Substituted hydroquinolines for the treatment of glioblastoma multiforme

Abstract

There is provided a compound according to formula (I) or a pharmaceutically acceptable salt or prodrug thereof.

Description

1SMALL COMPOUNDS FOR THE TREATMENT OF GLIOBLASTOMA MULTIFORME TECHNICAL FIELD

[0001] The present disclosure relates to the field of small compounds, inparticular small compounds for use in a method of treatment of glioma. BACKGROUND

[0002] Glioma is a broad term used to describe primary brain tumors classifiedaccording to their source cell. These include astrocytomas (astrocytomas, anaplastic astrocytomas, glioblastomas), oligodendrogliomas, ependymomas, and mixed gliomas (Agnihotri S et al., 2013). These are the most common tumors of the central nervous system (CNS), accounting for approximately 80% of all primary malignancies of the brain (Hanif et al., 2017). Glioblastoma multiforme (GBM) is the most malignant and most common form of primary astrocytoma (Mardinoglu A. et al., 2020). It constitutes more than 60% of all brain tumors in adults.

[0003] GBM is a disease that exhibits significant heterogeneity when it comes togenetic variations and cell origins. (Alcantara Llaguno and Parada, 2016). As part of GBM carcinogenesis, several of the cell systems undergo significant reprogramming and the metabolic system exhibits some of the most remarkable changes (Agnihotri and Zadeh, 2016).

[0004] GBM accounts for 50% of all gliomas in all age groups. Although it canoccur at any age, its incidence peaks between 55 and 60 years of age. GBM cells arehighly pathogenic and cannot be completely removed because they grow in normalbrain tissue. The success rate of the treatments developed in the last decade is verylow and the average patient survival time is usually about 14-15 months fromdiagnosis. In addition, GBM cells have developed resistance to the current multimodal treatment regimen consisting of the alkylating agent temozolomide (TMZ) and radiation. Because many targeted therapies do not effectively cross the blood-brain barrier (BBB), positive results have not been achieved in clinical trials. (Fang, C. et al, 2015). Taken together, these findings warrant the development of new therapeutic approaches to treat GBM.2SUMMARY

[0005] The present inventors realized that there is a need for further developmentof new therapeutic approaches to treat glioma such as GBM. The present inventorsthus hypothesized that by derivatizing cilostazol, a drug known to pass the blood-brain barrier (BBB), novel small compounds with the ability to pass the blood-brainbarrier and the potential to reduce proliferation of glioblastoma cells could beobtained.

[0006] According to a first aspect, there is provided a compound according toformula (I)or a pharmaceutically acceptable salt or prodrug thereof; wherein R1 is selected from optionally branched C3-C7 alkyl, optionally branched C2-3is independently a single bond or a double bond;W is independently selected from carbon and nitrogen;R3 is selected from optionally substituted naphthalene,A is selected from H, X and OMe ; D is selected from H, X , OMe and CX3; Q is selected from H, X and OMe; X is a halogen;4R5 is selected fromR6 is selected from H, X, C3 alkyl,R7 is selected from H, Me; R8 is selected from H and X;5R10 is selected from X, CX3 and acetyl; R11 is selected from a phenyl, C1-C3 alkyl and isopropyl; R12 is selected from H and OMe;R13 is selected from OMe, phenyl, acetyl, morpholine and N-methyl piperazine;R14 is selected from H and OMe provided that when R12 is H, R13 and / or R14 isalso H;R15 is selected from H, X, Me, OMe and CF3;R16 is selected from H and X;R17 is selected from H and X;R18 is selected from H, X and OMe;R19 is selected from H, NO2, OMe and X;R20 is selected fromHand X;R22 is selected from X and NO2;R2 is selected from H, optionally branched C3-C7 alkyl,,R23 is selected from C1-C4 alkyl and C3-C4 alkenyl;R24 is selected from, F, phenyl and C2-C4 alkyl;R25 is selected from Me and X , provided that R1 is notwhen R2 is H .6

[0007] Treatment with a compound according to the first aspect has the ability toreduce the proliferation of glioblastoma cells. Furthermore, it has been shown thattreating rats with induced GBM with a compound according to the first aspectsignificantly prolongs their survival and decelerates or reduces tumor growth. Acompound of the first aspect is thus well-suited for use in a method of treatment ofglioblastomas such as GBM.

[0008] According to a second aspect, there is provided a pharmaceuticalcomposition comprising a compound according to the first aspect.

[0009] According to a third aspect, there is provided a compound according to thefirst aspect or a pharmaceutical composition according to the second aspect for use asa medicament.

[0010] According to a fourth aspect, there is provided a compound according tothe first aspect or a pharmaceutical composition according to the second aspect foruse in a method of treatment of glioma.

[0011] In an embodiment of the fourth aspect, the compound or thepharmaceutical composition is used in a method of treatment of glioblastoma, suchas glioblastoma multiforme.BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Fig 1 shows the alkylation reactions for synthesizing 6-hydroxy-3,4-dihydroquinolin-2(1H)-one analogues.

[0013] Fig 2 shows the acylation reactions for synthesizing 6-hydroxy-3,4-dihydroquinolin-2(1H)-one analogues.

[0014] Fig 3 shows the hydrazide formation for synthesizing 6-hydroxy-3,4-dihydroquinolin-2(1H)-one analogues.

[0015] Fig 4 shows the synthesis of 2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy) acetohydrazide-hydrazone analogues.

[0016] Fig 5 shows the synthesis of triazole analogues of 6-(prop-2-yn-1-yloxy)-3,4-dihydroquinolin-2(1H)-one.

[0017] Fig 6 shows the synthesis of oxazole analogues of allyl or propargyldihydroquinolin-2(1H)-one derivatives.7

[0018] Fig 7 shows the synthesis of 2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy) carbamate derivatives.

[0019] Fig 8 shows the synthesis of 2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy) acetamide derivatives.

[0020] Fig 9 shows the synthesis of 2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy) carbamate derivatives from isocyanate.

[0021] Fig 10 shows the synthesis of sulfonate derivatives of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one.

[0022] Fig 11 shows the timeline diagram of the in Vivo study.

[0023] Fig 12 shows the IC50 values of compounds TR-G053 and TR-G078 in U87and IC50 values of TR-G053 and TR-G052 in U138-MG cell lines.

[0024] Fig 13 shows the IC50 values of TR-G143, TR-G089 and TR-G075 in U87-MG and IC50 values of TR-G143, TR-G131 and TR-G136 in U138-MG cell lines.

[0025] Fig 14 shows the IC50 values of TR-G091, TR-G002 and TR-G045 scale-upcompounds in U87 and IC50 values of TR-G091, TR-G002 and TR-G045 scale-upcompounds in U138-MG cell lines.

[0026] Fig 15 shows the IC50 values of TR-G103, TR-G066 and TR-G141 in U87and IC50 values of TR-G050, TR-G066 and TR-G027 in U138-MG cell lines.

[0027] Fig 16 shows the IC50 values of TR-G138 in U87 and TR-G145 in both U87-MG and U138-MG cell lines.

[0028] Fig 17-19 shows the permeability rates of compounds through the blood-brain-barrier mimicking membrane.

[0029] Fig 20-22 shows the permeability rates of compounds through thegastrointestinal mimicking membrane.

[0030] Fig 23 shows the survival of rats in the in Vivo study.

[0031] Fig 24 shows the MRI follow-up of tumor progression in the in Vivo studyafter treatment with target compounds and TMZ, respectively.

[0032] Fig 25 shows the relative tumor progression in the in Vivo study aftertreatment with target compounds and TMZ, respectively.8

[0033] Fig 26 shows the MRI of the rat brain with GBM. (a) Axial T2 weightedMRI image on the 14th day after implantation; (b) Axial T2 weighted MRI image onthe 28thday after implantation; (c) Coronal T2 weighted MRI image on the 14thdayafter implantation; (d) Coronal T2 weighted MRI image on the 28th day afterimplantation.

[0034] Fig 27 shows the MRI of the rat brain with GBM treated with TMZ. (a)Axial T2 weighted MRI image on the 14th day after implantation; (b) Axial T2weighted MRI image after treatment with TMZ (28th day); (c) Coronal T2 weightedMRI image on the 14th day after implantation; (d) Coronal T2 weighted MRI imageafter treatment with TMZ (28thday).

[0035] Fig 28 shows the MRI of the rat brain with GBM treated with TR-G002.(a) Axial T2 weighted MRI image on the 14th day after implantation; (b) Axial T2weighted MRI image after treatment with TR-G002 (28th day); (c) Coronal T2weighted MRI image on the 14th day after implantation; (d) Coronal T2 weighted MRIimage after treatment with TR-G002 (28thday).

