased cell count and a decreased level of total protein concentration in the bronchoalveolar fluid compared to the group administered only the compound vehicle (B+V).

[0101] Furthermore, sections of lung tissue isolated from the animals were stained with hematoxylin and eosin and then evaluated for fibrosis. Figure 8 shows representative images of each group. The B+V group, which did not receive an ATX inhibitor, showed significantly more fibrotic areas than the control group, which received the novel pharmaceutical compound A-1, which showed significantly less fibrotic areas.

[0102] The mRNA levels of the fibrosis-related gene col1α1 (collagen 1α1) in whole lung RNA samples were also estimated. As shown in Figure 9, novel pharmaceutical compound A-1 statistically significantly reduced the mRNA levels (expression) of col1α1, restoring them to the same level as the control group administered saline (S+V).

[0103] The pharmaceutical compound A-1 of the above example has excellent effects in the simultaneous treatment of type 2 diabetes on the one hand and restrictive lung disease and / or pulmonary fibrosis and / or pulmonary sarcoidosis and / or lung allograft fibrosis on the other hand, and also has excellent effects in alleviating cardiotoxicity and hepatotoxicity as well as fibrosis phenomena after the onset of type 2 diabetes.

[0104] To investigate the therapeutic potential of ATX inhibition in pulmonary fibrosis, 8-10 week-old C57B16 / J mice were administered BLM. Subsequently, in the pharmaceutical compound A-1 treatment mode (day 7 after BLM administration), conscious, mildly restrained mice were inhaled with pharmaceutical compound A-1 (1 ml of 6.5 mg / ml for 10 min, equivalent to 15 mg / kg per mouse) twice daily for 7 days. Inflammatory cells in bronchoalveolar lavage fluid (BALF) were measured using a hemocytometer and found to be significantly reduced by ATX inhibition in WT mice after BLM administration (Figure 10). Furthermore, pharmaceutical compound A-1 administration significantly reduced vascular leakage and pulmonary edema, as evidenced by total protein concentration (Figure 10). Histological analysis showed that ATX inhibition inhibited BLM-induced structural distortion by H&E staining (Figure 11). The relative protective effect of ATX inhibition against BLM-induced tissue distortion was also reflected in pulmonary respiratory function measured by FlexiVent (Figure 12). Overall, these findings highlight the profound impact of ATX expression in BLM-induced pulmonary fibrosis and suggest potential relevance to IPF.

[0105] [Example 2] Synthesis and activity evaluation of pharmaceutical compound A-2. The synthesis of pharmaceutical compound A-2 follows synthetic route Scheme 13.

[0106] The synthesis of derivative A-2 is as follows.

[0107] [Synthesis of tert-butyl(2-(4-formylphenoxy)ethyl)carbamate (v)] To a solution of 2-(boc-amino)ethanol (1 g, 6.20 mmol), 4-hydroxybenzaldehyde (0.91 g, 7.44 mmol), and triphenylphosphine (2.44 g, 9.30 mmol) in anhydrous THF (25 mL) was added diisopropyl azodicarboxylate dropwise at 0 °C. The mixture was stirred at room temperature for 2.5 h. The solvent was evaporated in vacuo, and the residue was dissolved in ethyl acetate (50 mL), washed with 1N NaOH (10 mL), water (10 mL), and brine (10 mL), dried (Na SO ), filtered, and concentrated in vacuo. The residue was purified by flash column chromatography eluting with hexane:ethyl acetate (4:1) to give the desired product as a white solid. Yield = 1.64 g (quantitative). 1 H-NMR(CDCl3,400MHz)δ1.46(s,9H),3.58(d,J=4.5Hz,2H),4.12(t,J=5.0Hz, 2H),5.10(brs,1H),7.01(d,J=8.5Hz,2H),7.84(d,J=9.2Hz,2H),9.89(s,1H). MS [ESI+] m / z 266.1 [M + H] + .

