Prenylated tetrahydroquinolines and quinolines with PPAR agonist activity

Abstract

Prenylated tetrahydroquinolines and quinolines and pharmaceutical compositions comprising the same. Prenylated tetrahydroquinoline and quinolines and pharmaceutical compositions comprising the same, for use in the prevention and / or treatment of peroxisome proliferator-activated receptor (PPAR)-mediated diseases such as metabolic syndrome, type 2 diabetes mellitus, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, obesity, dyslipidemic atherosclerosis, metabolic dysfunction- associated fatty liver disease (MAFLD), cardiovascular disease, cardiometabolic disease, neurodegenerative disease, Friedreich's ataxia, Parkinson's disease, multiple sclerosis, Alzheimer's disease, autoimmune disease, rheumatoid arthritis, autoimmune thyroid disease, dermatological disease, and cancer.

Description

[0001] DESCRIPTION PRENYLATED TETRAHYDROQUINOLINES AND QUINOLINES WITH PPAR AGONIST ACTIVITY TECHNICAL FIELDThe present invention refers to prenylated tetrahydroquinoline compounds or prenylatedquinoline compounds and to pharmaceutical compositions comprising the same and totheir use in the prevention or treatment of peroxisome proliferator-activated receptor (PPAR)-mediated diseases. BACKGROUND ART The peroxisome proliferator-activated receptors (PPARs) are nuclear receptors capable of regulating glucose homeostasis, lipid metabolism, inflammatory processes, cell differentiation processes and mitochondrial biogenesis, among others. These receptors are therapeutic targets for the treatment of cardiometabolic diseases, metabolic syndrome, type 2 diabetes mellitus, hyperlipidemias, dyslipidemic atherosclerosis, obesity, metabolic dysfunction-associated fatty liver disease (MAFLD), neurodegenerative diseases, Friedreich's ataxia, Parkinson's disease, Alzheimer's disease, autoimmune diseases, rheumatoid arthritis, autoimmune thyroid disease,dermatological diseases, and cancer. Three isoforms of PPARs have been identified:PPARα, PPARδ and PPARγ. PPARδ is also known as PPARβ.Selective PPARα agonists of the fibrates group (fenofibrate, gemfibrozil, fenofibric acid, bezafibrate, etofibrate and ciprofibrate), are used for the treatment of dyslipidemias (hypertriglyceridemia, hypercholesterolemia).Glitazone agonists (rosiglitazone, pioglitazone and troglitazone) are potent PPARγ-selective agonists for the treatment of type 2 diabetes, but with important clinical limitations. Potent activation of PPARγ has been associated with the development ofserious adverse effects (cardiovascular risk, hepatotoxicity and bladder cancer) leadingto the market removal of troglitazone in several countries, and to the market removal ofrosiglitazone in the European Union. In several countries, clinical use of pioglitazone hasbeen limited. In the United States, clinical use of rosiglitazone has been limited.Glitazar agonists (aleglitazar, muraglitazar, tesaglitazar, and saroglitazar) are dualPPARα / γ agonists for treatment of metabolic syndrome. Aleglitazar, muraglitazar,tesaglitazar have been removed from the market due to the adverse effects associatedwith their potent PPARγ agonism. Saroglitazar has been approved in India for thetreatment of metabolic syndrome. The pan-PPAR agonist lanifibranor is currently under a phase III clinical trial in China for the treatment of non-alcoholic fatty liver disease.The prior art document EP3733658 from the inventors discloses the dual PPARα / γagonist activity of polycerasidol and polycerasoidin, prenylated benzopyran naturalcompounds from plants, and discloses several synthetic prenylated benzopyran compounds with dual PPARα / γ or pan-PPAR agonist activity. There is a need to develop new PPAR agonists, to increase the treatment options for the patients, provide safer, more effective and / or better benefit / risk ratio alternatives, and make it possible to select therapies according to the patient's profile. SUMMARY OF INVENTION As used herein, the term “alkyl” refers to a hydrocarbon chain, fully saturated, that can be linear or branched. As used herein, the term “allyl” refers to a hydrocarbon chain, linear or branched, whichcomprises at least one -CH=CH-CH2- group.As used herein, the term “alkylamide” refers to a hydrocarbon chain, linear or branched, substituted with an amide group. As used herein, the term “alkylamine” refers to a hydrocarbon chain, linear or branched, substituted with an amine group. As used herein, the term “alkylaryl” refers to a hydrocarbon chain substituted with an aryl group, as defined below. As used herein, the term “aryl” refers to a group derived from an aromatic hydrocarbon formed by removing one hydrogen atom from an aromatic ring in said aromatic hydrocarbon. As used herein, said aryl groups can be substituted. As used herein, the term “alkyl-ether” refers to a saturated hydrocarbon chain substituted with an alkoxide group, as defined below.As used herein, the term “alkoxide” refers to an oxygen atom linked to a hydrocarbonchain, where said hydrocarbon chain may comprise an alkyl and / or an aryl group, asdefined above.As used herein, the term “acyl” refers to a carbonyl group linked to a hydrocarbon chain,where said hydrocarbon chain may comprise an alkyl and / or an aryl group, as definedabove.As used herein, the expression “effective amount” refers to a quantity of a compound,salt, solvate or pharmaceutical composition of the invention sufficient to achieve a desired effect, for example, in a subject being administered with said compound, salt, solvate or pharmaceutical composition of the invention for prevention and / or treatmentof a disease. An effective amount may be an amount sufficient to prevent or treat adisease in a subject. An effective amount may be an amount sufficient to reduce or ameliorate one or more symptoms of a disease in a subject. The effective amount (forexample an amount treating, preventing, and / or ameliorating a disease in a subject) willbe dependent on, for example, the particular disease being treated, the subject, and the route of administration.The compounds of the present invention differ from those of EP3733658 in that theyhave a quinoline or tetrahidroquinoline core, which is a structurally distant core with respect to the benzopyran core of the compounds of EP3733658. The problem to be solved consists in providing improved or alternative compounds for the treatment of PPAR-mediated diseases. The present invention solves this problem by providing prenylated tetrahydroquinolinecompounds or prenylated quinoline compounds, of Formula I or Formula II, respectively.Compared with benzopyrans of EP3733658, the compounds of the present invention,advantageously, decrease levels of total cholesterol in plasma, decrease levels of non-HDL cholesterol (“bad cholesterol”) in blood and decrease the HOMA-IR index(Homeostasis Model Assessment - Insulin Resistance), and increase the expression ofgenes involved in lipid metabolism and energy expenditure, such as the Pdk4 gene inliver and fat, and Acox1 and Cpt1a in mouse fat.Furthermore, unlike benzopyrans, quinolines and tetrahydroquinolines are nitrogenous heterocycles with a weak basicity and can form salts in the presence of acids, improving bioavailability in the formulation of medications that contain them.The present invention provides a prenylated tetrahydroquinoline compound orprenylated quinoline compound, of Formula I or Formula II, respectively, or a salt, or solvate thereof: wherein: -R1 is independently selected from H or CH2-CH=C(CH3)-CH2-CH2-COOR3;- R2 is independently selected from the group consisting of CH3, CH2-CH2-CH=C(CH3)-CH2-CH2-COOR3, and CH2-CH2-CH=C(CH3)-CH2-CH2-CH=C(CH3)- COOR3; -R3 is independently selected from the group consisting of H, alkyl, alkylamide,alkylamine, alkylaryl, alkyl-ether, and acyl; andwherein: -when R1 is H, then R2 is CH2-CH2-CH=C(CH3)-CH2-CH2-COOR3, or CH2-CH2-CH=C(CH3)-CH2-CH2-CH=C(CH3)-COOR3; and -when R2 is CH3, then R1 is CH2-CH=C(CH3)-CH2-CH2-COOR3.In embodiments of the compound, salt, or solvate of the present invention, the alkyl is a C1-6alkyl. In embodiments of the compound, salt, or solvate of the present invention, R3 is independently selected from H or C1-6alkyl. In embodiments of the compound, salt, or solvate of the present invention, R3 is independently selected from H or CH2-CH3. The compounds of the present invention have pan-PPAR agonist activity, dual PPARα / γagonist activity, PPARα / δ agonist activity or selective PPARα agonist activity, regulateinflammation and have low or no cytotoxicity. In embodiments of the compound, salt, or solvate of the present invention, saidcompound is selected from the group consisting of 5a, 5b, 6a, 6b, 8a, 8b, 9a, 9b, and11a: 8b: R3 = CH2CH3, 9b: R3 = H,