[0036] Fig 29 shows the MRI of the rat brain with GBM treated with TR-G045. (a)Axial T2 weighted MRI image on the 14th day after implantation; (b) Axial T2weighted MRI image after treatment with TR-G045 (28th day); (c) Coronal T2weighted MRI image on the 14th day after implantation; (d) Coronal T2 weighted MRIimage after treatment with TR-G045 (28thday).

[0037] Fig 30 shows the MRI of the rat brain with GBM treated with TR-G053. (a)Axial T2 weighted MRI image on the 14th day after implantation; (b) Axial T2weighted MRI image after treatment with TR-G053 (28th day); (c) Coronal T2weighted MRI image on the 14th day after implantation; (d) Coronal T2 weighted MRIimage after treatment with TR-G053 (28thday).

[0038] Fig 31 shows the MRI of the rat brain with GBM treated with TR-G066. (a)Axial T2 weighted MRI image on the 14th day after implantation; (b) Axial T2weighted MRI image after treatment with TR-G066 (28th day); (c) Coronal T2weighted MRI image on the 14th day after implantation; (d) Coronal T2 weighted MRIimage after treatment with TR-G066 (28thday).

[0039] Fig 32 shows the MRI of the rat brain with GBM treated with TR-G071. (a)Axial T2 weighted MRI image on the 14th day after implantation; (b) Axial T29weighted MRI image after treatment with TR-G071 (28th day); (c) Coronal T2weighted MRI image on the 14th day after implantation; (d) Coronal T2 weighted MRIimage after treatment with TR-G071 (28thday).

[0040] Fig 33 shows the MRI of the rat brain with GBM treated with TR-G091. (a)Axial T2 weighted MRI image on the 14th day after implantation; (b) Axial T2weighted MRI image after treatment with TR-G091 (28th day); (c) Coronal T2weighted MRI image on the 14th day after implantation; (d) Coronal T2 weighted MRIimage after treatment with TR-G091 (28thday).

[0041] Fig 34 shows brain tissues, GBM H&E, 10X Bar:70µm, 40X Bar: 40µm,Nuclear protein Ki67 (Ki67), Cytidine / uridine monophosphate kinase 2 (CMPK2) and Glial fibrillary acidic protein (GFAP) expressions, IHC-P, Bar: 40µm.

[0042] Fig 35 shows the histopathological findings observed in brain tissues. (A)Tumor Mass: (****p < 0.0001, T02 vs T66 *p = 0.0402, TMZ vs T66 *p = 0.0465, ns: no significant difference = p > 0.9999), (B) Focus of Necrosis: (****p < 0.0001, ***p = 0.0004), (C) Vascular Proliferation: (****p < 0.0001, *p = 0.0154, ns: no significant difference p = 0.6780), (D) Cellular Proliferation: (****p < 0.0001, **p = 0.0022, ns: no significant difference p = 0.9959).

[0043] Fig 36 shows the brain tissues, GBM, NOP10 and H2A.X expressions inneurons, IF, Bar: 50µm.

[0044] Fig 37 shows the glioblastoma immunohistochemical andimmunofluorescence staining data and statistical analysis findings. (A) Ki67: (****p < 0.0001, ***p = 0.0002, **p = 0.0019, ns: no significant difference = 0.1125), (B) CMPK2: (****p < 0.0001, ***p = 0.0008, ns: no significant difference = 0.7175), (C) GFAP: (****p < 0.0001, *p = 0.0171, ns: no significant difference = 0.3553), (D) NOP10: (****p < 0.0001, **p = 0.0039, ns: no significant difference = 0.2536), (E) H2A.X: (****p < 0.0001, **p = 0.0040, *p = 0.0152, ns: no significant difference = 0.1232)

[0045] Fig 38-40 shows the cell viability (MTT assay) of KALS1 cells treated withcompounds of the present disclosure.10 DETAILED DESCRIPTION

[0046] Glioblastoma multiforme (GBM) is the most malignant and most commonform of primary astrocytoma (Mardinoglu A. et al., 2020). It constitutes more than 60% of all brain tumors in adults. It is thus crucial to develop new therapeutictreatments with improved efficacy.

[0047] Advances in biotechnology have resulted in the creation of new high-throughput analytical methods that can provide large amounts of data. These approaches often focus on studying the genome, transcriptome, and proteome, resulting in a variety of omics data. Systems biologists interpret omics data to gain biological understanding using statistical analysis, network development, and mathematical modelling (Nielsen and Hohmann, 2017). A new and specific treatmenttarget can be identified and validated with multi-omics data. In target determination,firstly, a preliminary list is created according to the differences in expression level in the patient population in the results of multi-omics data. Candidate targets are evaluated if they can be used as therapeutic targets based on their expression in different tissues, their expression in known cancer cell lines and other literatureinformation that is available. This systems biology approach has been applied to GBMand the CMPK2 protein was found to be a candidate target for the treatment of GBM.

[0048] CMPK2, encodes mitochondrial UMP-CMP kinase 2 and may have afunction in the synthesis of dUTP and dCTP (UniProt Consortium, T., 2018). In terms of function, CMPK2 appears to be an anomaly. dUTP and dCTP nucleotides are thought to be involved in mitochondrial synthesis (UniProt Consortium, 2018). Since CMPK2 is a critical gene in DNA synthesis, it is required for cell development, which is increased in tumor cells but not in normal brain cells. According to the findings, CMPK2 is involved in the cellular response to a viral infection. Thus, when examining the CMPK2 co-expression cluster and performing enrichment analysis on the 90 included genes, both enriched KEGG pathways found are fully linked to viralinfection and cellular defence response. The presence of human cytomegalovirus(HCMV) in brain tumor cells and its possible relevance in the formation and progression of GBM has been previously implicated in GBM research.

[0049] In silico computational chemistry methods including molecular dockingand ADME (Absorption, Distribution, Metabolism and Elimination) properties of innovative molecules designed by derivatization were analyzed in silico using the11 Autodock VIna and SwissADME, PreADMET database. The binding sites of the designed compounds in the protein-ligand complex were determined; molecular interactions were described in silico docking, bonding, and interaction analyses.

[0050] In order to develop new effective compounds for use in the treatment ofglioblastomas, the present inventors derivatized a known drug, Cilostazol, that isknown to pass the blood-brain barrier. Cilostazol, an oral anti-platelet drug, is aspecific cAMP phosphodiesterase type III inhibitor and has been clinically used to treat thrombosis patients. It has further been shown that Cilostazol can suppress colon cancer cell motility and might be effective as an anti-metastasis drug for cancerpatients. Metastasis of cancer cells is initiated by the cellular migration intoextracellular matrix and surrounding vessels and drugs that can elevate cAMP levelsin cancer cells effectively may be applied to prevent metastasis in cancer patients.(Murata, Kohei, et al. 1999). Furthermore, the big-conductance calcium-activatedpotassium channel (BK channel) is highly expressed and activated in GBM. Cilostazolis a phosphodiesterase-3 inhibitor and has been shown to reverse CIIR-induced BKchannel inactivation. Cilostazol inhibited CIIR-induced cell motility, proliferation,delayed tumor in vivo growth, the ability to form tumor spheres and prolongedsurvival. As such, inactivation of the BK channel can assist GBM in developingradiation resistance (Liu, Chan-Chuan, et al., 2021). Cilostazol has further beenshown to neuro2A (N2a) Swe cells, and significantly improved spatial learning and memory in -injected mice (Park SH, Kim JH, et al.2011).

[0051] According to a first aspect, there is provided a compound according toformula (I)or a pharmaceutically acceptable salt or prodrug thereof; wherein R1 is selected from optionally branched C3-C7 alkyl, optionally branched C2-12W is independently selected from carbon and nitrogen;R3 is selected from optionally substituted naphthalene,13A is selected from H, X and OMe ; D is selected from H, X , OMe and CX3; Q is selected from H, X and OMe; X is a halogen;R5 is selected fromR6 is selected from H, X, C3 alkyl,R7 is selected from H, Me; R8 is selected from H and X;14R10 is selected from X, CX3 and acetyl; R11 is selected from a phenyl, C1-C3 alkyl and isopropyl; R12 is selected from H and OMe;R13 is selected from OMe, phenyl, acetyl, morpholine and N-methyl piperazine;R14 is selected from H and OMe provided that when R12 is H, R13 and / or R14 isalso H;R15 is selected from H, X, Me, OMe and CF3;R16 is selected from H and X;R17 is selected from H and X;R18 is selected from H, X and OMe;R19 is selected from H, NO2, OMe and X;R20 is selected fromHand X;R22 is selected from X and NO2;R2 is selected from H, optionally branched C3-C7 alkyl,,15R23 is selected from C1-C4 alkyl and C3-C4 alkenyl;R24 is selected from, F, phenyl and C2-C4 alkyl;R25 is selected from Me and X , provided that R1 is notwhen R2 is H .