[0108] [Synthesis of tert-butyl (E)-(2-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)ethyl)carbamate (vi)] To a solution of compound v (1.50 g, 5.6 mmol) in anhydrous toluene (15 mL) was added 2,4-thiazolidinone (0.80 g, 6.79 mmol), followed by piperidine (0.28 mL, 2.83 mmol) and acetic acid (0.162 mL, 0.83 mmol). The mixture was stirred at reflux for 8 hours and then allowed to stand at room temperature overnight. The resulting solid precipitate was filtered, washed with toluene (3 mL) and hexane (5 mL), and dried at 50 °C overnight to give the desired product as a beige / brownish amorphous solid. Yield: 1.63 g (80%). 1H-NMR(DMSO-d6,400MHz)δ1.38(s,9H),3.31(m,2H),4.06(m,2H),7.01(s,1H ),7.10(d,J=7.4Hz,2H),7.55(d,J=8.7Hz,2H),7.75(s,1H),12.49(brs,1H). MS [ESI+] m / z 365.2 [M + H] + .

[0109] [Synthesis of tert-butyl(2-(4-((2,4-dioxothiazolidin-5-yl)methyl)phenoxy)ethyl)carbamate (vii)] The thiazolidinone derivative vi (0.80 g, 2.20 mmol) and magnesium turnings (1.07 g, 43.9 mmol) were added to a flask, and the air was removed under vacuum. The flask was then filled with argon, and anhydrous methanol (27 mL) was added. The mixture was stirred at room temperature under Ar for 4 h. The reaction mixture was acidified to pH 5-6 with 6 N HCl, extracted with dichloromethane (2 × 25 mL), and the combined organic phases were washed with water (15 mL) and brine (15 mL), dried (NaSO), filtered, and concentrated in vacuo. The residue was purified by flash column chromatography eluting with hexane:ethyl acetate (3:2) to give the desired compound as a yellow oil. Yield = 0.37 g (46%). 1 H-NMR(CDCl3,400MHz)δ1.48(s,9H),3.12(dd,J1=3.5Hz,J2=14Hz,1H),3.47(dd,J1=3.5Hz,J2=14.0Hz,1H),3.55(brd,J=4Hz,2H), 4.03(t,J=5Hz,2H),4.51(dd,J1=3.5Hz,J2=9.5Hz,1H),5.06(brs,1H),6.87(d,J=8.0Hz,2H),7.17(d,J=8.0Hz,2H),8.96(brs,1H). MS [ESI+] m / z 367.1 [M + H] + .

[0110] [Synthesis of compounds viii and ix] A solution of 4N HCl in dioxane (1.90 mL, 7.61 mmol) is added in one portion to compounds vi and vii (0.22 g, 0.61 mmol), and the mixture is stirred at room temperature for 4 h. The solvent is evaporated in vacuo, and the residue is washed with diethyl ether (15 mL) and dried to give the desired product as a white solid.

[0111] (E)-5-(4-(2-aminoethoxy)benzylidene)thiazolidine-2,4-dione hydrochloride (viii): Yield=0.111 g (quantitative). 1 H-NMR(CH3OD,400MHz)δ. 3.45 (dd, J1 = 4.2 Hz, J2 = 14.1 Hz, 1H), 4.55 (brs, 2H), 6.98 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 7.91 (s, 1H). MS [ESI+] m / z 302.0 [M + H] + .

[0112] 5-(4-(2-aminoethoxy)benzyl)thiazolidine-2,4-dione hydrochloride (ix): Yield = 0.115 g (quantitative). 1 H-NMR(CH3OD,400MHz)δ3.16(dd,J1=9.0Hz,J2=14.0Hz,1H),3.38(brs,2H),3.41(dd,J1=4.0Hz,J2=14.0 Hz,1H),4.23(brs,2H),4.73(dd,J1=4.0Hz,J2=9.5Hz,1H),6.98(d,J=8.0Hz,2H),7.23(d,J=8.0Hz,2H). MS [ESI+] m / z 304.1 [M + H] + .

