4-(2-(4-((2, 4-dioxothiazolidin-5-yl) methyl) phenoxy) derivatives as PPAR gamma agonists and autotaxin inhibitors for treatment of fibrosis

Abstract

The pharmaceutical compound or the pharmaceutically acceptable salt thereof is used for preventing or treating the following diseases by simultaneously inhibiting autotaxin (ATX) and activating peroxisome proliferator-activated receptor gamma (PPAR gamma): a) fibroproliferative diseases, in particular interstitial lung diseases (ILD) and / or liver diseases, and b) fibroproliferative diseases, in particular interstitial lung diseases (ILD) and / or liver diseases; the present invention relates to a pharmaceutical composition for treating hepatitis, such as various hepatitis and / or non-alcoholic fatty liver disease (NAFLD) and / or non-alcoholic steatohepatitis (NASH) and / or cirrhosis, where said ILD may be a primary disease, preferably idiopathic pulmonary fibrosis and / or sarcoidosis and / or interstitial pneumonia, or said ILD is a complication associated with an autoimmune and / or inflammatory and / or metabolic disease, or a pharmaceutical composition comprising said ILD. Preferably rheumatoid arthritis ILD and / or scleroderma ILD and / or myositis ILD and / or diabetes ILD and / or cardiovascular disease ILD; and / or b) inflammatory and / or autoimmune diseases, preferably rheumatoid arthritis and / or scleroderma; and / or c) cancer, in particular lung and / or hepatocellular carcinoma and / or pancreatic cancer and / or glioblastoma and / or neuroblastoma; and / or d) a metabolic disease, in particular diabetes mellitus type 1 and / or diabetes mellitus type 2 and / or obesity, having a formula selected from the group consisting of formulae (A), (B), (C), (D), (E), (F), (G) and (H).

Description

SUMMARY OF THE INVENTION

[0002] The pharmaceutical compound or pharmaceutically acceptable salt thereof of the present invention is used for preventing or treating the following by simultaneously inhibiting autotaxin (ATX) and activating peroxisome proliferator-activated receptor γ (PPARγ):

[0003] a) fibroproliferative diseases, in particular interstitial lung diseases (ILD) and / or liver diseases, such as various forms of hepatitis and / or non-alcoholic fatty liver disease (NAFLD) and / or non-alcoholic steatohepatitis (NASH) and / or cirrhosis, wherein the ILD may be a primary disease, preferably idiopathic pulmonary fibrosis and / or sarcoidosis and / or interstitial pneumonia, or an ILD comorbid 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; and / or

[0004] b) inflammatory diseases and / or autoimmune diseases, preferably rheumatoid arthritis and / or scleroderma; and / or

[0005] c) cancer, in particular lung cancer and / or hepatocellular carcinoma and / or pancreatic cancer and / or glioblastoma and / or neuroblastoma; and / or

[0006] d) metabolic diseases, in particular type 1 diabetes and / or type 2 diabetes and / or obesity,

[0007] The pharmaceutical compound has a chemical formula selected from the group consisting of chemical formulas (A), (B), (C), (D), (E), (F), (G) and (H),

[0008]

[0009]

[0010] Fibrosis refers to the excessive deposition of collagen and other extracellular matrix components, which leads to tissue structural modification, thereby destroying the functional characteristics of the corresponding organs (such as the lungs, liver, skin, kidneys, heart and pancreas), and ultimately causing partial or complete failure. It is estimated that fibrosis and its related fibroproliferative diseases (including but not limited to pulmonary fibrosis and liver fibrosis) account for ~50% of the causes of death in developed countries. In addition, the presence of fibrosis can significantly promote the spread of cancer and accelerate chronic transplant rejection. At the same time, the development of fibrosis is also a common side effect of radiotherapy and COVID-19, indicating that fibrosis has a great impact on human health (Rockey, DC, PDBell and JAHill (2015). "Fibrosis—A Common Pathway to Organ Injury and Failure." N Engl J Med 372 (12): 1138-1149).

[0011] Interstitial lung disease (ILD) encompasses a complex group of pulmonary fibroproliferative disorders that primarily affect the lung parenchyma and have a wide range of prognoses and clinical manifestations. It is estimated that over 200 different diseases can cause ILD, including systemic autoimmune diseases such as scleroderma (SSc-ILD) and rheumatoid arthritis (RA-ILD) (Wijsenbeek, M., A. Suzuki and T. M. Maher (2022). "Interstitial lung diseases." The Lancet 400(10354):769-786). Idiopathic pulmonary fibrosis (IPF) is the most common and most lethal ILD, a chronic, progressive, and often fatal lung disease. It primarily affects people over 60 years of age, and the average survival from diagnosis is 3-5 years, regardless of treatment, making its prognosis inferior to that of many types of cancer.

[0012] Fibrotic lungs share many characteristics with aging lungs, such as genomic instability, loss of protein homeostasis, telomere shortening, cellular senescence, and disturbances in mitochondrial homeostasis. Therefore, IPF patients have significant aging-related comorbidities, such as emphysema, lung cancer, pulmonary hypertension, gastroesophageal reflux, and endocrine / metabolic disorders, such as diabetes, hypothyroidism, and dyslipidemia, which seriously affect patients' survival and quality of life (Oldham, JMand HRCollard (2017). "Comorbid Conditions in Idiopathic Pulmonary Fibrosis: Recognition and Management." Front Med (Lausanne) 4:123). More specifically, in terms of metabolic diseases, studies have shown that hypothyroidism, diabetes, and dyslipidemia are more common in IPF patients (prevalence rate 10-39%) and are associated with poor prognosis (Oldham, JMand HRCollard (2017)). Metabolic reprogramming involved in IPF is a hallmark of cancer, including enhanced glycolysis, glutamine decomposition, and fatty acid oxidation, leading to disturbances in mitochondrial homeostasis and function (Selvarajah, B., I. Azuelos, D. Anastasiou and RC Chambers (2021). "Fibrometabolism-An emerging therapeutic frontier in pulmonary fibrosis." Sci Signal 14 (697)). Adipokines, cell signaling molecules produced by adipose tissue (such as adiponectin, leptin, ATX) and nuclear receptors such as PPARγ, play a central role in the regulation of metabolic reprogramming, transmitting signals from nutritional, hormonal, metabolic, and redox stimuli. Nuclear receptors also regulate the expression of genes involved in cellular processes related to energy production, including mitochondrial biogenesis and autophagy (Scholtes, C. and V. Giguère (2022). "Transcriptional control of energy metabolism by nuclear receptors." Nature Reviews Molecular Cell Biology 23(11):750-770).

[0013] ATX is a secreted lysophospholipase D that is widely present in biological fluids. It can catalyze the extracellular conversion of lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA), a signaling phospholipid similar to a growth factor (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. Astylianaki, E. 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 various 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 Cancer." Carcinogenesis."CancerResearch78(13):3634-3644), liver (Kaffe, E., A. Katsifa, N. V.Aidinis(2017)."Hepatocyteautaxin expression promotes liver fibrosis and cancer."Hepatology 65(4):1369-1383; Kaffe, E., C. Magkrioti and V. Aidinis(2019). Cancer."Cancers(Basel)11(11))and(Auciello,FR,V.Bulusu,C.Oon,J.Tait-Mulder,M.Berry,S.Bhattacharyya,S.Tumanov,BLAllen-Pete rsen,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-AutotoxinSignaling Axis Promotes Pancreatic Tumor Progression."Cancer Discov 9(5):617-627), a strong anti-inflammatory, active IPF(Oikonomou,N.,MAMouratis,A.Tzouvelekis,E.Kaffe,C.Valavanis,G.Vilaras,A.Karameris,GDPrestwich,D.Bouros). andV.Aidinis(2012)."Pulmonary autotaxin expression contributes to thepathogenesis of pulmonary fibrosis."Am J Respir Cell Mol Biol 47(5):566-574) with an active ingredient(Kaffe,E.,A.Katsifa,N.Xylourgidis,I.Ninou,M.Zannikou,V.Harok). opos,P.Foka,A.Dimitriadis,K.Evangelou,ANMoulas,U.Georgopoulou,VGGorgoulis,GNDalekos and V. Aidinis (2017)."Hepatocyte autotaxinexpression promotes liver fibrosis and cancer."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, GB Mills, S. Gay, G. Kollias and V.Aidinis(2012). "Autotaxin expression from synovialfibroblasts is essential for the pathogenesis of modeled arthritis." J Exp Med209(5):925-933). Genetic or pharmacological targeting of ATX can alleviate bleomycin (BLM)-induced pulmonary fibrosis, collagen-induced arthritis (CIA), and carbon tetrachloride (CCl4)-induced hepatitis, thus confirming that ATX can be used as a potential therapeutic target for fibroproliferative diseases and interstitial lung diseases (Magkrioti, C., A. Galaris, P. Kanellopoulou, E. A. Astylianaki, E. A. Kaffe and V. Aidinis (2019). "Autotaxin and chronic inflammatory diseases." J Autoimmun 104: 102327).