[0052] Treatment with a compound according to the first aspect is associated witha significant reduction in the proliferation of glioblastoma cells. Furthermore, treatment with a compound according to the first aspect is further associated with aprolonged survival and deceleration or reduction of tumor growth in rats withinduced GBM. These compounds are thus particularly well-suited for use in apharmacological treatment of glioblastoma such as GBM.

[0053] Below, various embodiments of the first aspect as well as certaincompounds identified in the Examples section are discussed.

[0054] In one embodiment, the compound is a compound according to formula(II)may be H.

[0055] This embodiment is associated with some of the most potent compoundsand treatment with these compounds results in an especially large reduction in theproliferation of glioblastoma cells as well as a prolonged survival and a decelerationin tumor growth in rats with induced GBM. Compounds such as TR-G002, TR-G014,TR-G045, TR-G-053, TR-G066, TR-G078 and TR-G143 are included in this16embodiment and are shown to be exceptionally effective since reduced proliferationof glioblastoma cells is obtained in vitro together with a prolonged survival anddeceleration in tumor growth in rats with induced GBM.

[0056] In another embodiment, R2 is selected fromG103 and TG-112 are included in this embodiment and treatment with thesecompounds is associated with an exceptionally low proliferation of glioblastoma cells.

[0057] In one embodiment,preferably17TR-G025, TR-G-028, TR-G055, TR-G056, TR-G066, TR-G138 and TR-G145 areincluded in this embodiment. Treatment with these compounds is shown tosignificantly reduce the proliferation of glioblastoma cell lines and also prolongsurvival and decelerate the tumor growth in rats with induced GBM. In some cases,the tumor size was significantly reduced after treatment with a compound of thisembodiment. As an example, R2 may be H in this embodiment.

[0058] In one embodiment, R1 is a substituted benzyl, preferably R1 is selected. Compounds TR-G053 and TR-G030 are included in thisembodiment and treatment with these compounds exhibits a reduction in theproliferation of glioblastoma cells and prolongs the survival of rats with inducedGBM. As an example, R2 may be H in this embodiment.18

[0059] In one embodiment, both R1 and R2 are. CompoundTR-G013A is included in this embodiment and treatment with this compound isassociated with a significantly reduced proliferation of glioblastoma cells.

[0060] In one embodiment, R1 is a branched C3-C7 alkyl, preferably branched C4-C7 alkyl, more preferably R1 is. Compound TR-G002 is included inthis embodiment and treatment with these compounds results in a reduction in theproliferation of glioblastoma cells as well as a significantly prolonged survival anddeceleration in tumor growth in rats. Furthermore, it has been shown that treatmentwith these compounds can result in a decrease in both vascular and cellularproliferation in rats with induced GBM. As an example, R2 may be H in this embodiment.

[0061] In one embodiment,. Preferably R1 isG091 and TR-G143 are included in this embodiment and treatment with thesecompounds results in a reduction in proliferation of glioblastoma cells. While treatment with TR-091 did not exhibit a significant reduction in cell proliferation invitro, treatment of rats with induced GBM with this compound resulted in aprolonged survival. As an example, R2 may be H in this embodiment.19

[0062] In another embodiment, R1 isAs an example, R2 may be H in this embodiment.Compounds TR-G085, TR-G063, TR-G048 and TR-G045 are included in thisembodiment and treatment with these compounds results in a reduction in theproliferation of glioblastoma cells as well as a prolonged survival and a decelerationin tumor growth in rats with induced GBM. In some cases, the tumor size wassignificantly reduced after treatment with a compound in this embodiment. As anexample, R2 may be H in this embodiment.20

[0064] In one embodiment,Preferably R1 isselected fromCompounds TR-G092, TR-G116, TR-G142 and TR-G150 are included in thisembodiment and treatment with these compounds is shown to reduce theproliferation of glioblastoma cells. As an example, R2 may be H in this embodiment.

[0065] In one embodiment, R1 is,preferably R1 is selected fromWhile treatment with TR-071 did not exhibit a reduction in cell proliferation in vitro, treatment with this compound showed a prolonged survival ofrats with induced GBM. As an example, R2 may be H in this embodiment.embodiment R2 is selected from optionally branched C3-C7 alkyl, C3-C5 alkenyl,21preferably R2 is selected from,G103, TR-G105 and TR-G112 are included in this embodiment and treatment withthese compounds is shown to exhibit a significant reduction in the proliferation ofglioblastoma cells.

[0067] The compounds TR-G002, TR-G13A, TR-G014, TR-G045, TR-G053, TR-G066, TR-G078 and TR-G112 are particularly preferred as treatment with thesecompounds results in a significant reduction in the proliferation of glioblastoma cellsas well as a prolonged survival and deceleration in tumor growth in rats induced with GBM. Furthermore, treatment with these compounds, especially TR-G002 and TR- G066, can lead to a decrease in both vascular and cellular proliferation in rats with induced GBM.22. In this embodiment, R2 is preferably H. The compounds TR-G193 and TR-G194 in the Examples section are part of this embodiment and treatment with these compounds results in a significant reduction in the proliferation of KALS1 cells.

[0069] The compounds TR-G193 and TR-G194 in the Examples section areespecially preferred.

[0070] In one embodiment,

[0071] The compound of the first aspect may be a compound according to formula(III). Preferably, R2 is H.(III)

[0072] R1 may be selected from optionally branched C3-C7 alkyl, substituted,mpound TR-G201 in theExamples section is part of this embodiment and treatment with these compounds results in a significant reduction in the proliferation of KALS1 cells.

[0073] According to a second aspect, there is provided a pharmaceuticalcomposition comprising a compound according to the first aspect.23

[0074] According to a third aspect, there is provided a compound according to thefirst aspect or a pharmaceutical composition according to the second aspect for use asa medicament.

[0075] According to a fourth aspect, there is provided a compound according tothe first aspect or a pharmaceutical composition according to the second aspect foruse in a method of treatment of glioma. The method may for example comprise oraladministration of the compound or pharmaceutical composition.

[0076] In an embodiment of the fourth aspect, the compound or thepharmaceutical composition is used in a method of treatment of glioblastoma, suchas glioblastoma multiforme (GBM).EXAMPLES Synthesis of target compounds

[0077] To synthesize the target compounds, different synthesis strategies wereapplied, and the multi-step syntheses were optimized. Optimization was directedtowards minimizing the toxicities of the target compounds by using reactionstrategies that fall within the green chemistry approach. The use of auxiliaries such as solvents, release agents and catalysts was kept to a minimum. Attention was paid to reducing reagent waste and preventing undesirable side reactions.

[0078] UV / Visible Spectroscopy, FTIR, LC-MS-MS, NMR, HPLC and X-Raycrystallography was used to elucidate the structure and impurities of intermediate and target compounds.

[0079] The R-groups in the Examples section and the corresponding figures aredifferent from the R-groups in the rest of this specification.General Experimental

[0080] All reactions were performed with oven-dried glassware and under aninert atmosphere (nitrogen) unless otherwise stated. All reagents and dried solvents were obtained from commercial supplier Sigma-Aldrich and used without further purification. Organic solutions were concentrated under reduced pressure on a Heidolph rotary evaporator.

[0081] Reactions were monitored by LCMS / MS (Thermo Fisher TSQ Series,Athena C18- using water: MeOH (0.01 formic acid)) as24 eluent or by Thin-Layer Chromatography (TLC) using silica gel pre-coatedaluminium plates (Kieselgel 60, 254, E. Merck, Germany). The chromatograms werevisualized using ultraviolet light (254 and 366 nm) and stained with vanillin dips or aqueous potassium permanganate solution.

[0082] 1H NMR spectra were recorded on Avance Bruker 500 MHz spectrometerNMR spectra were recorded in deuterated solvents on Bruker spectrometer at 126 MHz, with the central peak of the deuterated solvent as the internal standard. The1tetramethylsilane (multiplicity, number of protons, coupling constant J / Hz). The13C million (ppm) relative to the residual solvent peak. The following abbreviations are used to denote signal patterns: (s) singlet, (d) doublet, (t) triplet, (q) quartet, (m) multiplet, and (br) broad unless otherwise noted.