[0113] [Synthesis of 2-chloro-4-(4-fluorophenyl)thiazole-5-carbonitrile (x)] To a solution of anhydrous CuCl2 (0.47 g, 3.47 mmol) in anhydrous CH3CN (6.5 mL) was added tert-butoxynitrite (0.45 g, 4.34 mmol) dropwise, and the mixture was stirred at room temperature for 45 min. Compound xi (0.63 g, 2.89 mmol) was then added portionwise, and stirring was continued for an additional 2 h. The reaction mixture was carefully quenched with 1 N HCl (10 mL) and stirred for 15 min. The organic phase was separated, the aqueous phase was extracted with ethyl acetate (20 mL), and the combined organic phases were washed with brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was filtered through a silica plug and eluted with dichloromethane. The solvent was evaporated in vacuo, and the residue was triturated with hexane, filtered, and dried. The product was isolated as a bright orange, thick solid. Yield = 0.49 g (71%). 1 H-NMR (CDCl3, 400MHz) δ7.19-7.25(m,2H),8.12-8.17(m,2H). MS [ESI+] m / z 240.0 [M + H] + .

[0114] [Synthesis of 2-amino-4-(4-fluorophenyl)thiazole-5-carbonitrile (xi)] To a solution of 4-fluorobenzoylacetonitrile (0.47 g, 2.89 mmol) in anhydrous ethanol (6 mL), add anhydrous pyridine (0.24 mL, 2.89 mmol). Stir the mixture at 70 °C for 20 min and then cool to room temperature. Slowly add a pre-stirred suspension of thiourea (0.44 g, 5.79 mmol) and iodine (0.73 g, 2.89 mmol) in anhydrous ethanol (4 mL), and stir the mixture at room temperature for 2 h. Add cold water (40 mL), and filter the resulting precipitate, wash with water (10 mL) and hexane (15 mL), and dry under vacuum to obtain the desired product as a yellow solid. Yield = 0.63 g (quantitative). 1 H-NMR (DMSO-D6, 400MHz) δ7.37 (t, J=8.9Hz, 2H), 7.93-8.01 (m, 2H), 8.25 (s, 2H). MS [ESI+] m / z 220.0 [M + H] + .

[0115] [Synthesis of Compounds 3 and 4] Compounds vii or ix and X are dissolved in anhydrous DMSO (7 mL), DIPEA (0.33 mL, 1.89 mmol) is added, and the mixture is stirred at 100 °C for 8 h and at room temperature overnight. Water (15 mL) is added, and the mixture is extracted with ethyl acetate (2 × 30 mL). The combined organic phases are washed with water (2 × 20 mL) and brine (20 mL), dried (NaSO), filtered, and concentrated in vacuo. The residue is purified by flash column chromatography eluting with hexane:ethyl acetate (7:3 to 1:1) to give the final product.

[0116] 2-((2-(4-((2,4-dioxothiazolidin-5-yl)methyl)phenoxy)ethyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile (4). Light yellow amorphous solid. Yield = 0.20 g (56%). 1 H-NMR(DMSO-d6,400MHz)δ. MS [ESI+] m / z 469.1 [M + H] +

[0117] (E)-2-((2-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)ethyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile (3) (Compound A-2). Light brown solid. Yield = 0.34g (95%). 1H-NMR(dmso-d6,400MHz)δ2.51-2.52(m,6H),3.29-33.8(m,4H),3.79-3.82(m,2H),4.28(s,2H),7.14(d,J=8.5Hz ,2H),7.37(t,J=8.7Hz,2H),7.55(d,J=8.4Hz,2H),7.71(s,1H),8.00(dd,J1=5.5Hz,J2=8.6Hz,2H),9.02(brs,1H). MS [ESI+] m / z 467.1 [M + H] + .

[0118] [ATX inhibitory activity evaluation] Inhibition of the enzymatic activity of ATX by pharmaceutical compound A-2 was carried out as described above for Example 1 of the present invention.

[0119] In Figure 2, compound A-2 is IC 50 The results show that the activity of pharmaceutical compound A-2 (0.47 μM) is lower than that of TGL (0.61 μM). Furthermore, as shown in Figure 3, pharmaceutical compound A-2 exhibits noncompetitive inhibition of ATX. Furthermore, as shown in Figure 4, pharmaceutical compound A-2 did not exhibit inhibition of the enzymes choline oxidase and HRP peroxidase. Therefore, it is a specific inhibitor of ATX.

[0120] [In vitro ADMET (absorption, distribution, metabolism, excretion, and toxicity) analysis] The physicochemical properties of pharmaceutical compound A-2 were evaluated as described in Example 1 of the present invention.