[0002] 11a: R3= CH2CH3.In embodiments, the present invention refers to a prenylated tetrahydroquinolinecompound or prenylated quinoline compound, of Formula I or Formula II, respectively, or a salt, or solvate thereof: wherein: -R1 is independently selected from H or CH2-CH=C(CH3)-CH2-CH2-COOR3;- R2 is independently selected from CH3 or CH2-CH2-CH=C(CH3)-CH2-CH2-COOR3; -R3 is independently selected from the group consisting of H, alkyl, alkylamide,alkylamine, alkylaryl, alkyl-ether, and acyl; andwherein: -when R1 is H, then R2 is CH2-CH2-CH=C(CH3)-CH2-CH2-COOR3; and- when R2 is CH3, then R1 is CH2-CH=C(CH3)-CH2-CH2-COOR3.In embodiments of the compound, salt, or solvate of the present invention, the alkyl is aC1-6 alkyl. In embodiments of the compound, salt, or solvate of the present invention, R3is independently selected from H or C1-6alkyl. In embodiments of the compound, salt, or solvate of the present invention, R3is independently selected from H or CH2-CH3.In embodiments of the compound, salt, or solvate of the present invention, saidcompound is selected from the group consisting of 5a, 5b, 6a, 6b, 8a, 8b, 9a and 9b: 8b: R3= CH2CH3, 9b: R3= H.The present invention also provides a pharmaceutical composition comprising at least acompound, salt, or solvate of the invention as active ingredient, and at least apharmaceutically acceptable excipient or carrier.In embodiments, the pharmaceutical composition of the invention further comprises atleast one additional active ingredient. The pharmaceutically acceptable excipient or carrier is selected, without limitation, from the group consisting of diluent, thickener, buffer, binder, disintegrant, coating agent, filler, lubricant, glidant, sweetener, flavour, preservative and surfactant. The pharmaceutical composition of the invention may be administered to a subject by aroute of administration selected, without limitation, from the group consisting of oral,ocular, topical, transdermal, intranasal, rectal, inhalation, parenteral, intradermal, subcutaneous, intramuscular, intraperitoneal, intra-arterial, intralymphatic, intravenous, intrathecal, intracranial and intratracheal. The form of the pharmaceutical composition of the invention is selected, without limitation, from the group consisting of crystalline, powder, granular, compacted solid, liquid, solution, suspension, elixir, syrup, emulsion, cream, gel, droplet, mist, vapor and spray. The pharmaceutical composition of the invention may be formulated as, or becontained in, without limitation, from the group consisting of capsule, tablet, pill, caplet,ampoule, sachet, syringe, cartridge, and nebulizer.The pharmaceutical composition of the invention may be administered in single or multiple doses. The pharmaceutical composition of the invention may be formulated to provide controlled release of the active ingredient such as sustained or prolonged release. In embodiments, the compound, salt, solvate or pharmaceutical composition of the present invention is for use as a medicament. In embodiments, the present invention provides the use of the compound, salt, solvate, or pharmaceutical composition of the present invention for the preparation of a medicament.In embodiments, the compound, salt, solvate, or pharmaceutical composition of thepresent invention is for use in the prevention and / or treatment of a peroxisome proliferator-activated receptor (PPAR)-mediated disease.In embodiments, the present invention provides a method for preventing and / or treatinga peroxisome proliferator-activated receptor (PPAR)-mediated disease, said method comprising administering an effective amount of the compound, salt, solvate, or pharmaceutical composition of the present invention, to a subject in need thereof.In embodiments, the present invention provides the use of the compound, salt, solvate,or pharmaceutical composition of the present invention for the preparation of a medicament for the prevention and / or treatment of a peroxisome proliferator-activated receptor (PPAR)-mediated disease. In embodiments of the compound, salt, solvate, or pharmaceutical composition for use of the present invention, said compound is an agonist of at least one PPAR protein, wherein said PPAR protein is selected from the group consisting of PPARα, PPARβ / δ and PPARγ. In embodiments of the compound, salt, solvate, or pharmaceutical composition for use of the present invention, said compound is a PPARγ agonist with partial PPARγ agonistactivity. The effects of PPARγ agonists with partial PPARγ agonist activity of theinvention are safety improvement and avoidance of the adverse effects associated withthis isoform (PPARγ).As used herein, rosiglitazone is considered a PPARγ agonist with full PPARγ agonistactivity. As used herein, the term “partial PPARγ agonist activity” refers to a PPARγagonist activity from 15% to 85% of the activity of the rosiglitazone.In embodiments of the compound, salt, solvate, or pharmaceutical composition for useof the present invention, said compound is a dual PPARα / γ agonist. The effect of dualPPARα / γ agonists of the invention is more effectivity in the treatment of metabolic diseases, reduction the risk of atherosclerosis associated with metabolic diseases, and lower toxicity. In embodiments of the compound, salt, solvate, or pharmaceutical composition for use of the present invention, said compound is an agonist of PPARα, PPARβ / δ and PPARγ(a pan-PPAR agonist). The effect of pan-PPAR agonists of the invention is moreeffectivity in the treatment of metabolic diseases, reduction the risk of atherosclerosis associated with metabolic diseases, and lower toxicity. In embodiments of the compound, salt, solvate, or pharmaceutical composition for use of the present invention, said disease is selected from the group consisting of PPARα- mediated disease, PPARβ / δ-mediated disease, and PPARγ-mediated disease. In embodiments of the compound, salt, solvate, or pharmaceutical composition for use of the present invention, said disease is associated to the expression of a gene selected from the group consisting of Pdk4, NF-κB, Ccl2, Ccl5, Il6, Tnf, Cpt1a, and Acox1. The compounds of the invention regulate neuroinflammation and autoimmuneinflammatory processes and has therapeutic potential for neurodegenerative diseasessuch as Friedreich’s ataxia, Parkinson’s disease, Alzheimer’s disease and multiple sclerosis. Therefore, in embodiments of the compound, salt, solvate, or pharmaceutical composition for use of the present invention, said disease is associated withinflammation. Preferably, said inflammation is selected from autoimmune inflammationor neuroinflammation. In embodiments of the compound, salt, solvate, or pharmaceutical composition for use of the present invention, said wherein said disease is selected from the group consisting of metabolic syndrome, type 2 diabetes mellitus, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, obesity, dyslipidemic atherosclerosis, metabolic dysfunction-associated fatty liver disease (MAFLD), cardiovascular disease,cardiometabolic disease, neurodegenerative disease, Friedreich's ataxia, Parkinson’sdisease, multiple sclerosis, Alzheimer's disease, autoimmune disease, rheumatoid arthritis, autoimmune thyroid disease, dermatological disease, and cancer.The examples of the present invention show pan-PPAR agonist activity of thecompounds of the invention 5a, 6a, and 8a and dual PPARα / γ agonist activity of thecompounds of the invention 9a, 8b, and 9b, always with partial activity on the PPARγisoform. The 3-substituted tetrahydroquinoline compounds of the invention 5b and 6bwere selective PPARα, with efficiencies 3-4 times higher than the prior art compound WY-14,643. All compounds showed low or no toxicity at the dose of 100 μM and 30 μM,respectively, in human THP-1 cells differentiated into macrophages. In vitro studiesrevealed that tetrahydroquinoline compounds of the invention 5a and 5b and quinolinecompound of the invention 8a promote lipid metabolism and minimize inflammation, asthey increased the transactivation of the PDK4-Luc+ indicator and the expression of thePdk4 gene, repressed the transactivation of NF-κB-TNFα-dependent Luc+ anddownregulated the transcription of several TNFα-induced proinflammatory genes inL929sA WT cells at the dose of 10 μM. Regarding in vivo studies in preclinical models,tetrahydroquinoline compound of the invention 5a administered (orally, 10 mg / kg / d for15 days) to an obese and diabetic mouse model (ob / ob), improved lipid and carbohydrate parameters. These changes consisted of a decrease in total cholesterol and non-HDL cholesterol levels, as well as insulin levels and the HOMA-IR index in the blood of ob / obmice treated with tetrahydroquinoline compound of the invention 5a compared to micetreated with vehicle. The tetrahydroquinoline compound of the invention 5a alsoincreased the expression of genes involved in lipid metabolism and energy expenditure,such as the Pdk4 gene in liver and fat, and Acox1 and Cpt1a in ob / ob mouse fat.Unless defined otherwise, all the technical and scientific terms used herein have the same meaning as those commonly understood by a person skilled in the art in the field of the invention. The term “comprise”, “comprising” and their variants, throughout the description and the claims, includes, specifically, the term “consisting” or “consisting of”. As used in the description and the claims, the singular forms “a”, “an”, and “the” include plural referents unless the content clearly dictates otherwise. BRIEF DESCRIPTION OF DRAWINGSFigure 1. Effects of tetrahydroquinoline compounds 5a and 5b, and quinolinecompounds 8a and 8b on the viability of human macrophage cell line. THP-1 cells weretreated with concentrations of 30 and 100 µM for 24 h and then cell lysates were processed with an Annexin V-assay kit according to the manufacturer’s instructions,using flow cytometry. Data are presented as mean ± SEM of n = 3 independentexperiments. *p < 0.05, relative to vehicle group.Figure 2. Effects of tetrahydroquinolines and quinolines on PPAR target genePdk4. (A) L929sA cells stably transfected with PDK4-(PPRE)3-Luc+ and a constitutiveβ-gal expressing plasmid, were treated with solvent, compound GW7647 (1 μM), 5a, 5b,8a, or 8b (10 μM) for 6 h. Cell lysates were assayed for luciferase activity and normalisedto β-gal activity and expressed as the relative induction (% of maximal GW7647response). (B) L929sA WT cells were incubated with solvent, 5a or 5b (10 µM) for 6 h.mRNA was isolated, reverse-transcribed, and subjected to RT-qPCR using primers to detect Pdk4. Results were normalised to household genes. RT-qPCR measurementswere performed in triplicates. (ns, non-significant; *p < 0.05, ***p < 0.001, ****p < 0.0001; Figure 3. Evaluation of anti-inflammatory effects of PPAR agonists. (A) L929 cells stablytransfected with NF-^B-IL8P-Luc+ were incubated with solvent, compound GW7647 (1μM), 5a, 8a, 5b or 8b (10 μM), for 1 h, before TNF (2000 IU / ml) was added for a totalinduction time of 6 h. Cell lysates were assayed for luciferase activity, normalised to β- gal activity and expressed as the relative induction (% of maximal TNFα response). Results were obtained from three independent biological replicates (n=3) with duplicatemeasurements. (B) L929sA WT cells were incubated with solvent, 5a, 5b, or 8b (10 µM)for 1 h, before TNF (2000 IU / ml) was added, for a total induction time of 6 h. mRNA wasisolated, reverse-transcribed, and subjected to RT-qPCR using primers to detect Ccl2,Ccl5, Il6, and Tnf. Results were normalised to household genes. RT-qPCRmeasurements were obtained from three independent biological replicated (n=3) and performed in triplicates.Figure 4. Biochemical parameters in blood of ob / ob mice treated withtetrahydroquinoline 5a (10 mg / kg / d, orally, 15 days) or vehicle. Tetrahydroquinoline 5areduces the plasma levels of total cholesterol (A), non-HDL-c (B), insulin (C), andHOMA-IR index (D) in ob / ob mice. Tetrahydroquinoline 5a does not increase ASThepatic transaminase (E) and ALT hepatic transaminase (F) in ob / ob mice. Note: non-HDL-c (mg / L) = total cholesterol (mg / L) – HDL-c (mg / L); HOMA-IR index= fastingglucose (mmol / L) × fasting insulin (mU / mL)] / 22.5. Values are presented as mean ± SEM of 5–12 independent experiments. *P < 0.05 relative to vehicle-treated mice.Figure 5. Treatment with tetrahydroquinoline 5a (10 μM) modulates the expression ofrelevant PPARs target genes in the liver and epididymal fat of ob / ob mice. mRNAexpression of Pdk4 (A) and Cpt1a (B) in liver were analysed by RT-PCR. mRNAexpression of Cpt1a (C) and Acox1 (D) in epididymal white adipose tissue were analysedby RT-PCR. The mRNA levels were normalized to the expression of the constitutive cyclophilin gene. Values are presented as mean ± SEM of 5 independent experiments. *P < 0.05 relative to vehicle-treated mice. DESCRIPTION OF EMBODIMENTSExample 1. Materials and methodsAnalytical chemistry High-resolution mass spectrometry electrospray ionization (HRMS(ESI)) data werecollected on a TripleTOF™ 6600 (AB SCIEX). Liquid chromatography-massspectrometry was performed using a liquid chromatography (UHPLC) platform (Shimadzu, LCMS-8040) coupled with a tandem mass spectrometry (MS / MS) triple quadrupole mass spectrometer equipped with an electrospray ionization (ESI) source (Shimadzu, Kyoto, Japan).1H and13C NMR spectra, COSY 45 and HSQC were recorded on a Bruker Avance III 300 spectrometer, with CDCl3or CDCl3+ 1 drop CD3OD as solvent. Chemical shifts (δ) are reported in ppm relative to the internal reference deuterated solvent, with multiplicities indicated as s (singlet), d (doublet), t (triplet), q (quartet) and m (multiplet). The coupling constants (J) are expressed in hertz (Hz). All reactions were monitored by analytical thin-layer chromatography with silica gel 60 F254(Merck 5554; Merck Group, Darmstadt, Germany). The residues were purified by silica gel column chromatography (40-63 µm, Merck Group). The solvents and reagents were purchased from Scharlab S.L. (Barcelona, Spain) and Sigma-Aldrich (St. Louis, MO, USA) and used