[0014] PPARγ is one of the 48 nuclear receptors currently in existence and plays a central role in regulating metabolic reprogramming. It can integrate signals from major metabolic sensing systems, such as AMP-activated protein kinase (AMPK) and mTOR, and synchronize their activity with the circadian clock. Therefore, nuclear receptors are commonly used multi-drug targets for various diseases (Scholtes, C. and V. Giguère (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) regulates the expression of genes involved in lipid and glucose metabolism, thereby playing a key role in maintaining metabolic homeostasis (Ahmadian, M., J.M.Suh, N.Hah, C.Liddle, A.R.Atkins, M.Downes and R.M.E.vans (2013). "PPARγ signaling and metabolism: the good, the bad and the future." Nat Med 19(5):557-566). PPARγ agonists include thiazolidinediones (TZDs), also known as glitazones (tro-, pio-, rosi-).Diabetes and dyslipidemia are common comorbidities in 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). Studies have shown that metabolic abnormalities regulated by PPARγ are associated with the development of pulmonary fibrosis: the major pro-fibrotic factor TGF-β has been shown to inhibit PPARγ expression, and PPARγ activation can inhibit TGF-β-induced mitochondrial activation (Calvier, L., P. Chouvarine, E. Legchenko, N. Hoffmann, J. Geldner, P. Borchert, D. Jonigk, MM 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).Recent studies have suggested that the pathogenesis of pulmonary fibrosis involves TGF-β-induced differentiation of pulmonary lipofibroblasts (a novel pulmonary fibroblast subset) into myofibroblasts, and that activation of PPARγ can inhibit this differentiation process, thereby inhibiting the formation of pulmonary fibrosis (El Agha, E., A. Moiseenko, V. Kheirollahi, S. De Langhe, 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. Günther, 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).In animal models, genetic knockout of PPARγ exacerbates pulmonary fibrosis (Malur, A., A. Mohan, RA Barrington, N. Leffler, A. Malur, B. Muller-Borer, G. Murray, K. Kew, C. Zhou, J. Russell, J. L Jones, C. J Wingard, BP Barna and M. J. Thomassen (2019). "Peroxisome Proliferator-activated Receptor-γ Deficiency Exacerbates Fibrotic Response to Mycobacteria Peptide in Murine Sarcoidosis Model." American Journal of Respiratory Cell and Molecular Biology 61(2):198-208), while pharmacological activation using PPARγ agonists can alleviate 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. Günther, S. Bellusci and E. El Agha (2019). "Metformin induces slipogenic differentiation in myofibroblasts to reverse lung fibrosis." Nat Commun 10(1):2987), suggesting that PPARγ activation has a beneficial role in the pathogenesis of the disease.

[0015] Interestingly, the enzymatic product of ATX, LPA, has been controversially suggested to inhibit (D'Souza, K., GV Parameland 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 relevant mechanism is still unclear and may involve Wnt pathway-mediated signal activation (Burkhalter, RJ, SD Westfall, Y. Liu and M. S. Stack (2015). "Lysophosphatidic Acid Initiates Epithelial to Mesenchymal Transition and Inducesβ-Catenin-mediated Transcription in Epithelial Ovarian Carcinoma." Journal of Biological Chemistry 290(36):22143-22154), and the negative regulation of PPARγ on the ATX / LPA axis, but there is still a lack of clear understanding.

[0016] Document US9051320B1 relates to a method for preventing or delaying the onset of metabolic diseases by combining an ATX inhibitor with a hypoglycemic agent. Documents EP3302490B1, US10183949B2, US20170037030A1, and US10125132B2 relate to chemical compounds having ATX inhibitory activity. GR1010268B (N-[2-(4-bromophenyl)-2,5-dihydro-4H-thieno[3,4-c]pyrazol-3-yl]acetamide compounds with ATX inhibitory activity), GR1010099B (thieno[3,4-c]pyrazol-3-ylacetamide compounds with ATX inhibitory activity) and PCT international patent WO2022003377A1 (thieno[3,4-c]pyrazol-3-ylacetamide compounds as ATX inhibitors) also relate to chemical compounds with ATX inhibitory activity.

[0017] However, there is no disclosure in the prior art regarding the prevention or treatment of the following diseases by simultaneously achieving the dual effects of ATX inhibition and PPARγ agonism:

[0018] a) fibroproliferative diseases, in particular ILD and / or liver diseases, such as various types of hepatitis and / or non-alcoholic fatty liver disease (NAFLD) and / or non-alcoholic steatohepatitis (NASH) and / or cirrhosis, wherein the ILD can be a primary disease, preferably idiopathic pulmonary fibrosis and / or sarcoidosis and / or interstitial pneumonia, or the ILD is a situation with autoimmune and / or inflammatory and / or metabolic diseases, preferably rheumatoid arthritis ILD and / or scleroderma-ILD and / or myositis-ILD ​​and / or diabetes-ILD ​​and / or cardiovascular disease-ILD, and / or

[0019] b) inflammatory diseases and / or autoimmune diseases, preferably rheumatoid arthritis and / or scleroderma, and / or

[0020] c) cancer, in particular lung cancer and / or hepatocellular carcinoma and / or pancreatic cancer and / or glioblastoma and / or neuroblastoma, and / or

[0021] d) Metabolic diseases, in particular type I diabetes and / or type II diabetes and / or obesity.

[0022] A novel class of drug compounds has been synthesized, in which the molecular structure simultaneously incorporates a thiazolidinedione functional group with PPARγ agonist activity and functional groups of the ATX inhibitors PF8380, GLPG1690, and HA-155. Among the synthesized novel compounds, only the drug compounds having chemical formulas selected from the present invention (A), (B), (C), (D), (E), (F), (G), and (H) exhibit nanomolar ATX inhibitory activity (IC 50 0.19 μM and 0.47 μM, respectively), wherein the R group is a structural analogue of the functional group of PF8380 and GLPG1690; in contrast, the IC 50 It is 20.67μM.

[0023] Surprisingly, the pharmaceutical compounds having a formula selected from the group consisting of Formula (A), (B), (C), (D), (E), (F), (G) and (H) of the present invention exhibit PPARγ agonistic and ATX inhibitory properties.

[0024] Surprisingly, the novel pharmaceutical compounds having a chemical formula selected from the group consisting of chemical formulas (A), (B), (C), (D), (E), (F), (G) and (H) of the present invention exhibited significant results in all of the above-mentioned treatments by simultaneously activating PPARγ and inhibiting ATX.

[0025] Surprisingly, the novel pharmaceutical compounds having a chemical formula selected from the group consisting of chemical formulas (A), (B), (C), (D), (E), (F), (G) and (H) of the present invention, by simultaneously activating PPARγ and inhibiting ATX, show significant results in the anti-fibrotic treatment of ILD, either primary or concurrent with autoimmune and / or inflammatory and / or metabolic diseases.