[0121] According to in vitro absorption tests, the permeability of pharmaceutical compound A-2 from A to B is 7.8x10 -6 cm / s, and the permeability from B to A is 3.2x10 -6 cm / s. Therefore, the pharmaceutical compound A-2 is well absorbed in vivo.

[0122] In vitro metabolic analysis showed that the half-life (t 1 / 2 ) was estimated to be greater than 60 minutes, suggesting that pharmaceutical compound A-2 is not rapidly cleared from the circulation and remains in the circulation for a sufficient period of time. This conclusion is further supported by the Clint value, which is lower than that of many other drugs (<115.5 μL / min / mg).

[0123] Cardiotoxicity analysis showed that the IC 50 The IC value for ATX was estimated to be over 100 μM for hERG inhibition (Figure 5). 50 ), therefore, pharmaceutical compound A-2 is not cardiotoxic.

[0124] [In vitro evaluation of pharmaceutical compound A-2 in pulmonary fibrosis in mice] In vivo evaluation of pulmonary fibrosis in mice after administration of pharmaceutical compound A-2 was performed as described in Example 1 of the present invention. The groups administered pharmaceutical compound A-2 showed no adverse side effects compared to the untreated group throughout the model. As shown in Figure 6, ALT and AST levels were normal (ALT 28-132 U / L, AST 59-247 U / L, respectively, within the normal range), indicating that pharmaceutical compound A-2 does not cause adverse liver toxicity in the animals. Furthermore, the groups administered pharmaceutical compound A-2 showed reduced cell counts and total protein levels compared to the untreated group (B+V) (Figure 7). Animals administered A-2 (B+A-2) showed less severe striatalization than the untreated group (B+V) (Figure 8). Finally, as shown in Figure 9, pharmaceutical compound A-2 significantly reduced the mRNA level (expression) of col1α1 to the same level as the control group administered saline (S+V).

[0125] The pharmaceutical compound A-2 of Example 2 has excellent effects in simultaneously treating type 2 diabetes on the one hand and restrictive lung disease and / or pulmonary fibrosis and / or pulmonary sarcoidosis and / or lung transplant fibrosis on the other hand, and also has excellent effects in alleviating cardiotoxicity, hepatotoxicity, and fibrosis phenomena after the onset of type 2 diabetes.

[0126] [Example 3] Synthesis and activity evaluation of pharmaceutical compound A-3. The synthesis of derivative A-3 follows synthetic scheme 14.

[0127] The synthesis of pharmaceutical compound A-3 is as follows.

[0128] [Synthesis of tert-butyl 4-(2-bromoethyl)piperidine-1-carboxylate (i)] In an oven-dried microwave vial equipped with a magnetic stirrer, N-Boc-4-piperidineethanol (0.521 g, 2.274 mmol) was dissolved in dichloromethane (10 mL). Triphenylphosphine (0.835 g, 3.184 mmol) and carbon tetrabromide (1.207 g, 3.640 mmol) were then added portionwise, and the reaction mixture was stirred at room temperature for 72 h. Upon completion, the solvent was evaporated, and the residue was purified by silica gel flash column chromatography eluting with hexane:ethyl acetate (100% hexane to 5% ethyl acetate in hexane). Colorless oil. Yield: 0.530 g (79%). 1 H-NMR (dmso-d6, 400MHz) δ

[0129] [Synthesis of tert-butyl 4-(2-(4-formylphenoxy)ethyl)piperidine-1-carboxylate (II)] To a round-bottom flask equipped with a magnetic stirrer, tert-butyl 4-(2-bromoethyl)piperidine-1-carboxylate (i) (0.530 g, 1.814 mmol), 4-hydroxybenzaldehyde (0.277 g, 2.268 mmol), cesium carbonate (1.478 g, 4.535 mmol), and anhydrous DMF (3 mL) were added sequentially. The reaction mixture was stirred at 70 °C for 6 h and at room temperature overnight. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (3 × 20 mL). The combined extracts were washed with water (2 × 15 mL), saturated aqueous sodium carbonate (2 × 10 mL), and brine (15 mL), dried (NaSO), filtered, and concentrated in vacuo. The product was purified by silica gel flash column chromatography eluting with hexane:ethyl acetate (0-20% ethyl acetate). An off-white / yellowish solid was obtained. Yield = 0.535 g (88%). 1 H-NMR(CDCl3,400MHz)δ1.17-1.28(m,2H),1.48(s,9H),1.76-1.82(m,5H),2.66-2.76( m,2H),4.12(t,J=6.2Hz,4H),7.01(d,J=8.7Hz,2H),7.86(d,J=8.8Hz,2H),9.91(s,1H).