without further purification unless otherwise stated. Dry and freshly distilled solvents were used in the reactions carried out under N2atmosphere. Quoted yields were obtained from the purified materials. The final compounds were purified to ≥95% purity, as assessed by1H NMR and LC-MS / MS. Cell cultures THP-1 cells were maintained under standard culture conditions (Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 10% fetal calf serum (FCS) (both from Thermo Fisher Scientific, Waltham, MA, USA) at 37 °C in a 5% CO2 humidified atmosphere. The medium was changed every two days. L929sA cells were grown in DMEM supplemented with 10% fetal calf serum, 100 U / mL penicillin and 0.1 mg / mL streptomycin. The cells were maintained in a humidified atmosphere containing 5% CO2 at 37 °C. Plasmids and reagents PDK4-(PPRE)3-Luc+ reporter gene construct was generated by amplification of thePPAR response elements (PPRE) peak sequences in the Pdk4 enhancer region frommouse liver genomic DNA and ligation in a pGL3-basic vector (Promega Biotec, Madison, Wisconsin). The p1481.IL8P-Luc+ reporter gene construct contains an IL-8 promoter fragment with one NF-^B-binding element. Compounds WY-14,643, GW7647,GW501516 and rosiglitazone were purchased from Sigma-Aldrich. Table 1 discloseschemical data of said compounds. Recombinant murine TNFα was produced andpurified. TNFα was used at a final concentration of 2000 IU / ml, where indicated. Table 1 PPAR transactivation assays PPAR transcriptional activity was monitored using a human chimeric PPAR / Gal4 reporter luciferase system in Cos-7 cells (CRL-1651; ATCC, Manassas, VA, USA), transiently transfected with a luciferase reporter plasmid in the presence of expression vectors of pGAL4hPPARα, pGAL4hPPARβ / δ, and pGAL4hPPARγ. The responses of the compounds of the invention were compared with those of the following prior art compounds: WY-14,643 for PPARα, GW501516 for PPARβ / δ, and rosiglitazone for PPARγ. EC50was determined using a concentration range of 0.001–10 μmol / L. Luciferase activity was normalised to that of the internal control, β-galactosidase. Cells(5.5 x 105 cells / mL) were seeded in 60-mm dishes in DMEM / 10% FCS and incubated at37 °C in a 5% solution for 16 h prior to transfection. Cells were transfected in DMEM with the jetPEI transfection reagent (Polyplus-Transfection S.A., Strasbourg, France) using the reporter plasmid pG5-TK-pGL3 in combination with one of the following expressionplasmids: pGal4hPPARα, pGal4hPPARβ / δ, or pGal4hPPARγ. The pCMV-β-galactosidase expression plasmid was used as a control for the transfection efficiency. Transfections were stopped after 16 h by adding DMEM / 10% FCS. Cells were detached with trypsin, re-seeded in 96-well plates for 6 h in DMEM / 10% FCS, and incubated for 24 h in DMEM / 0.2% FCS with increasing concentrations of the test compounds or vehicle (DMSO, 0.1% final concentration). At the end of the experiment, cells were washed once with ice-cold PBS, lysed, and luciferase and β-galactosidase activities were measured. Luciferase activity was normalised to that of the internal control, β-galactosidase. All transfection experiments were performed at least five times. Cytotoxicity studiesThe cytotoxicity of tetrahydroquinoline and quinoline esters 5a, 5b, 8a and 8b wasevaluated at 30 and 100 μM by flow cytometry to assess cell survival using an AnnexinV-FITC / PI dual staining assay. THP-1 cells (3 x 104cells per well) were seeded in 24- well plates and allowed to grow overnight. The medium was then replaced and incubations with the different compounds or DMSO were performed during 24 h. Then, all cells were processed with the Annexin V-assay kit (ANXCFK7, Immunostep, Salamanca, Spain) according to the manufacturer’s instruction. A Becton Dickinson LSR Fortessa cytometer (BD Biosciences, Franklin Lakes, NJ, USA) was used for samples, and cell analysis were performed using FACSDiva X20 software. Pdk4 transactivation assays Transfection of L929sA cells stably expressing reporter genes was performed using the calcium phosphate precipitation protocol according to standard procedures with a 10- fold excess of the plasmid of interest in a pGL3-basic vector containing Luc+, a modifiedfirefly luciferase gene (Promega Biotec, Madison, Wis,) USA. USA). The Pdk4 reporterwas created using an enhancer site linked to the Pdk4 promoter containing three PPREextracted from mouse liver genomic DNA. The aforementioned plasmid construct wasthen introduced into a pMet7 backbone, which had previously been cloned with a luciferase gene site, using Xhol and Sacl cut sites. The resulting construct was subjected to geneticin (neomycin) antibiotic selection to isolate individual clones. A stable cell line, designated Pdk4-Luc+, was subsequently established in L929sA cells, which also contained a constitutively expressed galactosidase reporter and a neomycin selection cassette. NF-^B-IL8P transactivation assays L929sA mouse fibroblasts were stably transfected using the calcium phosphate precipitation protocol, as described previously with p1481.IL8P-Luc+ plasmid construct. The indicated induction was performed at least in triplicates. All conditions were solvent- controlled. Subsequently, the cells were washed with PBS and lysed using TROPIX lysis buffer. Cellular luciferase levels were normalised to those of β-galactosidase (TROPIX, Bedford, MA, USA). Determination of mRNA expression by quantitative RT-qPCR RNA was isolated using the RNeasy Purification Kit (Qiagen) according to the manufacturer’s instructions. cDNA was synthesised using a PrimeScript kit (Takara). RT- qPCR was performed using Light Cycler 480 SYBR Green I Master Mix (Roche). RT-qPCR data were normalised and quantified relative to the two most stable referencegenes. In vivo studies Animal studies were carried out in accordance with Directive 2010 / 63 / EU for experimentation on animals. The handling of the animals and the experimental protocols were approved by the Animal Experimentation Ethics Committee of the University ofValencia (Protocol No. A1469445706311). Six-week-old male ob / ob mice (C57BL / 6.C8-Lepob / J) were supplied by Charles River Laboratories International (Wilmington, MA). Blood samples were collected from mice fasted for 6 hours to determine basal blood glucose levels. The animals, randomly divided into two groups (N ≈ 10-11 per group), were treated daily with vehicle (1% hydroxyethyl cellulose, Sigma-Aldrich) or withtetrahydroquinoline 5a at 10 mg / kg / day, for 15 days orally. After 15 days of treatment,and 6 h of fasting, the mice were anesthetized by inhalation of isoflurane and blood samples were collected in tubes with heparin or EDTA by intracardiac puncture. Plasma samples were obtained and stored at -80°C. Liver and epididymal white adipose tissue were removed and part of both organs were quickly frozen in liquid N2for qPCR studies. Biochemical analysis Plasma levels of total cholesterol and HDL-cholesterol (HDL-c) were determined byenzymatic processes using commercial kits: LabAssay™ Cholesterol (Wako PureChemicals Industries, Cape Charles, VA) and Mouse HDL-Cholesterol Assay Kit (Crystal Chem, Elk Grove Village, IL), respectively. Non-HDL cholesterol levels were calculated(total cholesterol – HDL-c). Fasting blood glucose levels were measured using aglucometer (Contour Next, Bayer HealthCare Pharmaceuticals LLC, Berlin, Germany),while insulin levels were determined using the commercial Mouse Insulin ELISA kit(Mercodia, Uppsala, Sweden). The HOMA-IR index was calculated using the following formula: fasting blood glucose (mmol / L) * fasting insulinemia (µU / mL) / 22.5. Gene expression studies Gene expression analysis was carried out by real-time qPCR. To this end, total RNA was extracted from liver and epididymal white adipose tissue biopsies using TRIzol reagent (Invitrogen, Carlsbad, CA, USA). The isolated RNA was retro-transcribed using the Maxima First-Strand kit and amplified with a Luminaris Color qPCR MasterMIX (Fermentas, Whaltham, MA, USA) in a 7900 FastSystem thermal cycler. The mRNA levels were normalized to the expression of the constitutive gene cyclophilin. Molecular modelling Molecular modelling was performed using two combined techniques (docking calculations and molecular dynamics simulations). First, docking calculations were performed to localize the different ligands in the binding pockets of different moleculartargets using the Autodock 4.2 program. The starting structures were used for moleculardynamics simulations based on the results obtained in the docking study. The 3D crystal structures of PPARγ in complex with rosiglitazone (PDB code:4eMA), PPARα in complex with WY-14643 (PDB code:4BcR), and PPARδ in complex with GW501516 (PDB code:5U46) were used for molecular dynamics simulations. The missing loop (261−275) in PPARγ was modeled based on a previously reported 3D structure (PPARγ1PRGmodel) (Nolte et al. (1998)). The geometries of the complexes obtained from dockingwere soaked in boxes of explicit water using the TIP3P model and subjected to molecular dynamics simulation. Molecular dynamics simulations were performed using the Amber 22 software package. The geometry of the system went through a two-step energy minimization process: in the first step, the backbone atoms of the complex were constrained with 10.0 kcal / (mol Å2) force constants; in the second step, all solute and solvent atoms were allowed to move with no constraint to obtain the final relaxed geometry. The non-bonded interaction cutoff was maintained at its default value and the particle mesh Ewald method was used. Simulations were performed for 90 ns for each complex (three runs of 30 ns each). The clustering process was carried out in the following manner: using the 90 ns obtained from the three runs, 15 ns were discarded (the first 5 ns of each individual run). The remaining 75 ns were subjected to a clustering process, from which 10 different families of complexes were obtained. The free energy of decomposition of the residue was calculated using the de mm_pbsa program in Amber22. Each ligand-residue pair includes four energy terms: the van der Waals contribution (ΔEvdw), electrostatic contribution (ΔEele), polar desolvation term (ΔGGB), and nonpolar desolvation term (ΔGSA), which are summarized in the following equation:ΔGligand residue = ΔEvdW + ΔEele + ΔGGB + ΔGSA. Molecular dynamics trajectoriesand explicit water molecules were removed from the snapshots. Statistical analysis All data are presented as the mean ± SD or ± SEM. Differences between multiple groupswere analyzed by one-way analysis of variance (ANOVA), followed by Tukey's orDunnett's multiple comparisons test (GraphPad Prism 9). Differences with a p-value < 0.05 were considered statistically different. Example 2. Synthesis of compounds of Formula I and II Materials and methods Synthesis of 5-(benzyloxy)-2-nitrobenzaldehyde A mixture of 5-hydroxy-2-nitrobenzaldehyde (1 g, 5.9 mmol) and K2CO3 (0.82 g, 6.51 mmol) was dissolved in dry DMF (12 mL) under N2, followed by addition of benzyl chloride (1.51 g, 11.9 mmol). The mixture was refluxed for 4 h. The reaction mixture was extracted with CH2Cl2 (3 x 10 mL), and the organic layers were combined, washed with brine (1 x 10 mL) and H2O (2 x 10 mL), dried over anhydrous Na2SO4, filtered and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / EtOAc, 9:1) to obtain 1.15 g of 5-(benzyloxy)-2- nitrobenzaldehyde as yellow crystals (75% yield).1H NMR (300 MHz, CDCl3): δ 10.46(s, CHO, 1H), 8.15 (d, J = 9.0 Hz, 1H, H-3), 7.43-7.36 (m, 6H, Ph-H, H-6), 7.21 (dd, J =9.0, 2.9 Hz, 1H, H-4), 5.20 (s, 2H, OCH2Ph).13C NMR (75 MHz, CDCl3): δ 188.5 (CHO), 163.1 (C-5), 142.4 (C-2), 135.0 (C-1'), 134.3 (C-1), 128.9, 128.7 and 127.6 (6C, Ph),127.3 (CH-3), 119.3 (CH-4), 114.3 (CH-6), 71.1 (OCH2Ph). MS (ESI) m / z 256 [M-H]+.General procedure for the synthesis of quinolines 1a and 1bA mixture of 5-(benzyloxy)-2-nitrobenzaldehyde (5.88 mmol), Fe (26.5 mmol), and 0.1 NHCl (3.2 mL) was dissolved in absolute ethanol (25 mL) under N2, refluxed for 30 min, and monitored by TLC. After the reaction was completed, iron solids were removed by centrifugation at 5000 RPM for 5 min. Then, pyrrolidine (1.5 mL, 17.5 mmol) and ethyl levulinate (1.6 mL, 11.6 mmol) were added dropwise, and the reaction mixture was refluxed for additional 4 h. The reaction mixture was extracted in CH2Cl2(3 x 20), washed with brine (3 x 15 mL) and H2O (3 x 15 mL), dried over anhydrous Na2SO4, filtered, andevaporated to dryness. Crude mixture of quinoline isomers 2- and 3- substituted. Theresidue was purified using silica gel column chromatography (hexane / EtOAc, 8:2).6-(Benzyloxy)-2-(ethylpropanoate)-quinoline (1a): 0.96 g, yellow crystals (50% yield).1HNMR (300 MHz, CDCl3): δ 7.80-7.76 (m, 2H, H-4, H-8), 7.35-7.19 (m, 6H, Ph-H, H-7), 7.12 (d, J = 7.1 Hz, 1H, H-3), 6.98 (d, J = 2.8 Hz, 1H, H-5), 5.02 (s, 2H, OCH2Ph), 4.0 (q, J = 7.1 Hz, 2H, OCH2CH3), 3.12 (t, J = 7.5 Hz, 2H, CH2-1'), 2.74 (t, J = 7.5 Hz, 2H, CH2-2'), 1.09 (t, J = 7.1 Hz, 3H, OCH2CH3).13C NMR (75 MHz, CDCl3): δ 173.2 (CO2CH2CH3),158.1 (C-6), 156.4 (C-2), 144.0 (C-8a), 136.6 (C-1"), 135.2 (CH-4), 130.4 (CH-8), 128.7 (2C, CH-3", CH-5"), 128.1 (CH-4"), 127.7 (C-4a), 127.6 (2C, CH-2", CH-6"), 122.3 (CH- 7), 121.8 (C-3), 106.6 (CH-5), 70.3 (OCH2Ph), 60.4 (OCH2CH3), 33.5 and 33.4 (2C, CH2-1', CH2-2'), 12.3 (OCH2CH3). MS (ESI) m / z 336 [M+H]+.6-(Benzyloxy)-2-(methyl)-3-(ethylethanoate)-quinoline (1b): 0.71 g, yellow crystals (36%yield).1H NMR (300 MHz, CDCl3): δ 7.96 (d, J = 9.1 Hz, 1H, H-8), 7.85 (s, 1H, H-4), 7.49-7.35 (m, 6H, Ph-H, H-7), 7.09 (d, J = 3.0 Hz, 1H, H-5), 5.16 (s, 2H, OCH2Ph), 4.18 (q, J= 7.1 Hz, 2H, OCH2CH3), 3.76 (s, 2H, CH2-1'), 2.70 (s, 3H, CH3-2), 1.26 (t, J = 7.1 Hz,3H, OCH2CH3).13C NMR (75 MHz, CDCl3): δ 170.8 (CO2CH2CH3), 156.5 (C-6), 155.9 (C-2), 143.2 (C-8a), 136.6 (C-1”), 135.8 (CH-4), 130.0 (CH-8), 128.7 (2C, CH-3", CH-5"), 128.2 (CH-4"), 128.0 (C-4a), 127.9 (2C, CH-2", CH-6"), 127.0 (C-3), 122.2 (CH-7), 106.3 (CH-5), 70.3 (OCH2Ph), 61.2 (OCH2CH3), 39.1 (CH2-1'), 23.2 (CH3-2), 14.2 (OCH2CH3).MS (ESI) m / z 336 [M+H]+.