[0026] Surprisingly, the pharmaceutical compounds having a chemical formula selected from the group consisting of chemical formulas (A), (B), (C), (D), (E), (F), (G) and (H) of the present invention exhibited significant results in the treatment of bleomycin-induced pulmonary fibrosis and idiopathic pulmonary fibrosis by simultaneously activating PPARγ and inhibiting ATX.

[0027] Surprisingly, the pharmaceutical compounds having a chemical formula selected from the group consisting of Chemical Formulas (A), (B), (C), (D), (E), (F), (G) and (H) of the present invention exhibit excellent results in the treatment of diabetes by simultaneously activating PPARγ and inhibiting ATX, resulting in lowering of blood glucose levels.

[0028] Surprisingly, the novel pharmaceutical compounds having a chemical formula selected from the group consisting of Chemical Formulas (A), (B), (C), (D), (E), (F), (G) and (H) of the present invention exhibited significant results in combating scleroderma by simultaneously activating PPARγ and inhibiting ATX.

[0029] Surprisingly, the novel pharmaceutical compounds having a chemical formula selected from the group consisting of Chemical Formulas (A), (B), (C), (D), (E), (F), (G) and (H) of the present invention exhibited significant results in combating rheumatoid arthritis by simultaneously activating PPARγ and inhibiting ATX.

[0030] Surprisingly, the novel pharmaceutical compounds having a chemical formula selected from the group consisting of Chemical Formulas (A), (B), (C), (D), (E), (F), (G) and (H) of the present invention exhibited significant results in the simultaneous treatment of pulmonary fibrosis and rheumatoid arthritis by simultaneously activating PPARγ and inhibiting ATX.

[0031] Surprisingly, the novel pharmaceutical compounds having a chemical formula selected from the group consisting of Chemical Formulas (A), (B), (C), (D), (E), (F), (G) and (H) of the present invention exhibited significant results in the simultaneous treatment of pulmonary fibrosis and scleroderma by simultaneously activating PPARγ and inhibiting ATX.

[0032] Surprisingly, the novel pharmaceutical compounds having a chemical formula selected from the group consisting of chemical formulas (A), (B), (C), (D), (E), (F), (G) and (H) of the present invention exhibited significant results in the simultaneous treatment of pulmonary fibrosis and diabetes by simultaneously activating PPARγ and inhibiting ATX.

[0033] Surprisingly, the novel pharmaceutical compounds having a chemical formula selected from the group consisting of Formulae (A), (B), (C), (D), (E), (F), (G) and (H) of the present invention do not exhibit cardiotoxicity compared to other thiazolidinedione derivatives used for diabetes treatment.

[0034] Surprisingly, the new pharmaceutical compounds having a formula selected from the group consisting of Formula (A), (B), (C), (D), (E), (F), (G) and (H) of the present invention do not exhibit hepatotoxicity.

[0035] The present invention is defined by the following definitions:

[0036] Definition 1. A pharmaceutical compound or a pharmaceutically acceptable salt thereof for use in preventing or treating the following by simultaneously inhibiting ATX and activating PPARγ:

[0037] a) fibroproliferative diseases, in particular ILD and / or liver diseases, such as various forms of hepatitis and / or NAFLD and / or NASH and / or cirrhosis, wherein the ILD may be a primary disease, preferably idiopathic pulmonary fibrosis and / or sarcoidosis and / or interstitial pneumonia, or the ILD may be a complication of 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, and / or

[0038] b) inflammatory diseases and / or autoimmune diseases, preferably rheumatoid arthritis and / or scleroderma, and / or

[0039] c) cancer, in particular lung cancer and / or hepatocellular carcinoma and / or pancreatic cancer and / or glioblastoma and / or neuroblastoma, and / or

[0040] d) metabolic diseases, in particular type 1 diabetes and / or type 2 diabetes and / or obesity,

[0041] The compound has a chemical formula selected from the group consisting of chemical formulas (A), (B), (C), (D), (E), (F), (G) and (H),

[0042]

[0043] in:

[0044] -n=1-5;

[0045] -R group is selected from groups (i), (ii), and (iii):

[0046]

[0047] in:

[0048] -X group is selected from O, N and (CH2) m , where m = 0-5;

[0049] -Ar is an aromatic ring or a heteroaromatic ring, which has one or more substituents selected from hydrogen, halogen, (C 1-6 ) alkyl, nitro, methoxy and trifluoromethoxy;

[0050] -R1, -R2 are selected from cyano, fluoro, chloro, bromo and methyl.

[0051] Definition 2. The pharmaceutical compound according to definition 1, wherein n=1 or 2, more preferably n=1.

[0052] Definition 3. The pharmaceutical compound according to any one of definitions 1 to 2, wherein X is preferably selected from oxygen and nitrogen, more preferably oxygen.

[0053] Definition 4. The pharmaceutical compound according to any one of definitions 1 to 3, wherein Ar is preferably an aromatic ring or a heteroaromatic ring, wherein the ring carries one or more halogens, more preferably a 3,5-dichlorophenyl group.

[0054] Definition 5. The pharmaceutical compound according to any one of definitions 1 to 4, wherein n=1, X is oxygen, and Ar is a 3,5-dichlorophenyl group (A-1),

[0055]

[0056] Definition 6. The pharmaceutical compound according to any one of definitions 1 to 2, wherein R1 is preferably selected from cyano, fluoro and chloro, more preferably cyano, and R2 is preferably selected from fluoro, chloro, bromo and methyl, more preferably fluoro.

[0057] Definition 7. The pharmaceutical compound according to Definition 6, wherein n=1, R1 is a cyano group, and R2 is a fluoro group (A-2) located at the 4th position of the phenol ring,

[0058]

[0059] Definition 8. The pharmaceutical compound according to any one of definitions 1 to 2, which carries an R group having structure (iii), wherein X is oxygen and Ar is a 3,5-dichlorophenyl group (A-3),

[0060]

[0061] Definition 9. A pharmaceutical composition comprising a compound according to any one of definitions 1 to 8, further comprising one or more pharmaceutically acceptable excipients, for use in preventing or treating:

[0062] a) fibroproliferative diseases, in particular ILD and / or liver diseases, such as various forms of hepatitis and / or NAFLD and / or NASH and / or cirrhosis, wherein the ILD may be a primary disease, preferably idiopathic pulmonary fibrosis and / or sarcoidosis and / or interstitial pneumonia, or the ILD may be coexisting 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, and / or

[0063] b) inflammatory diseases and / or autoimmune diseases, preferably rheumatoid arthritis and / or scleroderma, and / or

[0064] c) cancer, in particular lung cancer and / or hepatocellular carcinoma and / or pancreatic cancer and / or glioblastoma and / or neuroblastoma, and / or

[0065] d) Metabolic diseases, in particular type 1 diabetes and / or type 2 diabetes and / or obesity.

[0066] Definition 10. The pharmaceutical composition according to definition 9, formulated with one or more excipients, wherein the composition is suitable for inhalation or intraperitoneal or oral or intranasal or subcutaneous or intravenous or topical administration, preferably inhalation administration.

[0067] Formulas (B), (C), (D), (E), (F), (G) and (H) are (bio)isosteres of formula (A), i.e., 4-(2-(4-((2,4-dioxothiazolidin-5-yl)methyl)phenoxy) derivatives.

[0068] According to the present invention, the pharmaceutical compound having a formula selected from the group consisting of Formulae (A), (B), (C), (D), (E), (F), (G) and (H) has an R group, wherein R is a substituted piperazine derivative.

[0069] According to the present invention, the pharmaceutical compound having a chemical formula selected from the group consisting of formula (A), (B), (C), (D), (E), (F), (G) and (H) has an R group having structure (i), wherein the X group is selected from oxygen, nitrogen or 0-5 methylene ((CH2) m , m=0-5).

[0070] According to the present invention, the pharmaceutical compound having a formula selected from the group consisting of Formula (A), (B), (C), (D), (E), (F), (G) and (H) has an R group having structure (i), wherein the X group is selected from oxygen and nitrogen.