[0130] [Synthesis of 4-(2-(piperidin-4-yl)ethoxy)benzaldehyde (iii)] tert-Butyl 4-(2-(4-formylphenoxy)ethyl)piperidine-1-carboxylate (II) (0.531 g, 1.593 mmol) was dissolved in dichloromethane (4 mL) in a round-bottom flask, followed by the addition of trifluoroacetic acid (3.50 mL, 5.447 g, 47.776 mmol). The reaction mixture was stirred at room temperature for 2 hours, the solvent was evaporated in vacuo, saturated aqueous sodium carbonate (5 mL) was added, and the product was extracted with ethyl acetate (3 x 15 mL). The combined organic phases were washed with brine (15 mL), dried (NaSO), filtered, and concentrated in vacuo to give a yellowish semi-solid. Yield = 0.300 g (81%). 1 H-NMR(dmso-d6,400MHz)δ1.34-1.44(m,2H),1.76-1.85(m,5H),2.74(t,J=13.7Hz,2H),3.23(d,J=12.3 Hz,2H),4.11(t,J=6.0Hz,2H),5.20(brs,1H),7.00(d,J=8.5Hz,2H),7.85(d,J=8.7Hz,2H),9.90(s,1H).

[0131] [Synthesis of 3,5-dichlorobenzyl 4-(2-(4-formylphenoxy)ethyl)piperidine-1-carboxylate (iv)] To a solution of 3,5-dichlorobenzyl alcohol (0.284 g, 1.607 mmol) in anhydrous DMF (2.3 mL) was added carbonyldiimidazole (CDI 0.365, 2.251 mmol), and the mixture was stirred at 45 °C for 3 h. Then, 4-(2-(piperidin-4-yl)ethoxy)benzaldehyde (iii) (0.300 g, 1.286 mmol) dissolved in anhydrous DMF (2 mL) was added dropwise to the reaction mixture, which was stirred at 45 °C for 3 h and at room temperature overnight. Water (15 mL) was added, and the mixture was extracted with diethyl ether (3 × 10 mL). The combined organic phase was washed with water (12 mL) and brine (12 mL), dried (NaSO), filtered, and concentrated in vacuo. The product was purified by silica gel flash column chromatography eluting with hexane-ethyl acetate (85:15 to 70:30). Off-white semi-solid. Yield = 0.533 g (95%). 1 H-NMR(CDCl3,400MHz)δ1.23-1.30(m,2H),1.79-1.82(m,5H),2.77-2.95(brm,2H),4.10-4.24(m,4H ),5.09(s,2H),7.01(d,J=8.4Hz,2H),7.25(s,2H),7.32(s,1H),7.86(d,J=8.5Hz,2H),9.91(s,1H).

[0132] [Synthesis of 3,5-dichlorobenzyl(E))-4-(2-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)ethyl)piperidine-1-carboxylate (v)] 3,5-Dichlorobenzyl 4-(2-(4-formylphenoxy)ethyl)piperidine-1-carboxylate (iv) (0.521 g, 1.194 mmol) and 2,4-thiazolidinedione (0.168 g, 1.433 mmol) were placed in an oven-dried microwave vial equipped with a magnetic stirrer, followed by anhydrous toluene (5 mL), piperidine (59.2 μL, 0.051 g, 0.597 mmol), and acetic acid (34.2 μL, 0.036 g, 0.597 mmol). The mixture was stirred at reflux (111 °C) overnight. Upon cooling to room temperature, a yellow solid precipitated. The solid was filtered, washed with toluene and hexane, and dried overnight at 50 °C. Yellow powder. Yield = 0.500 g (78%). 1 H-NMR(dmso-d6,400MHz)δ1.09-1.12(m,2H),1.66-1.71(m,5H),2.76-2.91(brm,2H),4.00(d,J=13.2Hz,2H),4.10 (t,J=5.8Hz,2H),5.07(s,2H),7.10(d,J=8.8Hz,2H),7.41(s,2H),7.54-7.56(m,3H),7.75(s,1H),12.51(brs,1H).