[0003] General procedure for the synthesis 1,2,3,4-tetrahydroquinolines 2a and 2bA solution quinoline 1a (4.77 mmol) or 1b (4.47 mmol) in dry methanol (40 mL) wastreated with sodium cyanoborohydride (38.16 mmol) and boron trifluoride diethyl etherate (38.16 mmol) and refluxed for 4 h under N2. Then, the reaction mixture was cooled, treated with 15% aqueous NH3and extracted with EtOAc (3 x 10 mL). The organic layers were combined and washed with H2O (3 x 10 mL) and brine (3 x 10 mL), dried over anhydrous Na2SO4,filtered and dried under vacuum. The crude was subjected to purification by silica gel column chromatography (hexane / EtOAc, 8:2) to affordtetrahydroquinolines 2a or 2b.6-(Benzyloxy)-2-(ethylpropanoate)-1,2,3,4-tetrahydroquinoline (2a): 1.05 g, yellow oil(65 % yield). 1H NMR (300 MHz, CDCl3): δ 7.47-7.29 (m, 5H, Ph-H), 6.72-6.62 (m, 2H,H-5, H-7), 6.45 (d, J = 8.7 Hz, 1H, H-8), 4.97 (s, 2H, OCH2Ph), 4.15 (q, J = 7.1 Hz, 2H, OCH2CH3), 3.30-3.22 (m, 1H, CH-2), 2.82-2.67 (m, 2H, CH2-4), 2.47-2.41 (m, 2H, CH2-2'), 1.99-1.80 (m, 3H, CH2-3, CH2a-1'), 1.68-1.61 (m, 1H, CH2b-1'), 1.27 (t, J = 7.1 Hz, 3H,OCH2CH3).13C NMR (75 MHz, CDCl3): δ 173.6 (CO2CH2CH3), 151.2 (C-6), 138.7 (C- 8a), 137.7 (C-1''), 128.5 (2C, CH-3'', CH-5''), 127.7 (CH-4''), 127.5 (2C, CH-2'', CH-6''), 122.5 (C-4a), 115.9 (CH-5), 115.4 (CH-7), 114.1 (CH-8), 70.8 (OCH2Ph), 60.5 (OCH2CH3), 51.1 (CH-2), 31.3 (CH2-2'), 30.5 (CH2-1'), 27.6 (CH2-3), 26.4 (CH2-4), 14.3(OCH2CH3). MS (ESI) m / z 340 [M+H]+.6-(Benzyloxy)-3-(ethylethanoate)-2-(methyl)-1,2,3,4-tetrahydroquinoline (2b): 0.91 g,yellow oil (60% yield).1H NMR (300 MHz, CDCl3): δ 7.43-7.30 (m, 5H, Ph-H), 6.70-6.63(m, 2H, H-5, H-7), 6.45 (d, J = 8.9 Hz, 1H, H-8), 4.99 (s, 2H, OCH2Ph), 4.13 (q, J = 7.1 Hz, 2H, OCH2CH3), 3.53-3.46 (m, 1H, CH-2), 2.99-2.91 (m, 2H, CH2a-4), 2.61-2.39 (m, 3H, CH2b-4, CH2a-1', CH-3), 2.24-2.14 (m, 1H, CH2b-1'), 1.25 (t, J = 7.1 Hz, 3H,OCH2CH3), 1.14 (d, J = 6.5 Hz, 3H, CH3-2). 13C NMR (75 MHz, CDCl3): δ = 173.4(CO2CH2CH3), 155.6 (C-6), 137.6 (2C, C-8a, C-1''), 128.5 (2C, CH-3'', CH-5''), 127.8 (CH-4''), 127.5 (2C, CH-2'', CH-6''), 120.3 (C-4a), 116.4 (CH-5), 115.8 (CH-7), 114.2 (CH-8), 70.7 (OCH2Ph), 49.6 (OCH2CH3), 49.6 (CH-2), 33.7 (CH2-1'), 32.9 (CH-3), 32.1 (CH2-4), 17.8 (CH3-2), 14.3 (OCH2CH3). MS (ESI) m / z 340 [M+H]+.General procedure for the synthesis of N-methyl 1,2,3,4-tetrahydroquinolines 3a and 3bA mixture of tetrahydroquinoline 2a (1.47 mmol) or 2b (1.47 mmol), and iodomethane (7.2 mmol) in anhydrous DMF (15 mL) was refluxed at 140 °C for 15 min. The reaction mixture was then cooled, diluted with distilled water (10 mL), and extracted with CH2Cl2 (3 x 10 mL). The organic layers were combined, washed with H2O (3 x 10 mL), brine (3 x 10 mL), dried over anhydrous Na2SO4, filtered and evaporated to dryness. The residue was purified by silica gel column chromatography (hexane / EtOAc, 9:1) to afford N-methyltetrahydroquinolines 3a or 3b.6-(Benzyloxy)-2-(ethylpropanoate)-N-(methyl)-1,2,3,4-tetrahydroquinoline (3a): 413.5mg, brown oil (80% yield). 1H NMR (300 MHz, CDCl3): δ 7.44-7.27 (m, 5H, Ph-H), 6.79(dd, 1H, J = 8.8, 3.0, H-7), 6.73 (d, J = 3.0, H-5), 6.52 (d, J = 8.8, H-8), 4.98 (s, 2H,OCH2Ph), 4.13 (q, J = 7.1 Hz, 2H, OCH2CH3), 3.25-3.12 (m, 1H, CH-2), 2.91 (s, 3H, N-CH3), 2.77-2.63 (m, 2H, CH2-4), 2.38-2.33 (m, 2H, CH2-2'), 1.92-1.55 (m, 4H, CH2-3,CH2-1'), 1.25 (t, J = 7.1 Hz, 3H, OCH2CH3). 13C NMR (75 MHz, CDCl3): δ 173.5(CO2CH2CH3), 150.1 (C-6), 140.2 (C-8a), 137.8 (C-1''), 128.5 (2C, CH-3'', CH-5''), 127.7 (CH-4''), 127.5 (2C, CH-2'', CH-6''), 123.4 (C-4a), 116.1 (CH-5), 113.6 (CH-7), 112.3 (CH-8), 70.9 (OCH2Ph), 60.5 (OCH2CH3), 58.0 (CH-2), 38.8 (N-CH3), 30.9 (CH2-2'), 26.3 (CH2-1'), 24.6 (CH2-3), 23.9 (CH2-4), 14.3 (OCH2CH3). MS (ESI) m / z 354 [M+H]+. 6-(Benzyloxy)-3-(ethylethanoate)-2-(methyl)-N-(methyl)-1,2,3,4-tetrahydroquinoline(3b): 388.7 mg, brown oil (75% yield). 1H NMR (300 MHz, CDCl3): δ 7.46-7.29 (m, 5H,Ph-H), 6.79 (dd, J = 8.7, 3.1 Hz, 1H, H-7), 6.72 (d, J = 3.1 Hz, 1H, H-5), 6.47 (d, J = 8.7Hz, 1H, H-8), 4.99 (s, 2H, OCH2Ph), 4.14 (q, J = 7.1 Hz, 2H, OCH2CH3), 3.20-3.17 (m, 1H, CH-2), 3.11-3.04 (m, 1H, CH2a-4), 2.87 (s, 3H, N-CH3), 2.50-2.48 (m, 1H, CH2b-4), 2.43-2.25 (m, 3H, CH2-1', CH-3), 1.25 (t, J = 7.1 Hz, 3H, OCH2CH3), 1.09 (d, J = 6.5 Hz, 3H, CH3-2).13C NMR (75 MHz, CDCl3): δ 173.4 (CO2CH2CH3), 150.1 (C-6), 139.0 (C- 8a), 137.8 (C-1''), 128.5 (2C, CH-3'', CH-5''), 127.7 (CH-4''), 127.5 (2C, CH-2'', CH-6''), 120.3 (C-4a), 116.9 (CH-5), 113.7 (CH-7), 111.3 (CH-8), 70.8 (OCH2Ph), 60.2 (OCH2CH3), 58.1 (CH-2), 38.3 (CH2-1'), 37.7 (N-CH3), 33.5 (CH-3), 28.6 (CH2-4), 16.7 (OCH2CH3), 14.3 (CH3-2). MS (ESI) m / z 353 [M]+.General procedure for the synthesis of aldehydes 4a, 4b, 7a and 7bSolutions of quinoline or tetrahydroquinolines esters 1a, 1b, 3a or 3b (0.60 mmol) in dryCH2Cl2 (5 mL) were treated with 1 M DIBAL-H (1.2 mmol) at -78 ºC under N2 and stirred for 15 min. Then, methanol (1 mL) was added dropwise at -78 ºC to quench the reaction, and the mixture was stirred for 15 min, followed by saturated NH4Cl (1 mL) and stirred for 15 min to room temperature. The reaction mixture was extracted with EtOAc (3 x 10 mL) and the organic layers were combined and washed with brine (2 x 10 mL) and H2O (2 x 10 mL), dried over anhydrous Na2SO4, filtered and evaporated to dryness. The residues were purified by silica gel column chromatography (hexane / EtOAc, 7:3) toobtain tetrahydroquinoline aldehydes 4a and 4b, and quinoline aldehydes 7a and 7b.6-(Benzyloxy)-N-(methyl)-2-(propanal)-1,2,3,4-tetrahydroquinoline (4a): 130 mg, light-yellow oil (70% yield).1H NMR (300 MHz, CDCl3): δ 9.70 (t, J = 2.2 Hz, 1H, CHO), 7.46-7.32 (m, 5H, Ph-H), 6.80 (dd, J = 8.8, 2.9 Hz, 1H, H-7), 6.72 (d, J = 2.9 Hz, 1H, H-5), 6.57 (d, J = 8.8 Hz, 1H, H-8), 5.01 (s, 2H, OCH2Ph), 3.26-3.11 (m, 1H, CH-2), 2.90 (s, 3H, N-CH3), 2.85-2.62 (m, 2H, CH2-4), 2.58-2.34 (m, 2H, CH2-2'), 2.08-1.62 (m, 4H, CH2- 3, CH2-1').13C NMR (75 MHz, CDCl3): δ 201.8 (CHO), 150.6 (C-6), 140.1 (C-8a), 137.8 (C-1"), 128.5 (2C, CH-3", CH-5"), 127.8 (CH-4"), 127.5 (2C, CH-2", CH-6"), 123.8 (C- 4a), 115.9 (CH-5), 113.8 (2C, C-7, C-8), 70.8 (OCH2Ph), 58.2 (CH-2), 40.7 (CH2-2'), 39.7 (N-CH3), 24.3, 24.1 and 23.9 (3C, CH2-3, CH2-1', CH2-4). MS (ESI) m / z 310 [M+H]+. 6-(Benzyloxy)-3-(ethanal)-2-(methyl)-N-(methyl)-1,2,3,4-tetrahydroquinoline (4b): 148.5mg, light-yellow oil (80% yield). 1H NMR (300 MHz, CDCl3): δ 9.76 (t, J = 1.3 Hz, 1H,CHO), 7.44-7.29 (m, 5H, Ph-H), 6.78 (dd, J = 8.8, 3.0 Hz, 1H, H-7), 6.69 (d, J = 3.0 Hz,1H, H-5), 6.47 (d, J = 8.8 Hz, 1H, H-8), 4.97 (s, 2H, OCH2Ph), 3.15-3.06 (m, 2H, CH-2,CH2a-4), 2.85 (s, 3H, N-CH3), 2.53-2.37 (m, 4H, CH2-1', CH2b-4, CH-3), 1.08 (d, J = 6.4 Hz, CH3-2).13C NMR (75 MHz, CDCl3): δ.202.1 (CHO), 150.4 (C-6), 138.9 (C-8a), 137.7 (C-1"), 128.5 (2C, CH-3", CH-5"), 127.8 (CH-4"), 127.6 (2C, CH-2", CH-6"), 120.3 (C- 4a), 116.8 (CH-5), 113.8 (CH-7), 111.6 (CH-8), 70.8 (OCH2Ph), 58.1 (CH-2), 48.1 (CH2- 1'), 37.7 (N-CH3), 31.1 (CH-3), 28.6 (CH2-4), 16.4 (CH3-2). MS (ESI) m / z 310 [M+H]+.6-(Benzyloxy)-2-(propanal)-quinoline (7a): 87.4 mg, light-yellow oil (50% yield). 