[0071] According to the present invention, a pharmaceutical compound having a chemical formula selected from the group consisting of formula (A), (B), (C), (D), (E), (F), (G) and (H) having an R group of structure (i), wherein the R group is an aromatic ring or heteroaromatic ring having one or more substituents selected from hydrogen, halogen, (C 1-6 ) alkyl, nitro, methoxy and trifluoromethoxy groups.

[0072] According to the present invention, the pharmaceutical compound having a chemical formula selected from the group consisting of chemical 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 ring or a heteroaromatic ring having one or more halogen atoms.

[0073] In a preferred embodiment, the pharmaceutical compound has a chemical formula selected from the group consisting of chemical formula (A), (B), (C), (D), (E), (F), (G) and (H), wherein n=1, has an R group of structure (i), wherein the X group is oxygen, and the Ar group is a 3,5-dichlorophenyl group (A-1).

[0074] According to the present invention, a pharmaceutical compound having a chemical formula selected from the group consisting of chemical formulas (A), (B), (C), (D), (E), (F), (G) and (H) has a substituted aminothiazole derivative as the R group.

[0075] According to the present invention, the pharmaceutical compound having a chemical formula selected from the group consisting of chemical formulas (A), (B), (C), (D), (E), (F), (G) and (H) has an R group of structure (ii), wherein the R1 and R2 groups are selected from cyano, fluoro, chloro, bromo or methyl groups.

[0076] According to the present invention, the pharmaceutical compound having a chemical formula selected from the group consisting of chemical formulas (A), (B), (C), (D), (E), (F), (G) and (H) has an R group of structure (ii), wherein the R1 group is selected from the group consisting of cyano, fluoro and chloro groups.

[0077] According to the present invention, the pharmaceutical compound having a chemical formula selected from the group consisting of chemical formula (A), (B), (C), (D), (E), (F), (G) and (H) has an R group of structure (ii), wherein the R2 group is preferably selected from a fluoro group, a chloro group, a bromo group and a methyl group.

[0078] In a preferred embodiment, the pharmaceutical compound has a chemical formula selected from the group consisting of chemical formulas (A), (B), (C), (D), (E), (F), (G) and (H), wherein n=1, has an R group of structure (ii), the R1 group is a cyano group, and the R2 group is a fluoro group (A-2) located at the 4-position of the phenol ring.

[0079] According to the present invention, a pharmaceutical compound having a formula selected from the group consisting of formula (A), (B), (C), (D), (E), (F), (G) and (H) has a substituted piperine derivative as the R group.

[0080] According to the present invention, a pharmaceutical compound having a chemical formula selected from the group consisting of chemical 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).

[0081]

[0082] Surprisingly, it was found that the drug compound A-1 exhibited inhibitory activity against ATX when tested in a well-established in vitro experimental protocol with an IC 50 The value was 0.19 μM, which was superior to the existing non-toxic inhibitors.

[0083] Surprisingly, it was found that the drug compound A-1 exhibited significant results in each of the above treatments.

[0084] Surprisingly, it was found that the drug compound A-1 has a clear therapeutic effect in the anti-fibrotic treatment of ILD, regardless of whether the ILD is primary or comorbid with autoimmune and / or inflammatory and / or metabolic diseases.

[0085] Surprisingly, it was found that the drug compound A-1 has excellent therapeutic effects in treating pulmonary fibrosis and associated interstitial lung disease and / or lung allograft fibrosis because it simultaneously inhibits ATX and activates PPARγ.

[0086] Surprisingly, it was found that the drug compound A-1 has a clear therapeutic effect in treating type 2 diabetes.

[0087] Surprisingly, it was found that the drug compound A-1 has significant results in treating pulmonary fibrosis or cardiac fibrosis after type 2 diabetes.

[0088] Surprisingly, it was found that the drug compound A-1 has significant results in treating rheumatoid arthritis-associated pulmonary fibrosis.

[0089] Surprisingly, it was found that the drug compound A-1 has significant results in the treatment of combined skin and pulmonary fibrosis.

[0090] It was surprisingly found that the pharmaceutical compound A-1 does not exhibit cardiotoxicity.

[0091] It was surprisingly found that pharmaceutical compound A-1 does not exhibit hepatotoxicity.

[0092] It was surprisingly found that compound A-1 exhibits highly desirable pharmacokinetic characteristics.

[0093] Surprisingly, it was found that the drug compound A-2 exhibited inhibitory activity against ATX when tested in a well-established in vitro experimental protocol with an IC 50 The value was 0.47 μM, which was superior to the existing non-toxic inhibitors.

[0094] Surprisingly, it was found that the drug compound A-2 exhibited significant results in each of the above treatments.

[0095] Surprisingly, it was found that the drug compound A-2 has a clear therapeutic effect in the anti-fibrotic treatment of ILD, which is a primary disease or a comorbidity with autoimmune and / or inflammatory and / or metabolic diseases.

[0096] Surprisingly, it was found that the drug compound A-2 has significant therapeutic effects in treating pulmonary fibrosis and associated interstitial lung disease and / or lung allograft fibrosis due to its simultaneous inhibition of ATX and activation of PPARγ.

[0097] Surprisingly, it was found that the drug compound A-2 has a clear therapeutic effect in treating type 2 diabetes.

[0098] Surprisingly, it was found that the drug compound A-2 had significant results in treating pulmonary fibrosis or cardiac fibrosis following type 2 diabetes.

[0099] Surprisingly, it was found that the drug compound A-2 had significant results in treating rheumatoid arthritis-associated pulmonary fibrosis.

[0100] Surprisingly, it was found that the drug compound A-2 had significant results in treating combined skin and pulmonary fibrosis.

[0101] It was surprisingly found that the pharmaceutical compound A-2 did not exhibit cardiotoxicity.

[0102] It was surprisingly found that the pharmaceutical compound A-2 does not exhibit hepatotoxicity.

[0103] It was surprisingly found that compound A-2 exhibited a very desirable pharmacokinetic profile.

[0104] Surprisingly, it was found that the drug compound A-3 exhibited inhibitory activity against ATX when tested in a well-established in vitro experimental protocol with an IC 50 The value was 0.03 μM, which was superior to the existing non-toxic inhibitors.

[0105] Surprisingly, it was found that the drug compound A-3 exhibited significant results in each of the above treatments.

[0106] Surprisingly, it was found that the drug compound A-3 has a clear efficacy in the anti-fibrotic treatment of ILD, regardless of whether the ILD is primary or comorbid with autoimmune and / or inflammatory and / or metabolic diseases.

[0107] Surprisingly, it was found that the drug compound A-3 has excellent therapeutic effects in treating pulmonary fibrosis and associated interstitial lung disease and / or lung allograft fibrosis because it simultaneously inhibits ATX and activates PPARγ.

[0108] Surprisingly, it was found that the drug compound A-3 has a clear therapeutic effect in treating type 2 diabetes.

[0109] Surprisingly, it was found that the drug compound A-3 had significant results in treating pulmonary fibrosis or cardiac fibrosis after type 2 diabetes.

[0110] Surprisingly, it was found that the drug compound A-3 had significant results in treating rheumatoid arthritis-associated pulmonary fibrosis.

[0111] Surprisingly, it was found that the drug compound A-3 had significant results in the treatment of combined skin and pulmonary fibrosis.

[0112] It was surprisingly found that the pharmaceutical compound A-3 did not exhibit cardiotoxicity.

[0113] It was surprisingly found that the pharmaceutical compound A-3 did not exhibit hepatotoxicity.

[0114] Surprisingly, it was found that compound A-3 exhibited very ideal pharmacokinetic characteristics.

[0115] According to the present invention, the pharmaceutical compound having a chemical structure selected from the group consisting of chemical formulas (A), (B), (C), (D), (E), (F), (G) and (H) can be mixed with pharmaceutically acceptable excipients, formulated into various pharmaceutical dosage forms and used at appropriate doses to achieve the desired therapeutic effect.