[0083] Flash-column chromatography was performed on PuriFlash XS 520 PlusFlash chromatography system (Interchim) with built-in UV-detector, ELSD-detector, and fraction collector with Interchim silica gel columns.

[0084] General procedure A (Alkylation Reactions)

[0085] Hydroxyl or amino group-containing compounds (1 eq.) were dissolved inTHF and drops of DMF comprising potassium carbonate (K2CO3, 1.1-1.5 eq.) orcesium carbonate (Cs2CO3, 1.1-1.5 eq.). The mixture was stirred for 30 minutes at ambient temperature. After that, alkyl bromide or alkyl chloride (1-1.2 eq.) was addedto the reaction mixture which was monitored with TLC over 12-48 h. Iced water wasadded to the reaction mixture and then extracted using dichloromethane (DCM) orethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, evaporated, and purified by flash chromatography to afford the final product, see Fig. 1 and Table 1.25

[0086] Table 1 shows target compounds with their reagents for alkylationreactions.26272830313233

[0087] General procedure B (Acylation Reactions)

[0088] To a solution of compounds containing hydroxy / amino group (1 eq.) andK2CO3 (1.5 eq.) or triethylamine (TEA, 1.5 eq.) in THF, acetone, or DMF, acyl chloride derivatives were added to afford the acylated products. After the completion of reaction, the solvents were evaporated and the residues were washed with water, dried, and purified, see Fig.2 and Table 2.

[0089] Table 2 shows the target compounds and their reagents for acylationreactions.3435

[0090] General procedure C (Hydrazide Formation)

[0091] The hydrazide products were obtained by refluxing acetate-containingcompounds (1 eq.) and hydrazines (2 eq.) in ethanol. After the completion of the reaction, the product was cooled to room temperature and filtered out of ethanol, see Fig.3.

[0092] General procedure D Acetohydrazide-hydrazones (Schiff-basereactions)

[0093] The hydrazones were accomplished by reacting hydrazides andaldehydes / ketones in ethanol and drops of acetic acid at reflux temperature for 4-12 hours. After the reaction was cooled, the product was filtered and purified by column chromatography, see Fig.4 and Table 3.

[0094] Table 3 shows target compounds with their reagents for acetohyrazide-hydrazone reactions.363739

[0095] General procedure E Cycloaddition Reactions (Triazole Preparation)

[0096] The azides were prepared starting from alkyl bromide, amines and acetatederivative (1 eq.) which were reacted with azide salts (2 eq.) for 2 hours in appropriate solvents, see Fig.5 and Table 4.

[0097] Table 4 shows the target compounds with their reagents for triazolesformation.4041

[0098] General procedure F Cycloaddition Reactions (Oxazole Formation)

[0099] Firstly, TR-G014 was prepared according to procedure A. After that, toprepare TR-G051, TR-G070, and TR-G150, a solution of 4-fluorobenzaldehyde, 4-chlorobenzaldehyde or 2-chloro-6-fluorobenzaldehyde respectively (1 eq.),hydroxylamine hydrochloride (2 eq.) and NaHCO3 in ethanol were refluxed for 3h toprepare the corresponding oxime. The reaction was monitored by TLC untilcompletion of reaction. After that, the product was filtered, washed and dried. In thecyclization step, TR-G014 (1 eq.) with the corresponding oxime were dissolved in42 chloroform then NaOCl (12-16 grade) (2 eq.) were added slowly to the mixture in icebath at 0 °C for 8 h. Water was then added and the product was extracted withchloroform (3x 30 mL). The organic layer was dried over anhydrous magnesium phosphate and the solvent was evaporated under vacuum. The crude product was purified using flash chromatography.

[0100] For TR-G084, TR-G092, TR-G116 and TR-G142; TR-G006 was firstlyprepared according to procedure A. After that, the corresponding aldehyde (1 eq.),hydroxylamine hydrochloride (2 eq.) and NaHCO3 in ethanol were refluxed for 3h toprepare the corresponding oxime. The reaction was monitored by TLC untilcompletion of reaction. After that, the product was filtered, washed and dried. In thecyclization step, TR-G006 (1 eq.) with the corresponding oxime were dissolved inchloroform and then NaOCl (12-16 grade) (2 eq.) was added slowly to the mixture inan ice bath at 0 °C for 8 h. Water was then added, and the product was extracted withchloroform (3x 30 mL). The organic layer was dried over anhydrous magnesium phosphate and the solvent was evaporated under vacuum. The crude product was purified using flash chromatography.

[0101] The cycloaddition reaction for the oxazole formation can be seen in Fig. 6and Table 5.

[0102] Table 5 shows the target compounds with their reagents for oxazoleanalogues.43

[0103] Carbamate Formation Reaction (from carbamoyl chlorides)

[0104] The starting material 6-hydroxy-3,4-dihydroquinolin-2(1H)-one wasreacted with carbmoyl chlorides (1,2 eq.) under basic conditions (K2CO3) (1.3 eq.) atroom temperature for 8-16 h.

[0105] See Fig. 7 and Table 6 for the target compounds.

[0106] Table 6 shows target molecules with their reagents for carbamatederivatives.44

[0107] Acetamide Formation Reaction

[0108] In the first step, amines have been reacted with chloroacetyl chloride in thepresence of a base according to procedure B. In the second step the acetylated amine reacted with 6-hydroxy-3,4-dihydroquinolin-2(1H)-one under basic conditions according to procedure A, see Fig.8 and Table 7.

[0109] Table 7 shows the target compounds with their reagents for acetamidederivatives4546

[0110] Carbamate Formation Reaction (From Isocyanate Derivatives)

[0111] In two round bottom flask, 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1eq.) was stirred with TEA (1.3 eq.) for 1h in THF and drops of DMF, then the desire isocyanate (1.3 eq.) was added to the reaction mixture and stirred for 2-4 h at room47temperature. After that, the product was precipitated in ice water, filtered and air-dried. Finally, the product was purified using flash chromatography.

[0112] See Fig. 9 and Table 8 for the target compounds.

[0113] Table 8 shows the target molecules with their reagents for carbamatederivatives.48

[0114] General procedure H for sulfonyl chloride reactions (Sulfonate Ester)

[0115] 6-hydroxy-3,4-dihydroquinolin-2(1H)-one was dissolved intetrahydrofuran (THF), and a small amount of dimethylformamide (DMF) was added, along with either K2CO3, TEA or Cs2CO3 at a ratio of 1.1-1.5 equivalents. The mixture was stirred for approximately 30 minutes at room temperature. Following this, alkyl sulfonyl chloride (at a 1-1.2 molar ratio) was introduced into the reaction mixture, and the progress was monitored over 12-48 hours using TLC. The reactionmixture was subsequently treated with cold water and then subjected to extractionusing either DCM or ethyl acetate. The organic layer underwent drying through anhydrous magnesium sulfate, followed by evaporation. The resultant material was further refined through flash chromatography to yield the ultimate product, see Fig.10 and Table 9.

[0116] Table 9 shows the target compounds with their reagents for sulfonatederivatives of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one.4950

[0117] Carboxylic acid Formation Reactions

[0118] A solution of the ethyl 2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetate was prepared by dissolving it in tetrahydrofuran (THF, 5 mL). Upon mixture (1:1 v / v). The reaction mixture was then under reflux for 20 hours. On completion, THF was removed under reduced pressure. Concentrated hydrochloric acid (HCl) was dropwise added to the residue that was obtained. The obtained precipitation ceased once it was no longer possible. The precipitated solid was filtered and washed using distilled water and then dried. The crude product was purified to provide the corresponding carboxylic acid (TR-G177).

[0119] Synthesis of 6-(2-(benzyloxy)ethoxy)-3,4-dihydroquinolin-2(1H)-one(TR-G001)

[0121] Following procedure A, 250 mg of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.53 mmol.) was stirred with 317 mg of the base K2CO3 (2.3 mmol.) for 30 min in THF and drops of DMF, then 0.26 ml of ((2-chloroethoxy)methyl)benzene (1.6 mmol.) was added to the reaction mixture at room temperature. After that workup with brine and extraction by ethyl acetate, column chromatography (Hexane:EtOAc) (60:40) was done to obtain 313.72 mg of TR-G001 (86%) as yellowish powder. LCMS / MS: m / z 297.14 [M+H]+.