1H NMR(300 MHz, CDCl3): δ 9.78 (t, J = 1.3 Hz, 1H, CHO), 7.80-7.75 (m, 2H, H-4, H-8), 7.35- 7.18 (m, 6H, Ph-H, H-7), 7.11 (d, J = 9.1 Hz, 1H, H-3), 6.97 (d, J = 2.8 Hz, 1H, H-5), 5.01 (s, 2H, OCH2Ph), 3.13 (t, J = 7.0 Hz, 2H, CH2-1'), 2.88 (td, J = 7.0, 1.3 Hz, 2H CH2-2').13C NMR (75 MHz, CDCl3): δ: 201.8 (CHO), 157.7 (C-6), 156.5 (C-2), 144.0 (C-8a), 136.6 (C-1"), 135.3 (CH-4), 130.4 (CH-8), 128.7 (2C, CH-3", CH-5"), 128.2 (CH-4"), 127.7 (C- 4a), 127.6 (2C, CH-2", CH-6"), 122.4 (CH-3), 121.7 (CH-7), 106.6 (CH-5), 70.3(OCH2Ph), 42.4 (CH2-2'), 30.9 (CH2-1'). MS (ESI) m / z 290 [M-H]+.6-(Benzyloxy)-3-(ethanal)-2-(methyl)-quinoline (7b): 131.3 mg, light-yellow oil (75%yield).1H NMR (300 MHz, CDCl3): δ 9.82 (t, J = 1.8 Hz, 1H, CHO), 7.97 (d, J = 9.2 Hz,1H, H-8), 7.82 (s, 1H, H-4), 7.49-7.34 (m, 6H, Ph-H, H-7), 7.10 (d, J = 2.8 Hz, 1H, H-5),5.17 (s, 2H, OCH2Ph), 3.88 (d, J = 1.8 Hz, 2H, CH2-1'), 2.65 (s, 3H, CH3-2).13C NMR (75MHz, CDCl3): δ 197.9 (CHO), 156.8 (C-6), 155.4 (C-2), 142.6 (C-8a), 136.8 (CH-4), 136.4 (C-1"), 129.4 (CH-8), 128.7 (2C, CH-3", CH-5"), 128.2 (CH-4"), 128.0 (C-4a), 127.5 (2C, CH-2", CH-6"), 125.0 (C-3), 122.8 (CH-7), 106.1 (CH-5), 70.2 (OCH2Ph), 48.0 (CH2-1'),22.9 (CH3-2). MS (ESI) m / z 290 [M-H]+.General procedure for the synthesis of 2- and 3-prenylated of tetrahydroquinoline andquinoline esters 5a, 5b, 8a and 8bA mixture of aldehydes 4a, 4b, 7a or 7b (0.2 mmol) and 0.5 M isopropenylmagnesiumbromide (0.6 mmol) in THF (10 mL) at -78 ºC was stirred for 1 h under N2. The reaction mixture was quenched by adding saturated aqueous NH4Cl (1 mL) dropwise, and stirred for additional 15 min at room temperature. Then, H2O (5 mL) was then added and the mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with H2O (3 x 10 mL), brine (3 x 10 mL), dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. The residue, without further purification, was treated with triethyl orthoacetate (10 mL) and catalytic amounts of isobutyric acid (3 drops). The mixture was refluxed at 140 ºC for 2 h, and after concentrated under reduced pressure to remove excess triethyl orthoacetate. The residue was diluted with CH2Cl2(10 mL), washed with H2O (3 x 10 mL), brine (3 x 10 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude was purified by silica gel columnchromatography (hexane / EtOAc, 80:20) to afford compounds 5a, 5b, 8a or 8b.Ethyl (E)-7-(6-(benzyloxy)-1-methyl-1,2,3,4-tetrahydroquinolin-2-yl)-4-methylhept-4-enoate (5a): 37.9 mg, amber oil (45% yield).1H NMR (300 MHz, CDCl3): δ 7.44-7.30 (m,5H, Ph-H), 6.75 (dd, J = 8.8, 3.0 Hz, 1H, H-7), 6.70 (d, J = 3.0 Hz, 1H, H-5), 6.47 (d, J =8.8 Hz, 1H, H-8), 5.19-5.14 (m, 1H, CH-3'), 4.98 (s, 2H, OCH2Ph), 4.12 (q, J = 7.1 Hz,2H, OCH2CH3), 3.18-3.16 (m, 1H, CH-2), 2.88 (s, 3H, N-CH3), 2.85-2.56 (m, 2H, CH2-4), 2.45-2.24 (m, 4H, CH2-6', CH2-5'), 2.13-1.87 (m, 4H, CH2-2', CH2-3), 1.62 (s, 3H, CH3-4'), 1.63-1.61 (m, 1H, CH2a-1'), 1.43-1.39 (m, 1H, CH2b-1'), 1.24 (t, J = 7.1 Hz, 3H,OCH2CH3).13C NMR (75 MHz, CDCl3): δ 173.3 (CO2CH2CH3), 149.8 (C-6), 140.3 (C- 8a), 137.8 (C-1''), 133.7 (C-4'), 128.4 (2C, CH-3'', CH-5''), 127.6 (CH-4''), 127.4 (2C, CH- 2'', CH-6''), 124.7 (CH-3'), 123.3 (C-4a), 116.0 (CH-5), 113.4 (CH-7), 111.7 (CH-8), 70.8 (OCH2Ph), 60.2 (OCH2CH3), 58.2 (CH-2), 38.3 (N-CH3), 34.6 (CH2-5'), 33.1 (CH2-6'), 30.4 (CH2-1'), 24.6 and 24.4 (2C, CH2-3, CH2-2'), 23.9 (CH2-4) 15.9 (CH3-4'), 14.2 (OCH2CH3). HRMS (ESI+) m / z: calcd. for C27H36NO3 [M+H]+422.2690, found 422.2691. Ethyl (E)-6-(6-(benzyloxy)-1,2-dimethyl-1,2,3,4-tetrahydroquinolin-3-yl)-4-methylhex-4-enoate (5b): 32.0 mg, amber oil (38% yield).1H NMR (300 MHz, CDCl3): δ 7.41-7.25 (m,5H, Ph-H), 6.71 (dd, J = 8.7, 3.0 Hz, 1H, H-7), 6.64 (d, J = 3.0 Hz, 1H, H-5), 6.39 (d, J= 8.7 Hz, 1H, H-8), 5.14 (m, 1H, CH-2'), 4.93 (s, 2H, OCH2Ph), 4.08 (q, J = 7.1 Hz, 2H,OCH2CH3), 3.06-3.01 (m, 1H, CH-2), 2.93-2.86 (m, 1H, CH2a-4), 2.79 (s, 3H, N-CH3), 2.40-2.23 (m, 5H, CH2b-4, CH2-5', CH2-4'), 2.01-1.79 (m, 2H, CH2-1'), 1.65-1.60 (m, 1H,CH-3), 1.45 (s, 3H, CH3-3'), 1.21 (t, J = 7.2 Hz, 3H, OCH2CH3), 0.99 (d, J = 6.5 Hz, 3H, CH3-2).13C NMR (75 MHz, CDCl3+ 1 drop CD3OD): δ 173.8 (CO2CH2CH3), 149.8 (C-6), 139.4 (C-8a), 137.8 (C-1''), 134.8 (C-3'), 128.4 (2C, CH-3'', CH-5''), 127.7 (CH-4''), 127.5 (2C, CH-2'', CH-6''), 123.8 (CH-2'), 121.5 (C-4a), 116.8 (CH-5), 113.4 (CH-7), 110.8 (CH- 8), 70.9 (OCH2Ph), 60.4 (OCH2CH3), 57.3 (CH-2), 37.6 (CH-3), 34.8 (N-CH3), 33.3 (2C, CH2-4', CH2-5'), 31.8 (CH2-1'), 28.7 (CH-4), 17.1 (CH3-2), 15.9 (CH3-3'), 14.2 (OCH2CH3). HRMS (ESI+) m / z: calcd. for C27H36NO3[M+H]+422.2690, found 422.2686.Ethyl (E)-7-(6-(benzyloxy)quinolin-2-yl)-4-methylhept-4-enoate (8a): 36.3 mg, amber oil(45% yield).1H NMR (300 MHz, CDCl3): δ 8.01 (d, J = 9.3 Hz, 1H, H-8), 8.00 (d, J = 8.3Hz, 1H, H-4), 7.50-7.31 (m, 6H, Ph-H, H-7), 7.24 (d, J = 8.3 Hz, 1H, H-3), 7.14 (d, J =2.8 Hz, 1H, H-5), 5.29-5.22 (m, 1H, CH-3'), 5.17 (s, 2H, OCH2Ph), 4.09 (q, J = 7.2 Hz,2H, OCH2CH3), 3.00-2.95 (m, 2H, CH2-1'), 2.54-2.49 (m, 2H, CH2-2'), 2.39-2.26 (m, 4H,CH2-5', CH2-6'), 1.55 (s, 3H, CH3-3') 1.22 (t, J = 7.1 Hz, 3H, OCH2CH3). 13C NMR (75MHz, CDCl3): δ 173.5 (CO2CH2CH3), 159.7 (C-6), 156.5 (C-2), 136.6 (C-8a), 135.5 (CH- 4), 134.6 (2C, C-1", C-4'), 129.9 (CH-8), 128.7 (2C, CH-3", CH-5"), 128.2 (CH-4"), 127.6 (C-4a) 127.5 (2C, CH-2", CH-6"), 124.0 (CH-3'), 122.5 (CH-7), 121.8 (CH-3), 106.6 (CH- 5), 70.2 (OCH2Ph), 60.3 (OCH2CH3), 38.6 (CH2-1'), 34.6 and 33.2 (2C, CH2-5', CH2-6'), 28.4 (CH2-2'), 16.0 (CH3-4'), 14.3 (OCH2CH3). HRMS (ESI+) m / z: calcd. for C26H30NO3[M+H]+404.2220, found 404.2221.Ethyl (E)-6-(6-(benzyloxy)-2-methylquinolin-3-yl)-4-methylhex-4-enoate (8b): 37.9 mg,amber oil (47 % yield).1H NMR (300 MHz, CDCl3): δ 7.90 (d, J = 9.1 Hz, 1H, H-8), 7.70(s, 1H, H-4), 7.54-7.30 (m, 6H, Ph-H, H-7), 7.10 (d, J = 2.8 Hz, 1H, H-5), 5.38-5.32 (m,1H, CH-2'), 5.16 (s, 2H, OCH2Ph), 4.10 (q, J = 7.2 Hz, 2H, OCH2CH3), 3.48-3.37 (m, 2H, CH2-1'), 2.65 (s, 3H, CH3-2), 2.51-2.35 (m, 4H, CH2-4', CH2-5'), 1.76 (s, 3H, CH3-3'), 1.19 (t, J = 7.1 Hz, 3H, OCH2CH3).13C NMR (75 MHz, CDCl3 + 1 drop CD3OD): δ 173.8 (CO2CH2CH3), 149.8 (2C, C-6, C-2), 139.5 (C-8a), 137.8 (2C, C-1", C-4a), 134.8 (C-3'), 133.6 (C-3), 128.4 (2C, CH-3", CH-5"), 127.7 (CH-4"), 127.5 (2C, CH-2", CH-6"), 123.8 (CH-8), 121.45 (CH-4) 116.8 (CH-2'), 113.4 (CH-7), 110.8 (CH-5), 70.9 (OCH2Ph), 60.4 (OCH2CH3), 37.6 (CH2-4'), 34.8 (CH2-5'), 33.3 (CH2-1'), 17.1 (CH3-2), 15.9 (CH3-3'), 14.2 (OCH2CH3). HRMS (ESI+) m / z: calcd. for C26H30NO3 [M+H]+404.2220, found 404.2220.General procedure for the synthesis of 2- and 3-prenylated tetrahydroquinoline andquinoline 6a, 6b, 9a and 9b carboxylic acidsTetrahydroquinoline 5a or 5b and quinoline esters 8a or 8b (0.05 mmol) were treatedwith aqueous 20% KOH (200 µL) in ethanol (10 mL) at reflux for 4 h under N2. The reaction mixture was extracted with EtOAc (3 x 10 mL) and the combined organic layers were washed with H2O (3 x 10 mL) and brine (3 x 10 mL), dried over anhydrous Na2SO4, filtered and evaporated to dryness. The residue was purified by silica gel columnchromatography (CH2Cl2 / MeOH, 90:10) to afford tetrahydroquinolines 5a and 5b andquinoline carboxylic acids 9a and 9b.(E)-7-(6-(benzyloxy)-1-methyl-1,2,3,4-tetrahydroquinolin-2-yl)-4-methylhept-4-enoicacid (6a): 17.7 mg, light-yellow oil (90 % yield). 1H NMR (300 MHz, CDCl3): δ 7.45-7.31(m, 5H, Ph-H), 6.74 (dd, J = 9.0, 3.0 Hz, 1H, H-7), 6.67 (d, J = 3.0 Hz, 1H, H-5), 6.41 (d,J = 9.0 Hz, 1H, H-8), 5.20-5.16 (m, 1H, CH-3'), 4.99 (s, 2H, OCH2Ph), 3.20-3.15 (m, 1H,CH-2), 2.88 (s, 3H, N-CH3), 2.81-2.62 (m, 2H, CH2-4), 2.47-2.41 (m, 2H, CH2-6'), 2.33- 2.28 (m, 2H, CH2-5'), 2.05-1.86 (m, 4H, CH2-2', CH2-3), 1.63 (s, 3H, CH3-4'), 1.61-1.38 (m, 2H, CH2-1').13C NMR (75 MHz, CDCl3): δ 177.2 (CO2H), 150.0 (C-6), 140.3 (C-8a), 137.9 (C-1''), 133.7 (C-4'), 128.5 (2C, CH-3'', CH-5''), 127.7 (CH-4''), 127.5 (2C, CH-2'', CH-6''), 124.9 (CH-3'), 123.1 (C-4a), 116.1 (CH-5), 113.5 (CH-7), 111.9 (CH-8), 70.9 (OCH2Ph), 58.3 (CH-2), 38.4 (N-CH3), 34.5 (CH2-5'), 32.9 (CH2-6'), 30.4 (CH2-1'), 24.5 (CH2-3), 24.4 (CH2-2'), 24.0 (CH2-4), 16.0 (CH3-4'). HRMS (ESI+) m / z: calcd. for C25H32NO3[M+H]+394.2377, found 394.2377. (E)-6-(6-(benzyloxy)-1,2-dimethyl-1,2,3,4-tetrahydroquinolin-3-yl)-4-methylhex-4-enoicacid (6b): 18.1 mg, light-yellow oil (92 % yield). 1H NMR (300 MHz, CDCl3): δ 7.41-7.27(m, 5H, Ph-H), 6.74 (dd, J = 8.6, 1.8 Hz, 1H, H-7), 6.67 (d, J = 1.8 Hz, 1H, H-5), 6.41 (d, J = 8.6 Hz, 1H, H-8), 5.20-5.16 (m, 1H, CH-2'), 4.95 (s, 2H, OCH2Ph), 3.08-3.06 (m, 1H, CH-2), 3.01-2.85 (m, 1H, CH2a-4), 2.81 (s, 3H, N-CH3), 2.45-1.65 (m, 7H, CH2b-4, CH2- 5', CH2-4', CH2-1'), 1.48 (s, 3H, CH3-3'), 1.01 (d, J = 6.6 Hz, 3H, CH3-2).13C NMR (75 MHz, CDCl3): δ 179.0 (CO2H), 150.0 (C-6), 139.4 (C-8a), 137.8 (C-1''), 134.8 (C-3'), 128.5 (2C, CH-3'', CH-5''), 127.8 (CH-4''), 127.5 (2C, CH-2'', CH-6''), 123.9 (CH-2'), 121.4 (C-4a), 116.7 (CH-5), 113.5 (CH-7), 110.9 (CH-8), 70.9 (OCH2Ph), 57.7 (CH-2), 37.7 (CH-3), 34.6 (N-CH3), 32.3 (2C, CH2-4', CH2-5'), 31.7 (CH2-1'), 28.7 (CH-4), 17.0 (CH3- 2), 16.0 (CH3-3'). HRMS (ESI+) m / z: calcd. for C25H31NO [M]+394.2377, found 394.2368.