[0133] [Synthesis of 3,5-dichlorobenzyl 4-(2-(4-((2,4-dioxothiazolidin-5-yl)methyl)phenoxy)ethyl)piperidine-1-carboxylate (3) (A-3)]

[0134] [catalyst] Dissolve 9 mg (0.038 mmol) of CoCl2 6H2O and 49 mg (0.413 mmol) of dimethylglyoxime in 0.55 mL with stirring to give a clear blue-green solution.

[0135] [Reducing agent] Dissolve 0.177 g (4.670 mmol) of NaBH4 in 1.50 mL of a 0.1 M solution of H2O and 0.5 mL of NaOH under ice cooling (0 °C). This is stored on ice until consumed.

[0136] [reaction] 23.4 mg of NaOH was added, followed by dissolving 0.250 g (0.467 mmol) of 3,5-dichlorobenzyl 4-(2-(4-((2,4-dioxothiazolidin-5-yl)methyl)phenoxy)ethyl)piperidine-1-carboxylate (3) in 5 mL of HO. The resulting solution was stirred and heated at 55 °C until a solution was formed. The catalyst (0.15 mL of a DMF solution of CoCl-DMG) was added to the solution over 1 min, followed by the reducing agent (0.50 mL of NaBH in HO) over 2 min, and the mixture was stirred at 55 °C for 1 h. The same procedure was repeated three more times (each time adding 1 / 4 of the catalyst followed by 1 / 4 of the reducing agent, stirring at 55 °C for 1 h, i.e., once per hour). The mixture was then stirred overnight at 45 °C. The next day, 10 mL of 6 N HCl was added. After extraction, the aqueous phase is further extracted with EtOAc (2x20 mL). The combined organic phases are washed with water (20 mL) and brine (20 mL), dried, filtered and concentrated in vacuo. The product was purified by silica gel flash column chromatography eluting with hexane:ethyl acetate 3:2. White crystalline solid. Yield = 0.110 g (44%). 1 H-NMR(dmso-d6,400MHz)δ1.04-1.16(m,2H),1.66-1.74(m,5H),2.76-2.85(brm,2H),3.06(dd,J1=14.1Hz,J2=9.0Hz,1H),3.97-4.00(m,4H) ),4.87(dd,J1=9.0Hz,J2=4.3Hz,1H),5.06(s,2H),6.87(d,J=8.2Hz,2H),7.14(d,J=8.3Hz,2H),7.41(s,2H),7.56(s,1H),12.01(brs,1H). 13 C-NMR(dmso-d6,100MHz)δ32.0,32.6(2C),35.6,36.7,44.2(2C),53.5,65.0,65.5,114.8( 2C), 126.6 (2C), 127.9, 128.9, 130.8 (2C), 134.5 (2C), 141.9, 154.5, 158.1, 172.2, 176.2. MS [ESI+] m / z 538.2 [M + H] + .

[0137] [ATX inhibitory activity evaluation] Inhibition of ATX enzyme activity by pharmaceutical compound A-3 was carried out as described in Example 1 of the present invention above.

[0138] In Figure 2, compound A-3 is IC 50 It was shown that the activity of pharmaceutical compound A-3 (0.03 μM) was lower than that of TGL (0.61 μM). Furthermore, as shown in Figure 3, pharmaceutical compound A-3 exhibited non-competitive inhibition of ATX. Furthermore, as shown in Figure 4, pharmaceutical compound A-3 did not exhibit inhibition of the enzymes choline oxidase and HRP peroxidase. Therefore, it is a specific inhibitor of ATX. Of note, a cardiotoxicity test showed that pharmaceutical compound A-3 did not exhibit significant inhibitory activity against hERG (11% inhibition at 25 μM), demonstrating that pharmaceutical compound A-3 is not cardiotoxic. This is less cardiotoxic than any other ATX inhibitors mentioned in the prior art.