[0122] 1H NMR (500 MHz, DMSO- -H), 7.37-6.72 (m,8Harom), 4.55 (S, 2H.), 4.06-4.08 (t, J = 7.2 Hz, 2H.), 3.72-3.74 (t, J = 7.2 Hz, 2H.), 2.80-2.83 (t, J = 7.2 Hz, 2H. CH2-CH2-C=O), 2.38 -2.40 (t, 2H J = 7.2 Hz, 2H. CH2-C=O). 13127.90, 125.29, 116.21, 114.55, 113.53, 72.52, 68.77, 67.83, 40.15, 30.82, 25.56.51

[0123] Synthesis of 6-(isopentyloxy)-3,4-dihydroquinolin-2(1H)-one (TR-G002)

[0125] Following procedure A, a mixture of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.23 mmol, 200 mg) and K2CO3 (1.84 mmol, 254.09 mg) was stirred for 1 h in THF and drops of DMF in round bottom flask. After that, 1-bromo-3- methylbutane (1.47 mmol, 222.16 mg) was added to the solution at room temperature. The mixture was allowed to stir and the reaction was controlled by TLC. The product was precipitated in iced water. The desire product was filtered and purified using column chromatography (Hexane:EtOAc) (60:40), 210 mg (73%) of the desire product was obtained as white crystals. LCMS / MS: m / z 234.11 [M+H]+

[0126] 1H NMR (500 MHz, DMSO-d6 6.6 (m, 3Harom), 3.90(t, J = 6.6 Hz, 2H), 2.81 (t, J = 7.5 Hz, 2H), 2.39 (d, J = 15.1 Hz, 2H), 1.80 1.70 (m, 1H), 1.56 (q, J = 6.7 Hz, 2H), 0.91 (d, J = 6.7 Hz, 6H).13169.72, 153.86, 131.64, 124.80, 115.75, 113.95, 112.91, 66.07, 37.56, 30.39, 25.12, 24.59, 22.44.

[0127] Synthesis of (E)-N'-(3-methylbutylidene)-2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetohydrazide (TR-G003)

[0128]

[0129] According to procedure A, C and D starting from 6-hydroxy-3,4-dihydroquinolin-2(1H)-one. Firstly, 300 mg of 6-hydroxy-3,4-dihydroquinolin- 2(1H)-one (1.84 mmol) was stirred with 381 mg of the base K2CO3 (2.76 mmol) for 15 min in THF and drops of DMF, then 244 µL of ethyl 2-bromoacetate (2.21 mmol) was added slowly to the reaction mixture. After the completing of reaction, the solvent was evaporated and the residue was washed with water, filtered and air-dried to obtain ethyl 2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetate (TR-G012) which was further refluxed with 241 µL hydrazine hydrate 99% (4.81 mmol) for 5 hours then it was cooled to room temperature, filtered out of ethanol and dried to obtain 2- ((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetohydrazide TR-G019. Later, 300 mg52 of TR-G019 (1.28 mmol) was refluxed with 168 µL of isovaleraldehyde (1.53 mmol) in ethanol and drops of acetic acid for 5 hours. After that the precipitate was filtered out of ethanol to obtain the final product as white powder with a yield of 85%. LCMS / MS: m / z 304.11 [M+H]+

[0130] 1H NMR (500 MHz, DMSO- -(s, 1H. C-NH-N=), 9.93 (*9.95, s, 1H. C-NH-C), 7.63-6.72 m, 3Harom), 6.67 6.64 (m, 1H. N=CH-), 4.87 (s, 1H. O-CH2-C=O), 4.48 (s, 1H. O-CH2-C=O), 2.84-2.80 (m, 2H), 2.43 2.36 (m, 2H), 2.12-2.06 (m, 2H), 1.84-1.78 (m, 1H), 0.91 (d, J = 2.9 Hz,3H), 0.90 (d, J = 2.9 Hz, 3H). (* refer to the rotameric peak). 1C NMR (126 MHz,40.53, 30.32, 26.14, 25.12, 22.29, 22.26.

[0131] Synthesis of phenyl 2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetate (TR-G004)

[0133] Following procedure A, 150 mg of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (0.919 mmol) was stirred with 190.6 mg of the base K2CO3 (1.38 mmol) for 3h. in THF and drops of DMF, then 0.296 gr of phenyl 2-bromoacetate (1.38 mmol) was added to the reaction at room temperature. After workup and purification by flash chromatography (Hexane:EtOAc) (50:50) 220 mg (80.5%) of TR-G004 as yellowish white powder. LCMS / MS: m / z 298.31 [M+H]+

[0134] 1H NMR (500 MHz, DMSO- 6.84 (m, 8Harom),5.05 (s, 2H), 2.87 (t, J = 7.5 Hz, 2H), 2.4-2.42 (m, 2H). 13170.03 (O=C), 168.02 (O=C-O), 157.48, 144.34, 136.33, 129.59, 124.82, 121.35, 120.91, 120.11, 115.55, 114.55, 64.56 (O=C-CH2-O), 30.01, 24.68.

[0135] Synthesis of 2-oxo-1,2,3,4-tetrahydroquinolin-6-yl dimethylcarbamate(TR-G005)53

[0137] Following procedure B, 200 mg of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.23 mmol) was stirred with 254 mg of the base K2CO3 (1.84 mmol) for 30 min in EtOH, then 0.17 mL of dimethylcarbamic chloride (1.84 mmol) was added, after workup and column chromatography (Hexane:EtOAc) (60:40) then afford 260 mg (72%) of TR-G005 as white powder. LCMS / MS: m / z 234.42 [M+H]+

[0138] 1H NMR (500 MHz, DMSO- -H), 6.95-6.78 (m,3Harom.), 3.01 (S, 3H. N-CH3-), 2.89 (S, 3H. N-CH3-), 2.84 (t, 2H. J = 7 Hz. O=C-CH2-CH2-), 2.42 (m, 2H. J = 7 Hz. O=C-CH2-). 13170.00 (O=C), 154.32 (O=C-O), 145.84, 135.45, 124.38, 121.31, 120.36, 115.24, 36.29 (-CH3), 36.05 (-CH3), 30.12, 24.71.

[0139] Synthesis of 6-(prop-2-yn-1-yloxy)-3,4-dihydroquinolin-2(1H)-one (TR-G006)

[0141] According to procedure A, 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.53mmol, 250 mg) was dissolved in N,N-Dimethylacetamide in ice bath. NaH (2.6 mmol, 62.5 mg) was added, and the mixture was allowed to stir for 2 h. After that, propargyl bromide (3.83 mmol, 0.3 mL) was added to the mixture at 0°C for 6h., after workup and column chromatography (Hexane:EtOAc) (50:50), 206 mg (67%) of TR-G006 was obtained as off-white crystals.

[0142] According to this procedure two products (TR-G006 and TR-G006A) canbe obtained. However, when DMSO was used as a solvent TR-G006 was obtained as one product and in higher yield. LCMS / MS: m / z 202.28 [M+H]+

[0143] 1H NMR (500 MHz, DMSO- -H), 6.83-6.78 (m,3Harom.), 4.71 (S, 2H. O-CH2-), 3.52 (S, 1H. C C-H), 2.84-2.81(m, 2H. O=C-CH2-CH2-), 2.42-2.39 (m, 2H. O=C-CH2-). 13132.43, 124.83, 115.70, 114.54, 113.50, 79.50, 78.01, 55.72, 30.30, 25.10.

[0144] Synthesis of 1-(prop-2-yn-1-yl)-6-(prop-2-yn-1-yloxy)-3,4-dihydroquinolin-2(1H)-one (TR-G006A)54

[0145]

[0146] According to procedure A, 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.53mmol, 250 mg) was dissolved in N,N-Dimethylacetamide in ice bath. NaH (2.6 mmol, 62.5 mg) was added, and the mixture was allowed to stir for 2 h. After that, propargyl bromide (3.83 mmol, 0.3 mL) was added to the mixture at 0°C for 7 h., after workup and column chromatography (Hexane:EtOAc) (50:50), 68 mg (19%) of TR-G006A was obtained as off-white crystals. LCMS / MS: m / z 240.21 [M+H]+

[0147] 1H N1MR (500 MHz, DMSO- -6.90 (d, J = 9.1 Hz, 3H), 4.77 (d, J= 2.3 Hz, 2H. O-CH2-), 4.65 (d, J = 2.3 Hz, 2H. N-CH2-), 3.55 (t, J = 2.3 Hz, 1H. C-H), 3.16 (t, J = 2.3 Hz, 1H. C-H), 2.86-2.80 (m, 2H. CH2CH2-C=O), 2.55 (m, 2H.CH2-C=O). 13114.82, 112.99, 79.76, 79.38, 78.20, 73.96, 55.64, 31.03, 30.98, 24.70.