(E)-7-(6-(benzyloxy) quinolin-2-yl)-4-methylhept-4-enoic acid (9a): 15.0 mg, light-yellowoil (80 % yield). 1H NMR (300 MHz, CDCl3): δ 8.71 (d, J = 9.2 Hz, 1H, H-8), 8.28 (d, J =8.4 Hz, 1H, H-4), 7.58 (dd, J = 9.2, 3.0 Hz, 1H, H-7), 7.63-7.36 (m, 7H, Ph-H, H-5, H-3),5.23-5.19 (m, 1H, CH-3'), 5.19 (s, 2H, OCH2Ph), 3.35-3.30 (m, 2H, CH2-1'), 2.63-2.58 (m, 2H, CH2-2'), 2.38-2.34 (m, 2H, CH2-5'), 2.25-2.20 (m, 2H, CH2-6'), 1.45 (s, 3H, CH3- 4').13C NMR (75 MHz, CDCl3): δ 175.9 (CO2H), 158.3 (C-6), 157.7 (C-2), 147.7 (C-8a), 141.2 (CH-4), 136.0 (C-1''), 135.6 (C-4'), 128.8 (3C, CH-3'', CH-5'', C-4a), 128.5 (CH-4''), 127.6 (2C, CH-2'', CH-6''), 126.1 (CH-7), 125.3 (CH-8), 122.5 (CH-3'), 122.0 (CH-3), 106.7 (CH-5), 70.7 (OCH2Ph), 34.8 (CH2-1'), 34.7 (CH2-6'), 32.9 (CH2-5'), 27.9 (CH2-2'), 15.9 (CH3-4'). HRMS (ESI+) m / z: calcd. for C24H26NO3[M+H]+376.1907, found 376.1909. (E)-6-(6-(benzyloxy)-2-methylquinolin-3-yl)-4-methylhex-4-enoic acid (9b): 15.9 mg,light-yellow oil (85 % yield). 1H NMR (300 MHz, CDCl3): δ 8.03 (d, J = 9.2 Hz, 1H, H-8),7.79 (s, 1H, H-4), 7.51-7.30 (m, 6H, Ph-H, H-7), 7.07 (d, J = 2.7 Hz, 1H, H-5), 5.37-5.32 (m, 1H, CH-2'), 5.10 (s, 2H, OCH2Ph), 3.40 (d, J = 7.0 Hz, 2H, CH2-1'), 2.65 (s, 3H, CH3- 2), 2.55-2.51 (m, 2H, CH2-4'), 2.48-2.45 (m, 2H, CH2-5'), 1.76 (s, 3H, CH3-3').13C NMR (75 MHz, CDCl3+ 1 drop CD3OD): δ 175.7 (CO2H), 156.6 (C-6), 155.9 (C-2), 136.6 and 136.4 (C-8a, C-4a), 134.8 (2C, C-1'', C-3'), 133.8 (2C, CH-4, C-3), 128.6 (2C, CH-3'', CH-5''), 128.4 (CH-8), 128.1 (CH-4''), 127.5 (2C, CH-2'', CH-6''), 122.1 (CH-7), 121.3 (CH-2'), 106.3 (CH-5), 70.3 (OCH2Ph), 34.5 (CH2-5'), 32.7 (CH2-4'), 31.4 (CH2-1'), 21.7 (CH3-2), 16.1 (CH3-3'). HRMS (ESI+) m / z: calcd. for C24H25NO3[M]+376.1907, found 376.1907. Results The synthetic routes to prepare the 2-prenylated (series a) and 3-prenylated (series b) quinolines and tetrahydroquinolines are depicted in Scheme 1. The quinoline nucleus was obtained via a Friedländer reaction, which required o-nitrobenzaldehyde being reduced into o-aminobenzaldehyde, followed by the condensation of this intermediate (without further purification) with an enolizable ketone ethyl levulinate. Hence, the nitro group was reduced using iron powder in the presence of aqueous HCl. The best resultswere obtained after centrifuging the reaction mixture of the reduction of the nitro- to theamine-group to remove iron solids, and by treating the supernatant with ethyl levulinate in the presence of pyrrolidine. Under these conditions, Friedländer condensation allowedus to prepare both 2-substituted quinoline 1a (series a) and 2-methyl-3-substitutedquinoline 1b (series b) at the 1.4:1 ratio with a good yield. Four tetrahydroquinolines (5a,6a, 5b, 6b) and four quinolines (8a, 9a, 8b, 9b) from 2-monosubstituted quinoline 1a(series a) and 2-methyl-3-substituted quinoline 1b were prepared by the elongation ofthe side carbon chain at 2-position or 3-position, respectively. The pyridine rings of 1aand 1b were selectively reduced under Lewis acidic conditions using a combination ofsodium cyanoborohydride and boron trifluoride diethyl etherate to givetetrahydroquinolines 2a and 2b, respectively. Subsequently, the N-methylation of 2a and2b allowed N-methyl- tetrahydroquinolines 3a and 3b, respectively. In a secondapproach, 2-prenylated tetrahydroquinolines 5a and quinoline 8a bearing a seven-carbon chain were obtained, as well as 2-methyl-3-prenylated tetrahydroquinoline 5band quinoline 8b bearing a six-carbon chain. The hydrolysis of esters gavetetrahydroquinolines 6a and 6b as well as quinolines 9a and 9b for series a and b,respectively. Scheme 1. Synthesis of prenylated quinolines and 1,2,3,4-tetrahydroquinolines.Reagents and conditions: (a) K2CO3, PhCH2Cl, DMF, reflux, 4 h (75%); (b) Fe / HCl, EtOH,reflux, 30 min; (c) Pyrrolidine, EtOH, reflux, 4 h (50% for 1a, 36% for 1b); (d) NaBH3CN,BF3OEt, MeOH, reflux, 3 h (65% for 2a, 60% for 2b); (e) CH2O / HCO2H, EtOH, 1 h, reflux;NaBH4, 25 ºC, 30 min (80% for 3a, 75% for 3b); (f) DIBAL-H, CH2Cl2, -78 ºC, 15 min(80% for 4a, 7 % for 4b, 50% for 7a, 75% for 7b); (g) 0.5 M CH2=C(CH3)MgBr, THF, -78ºC, 1 h; (h) MeC(OEt)3, isobutyric acid, 140 ºC, 2 h (45% for 5a, 38% for 5b, 47% for8a, 40% for 8b); (i) 20% KOH, MeOH, reflux, 2 h (90% for 6a, 92% for 6b, 80% for 9a, 85% for 9b).Example 3. PPARα, PPARβ / δ and PPARγ agonist activity of compounds ofFormula I and II Tetrahydroquinolines 5a, 6a, 5b, and 6b, as well as quinolines 8a, 9a, 8b, and 9b, wereassayed in vitro for hPPARα, hPPARβ / δ and hPPARγ transactivation activity. Activitywas referred to as the maximal activity (Emax) obtained for each tetrahydroquinoline orquinoline at 10 µM expressed as a percentage of maximal activity of the following prior art compounds: WY-14,643 at 10 µM for hPPARα, and rosiglitazone or GW501516 at 1 µM for hPPARγ or hPPARβ / δ respectively. The synthesized quinolines and tetrahydroquinolines have shown pan-PPAR agonist activity (5a, 6a, 8a) and dual PPARα / γ agonist activity (9a, 8b, 9b), always with partialactivity on the PPARγ isoform. The 3-substituted tetrahydroquinolines (5b, 6b) wereselective PPARα, with efficiencies 3-4 times higher than the prior art compound WY-14,643. Table 2 shows the evaluation of agonist activity in a cell-based transactivationassays for human PPAR / Gal4receptors. EC50values against human PPARα / Gal4, PPARβ / δ / Gal4and PPARγ / Gal4receptors. Table 2 Example 4. Cytotoxicity of compounds of Formula I and IIThe potential cytotoxic effects of the compounds of the invention 5a, 5b, 8a, and 8b onthe human macrophage cell line THP-1 were evaluated by flow cytometry to assess cell survival using an Annexin V-FITC / PI dual staining assay. The THP-1 cells were treated with concentrations of 30 and 100 µM for 24 h. No cytotoxic effects were observed at any of the tested concentrations (Figure 1). Example 5. Compounds of Formula I and II regulate lipid metabolism by increasingthe expression of Pdk4 in L929sA WT cellsPyruvate Dehydrogenase Kinase 4 gene (Pdk4), a well-known target gene of PPARs, encodes a protein that regulates the phosphorylation and inactivation of the pyruvate dehydrogenase complex in response to physiological conditions. This response switches the energy source from glucose to fatty acids to maintain blood glucose levels to, thereby, increase lipid metabolism. Because it is a well-known target gene of PPARs,the effect of the 2- and 3-prenylated esters of tetrahydroquinolines and quinolines on aPdk4 region reported to bind PPARα, was evaluated. The L929sA cells that were stablytransfected with a PDK4-(PPRE)3-Luc+ reporter gene construct were used. Cells weretreated with tetrahydroquinolines 5a and 5b or quinolines 8a and 8b at 10 ^M for a totalinduction time of 6 h, and compared to GW7647 at 1 ^M as the positive control (EC50 = 1 nM for PPARα; 2.9 ^M for PPARβ / δ; 1.3 ^M for PPARγ). Efficacy was determined by calculating their maximal transactivation response, which was expressed as a percentage of maximum GW7647 activity. Results revealed that tetrahydroquinolines 5aand 5b and quinoline 8a promote lipid metabolism as they increased the transactivationof the PDK4-Luc+ indicator and the expression of the Pdk4 gene in L929sA WT cells. Inparticular, tetrahydroquinoline 5a outperformed the maximal activity of the prior artcompound GW7647. These findings were subsequently validated by RT-qPCR to assessthe expression of Pdk4 mRNA in the L929sA WT cells treated with tetrahydroquinolines5a and 5b as representative leads of pan-PPAR and selective PPARα agonism,respectively. As shown in Figure 2B, the treatment with both 5a and 5b at 10 µM led toincreased expression levels of Pdk4. Collectively, these results show thattetrahydroquinolines 5a and 5b promote lipid metabolism, which make them excellentcandidates for prevention and / or treatment of lipid-related diseases. Example 6. Compounds of Formula I and II minimize inflammation by decreasingTNFα-induced NF-^B transactivation and inhibiting TNFα-induced pro-inflammatory gene expression in L929sA cellsPPARs play crucial roles in controlling inflammatory responses. NF-^B is a transcriptionfactor