[0116] The present invention is illustrated by the following representative but non-limiting examples:

[0117] Example 1: Synthesis and activity evaluation of drug compound A-1

[0118] The synthesis of drug compound A-1 follows the following synthetic route: Figure 1 .

[0119] The synthesis of pharmaceutical compound A-1 is as follows:

[0120] Synthesis of 4-(2-bromoethoxy)benzaldehyde (i): 4-Hydroxybenzaldehyde (0.75 g, 6.14 mmol) was dissolved in anhydrous CHCN (45 mL), and 1,2-dibromoethane (5.29 mL, 61.4 mmol) and KCO (1.55 g, 11.2 mmol) were added. The mixture was stirred at reflux for 20 h, cooled to room temperature (rt), and water (45 mL) was added. The mixture was extracted with EtO (2 x 30 mL). The combined organic phases were washed with brine (25 mL), dried (NaSO), filtered, and concentrated in vacuo. The residue was recrystallized from EtO:hexane to afford the product as a white solid. Yield = 0.92 g (65%). 1H-NMR (CDCl3, 400MHz) δ3.69 (td, J1=1.7Hz, J2=6.2Hz, 2H), 4.40 (td, J1=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] + .

[0121] Synthesis of 3,5-dichlorobenzylpiperazine-1-carboxylate hydrochloride (ii): 4N HCl (16 mL, 63 mmol) in dioxane was 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 is described below. The mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and the remaining white solid was used in the next reaction 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 / z326.1[M+H] + .

[0122] Synthesis of 1-(tert-butyl)-4-(3,5-dichlorobenzyl)piperazine-1,4-dicarboxylate (iii): To a solution of (3,5-dichlorophenyl)methanol (1.50 g, 8.47 mmol) in anhydrous DMF (15 mL) was added CDI (1.92 g, 11.86 mmol) and the reaction was stirred at 45°C for 2 hours. 1-Boc-piperazine (1.97 g, 10.59 mmol) was then added and the reaction mixture was stirred at room temperature overnight. Water (30 mL) was added to the mixture and the precipitate was filtered, washed with water (2 x 10 mL) and hexane (10 mL), and dried. The crude product (white solid) was used in the next reaction without further purification. Yield = 3.30 g (74%). MS [ESI+] m / z 390.1 [M+H] + .

[0123] Synthesis of 3,5-dichlorobenzyl 4-(2-(4-formylphenoxy)ethyl)piperazine-1-carboxylate (iv): A mixture of compounds 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 hours and at 55°C for 12 hours. 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:EtOAc (7:3 to 100% ethyl acetate) to give a yellow oil that solidified upon refrigeration. 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=5.6 Hz,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] + .

[0124] 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 (1.68 g, 3.85 mmol) and 2,4-thiazolidinedione (0.54 g, 4.62 mmol) were dispersed in anhydrous toluene (16 mL). Piperidine (0.20 mL, 1.92 mmol) was then added, followed by acetic acid (0.11 mL, 1.92 mmol), and the mixture was refluxed overnight. The reaction mixture was cooled at room temperature, whereupon a tan solid precipitated. The mixture was filtered, washed with toluene (20 mL) and hexane (20 mL), and dried at 50°C overnight. Pale yellow powder. Yield = 2 g (quantitative). 1H-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=5.6 Hz,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] + .

[0125] 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 5 drops of 0.5 M aqueous NaOH were added dropwise until the pH was 11. A mixture of THF:DMF 2:1 (20 mL) 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 hours, and partial conversion of the starting material to the desired product was observed by TLC and MS. More 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 then added, and the mixture was stirred overnight. The pH of the reaction was adjusted to 3 with 6N HCl and then to 10 with 1N NaOH. The mixture was extracted with ethyl acetate (2 x 50 mL), and the combined organic phases were washed with water (30 mL) and brine (30 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash column chromatography using ethyl acetate as the eluent to afford the desired product (A-1) as a light yellow semisolid. Yield = 0.226 g (50%). 1H-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] + .

[0126] Evaluation of ATX inhibitory activity

[0127] The inhibition of ATX enzyme activity by drug compound A-1 was determined in vitro by applying the Amplex Red method. Briefly, 2 μL of the derivative (A4) at a concentration range of 0.001 to 5 μmol / L in DMSO was incubated with 50 μL of ATX 8nM (for human ATX, the final concentrations were 2nM and 1nM) and 48 μL of buffer (50 mM Tris-Cl and 5 mM CaCl2 at pH 8.0) at 37 ° C for 15 minutes. Subsequently, 50 μL of a buffer containing 200 μM LPC 16:0 (final concentration of 50 μM) was added to the reaction mixture, followed by incubation at 37 ° C for another 30 minutes. Finally, 50 μL of a working solution containing 200 μM Amplex Red reagent, choline oxidase (0.2 U / mL) and (kai) HRP (2 U / mL) was added to 50 mM Tris-HCl and 5 mM CaCl2 at pH 8.0 to start the reaction. The reaction was monitored every 5 minutes at 37°C for 30 minutes using a fluorescence microplate reader (Tecan Infinite200) with excitation at 530 nm and reading at 590 nm. 50 The values ​​were calculated from two independent experiments using sigmoid dose-response curves from the equation f=y0+a / (1+exp(-(x-x0) / b) provided by SigmaPlot 11.0 (PrismH software).

[0128] To determine the inhibitory effect of each inhibitor on ATX, a modified Amplex assay was used. Briefly, different concentrations of inhibitor (1, 2.5, 5, and 7.5 μM) were tested against different substrate concentrations (LPC 25, 50, and 100 μM). All inhibitory assays were performed using mouse ATX provided by Sino Biological. Reaction rates (V) were then calculated and plotted in a Lineweaver-Burk plot using GraphPad software (GraphPad Software, San Diego, CA, USA) as the inverse of the reaction rate (1 / V) versus the inverse of the substrate concentration (1 / S).

[0129] Hint Figure 2 The results showed that drug compound A-1 had a lower IC than TGL (0.61 μM). 50 (0.19μM). In addition, as shown Figure 3 As shown, compound A-1 exhibits non-competitive inhibition of ATX. Figure 4 As shown, A-1 showed no inhibition of choline oxidase and HRP peroxidase, and thus it is a specific inhibitor of ATX.

[0130] In vitro ADMET (absorption, distribution, metabolism, excretion, and toxicity) assays

[0131] The physicochemical properties evaluated were: in vitro membrane permeability, in vitro metabolism, and cardiotoxicity.

[0132] In vitro absorption assays were performed in the renal MDCKII cell line and involve the permeability from A to B when A and B are separated by the MDCKII cell membrane. Ideally, a compound should have high permeability from A to B but low permeability from B to A for better absorption. The permeability of AB for A-1 was calculated to be 3.7 × 10 -6 cm / s, while the permeability of BA was found to be 0.8×10 -6 cm / s. The permeability of AB is much higher than that of BA, so both compounds are well absorbed in vitro.

[0133] In vitro metabolism assays were performed in liver microsomes. The calculated half-life (t½) of Compound A-1 was 21 minutes. This half-life is higher than that of known drugs, such as imipramine and others, suggesting that Compound A-1 does not undergo rapid clearance from the circulation, thus remaining in the circulation for a sufficiently long time. This conclusion is further supported by the low Clint value, a parameter indicating intrinsic clearance (Compound A-1 has a Clint value of 328.6 μL / min / mg, which is lower than that of many other drugs).

[0134] Cardiotoxicity assays were performed in CHO cells expressing the human ether-a-go-go related gene (hERG), which encodes an inwardly rectifier voltage-gated potassium channel present in the heart and involved in cardiac repolarization. Inhibition of hERG may lead to potentially fatal ventricular arrhythmias. The IC of hERG inhibition by Compound A-1 was 2. 50 The value is estimated to be 12 μM ( Figure 5 This value is quite high (higher than their IC for ATX 50 Therefore, the drug compound A-1 has no cardiotoxicity.