[0148] Synthesis of 2-oxo-1,2,3,4-tetrahydroquinolin-6-yl 2-phenylacetate (TR-G007)

[0149]

[0150] Following procedure B, 150 mg of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (0.920 mmol) was stirred with 190 mg of the base K2CO3 (1.38 mmol) for 2 h. in THF and drops of DMF, then 219.5 mg 2-phenylacetyl bromide (1.1 mmol) was added to the reaction at room temperature. After workup 226 mg (87.4%) of TR-G007 was obtained as white powder. LCMS / MS: m / z 282.11 [M+H]+

[0151] 1H NMR (500 MHz, DMSO- -H), 8.02-6.76 (m,8Harom), 5.49 (S, 2H), 2.83 (t, J = 7.5 Hz, 2H. CH2CH2-C=O), 2.41-2.38 (m, 2H.CH2-C=O). 13 -C=O), 170.22 (C=O), 153.58,134.90, 134.21, 132.55, 129.28, 128.32, 125.25, 116.14, 114.60 (2C), 113.65 (2C), 70.91, 30.79, 25.53.55

[0152] Synthesis of 2-oxo-1,2,3,4-tetrahydroquinolin-6-yl 3,4-dimethoxybenzoate (TR-G008)

[0154] Following procedure B, 250 mg of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.5 mmol) was stirred with 317 mg of the base K2CO3 (2.3 mmol) for 30 min in THF and drops of DMF, then 306 mg of 3,4-dimethoxybenzoyl chloride (1.84 mmol) was added to the reaction at room temperature. After workup 405.00 mg (81%) of TR-G008 as white powder. LCMS / MS: m / z 328.31 [M+H]+

[0155] 1H NMR (500 MHz, DMSO- -H), 7.76-6.90 (m,6Harom.), 3.87 (S, 3H.), 3.84 (S, 3H.), 2.91-2.82 (t, J = 5 Hz, 2H - O=C-CH2-CH2),2.48-2.45 (t, J = 5 Hz, 2H. O=C-CH2). 13153.96, 149.01, 145.64, 136.52, 125.18, 124.42, 121.70, 121.41, 120.85, 115.95, 112.43, 111.71, 56.26, 56.06, 30.54, 25.17.

[0156] Synthesis of 2-oxo-1,2,3,4-tetrahydroquinolin-6-yl 2,4-dimethoxybenzoate (TR-G009)

[0158] Following procedure B, 200 mg of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.23 mmol) was stirred with 254 mg of the base K2CO3 (1,84 mmol) for 30 min in THF and drops of DMF, then 295 mg of 2,4-dimethoxybenzoyl chloride (1.47 mmol) was added to the reaction at room temperature. After workup 320 mg (79.8%) of TR-G009 was obtained as yellowish white powder. LCMS / MS: m / z 328.42 [M+H]+56

[0159] 1H NMR (500 MHz, DMSO- -H), 7.76-6.88 (m,8Harom), 3.87 (S, 3H), 3.83 (S, 3H), 2.89 (t, J = 7.6 Hz, 2H. CH2CH2-C=O), 2.46 (t,J = 7.6-C=O),165.03 (C=O), 153.97, 149.01, 145.63, 136.52, 125.19, 124.43, 121.71, 121.41, 120.86, 115.94, 112.44, 111.74, 56.28, 56.08, 30.55, 25.17.

[0160] Synthesis of 6-(cyclopropylmethoxy)-3,4-dihydroquinolin-2(1H)-one(TR-G010)

[0162] According to procedure A, 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.23mmol, 200 mg) was dissolved in THF and drops of DMF. K2CO3 (1.84 mmol, 254 mg) was added, and the mixture was allowed to stir for 2 h. After that, (chloromethyl)cyclopropane (1.59 mmol, 0.147 mL ) was added to the mixture at room temperature. After workup and column chromatography (Hexane:EtOAc) (50:50), 251 mg of TR-G010 (94.25%) was obtained as light yellow crystals. LCMS / MS: m / z 217.98 [M+H]+

[0163] 1H NMR (500 MHz, DMSO- N-H), 6.76-6.69 (m,3Harom), 3.73 (d, J = 5 Hz, 2H), 2.81 (t, J = 5 Hz, 2H. CH2CH2-C=O), 2.40-2.37 (t, 2H. J = 5Hz .CH2-C=O), 1.21-1.17 (m, 1H. CH), 0.56-0.53 (m, 2H. CH2), 0.30-0.27(m, 2H. CH2). 13C NMR (126 MHz, DMSO) 170.19 (NH-C=O), 154.27, 132.06,125.24, 116.19, 114.43, 113.47, 72.70, 30.84, 25.57, 10.70, 3.52 (2C).

[0164] Synthesis of 2-oxo-1,2,3,4-tetrahydroquinolin-6-yl 1-naphthoate (TR-G011)

[0166] Following procedure B, 300 mg of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.23 mmol) was stirred with 266 mg of the base TEA (1.84 mmol) for 30 min in THF and drops of DMF, then 222 ml of 1-naphthoyl chloride (1.5 mmol) was added, .57 After workup and column chromatography (Hexane:EtOAc) (70:30) 313 mg (81%) of TR-G011 was obtained as white powder. LCMS / MS: m / z 318.33 [M+H]+

[0167] 1H NMR (500 MHz, DMSO- N-H), 8.8-6.92 (m,10Harom.), 2.92 2.89 (m, 2H. O=C-CH2-), 2.48 -2.45 (m, 2H. O=C-CH2-CH2-). 13CNMR (126 MHz, DMSO- 130.62, 128.90, 128.23, 126.60, 125.63, 125.00, 124.85, 121.38, 120.51, 115.59, 30.11, 24.75.

[0168] Synthesis of ethyl 2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetate(TR-G012)

[0170] Following procedure A, 6-hydroxy-3,4-dihydroquinolin-2(1H)-one 250 mg(1.23 mmol) was stirred with 317.61 mg of the base K2CO3 (2.3 mmol) for 1 h. in THF and drops of DMF. Then 0.204 mL (1.51 g / cm³) of ethyl 2-bromoacetate (1.5 mmol) was added, after workup and column chromatography (Hexane:EtOAc) (50:50) then afford 313 mg (81%) of TR-G012 as white crystals. LCMS / MS: m / z 249.96 [M+H]+

[0171] 1H NMR (500 MHz, DMSO- -H), 6.79-6.70 (m,3Harom), 4.68 (s, 2H. O=C-CH2-O), 4.15 (q, J = 7.1 Hz, 2H. O-CH2-CH3), 2.82 (t, J = 7.5 Hz, 2H. O=C-CH2-CH2-), 2.39 (m, 2H.2H. O=C-CH2-), 1.20 (t, J = 7.1 Hz, 3H.CH3). 13C NMR (126114.93, 113.41, 65.97, 61.44, 30.54, 25.66, 14.24.

[0172] Synthesis of 4-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)butylbenzoate (TR-G013)

[0173]

[0174] Following procedure A, 6-hydroxy-3,4-dihydroquinolin-2(1H)-one 200 mg(1.23 mmol) was stirred with 254.09 mg of the base K2CO3(1.84 mmol) for 2 h. in THF and drops of DMF, then 0.204 mL (1.51 g / cm³) of 4-chlorobutyl benzoate (1.558 mmol, 0.296 mL, d:1,143 g / cm3) was added, . After workup and column chromatography (Hexane:EtOAc) (50:50) then afford 382 mg (91%) of TR-G013 as white powder. LCMS / MS: m / z 339.97 [M+H]+

[0175] 1H NMR (500 MHz, DMSO- N-H), 7.99-6.71 (m, 8H.Harom.), 4.34 (t, J = 6.0 Hz, 2H. O=C-O-CH2-), 3.97 (t, J = 5.9 Hz, 2H. -O-CH2-), 2.81 (t, J = 7.5 Hz, 2H. O=C-CH2-CH2-), 2.42 2.36 (m, 2H. O=C-CH2-), 1.86 (m,154.18, 133.72, 132.18, 130.26, 129.55 (2C), 129.19 (2C), 125.27, 116.21, 114.47, 113.44, 67.70, 64.89, 30.83, 25.92, 25.57, 25.48.