that plays a pivotal role in the expression of multiple genes involved in the immune and inflammatory responses. To study the potential anti-inflammatory effects of thetetrahydroquinolines and quinolines of the invention, the NF-κB-dependent physiologicalhuman IL-8 promoter construct, p1481.IL8P-Luc+, which is stably integrated into L929sA cells, was tested. After transfection, cells were treated at 10 µM with 5a, 5b, 8a, or 8bprior to TNFα stimulation. Figure 3A shows that tetrahydroquinolines 5a and 5b andquinoline 8b can repress the transactivation of the TNFα-dependent NF-^B-drivenreporter, compared to the prior art compound GW7647. Given the significant decreasein NF-^B-IL8P-Luc+ reporter gene activity observed after treatment with the 2- or 3-prenylated tetrahydroquinolines 5a and 5b and the 3-prenylated quinoline 8b, theirpotential anti-inflammatory effects at the transcriptional level for other inflammatorymediators was evaluated. To achieve this, the L929sA WT cells were treated with 5a, 5band 8b at 10 µM for 1 h, followed by TNFα stimulation for a total induction time of 6 h.The expression of inflammatory genes was evaluated by RT-qPCR. Interestingly,tetrahydroquinolines 5a and 5b and quinoline 8b repressed the transactivation of NF-κB-TNFα-dependent Luc+ and downregulated the transcription of TNFα-inducedproinflammatory genes such as Ccl5 and Il-6 in L929sA WT cells (Figure 3B).Example 7. Tetrahydroquinoline compound 5a improved lipid and carbohydratemetabolism in ob / ob miceTetrahydroquinoline 5a administered for 15 days (orally, 10 mg / kg / d) to an obese anddiabetic mouse model (ob / ob), improved lipid and carbohydrate parameters. Indeed, 5adecreased total cholesterol and non-HDL cholesterol levels, as well as insulin levels andthe HOMA-IR index in the blood of ob / ob mice, compared to vehicle-treated mice(Figures 4A-4D). Furthermore, as hepatotoxicity has been identified as an adverseeffect of some thiazolidinediones, it is noteworthy that the treatment withtetrahydroquinoline 5a did not increase levels of hepatic transaminases such as ALT andAST (Figures 4E-4F).Example 8. Tetrahydroquinoline compound 5a increased the expression of genesof fatty acid use and oxidation in liver and fat of ob / ob miceTetrahydroquinoline 5a also increased the expression of genes involved in mitochondrialand peroxisomal β-oxidation of fatty acids, such as Pdk4 (pyruvate dehydrogenasekinase 4), Cpt1a (carnitine palmitoyltransferase 1A) and Acox1 (acyl-CoA oxidase 1) inepididymal white adipose tissue and / or liver of ob / ob mice (Figure 5). These resultsindicate that tetrahydroquinoline 5a exerts a strong activation of the PPARα which mightpromote lipid metabolism and energy expenditure by increasing fatty acid transport to the mitochondria and oxidation. Example 9. Molecular modelling results with tetrahydroquinoline compound 5aA molecular modelling study of 2-prenylated tetrahydroquinoline 5a was carried out. ForPPARα, the combined analysis, performed using docking calculations and moleculardynamics simulations, predicted that tetrahydroquinoline 5a bind to the same region ofthe active site as previously reported for WY-14,643 (Bernardes et al. (2013)). Themolecular dynamics simulations indicated that 5a was spatially arranged in a slightlydifferent manner from that of WY-14,643. The interactions previously reported as themost important for stabilising ligand-receptor complexes are present (Bernardes et al. (2013)). Such interactions occur with the Ser280, Ile317, His440, and Tyr464 residues. However, it is interesting to note that, in general, the interactions observed for 2-prenylated tetrahydroquinoline 5a were weaker than those noted for WY-14,643. Thisresult is consistent with the experimental results of the previous examples, in which theagonist activity of 5a was weaker than that of the prior art compound WY-14643.With the PPARβ / δ receptor, although 5a was spatially arranged in a similar way toGW501516 (Wu et al. (2017)), the interactions of 5a were clearly significantly weakerthan those observed for the reference compound GW501516. The main interactions were for Cys249, Arg248, Thr253, Ile320, His413 and Lys331.With the PPARγ receptor, the molecular behaviour of 5a was compared to that previouslyreported for rosiglitazone (Kouskoumvekaki et al. (2013)). The molecular dynamicssimulations predicted that tetrahydroquinoline 5a binds to the active site in a similar wayto that reported for rosiglitazone. The main interactions were for Cys285, Arg288,Leu330, Ile342, His449 and Tyr473, and the interactions obtained for 5a were weakerthan those observed for rosiglitazone. Example 10. Synthesis and PPAR activity of prenylated quinoline 11a Synthesis of ethyl (2E,6E)-9-(6-(benzyloxy)quinolin-2-yl)-2,6-dimethylnona-2,6-dienoate (11a)The synthetic route to prepare prenylated quinoline 11a is depicted in Scheme 2. Scheme 2. Synthesis of prenylated quinoline 11a. Reagents and conditions: (a) DIBAL-H, CH2Cl2, -78 ºC, 15 minutes (54%); (b) THF, room temperature, N2, 24 hours (59%).Quinoline 8a (0.60 mmol) was reduced by DIBAL to give an aldehyde intermediate whichwas subjected to Wittig olefination. For Wittig reaction triphenylphosphine was dissolvedin ethyl acetate, and splashed into 2-bromoethyl propanoate under room temperature atreflux for 5 hours. The crude was dissolved in ethanol and treated with 20% NaOH (20minutes) to afford carbethoxyethylidene triphenylphosphorane (ylide). Then, thealdehyde intermediate was added to a solution of the ylide (0.97 mmol) in anhydrousTHF under N2 atmosphere, and the reaction was stirred for 24 hours at roomtemperature. Next, water was added and extracted with ethyl acetate, and the organiclayers were combined and washed with 5% aqueous NaHCO3 solution (3 x 10 mL), brine(3 x 10 mL) and water (3 x 10 mL). The organic phase was dried over anhydrous Na2SO4,filtered and the solvent was removed under reduced pressure. The residue was purified via silica gel column chromatography (hexane / EtOAc, 85:15) to afford the compound 11a. NMR characterization of prenylated quinoline 11a1H NMR (300 MHz, CDCl3) δ 7.99-7.90 (m, 2H, CH-4, CH-8), 7.51-7.32 (m, 6H, CH-7, OCH2Ph), 7.24 (d, J= 8.5 Hz, 1H, CH-3), 7.13 (d, J= 2.8 Hz, 1H, CH-5), 6.73 (t, J= 7.2 Hz, 1H, CH-7'), 5.27 (t, J= 7.1 Hz, 1H, CH-3'), 5.18 (s, 2H, OCH2Ph), 4.18 (q, J= 7.1 Hz, 2H, CO2CH2CH3), 3.00-2.92 (m, 2H, CH2-1'), 2.51 (q, J= 7.3 Hz, 2H, CH2-2'), 2.28-2.16 y 2.13-2.02 (m, 4H, CH2-5', CH2-6'), 1.81 (s, 3H, CH3-8'), 1.56 (s, 3H, CH3-4'), 1.29 (t, J= 7.1 Hz, 3H, CO2CH2CH3).13C NMR (75 MHz, CDCl3) δ 168.2 (CO2CH2CH3), 160.0 (C- 2), 156.3 (C-6), 141.8 (2C, C-8a, CH-7'), 136.6 (C-1''), 135.0 (CH-4), 130.3 (CH-8), 128.7, 128.1 y 127.5 (5C, OCH2Ph), 127.7 (C-4a), 124.1 (CH-3'), 122.2 (CH-7), 121.8 (CH-3), 106.6 (CH-5), 70.3 (OCH2Ph), 60.4 (CO2CH2CH3), 38.9 (CH2-1'), 38.2 (CH2-5'), 28.4 (CH2-2'), 27.3 (CH2-6'), 16.0 (CH3-4'), 14.3 (CH3-4'), 12.4 (CH3-8’). HRMS(ESI+) m / z: calcd for C29H34NO3[M+H]+444.2533, found 444.2545. PPAR activity of prenylated quinoline 11aPrenylated quinoline 11a was assayed in vitro for hPPARα, hPPARβ / δ and hPPARγtransactivation activity, as disclosed in Example 3. The results are shown in Table 3. Table 3 Prenylated quinoline 11a has shown, unexpectedly, a potent PPARα activity, and aremarkable PPARγ activity.CITATION LISTBernardes et al. (2013). Molecular mechanism of peroxisome proliferator-activatedreceptor α activation by WY14643: a new mode of ligand recognition and receptor stabilization. J Mol Biol.;425(16):2878-93. doi: 10.1016 / j.jmb.2013.05.010. Nolte et al. (1998). Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-gamma. Nature.;395(6698):137-43. doi: 10.1038 / 25931.Kouskoumvekaki et al. (2013). Discovery of a novel selective PPARγ ligand with partialagonist binding properties by integrated in silico / in vitro work flow. J Chem Inf Model.;53(4):923-37. doi: 10.1021 / ci3006148. Wu et al. (2017). Structural basis for specific ligation of the peroxisome proliferator- activated receptor δ. Proc Natl Acad Sci U S A.;114(13):E2563-E2570. doi: 10.1073 / pnas.1621513114.