[0135] In vivo evaluation of drug compound A-1 in mouse pulmonary fibrosis

[0136] 10-week-old male C57Bl6 / J wild-type animals were administered bleomycin (BLM) saline solution directly to the lungs via the orotracheal route. The bleomycin dose was 0.8U / kg. Drug compound A-1 was administered at a dose of 30mg / kg, and each animal received two doses daily starting from the day before BLM infusion. All animals were monitored daily until they were killed on the 14th day after BLM injection. The group receiving drug compound A-1 did not experience any undesirable side effects compared to the untreated group during the model. Serum, bronchoalveolar fluid and lung tissue samples were collected at the end of the experiment to assess the severity of fibrosis in each animal.

[0137] Serum was collected from each animal and the levels of ALT and AST aminotransferases, which are markers of liver damage, were assessed using an automated biochemical analyzer. Figure 6 As shown, the levels of ALT and AST in the five experimental groups were normal (within the normal range of ALT and AST, 28-132 U / L and 59-247 U / L, respectively). These results confirmed that the drug compound A-1 did not cause any adverse toxicity to the animal liver.

[0138] Next, the total cell count and total protein concentration in the collected bronchoalveolar fluid were evaluated as indicators of inflammation and endothelial permeability, respectively. Figure 7 As shown, the group receiving the novel drug compound A-1 (B+A-1) had a decreased number of cells and a decreased total protein concentration in the bronchoalveolar fluid compared to the group receiving only the compound vehicle (B+V).

[0139] In addition, the degree of fibrosis was assessed in lung tissue sections isolated from the animals after hematoxylin-eosin staining. Figure 8 Representative images of each group are shown. The B+V group, which did not receive ATX inhibitor treatment, appeared to have significant fibrotic areas compared to the control group that received the new drug compound A-1, while the latter showed significantly less fibrotic areas.

[0140] The mRNA level of col1α1 (collagen 1α1), a fibrosis-related gene, was also estimated in whole lung tissue RNA samples. Figure 9 As shown, the new drug compound A-1 statistically significantly reduced the mRNA level (expression) of col1α1 and even restored it to the same level as the control group receiving normal saline (S+V).

[0141] The drug compound A-1 in the above embodiment has excellent effects in simultaneously treating type 2 diabetes and restrictive lung disease and / or pulmonary fibrosis and / or pulmonary sarcoidosis and / or fibrosis after lung allotransplantation, and in reducing cardiotoxicity and hepatotoxicity after type 2 diabetes and fibrosis after type 2 diabetes.

[0142] To explore the potential of ATX inhibition in the treatment of pulmonary fibrosis, BLM was administered to 8-10 week old C57Bl6 / J mice. Subsequently, in treatment mode (7 days after BLM), the drug compound A-1 was administered by inhalation to awake and gently restrained mice twice a day for 7 consecutive days (1 mL of 6.5 mg / mL solution, inhaled for 10 minutes / 6 mice, equivalent to 15 mg / kg per mouse). As determined by hemocytometer, WT mice treated with BLM had a significant reduction in inflammatory cells in their bronchoalveolar lavage fluid (BALF) under the action of ATX inhibition (Figure 2). Figure 10 In addition, the administration of drug compound A-1 resulted in a significant decrease in the degree of vascular leakage and pulmonary edema, as shown by the total protein concentration ( Figure 10 Histological analysis showed that ATX inhibition prevented BLM-induced lung tissue structural deformation, as shown by H&E staining ( Figure 11 The protection of ATX inhibition against BLM-induced tissue structural deformation was also reflected in the lung respiratory function measured using FlexiVent ( Figure 12 Overall, these findings highlight the substantial impact of ATX expression in BLM-induced pulmonary fibrosis and suggest its potential relevance to IPF.

[0143] Example 2: Synthesis and activity evaluation of drug compound A-2.

[0144] The synthesis of drug compound A-2 is shown in the following synthetic route: Figure 13 .

[0145] The synthesis of A-2 derivative is as follows:

[0146] Synthesis of tert-butyl (2-(4-formylphenoxy)ethyl)carbamate (v): Diisopropyl azodicarboxylate (1.83 mL, 9.30 mmol) was added dropwise at 0°C 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). The mixture was then stirred at room temperature for 2.5 hours. The solvent was removed 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 (NaSO), filtered, and concentrated in vacuo. The residue was purified by flash column chromatography using hexane:ethyl acetate (4:1) to afford 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] + .

[0147] Synthesis of tert-butyl (E)-(2-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)ethyl)carbamate Synthesis of (vi): To a solution of compound v (1.50 g, 5.65 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 precipitated solid was filtered, washed with toluene (3 mL) and hexane (5 mL), and dried at 50°C overnight to afford the desired product as a beige / light brown amorphous solid. Yield = 1.63 g (80%). 1 H-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] + .

[0148] Synthesis of tert-butyl (2-(4-((2,4-dioxothiazolidin-5-yl)methyl)phenoxy)ethyl)carbamate (vii): Thiazolidinone derivative vi (0.80 g, 2.20 mmol) and magnesium turnings (1.07 g, 43.91 mmol) were placed in a flask and the air was removed by vacuum. The flask was purged with argon, and then anhydrous methanol (27 mL) was added. The mixture was stirred at room temperature under argon for 4 hours. The reaction mixture was acidified with 6N hydrochloric acid to pH 5-6 and extracted with dichloromethane (2×25 mL). The combined organic phases were washed with water (15 mL) and brine (15 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash column chromatography using hexane:ethyl acetate (3:2) as the eluent to afford the title 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] + .

[0149] Synthesis of Compounds viii and ix: A 4N HCl solution in dioxane (1.90 mL, 7.61 mmol) was added all at once to Compounds vi and vii (0.22 g, 0.61 mmol). The mixture was stirred at room temperature for 4 hours. The solvent was evaporated in vacuo, and the residue was washed with anhydrous ether (15 mL) and dried to afford the desired product as a white solid.

[0150] (E)-5-(4-(2-Aminoethoxy)benzylidene)thiazolidine-2,4-dione hydrochloride (viii): Yield = 0.111 g (quantitative). 1 H-NMR (CD3OD, 400MHz) δ3.45 (dd, J1=4.2Hz, J2=14.1Hz, 1H), 4.55 (brs, 2H), 6.98 (d, J=8.0Hz, 2H), 7.23 (d, J=8.0Hz, 2H), 7.91 (s, 1H). MS[ESI+]m / z:302.0[M+H] + .

[0151] 5-(4-(2-aminoethoxy)benzyl)thiazolidine-2,4-dione hydrochloride (ix):

[0152] Yield = 0.115 g (quantitative). 1 H-NMR (CD3OD, 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] + .

[0153] Synthesis of 2-chloro-4-(4-fluorophenyl)thiazole-5-carbonitrile (x): Tert-butyl nitrite (0.45 g, 4.34 mmol) was added dropwise to a solution of anhydrous CuCl2 (0.47 g, 3.47 mmol) in anhydrous CH3CN (6.5 mL) and stirred at room temperature for 45 minutes. Then, compound xi (0.63 g, 2.89 mmol) was added and stirring continued for a further 2 hours. The reaction mixture was carefully quenched with 1N HCl (10 mL) and stirred for 15 minutes. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (20 mL). The combined organic phases were washed with brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography using dichloromethane as the eluent. After evaporation of the solvent in vacuo, the residue was triturated with hexane, filtered, and dried. The product was 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 / z240.0 [M+H] + .

[0154] 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) was added anhydrous pyridine (0.24 mL, 2.89 mmol), stirred at 70°C for 20 minutes, and then cooled to room temperature. A suspension of thiourea (0.44 g, 5.79 mmol) and iodine (0.73 g, 2.89 mmol) previously stirred in anhydrous ethanol (4 mL) was slowly added and stirred at room temperature for 2 hours. Cold water (40 mL) was added, and the resulting precipitate was filtered, washed with water (10 mL) and hexane (15 mL), and dried under vacuum to afford 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] + .