[0176] Synthesis of 4-(6-(4-(benzoyloxy)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)butyl benzoate (TR-G013A)

[0178] According to procedure A, 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.23mmol, 200 mg) was dissolved in N,N-Dimethylacetamide and put it in ice bath. NaH (1.84 mmol, 44.12 mg) was added, and the mixture was allowed to stir for 1 h. After that, 4-chlorobutyl benzoate (1.84 mmol, 0.342 mL) was added to the mixture at 0°C for 8 h, after workup and column chromatography (Hexane:EtOAc) (50:50), 173.00mg (27 %) of TR-G013A was obtained as off-white oily product. LCMS / MS: m / z516.26 [M+H]+

[0179] Synthesis of 6-(allyloxy)-3,4-dihydroquinolin-2(1H)-one (TR-G014)

[0181] According to procedure A, 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.53mmol, 250 mg) was dissolved in N,N-Dimethylacetamide in ice bath. NaH (2.6 mmol, 62.5 mg) was added, and the mixture was allowed to stir for 2 h. After that, allyl59 bromide (3.83 mmol, 0.331 mL) was added to the mixture at 0°C for 8 h., after workup and column chromatography (Hexane:EtOAc) (50:50), 201 mg (65%) of TR- G014 was obtained as off-white crystals. LCMS / MS: m / z 204.22 [M+H]+

[0182] Note: According to this, two products (TR-G014 and TR-G014A) could beobtained. However, when DMSO was used as a solvent TR-G014 was obtained as one product and in higher yield.

[0183] 1H NMR (500 MHz, Chloroform-d N-H), 6.8-6.72 (m, 3H.Harom.), 6.06-5.98 (m, 1H. CH=CH2), 5.39-5.22 (m, 2H. C=CH2), 4.50-4.48 (t, J = 5.2,1.0 Hz, 2H. O-CH2-), 2.84-2.81 (m, 2H. O=C-CH2-), 2.41-2.38 (m, 2H. O=C-CH2- CH2-).13117.19, 115.74, 114.23, 113.18, 68.44, 30.36, 25.11.

[0184] Synthesis of 1-allyl-6-(allyloxy)-3,4-dihydroquinolin-2(1H)-one (TR-G014A)

[0185]

[0186] According to procedure A, 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.53mmol, 250 mg) was dissolved in N,N-Dimethylacetamide and put it in ice bath. NaH (2.6 mmol, 62.5 mg) was added, and the mixture was allowed to stir for 2 h. After that, allyl bromide (3.83 mmol, 0.331 mL) was added to the mixture at 0°C for 8 h., after workup and column chromatography (Hexane:EtOAc) (50:50), 80 mg (22 %) of TR-G014A was obtained as off-white crystals. LCMS / MS: m / z 244.21 [M+H]+

[0187] 1H NMR (500 MHz, DMSO- -6.76 (m, 3Harom), 6.06-5.98 (m,1H. -O-CH2-CH=), 5.87-5.77 (m, 1H. -N-CH2-CH=), 5.40-5.23 (m, 2H. -CH=CH2), 5.24 (m, 2H. -CH=CH2), 4.52 (dt, J = 5.1, 1.4 Hz, 2H. -O-CH2-), 4.49-4.43 (m, 2H. >N-CH2-), 2.87-2.80 (m, 2H. O=C-CH2-CH2-), 2.55 (dd, J = 8.4, 6.3 Hz, 2H. O=C-CH2-). 13117.72, 116.59, 116.18, 114.84, 113.14, 68.83, 44.30, 31.62, 25.44.

[0188] Synthesis of 2-oxo-1,2,3,4-tetrahydroquinolin-6-yl 2-chloroacetate (TR-G016)60

[0190] Following procedure B, 250 mg of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.5 mmol) was stirred with 317 mg of the base K2CO3 (2.3 mmol) for 30 min in THF and drops of DMF, then 0.146 mL of 2-chloroacetyl chloride (1.84 mmol) was added to the reaction in ice bath. After workup 295 mg (80%) of TR-G016 as yellowish white powder. LCMS / MS: m / z 240.36 [M+H]+

[0191] 1H NMR (500 MHz, DMSO- -H), 6.94 (m, 3 Harom),4.66 (s, 2H. -CH2-Cl), 2.87 (t, J = 7.6 Hz, 2H. O=C-CH2-CH2-), 2.47 2.42 (m, 2H.O=C-CH2-). 13120.77, 119.95, 115.57, 41.30, 30.00, 24.67.

[0192] Synthesis of 6-(2-bromoethoxy)-3,4-dihydroquinolin-2(1H)-one (TR-G017)

[0194] According to procedure A, 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.23mmol, 200 mg) was dissolved in THF and drops of DMF. K2CO3 (1.84 mmol, 254 mg) was added and the mixture was allowed to stir for 2 h. After that, 1,2-dibromoethane (1.59 mmol, 0.137 mL, d: 2.18 g / ml) was added to the mixture at room temperature. After workup and column chromatography (Hexane:EtOAc:MeOH) (49:50:1), 251 mg of TR-G017 (94.25%) was obtained as light yellow crystals.

[0195] 1H NMR (500 MHz, DMSO- N-H), 6.82-6.74 (m,3Harom), 4.26-4.23 (t, 2H. J = 5Hz .CH2), 3.277 (t, 2H. J = 5Hz .CH2), 2.83 (t, J = 5Hz, 2H. CH2CH2-C=O), 2.40 (t, J = 5 Hz, 2H. CH2C=O). 13C NMR (126 MHz,DMSO) 169.14 (NH-C=O), 152.38, 131.61, 124.33, 115.17, 113.73, 112.68, 67.45, 30.99, 29.68, 24.42.

[0196] Synthesis of 2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetohydrazide (TR-G019)61

[0198] According to procedure C, 300 mg of TR-G012 (1.2 mmol) was heated withhydrazine hydrate 99% (3.6 mmol) in ethanol at 70 °C. After workup, the product was obtained as white powder with a yield of 90%.

[0199] 1H NMR (500 MHz, DMSO- -H), 9.27 (s, 1H. O=C-N-H), 6.81-6.73 (m, 3Harom), 4.40 (s, 1H. O-CH2-C=O), 4.31 (s, 2H. NH2), 2.83-2.80(m, 2H. O=C-CH2-), 2.41-2.38 (153.44, 132.75, 125.22, 116.13, 114.76, 113.72, 67.16, 30.77, 25.56.

[0200] Synthesis of 2-oxo-1,2,3,4-tetrahydroquinolin-6-yl diphenylcarbamate(TR-G020)

[0202] Following procedure B, 250 mg of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.5 mmol) was stirred with 317.6 mg of the base K2CO3 (2.3 mmol) for 30 min in DMSO, then 0.462 mg of diphenylcarbamic chloride (1.99 mmol) was added slowly to the reaction at room temperature. The product precipitated in ice water the final product filtered and recrystallized by EtOH and obtained 525 mg (96.1%) of TR-G020 as white powder. LCMS / MS: m / z 259.11 [M+H]+

[0203] 1H NMR (500 MHz, Chloroform- N-H), 7.42-6.82 (m,13H. Harom.), 2.87 2.84 (m, 2H. O=C-CH2-), 2.44 2.41 (m, 2H. O=C-CH2-CH2-). 13127.18, 126.66, 124.58, 121.17, 120.25, 115.31, 30.06, 24.66.

[0204] Synthesis of N'-(4-chlorobenzylidene)-2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetohydrazide (TR-G021)62

[0206] 150 mg of TR-G019 (0.8 mmol) was heated with 134.45 mg of 4-chlorobenzaldehyde (0.956 mmol) in ethanol under reflux with presents of AcOH (2 drops). The desire molecule was precipitated, when the reaction finish (controlled by TLC) the solvent was evaporated and obtained compound was washed by ethanol to obtain 210 mg (92%) as white powder. LCMS / MS: m / z 357.91 [M+H]+

[0207] 1H NMR (500 MHz, DMSO- -NH-N=), 9.96(*9.92, s, 1H. C-NH-C), 8.33 (*7.99, s, 1H. N=CH-) 7.74-6.72 (m, 7Harom), 5.07 (s, 1H. O-CH2-C=O), 4.60 (s, 1H. O-CH2-C=O), 2.86-2.81 (m, 2H. CH2CH2-C=O), 2.42 2.38 (m, 2H. CH2C=O). (* refer to the rotameric peak). 13C NMR (126 MHz,129.04, 125.21, 116.13, 114.59, 113.52, 65.50, 30.81, 25.55.