Claims

CLAIMS1. A prenylated tetrahydroquinoline compound or prenylated quinoline compound, ofFormula I or Formula II, respectively, or a salt, or solvate thereof:wherein: -R1 is independently selected from H or CH2-CH=C(CH3)-CH2-CH2-COOR3;- R2 is independently selected from the group consisting of CH3, CH2-CH2-CH=C(CH3)-CH2-CH2-COOR3, and CH2-CH2-CH=C(CH3)-CH2-CH2-CH=C(CH3)-COOR3; -R3 is independently selected from the group consisting of H, alkyl, alkylamide,alkylamine, alkylaryl, alkyl-ether, and acyl; andwherein: -when R1 is H, then R2 is CH2-CH2-CH=C(CH3)-CH2-CH2-COOR3, or CH2-CH2-CH=C(CH3)-CH2-CH2-CH=C(CH3)-COOR3; and -when R2 is CH3, then R1 is CH2-CH=C(CH3)-CH2-CH2-COOR3.

2. The compound, salt, or solvate according to claim 1, wherein R3 is independentlyselected from H or CH2-CH3.

3. The compound, salt, or solvate according to claim 1 or 2, wherein said compound isselected from the group consisting of 5a, 5b, 6a, 6b, 8a, 8b, 9a, 9b, and 11a:11a: R3= CH2CH3.

4. The compound, salt, or solvate according to claims 1 to 3, wherein:- R1 is independently selected from H or CH2-CH=C(CH3)-CH2-CH2-COOR3;- R2 is independently selected from CH3 or CH2-CH2-CH=C(CH3)-CH2-CH2-COOR3; -R3 is independently selected from the group consisting of H, alkyl, alkylamide,alkylamine, alkylaryl, alkyl-ether, and acyl; andwherein: -when R1 is H, then R2 is CH2-CH2-CH=C(CH3)-CH2-CH2-COOR3; and- when R2 is CH3, then R1 is CH2-CH=C(CH3)-CH2-CH2-COOR3.

5. The compound, salt, or solvate according to claim 4, wherein R3 is independentlyselected from H or CH2-CH3.

6. The compound, salt, or solvate according to claim 4 or 5, wherein said compound isselected from the group consisting of 5a, 5b, 6a, 6b, 8a, 8b, 9a, and 9b.

7. A pharmaceutical composition comprising at least a compound, salt, or solvateaccording to any one of claims 1 to 6 as active ingredient, and at least apharmaceutically acceptable excipient or carrier.

8. The pharmaceutical composition according to claim 7, further comprising at least oneadditional active ingredient.

9. The compound, salt, or solvate according to any one of claims 1 to 6, or thepharmaceutical composition according to claim 7 or 8, for use as a medicament.

10. The compound, salt, or solvate according to any one of claims 1 to 6, or thepharmaceutical composition according to claim 7 or 8, for use in the preventionand / or treatment of a peroxisome proliferator-activated receptor (PPAR)-mediateddisease.

11. The compound, salt, or solvate or pharmaceutical composition for use according toclaim 9 or 10, wherein said compound is an agonist of at least one PPAR protein,wherein said PPAR protein is selected from the group consisting of PPARα, PPARβ / δ and PPARγ.

12. The compound, salt, or solvate, or pharmaceutical composition for use according toany one of claims 9 to 11 wherein said compound is a dual PPARα / γ agonist.

13. The compound, salt, or solvate, or pharmaceutical composition for use according toany one of claims 9 to 11, wherein said compound is an agonist of PPARα, PPARβ / δand PPARγ.

14. The compound, salt, or solvate, or pharmaceutical composition for use according toany one of claims 10 to 13, wherein said disease is selected from the groupconsisting of PPARα-mediated disease, PPARβ / δ-mediated disease, and PPARγ- mediated disease.

15. The compound, salt, or solvate, or pharmaceutical composition for use according toany one of claims 10 to 14, wherein said disease is associated to the expression ofa gene selected from the group consisting of Pdk4, NF-κB, Ccl2, Ccl5, Il6, Tnf, Cpt1a,and Acox1.

16. The compound, salt, or solvate, or pharmaceutical composition for use according toany one of claims 10 to 15, wherein said disease is associated with inflammation.

17. The compound, salt, or solvate, or pharmaceutical composition for use according toclaim 16, wherein said inflammation is selected from autoimmune inflammation or neuroinflammation.

18. The compound, salt, or solvate, or pharmaceutical composition for use according toany one of claims 10 to 17, wherein said disease is selected from the groupconsisting of metabolic syndrome, type 2 diabetes mellitus, dyslipidemia,hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, obesity, dyslipidemicatherosclerosis, metabolic dysfunction-associated fatty liver disease (MAFLD),cardiovascular disease, cardiometabolic disease, neurodegenerative disease,Friedreich's ataxia, Parkinson’s disease, multiple sclerosis, Alzheimer's disease,autoimmune disease, rheumatoid arthritis, autoimmune thyroid disease, dermatological disease, and cancer.

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