[0155] Synthesis of Compounds 3 and 4: Compounds viii or ix (0.25 g, 0.83 mmol) and compound x (0.18 g, 0.76 mmol) were dissolved in anhydrous DMSO (7 mL). DIPEA (0.33 mL, 1.89 mmol) was added, and the mixture was stirred at 100°C for 8 hours and at room temperature overnight. Water (15 mL) was added, and the mixture was extracted with ethyl acetate (2 × 30 mL). The combined organic phases were washed with water (2 × 20 mL) and brine (20 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography using hexane:ethyl acetate (7:3 to 1:1) as the eluent to provide the final product.

[0156] 2-((2-(4-((2,4-Dioxothiazolidin-5-yl)methyl)phenoxy)ethyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile (4). Pale yellow amorphous solid. Yield = 0.20 g (56%). 1 H-NMR(DMSO-d6, 400MHz)δ.MS[ESI+]m / z 469.1[M+H] + .

[0157] (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 = 0.34 g (95%). 1H-NMR (DMSO-d6, 400MHz) δ2.51-2.52 (m, 6H), 3.29-3.38 (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] + .

[0158] ATX inhibitory activity assessment

[0159] The inhibition experiment of drug compound A-2 on ATX enzyme activity was carried out according to the method described in Example 1 of the present invention.

[0160] Hint Figure 2 As shown in Figure 2, compound A-2 has a lower IC than TGL (0.61 μM). 50 (0.47μM). In addition, as shown Figure 3 As shown in FIG, drug compound A-2 exhibits non-competitive inhibition on ATX. Figure 4 As shown, drug compound A-2 showed no inhibition on choline oxidase and HRP peroxidase, and thus it is a specific inhibitor of ATX.

[0161] In vitro ADMET (absorption, distribution, metabolism, excretion, and toxicity) assays

[0162] The physicochemical properties of the drug compound A-2 were evaluated according to the method described in Example 1 of the present invention.

[0163] According to in vitro absorption assay, the AB permeability of drug compound A-2 was 7.8×10 -6 cm / s, and the BA permeability is 3.2×10 -6 cm / s, thus the drug compound A-2 was well absorbed in vitro.

[0164] Based on in vitro metabolism assays, the half-life (t1 / 2) of Compound A-2 was estimated to be >60 minutes. Therefore, Compound A-2 is not rapidly eliminated from the body and remains in the systemic circulation for a prolonged period. This conclusion is further supported by its low Clint value (<115.5 μL / min / mg), which is lower than that of many known drugs.

[0165] Estimation of the IC of drug compound A-2 for hERG inhibition based on cardiotoxicity assay 50 >100μM (illustrated Figure 5This value is very high (higher than its IC for ATX 50 ), therefore, the drug compound A-2 has no cardiotoxicity.

[0166] In vivo evaluation of drug compound A-2 on pulmonary fibrosis in mice

[0167] The in vivo evaluation of the drug compound A-2 in the mouse pulmonary fibrosis model was evaluated as described in Example 1 of the present invention. Compared with the untreated group, the group treated with the drug compound A-2 did not experience adverse side effects during the model experiment. Figure 6 As shown in Figure 2, the levels of ALT and AST were normal (within the normal range of ALT and AST, 28-132 U / L and 59-247 U / L, respectively), so the drug compound A-2 did not cause adverse liver toxicity in animals. In addition, the group treated with drug compound A-2 showed a decrease in cell number and total protein level compared to the untreated group (B+V) (Figure 2). Figure 7 Animals treated with A-2 (B+A-2) showed less fibrotic areas than the untreated group (B+V) ( Figure 8 ). Finally, as shown Figure 9 As shown, the drug compound A-2 significantly reduced the mRNA level (expression) of col1α1 to the same level as the saline control group (S+V).

[0168] The drug compound A-2 in Example 2 has excellent effects in simultaneously treating type 2 diabetes and restrictive lung disease and / or pulmonary fibrosis and / or pulmonary sarcoidosis and / or lung allograft fibrosis, and in reducing cardiotoxicity, hepatotoxicity and fibrosis after type 2 diabetes.

[0169] Example 3: Synthesis and activity evaluation of drug compound A-3.

[0170] The synthesis of drug compound A-3 is shown in the following synthetic route: Figure 14 .

[0171] The synthesis of pharmaceutical compound A-3 is as follows:

[0172] 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 hours. After completion of the reaction, the solvent was evaporated, and the residue was purified by flash column chromatography on silica gel, eluting with hexane:ethyl acetate (100% hexane to 5% ethyl acetate in hexane). The product was a colorless oil. Yield = 0.530 g (79%). 1 H-NMR (dmso-d6, 400MHz)δ.

[0173] Synthesis of tert-butyl-4-(2-(4-formylphenoxy)ethyl)piperidine-1-carboxylate (ii): In 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. The reaction mixture was stirred at 70°C for 6 hours and at room temperature overnight. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with water (2 x 15 mL), saturated aqueous sodium carbonate (2 x 10 mL), and brine (15 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography eluting with hexane:ethyl acetate (EtOAc 0-20%). Off-white / light yellow solid. 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).

[0174] 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 anhydrous dichloromethane (4 mL) in a round-bottom flask. Trifluoroacetic acid (3.50 mL, 5.447 g, 47.776 mmol) was then added. The reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated under vacuum, saturated aqueous sodium bicarbonate (5 mL) was added, and the mixture was extracted with ethyl acetate (3×15 mL). The combined organic phases were washed with brine (15 mL), dried (Na 2 SO 4 ), filtered, and concentrated under vacuum. A yellow semisolid was obtained. 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).

[0175] 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 g, 2.251 mmol) and stirred at 45°C for 3 hours. 4-(2-(piperidin-4-yl)ethoxy)benzaldehyde (iii) (0.300 g, 1.286 mmol) was then dissolved in anhydrous DMF (2 mL) and added dropwise to the reaction mixture, which was then stirred at 45°C for 3 hours and at room temperature overnight. Water (15 mL) was added, and the mixture was extracted with diethyl ether (3 x 10 mL). The combined organic phases were washed with water (12 mL) and brine (12 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography using hexane:ethyl acetate (85:15 to 70:30) as the eluent. 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).

[0176] Synthesis of 3,5-dichlorobenzyl (E)-4-(2-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)ethyl)piperidine-1-carboxylate (v): In an oven-dried microwave reaction vial equipped with a magnetic stirrer, 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 added, 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. A yellow solid precipitated after the mixture was cooled to room temperature. It was filtered, washed with toluene and hexane, and dried at 50°C overnight. 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).

[0177] Synthesis of 3,5-dichlorobenzyl 4-(2-(4-((2,4-dioxothiazolidin-5-yl)methyl)phenoxy)ethyl)piperidine-1-carboxylate (3) (A-3):

[0178] Catalyst: 9 mg (0.038 mmol) of CoCl2·6H2O and 49 mg (0.413 mmol) of dimethylglyoxime were dissolved in 0.55 mL of DMF under stirring to produce a clear blue-green solution.

[0179] Reducing agent: Dissolve 0.177 g (4.670 mmol) of NaBH4 in 1.50 mL of H2O + 0.5 mL of 0.1 M NaOH, cool in an ice bath (0°C), and maintain in an ice bath until completely consumed.

[0180] Reaction: 23.4 mg of sodium hydroxide and 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) were dissolved in 5 mL of water and heated at 55°C with stirring until completely dissolved. The catalyst solution (0.15 mL of CoCl2-DMG in DMF) was added dropwise over 1 minute, followed by the addition of the reducing agent solution (0.50 mL of NaBH4 in water) over 2 minutes. The mixture was stirred at 55°C for 1 hour. The same procedure was repeated three times (each time 1 / 4 of the catalyst was added, followed by 1 / 4 of the reducing agent, followed by stirring at 55°C for 1 hour, i.e., once every hour). The mixture was then stirred at 45°C overnight. 10 mL of 6N hydrochloric acid was added the next day. After extraction, the aqueous phase was further extracted with EtOAc (2×20 mL). The combined organic phases were washed with water (20 mL) and brine (20 mL), dried, filtered, and concentrated in vacuo. The product was purified by flash column chromatography using hexane:EtOAc 3:2 as the eluent. A white crystalline solid was obtained. 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). 13C-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] + .