[0139] The above examples will be explained in more detail and the above results will be better understood by referring to the following Figures 1 to 14. The present invention will be specifically explained, but the present invention is not limited thereto. [Brief explanation of the drawings]

[0140] The above examples will be explained in more detail and the above results will be better understood by referring to the attached Figures 1 to 14 below. [Figure 1] Synthetic route to pharmaceutical compound A-1. [Figure 2] 1 is a graph showing the inhibition of ATX by pharmaceutical compounds A-1, A-2, A-3 and troglitazone. [Figure 3] Inhibitory modes of pharmaceutical compounds A-1, A-2, and A-3 against ATX. [Figure 4] Amplex Red assay kinetics graphs of the second and third order reactions of pharmaceutical compounds A-1, A-2, and A-3. None of the compounds showed detectable inhibition of the second order (choline oxidase) or third order (HRP peroxidase) reactions. [Figure 5]Graph of hERG inhibition by pharmaceutical compounds A-1 and A-2. [Figure 6] Serum ALT and AST levels of all animals participating in the BLM model. (S+V): Control group, animals administered saline instead of BLM and the vehicle of the active pharmaceutical compound. (B+V): Animals administered BLM and the vehicle of the active pharmaceutical compound. (B+A-1): Animals administered BLM and pharmaceutical compound A-1. (B+A-2): Animals administered BLM and pharmaceutical compound A-2. [Figure 7] Cell counts (A) and total protein concentrations (B) in the bronchoalveolar fluid of animals. Groups with statistically significant differences are indicated with an "*". (S+V): Control group, animals administered saline instead of BLM and the vehicle for the active pharmaceutical compound. (B+V): Animals administered BLM and the vehicle for the active pharmaceutical compound. (B+A-1): Animals administered BLM and pharmaceutical compound A-1. (B+A-2): Animals administered BLM and pharmaceutical compound A-2. [Figure 8] Representative images of lung tissue sections from all groups following the BLM model. All images are magnified 40x. (S+V): Control group, animals administered saline instead of BLM and the vehicle for the active pharmaceutical compound. (B+V): Animals administered BLM and the vehicle for the active pharmaceutical compound. (B+A-1): Animals administered BLM and pharmaceutical compound A-1. (B+A-2): Animals administered BLM and pharmaceutical compound A-2. [Figure 9] Fold change in col1α1 and fibronectin mRNA levels in whole lung tissue samples after the bleomycin model. (S+V): Control group, animals administered saline instead of BLM and the vehicle of the active pharmaceutical compound. (B+V): Animals administered BLM and the vehicle of the active pharmaceutical compound. (B+A-1): Animals administered BLM and pharmaceutical compound A-1. (B+A-2): Animals administered BLM and pharmaceutical compound A-2. [Figure 10]Inhibition of ATX reduces inflammation and pulmonary edema after bleomycin (BLM) administration. a) Number of inflammatory cells in bronchoalveolar lavage fluid (BALF) counted with a hemocytometer. b) Total protein concentration in BALF measured by Bradford assay. Statistical significance was assessed by one-way ANOVA; ** / *** / **** indicate p<0.01, 0.001, and 0.0001, respectively. SAL = saline; BLM = bleomycin. [Figure 11] ATX inhibition reduces fibrotic lesion formation in murine pulmonary fibrosis. Representative images of H&E-stained mouse lung sections. SAL = saline, BLM = bleomycin. [Figure 12] ATX inhibition improves respiratory function in mice after bleomycin administration. Prior to sacrifice, mice were evaluated for respiratory function using a FlexiVent ventilator. Representative markers are shown. IC = peak inspiratory capacity, Crs = mean respiratory system compliance, Ers = mean respiratory system elastance, H = mean tissue elastance, Cst = mean static lung compliance, A = mean total lung capacity, K = upper curvature of the pressure-volume (PV) curve. Statistical significance was assessed by one-way ANOVA; * / ** indicate p<0.05 and 0.01, respectively. SAL = saline; BLM = bleomycin. [Figure 13] Synthetic route to pharmaceutical compound A-2. [Figure 14] Synthetic route to pharmaceutical compound A-3.