[0181] ATX inhibitory activity assessment

[0182] The inhibition of ATX enzyme activity by drug compound A-3 was carried out according to the method in Example 1 of the present invention.

[0183] Hint Figure 2As shown in Figure 2, compound A-3 has a lower IC than TGL (0.61 μM). 50 (0.03μM). In addition, as shown Figure 3 As shown in FIG, drug compound A-3 exhibits a non-competitive inhibition mechanism against ATX. Figure 4 As shown, compound A-3 exhibited no inhibition of choline oxidase and HRP peroxidase, making it a specific inhibitor of ATX. Notably, compound A-3 did not exhibit any significant inhibitory activity against hERG (11% inhibition at 25 μM concentration) according to a cardiotoxicity assay, thus demonstrating that compound A-3 is cardiotoxic. Its cardiotoxicity is lower than that of any other ATX inhibitors mentioned in the prior art.

[0184] Refer to the following attached diagram Figures 1 to 14 , the above embodiments are described in more detail and the above results are better understood:

[0185] Hint Figure 1 : The synthetic route of drug compound A-1.

[0186] Hint Figure 2 : Inhibition of ATX by drug compounds A-1, A-2, A-3 and troglitazone.

[0187] Hint Figure 3 : Diagram of the inhibition pattern of drug compounds A-1, A-2, and A-3 on ATX.

[0188] Hint Figure 4 : In the presence of drug compounds A-1, A-2, and A-3, the 2 nd and 3 rd The compounds did not show any kinetic curves for 2 nd (choline oxidase) or 3 rd (HRP peroxidase) detectable inhibition.

[0189] Hint Figure 5 : The hERG inhibition of drug compounds A-1 and A-2.

[0190] Hint Figure 6 : Levels of ALT and AST in the serum of animals involved in BLM model.

[0191] (S+V): Control group, animals received saline instead of BLM and active drug compound carrier; (B+V): animals received BLM and active drug compound carrier; (B+A-1): animals received BLM and drug compound A-1; (B+A-2): animals received BLM and drug compound A-2.

[0192] Hint Figure 7 : Cell number (A) and total protein concentration (B) in bronchoalveolar fluid of animals. Groups with statistically significant differences are indicated by "*".

[0193] (S+V): Control group, animals received saline instead of BLM and active drug compound carrier; (B+V): animals received BLM and active drug compound carrier; (B+A-1): animals received BLM and drug compound A-1; (B+A-2): animals received BLM and drug compound A-2.

[0194] Hint Figure 8 : Representative images of lung tissue sections from the BLM model. All images were taken at a magnification of 40×.

[0195] (S+V): Control group, animals received saline instead of BLM and active drug compound carrier; (B+V): animals received BLM and active drug compound carrier; (B+A-1): animals received BLM and drug compound A-1; (B+A-2): animals received BLM and drug compound A-2.

[0196] Hint Figure 9 : Fold changes in col1α1 and fibronectin mRNA expression levels in whole lung tissue samples in the bleomycin model.

[0197] (S+V): Control group, animals received saline instead of BLM and active drug compound carrier; (B+V): animals received BLM and active drug compound carrier; (B+A-1): animals received BLM and drug compound A-1; (B+A-2): animals received BLM and drug compound A-2.

[0198] Hint Figure 10 ATX inhibition reduces inflammation and pulmonary edema after bleomycin (BLM) administration. a) Number of inflammatory cells in bronchoalveolar fluid (BALF) counted using a hemacytometer; b) Total protein concentration in BALF determined by Bradford assay. Statistical significance was assessed by one-way analysis of variance; ** / *** / **** indicates p < 0.01, 0.001, or 0.0001; SAL = saline; BLM = bleomycin.

[0199] Hint Figure 11 ATX inhibition leads to fewer fibrotic lesions in mouse fibrotic lungs. Representative images of mouse lung sections, H&E staining; SAL - saline solution, BLM - bleomycin.

[0200] Hint Figure 12ATX inhibition improved respiratory function in mice after bleomycin administration. Respiratory function of mice was assessed using a FlexiVent mechanical ventilator before sacrifice. Representative indices are shown: IC = 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 = curvature of the upper portion of the expiratory curve of the pressure-volume (PV) curve. Statistical significance was assessed by one-way analysis of variance; * / ** = p < 0.05, 0.01; SAL = normal saline, BLM = bleomycin.

[0201] Hint Figure 13 : The synthetic route of drug compound A-2.

[0202] Hint Figure 14 : The synthetic route of drug compound A-3.

Claims

1. A pharmaceutical compound or a pharmaceutically acceptable salt thereof for preventing or treating the following by simultaneously inhibiting autotaxin (ATX) and stimulating peroxisome proliferator-activated receptor γ (PPARγ): a) fibroproliferative diseases, in particular interstitial lung diseases (ILD) and / or liver diseases, for example various forms of hepatitis and / or non-alcoholic fatty liver disease (NAFLD) and / or non-alcoholic steatohepatitis (NASH) and / or cirrhosis, wherein the ILD may be a primary disease, preferably idiopathic pulmonary fibrosis and / or sarcoidosis and / or interstitial pneumonia, or the ILD may be a disease coexisting 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, and / or b) inflammatory diseases and / or autoimmune diseases, 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 compound has a chemical formula selected from the group consisting of chemical formulas (A), (B), (C), (D), (E), (F), (G) and (H), in: -n＝1-5； -R group is selected from groups (i), (ii) and (iii): in: -X group is selected from O, N and (CH2)m, where m=0-5; -Ar is an aromatic ring or a heteroaromatic ring, wherein the ring carries one or more substituents selected from hydrogen, halogen, (C1-6) alkyl, nitro, methoxy and trifluoromethoxy; - R1, R2 are selected from cyano, fluoro, chloro, bromo and methyl groups.

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

3. The pharmaceutical compound according to any one of claims 1 to 2, 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, wherein Ar is preferably an aromatic ring or a heteroaromatic ring, wherein the ring carries one or more halogens, more preferably a 3,5-dichlorophenyl group.

5. The pharmaceutical compound according to any one of claims 1 to 4, wherein n=1, X is oxygen, and Ar is a 3,5-dichlorophenyl group (A-1), 6. The pharmaceutical compound according to any one of claims 1 to 2, wherein the R1 is preferably selected from cyano, fluoro and chloro, more preferably cyano, and the R2 is preferably selected from fluoro, chloro, bromo and methyl, more preferably fluoro.

7. The pharmaceutical compound according to claim 6, wherein n=1, R1 is a cyano group, and R2 is a fluoro group located at the 4th position of the phenol ring (A-2), 8. The pharmaceutical compound according to any one of claims 1 to 2, which carries a group R having structure (iii), wherein X is oxygen, and Ar is a 3,5-dichlorophenyl group (A-3), 9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8, comprising one or more pharmaceutically acceptable excipients, for use in preventing or treating: a) fibroproliferative diseases, especially ILD and / or liver diseases, such as various forms of hepatitis and / or NAFLD and / or NASH and / or cirrhosis, wherein the ILD can be a primary disease, preferably idiopathic pulmonary fibrosis and / or sarcoidosis and / or interstitial pneumonia, or the ILD is complicated by autoimmune and / or inflammatory and / or metabolic diseases, preferably rheumatoid arthritis ILD and / or scleroderma ILD and / or myositis ILD and / or diabetes ILD and / or cardiovascular disease ILD; and / or b) inflammatory diseases and / or autoimmune diseases, 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. The pharmaceutical composition according to claim 9, formulated with one or more excipients, said composition being suitable for inhalation or intraperitoneal injection or oral or intranasal or subcutaneous or intravenous or topical administration, preferably inhalation administration.

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