Claims

1. A pharmaceutical compound or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of: a) fibroproliferative diseases, in particular interstitial lung diseases (ILD), and / or liver diseases such as all types of hepatitis and / or non-alcoholic fatty liver disease (NAFLD) and / or non-alcoholic steatohepatitis (NASH) and / or cirrhosis, where the ILD is a primary disease, preferably idiopathic pulmonary fibrosis and / or sarcoidosis and / or interstitial pneumonia, or where the ILD is associated with an autoimmune and / or inflammatory and / or metabolic disease, preferably a combination of rheumatoid arthritis, ILD and / or scleroderma, ILD and / or myositis, ILD and / or diabetes, ILD and / or cardiovascular disease, and / or b) an inflammatory and / or autoimmune disease, preferably rheumatoid arthritis and / or scleroderma; and / or c) cancer, in particular lung cancer and / or hepatocellular carcinoma and / or pancreatic cancer and / or glioblastoma and / or neuroblastoma, and / or d) metabolic diseases, in particular type 1 diabetes and / or type 2 diabetes and / or obesity, The pharmaceutical compound or a pharmaceutically acceptable salt thereof is characterized in that it simultaneously inhibits autotaxin (ATX) and exerts PPARγ agonism, and comprises a chemical formula selected from the group consisting of formulas (A), (B), (C), (D), (E), (F), (G), and (H). 【Chemistry 1】 (Wherein, n=1 to 5. The R group is a group selected from groups (i), (ii), and (iii). 【Chemistry 2】 wherein the X groups are O, N, and (CH ２ ) ｍ and m=0 to 5. Ar is an aromatic ring or a heteroaromatic ring, and the ring is selected from the group consisting of hydrogen, halogen, (C １－６ ) has one or more substituents selected from an alkyl group, a nitro group, a methoxy group, and a trifluoromethoxy group. R １ , R ２ is selected from a cyano group, a fluoro group, a chloro group, a bromo group, and a methyl group.

2. 2. The pharmaceutical compound according to claim 1, wherein preferably n=1 or 2, more preferably n=1.

3. 3. The pharmaceutical compound according to claim 1, wherein X is preferably selected from oxygen and nitrogen, more preferably oxygen.

4. The pharmaceutical compound according to any one of claims 1 to 3, characterized in that Ar is preferably an aromatic ring or a heteroaromatic ring, the ring having one or more halogens, and more preferably a 3,5-dichlorophenyl group.

5. 5. The pharmaceutical compound according to claim 1, wherein n=1, X is oxygen, and Ar is a 3,5-dichlorophenyl group (A-1). 【Transformation 3】

6. The R １ is preferably selected from a cyano group, a fluoro group, and a chloro group, and is more preferably a cyano group, and ２ 3. The pharmaceutical compound according to claim 1, wherein is preferably selected from a fluoro group, a chloro group, a bromo group and a methyl group, more preferably a fluoro group.

7. n=1, and R １ is a cyano group, and R ２ is a fluoro group at the 4-position of the phenol ring. 【Chemistry 4】

8. 3. The pharmaceutical compound of claim 1, further comprising a group R having the structure (iii), wherein X is oxygen and Ar is a 3,5-dichlorophenyl group (A-3). 【Transformation 5】

9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 and one or more pharmaceutically acceptable excipients, for use in the prevention or treatment of: a) fibroproliferative diseases, in particular interstitial lung diseases (ILD), and / or liver diseases such as all types of hepatitis and / or non-alcoholic fatty liver disease (NAFLD) and / or non-alcoholic steatohepatitis (NASH) and / or cirrhosis, where the ILD is a primary disease, preferably idiopathic pulmonary fibrosis and / or sarcoidosis and / or interstitial pneumonia, or where the ILD is associated with an autoimmune and / or inflammatory and / or metabolic disease, preferably a combination of rheumatoid arthritis, ILD and / or scleroderma, ILD and / or myositis, ILD and / or diabetes, ILD and / or cardiovascular disease, and / or b) an inflammatory and / or autoimmune disease, preferably rheumatoid arthritis and / or scleroderma; and / or c) cancer, in particular lung cancer and / or hepatocellular carcinoma and / or pancreatic cancer and / or glioblastoma and / or neuroblastoma, and / or d) Metabolic diseases, in particular type 1 diabetes and / or type 2 diabetes and / or obesity.

10. 10. The pharmaceutical composition according to claim 9, characterized in that it is formulated with one or more excipients and is suitable for inhalation, or for intraperitoneal, or oral, or nasal, or subcutaneous, or intravenous, or topical administration, preferably for inhalation administration.

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