[0208] Synthesis of N'-(2,4-dimethoxybenzylidene)-2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetohydrazide (TR-G022)

[0210] Starting from 6-hydroxy-3,4-dihydroquinolin-2(1H)-one, TR-G022 wasprepared through 3 steps following procedures A, C and D respectively.200 mg of TR-G019 (0.8 mmol) was refluxed with 0.16 ml of 2,4-dimethoxybenzaldehyde (1 mmol) in ethanol and drops of acetic acid. After filtration obtained pure white powder TR-G022 product. LCMS / MS: m / z 383.97 [M+H]+

[0211] 1H NMR (500 MHz, DMSO- -NH-N=), 9.95(*9.91, s, 1H. C-NH-C), 8.58 (*8.25, s, 1H. N=CH-) 7.77-6.59 (m, 6Harom), 5.02 (s, 1H. O-CH2-C=O), 4.55 (s, 1H. O-CH2-C=O), 3.85 (s, 3H. O-CH3), 3.81 (s, 3H. O- CH3), 2.86-2.81 (m, 2H. CH2CH2-C=O), 2.43 2.38 (m, 2H. CH2C=O). (* refer tothe rotameric peak). 13153.93, 143.91 (-N=CH-), 139.95, 132.41, 127.16, 125.20, 116.13, 114.56, 113.51, 106.91, 98.56, 65.54, 56.23 (-O-CH3), 55.90 (-O-CH3), 30.81, 25.55.63

[0212] Synthesis of 2-oxo-1,2,3,4-tetrahydroquinolin-6-yl 2-(4-(pyrimidin-2-yl)piperazin-1-yl)acetate (TR-G023)

[0213]

[0214] Compound TR-G023 was synthesized according to procedure B and Arespectively. In the first step, compound TR-G016 was synthesized according to -(piperazin-1- yl)pyrimidine was (1.52 mmol, d=1.15 g / ml) was stirred with TEA (2.28 mmol, 0.330 ml, d=0.7 g / ml) for 1 h in THF, then 544 mg of TR-G016 (2.28 mmol) was added to the reaction mixture and stirred for 10h in THF. The reaction controlled by TLC and when it finished the solvent was evaporated and the product was washed with cold water filtered, dried and purified by column chromatography (Hexane:EtOAc:MeOH) (49:50:1), 291 mg of TR-G023 (86.16%) was obtained as light-yellow crystals. LCMS / MS: m / z 368.21 [M+H]+

[0215] 1H NMR (500 MHz, DMSO- -H), 8.40-8.39 (m,2Harom), 6.82 -6.66 (m, 4Harom) 4.79 (s, 2H. CH2).3.80 -3.55 (m, 8H. CH2 Piperazine), 2.83 (t, J = 5 Hz, 2H.CH2CH2-C=O), 2.40 (t, J=5 Hz, 2H. CH2C=O).13-C=O), 166.68, 161.54, 158.46, 153.63, 132.59, 125.21, 116.14, 114.69, 113.63, 110.95, 66.86, 44.40 (2C), 43.84, 43.51, 41.47, 30.80, 25.56.

[0216] Synthesis 2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)-N'-(thiophen-2-ylmethylene)acetohydrazide (TR-G024)

[0217]

[0218] 161 mg of TR-G019 (0.684 mmol) was heated with 134.45 mg ofthiophene-2-carbaldehyde (0.821 mmol) in ethanol under reflux with presents of AcOH (3 drops). The desire molecule was precipitated, when the reaction finish (controlled by TLC) the solvent was evaporated and obtained compound was washed64 by ethanol to obtain 200 mg of TR-G024 (88.7%) as white powder. LCMS / MS: m / z 329.97 [M+H]+

[0219] 1H NMR (500 MHz, Chloroform- -NH-N=), 9.95(*9.92, s, 1H. C-NH-C), 8.55 (*8.18, s, 1H. N=CH-) 7.67-6.70 (m, 6Harom), 4.97 (s, 1H. O-CH2-C=O), 4.57 (s, 1H. O-CH2-C=O), 2.85-2.80 (m, 2H), 2.42 2.38 (m, 2H).(* refer to the rotameric peak). 1152.88, 143.06, 138.90, 132.48, 131.15, 129.10, 127.88, 124.87, 115.75, 114.39, 113.33, 66.98, 30.30, 25.10.

[0220] Synthesis (E)-N'-(furan-2-ylmethylene)-2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetohydrazide (TR-G025)

[0222] Starting from 6-hydroxy-3,4-dihydroquinolin-2(1H)-one, TR-G025 wasprepared through 3 steps following procedures A, C and D respectively.210 mg of TR-G019 (0.892 mmol) was refluxed with 0.89 ml of furan-2-carbaldehyde (1.07 mmol, d=1.16 g / ml) in ethanol and drops of acetic acid. After filtration obtained pure white powder TR-G025 product. LCMS / MS: m / z 314.04 [M+H]+

[0223] 1H NMR (500 MHz, DMSO- -NH-N=), 9.95(*9.91, s, 1H. C-NH-C), 8.24 (*7.88, s, 1H. N=CH-) 7.84-6.62 (m, 6Harom), 4.98 (s, 1H. O-CH2-C=O), 4.58 (s, 1H. O-CH2-C=O), 2.85-2.82 (m, 2H. O=C-CH2-CH2-),2.42-2.38 (m, 2H. O=C-CH2-CH2-). (*refer to the rotameric peak). 13C NMR (126115.69, 113.79, 113.06, 112.16, 64.88, 30.35, 25.10.

[0224] Synthesis (E)-N'-(4-methoxybenzylidene)-2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetohydrazide (TR-G026)

[0225] 65

[0226] 190 mg of TR-G019 (0.807 mmol) was heated with 0.118 ml of 4-methoxybenzaldehyde (0.97 mmol, d=1.12 g / ml) in ethanol under reflux with presents of AcOH (3 drops). The desire molecule was precipitated. When the reaction finish (controlled by TLC). After workup, TR-G026 was obtain 217 mg (76%) as yellowish white powder. LCMS / MS: m / z 354.22 [M+H]+

[0227] 1H NMR (500 MHz, DMSO- -NH-N=), 9.96(*9.92, s, 1H. C-NH-C), 8.28 (*7.95, s, 1H. N=CH-) 7.65-6.72 (m, 7Harom), 5.05 (s, 1H. O-CH2-C=O), 4.58 (s, 1H. O-CH2-C=O), 3.80 (s, 3H. -O-CH3) 2.86-2.81 (m, 2H. O=C-CH2-CH2-), 2.43-2.38 (m, 2H. O=C-CH2-CH2-). (* refer to the rotamericpeak). 13 -NH=N-), 160.69,153.46, 143.61 (N=CH-), 131.98, 128.51, 126.57, 124.76, 115.69, 114.34, 114.28, 114.11, 113.30, 113.05, 65.04 (O-CH2-C=O), 55.31 (-CH3), 30.36, 25.10.

[0228] Synthesis of (E)-N'-((2-methyl-1H-indol-3-yl)methylene)-2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetohydrazide (TR-G027)

[0230] Starting from 2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetohydrazide (TR-G019) was prepared through 3 steps following procedures A, C and D respectively.200 mg of TR-G019 (0.8 mmol) was refluxed with 162.41mg of 2-Methylindole-3-carboxaldehyde (1 mmol) in ethanol and drops of acetic acid. After workup and recrystallization by EtOH obtained 110 mg (34.5%) of TR-G027 as white powder. LCMS / MS: m / z 377.12 [M+H]+

[0231] 1H NMR (500 MHz, DMSO- -H), 12.45 (O=C-NH-N),11.25 (s, 1H. N=CH-), 9.97 (s, 1H. C-NH-), 7.58-6.81 (m, 7 Harom), 4.78 (s, 2H O- CH2-), 2.91-2.78 (m, 2H. O=C-CH2-CH2-), 2.50 (s, 3H. CH3), 2.41 (t, J = 6.9 Hz,2H. O=C-CH2-). 13 -NH-N=),152.19, 142.67, 135.57, 131.99, 132.95, 125.06, 122.70, 121.07, 119.71, 115.84 (2C), 114.48, 113.47, 111.22 (2C), 67.45 (O-CH2-C=O), 30.26, 25.21, 25.06 (-CH3).

[0232] Synthesis of (E)-2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)-N'-(4-propylbenzylidene)acetohydrazide (TR-G028)66

[0234] Starting from 6-hydroxy-3,4-dihydroquinolin-2(1H)-one, TR-G028 wasprepared through 3 steps following procedures A, C and D respectively.210 mg of TR-G019 (0.893 mmol) was refluxed with 0.158 ml of 4-propylbenzaldehyde (1.07mmol, d=1.005 g / ml) in ethanol and drops of acetic acid. After filtration obtainedpure white powder TR-G028 product (285 mg, 87.3%). LCMS / MS: m / z 366.20 [M+H]+

[0235] 1H NMR (500 MHz, DMSO- -NH-N=), 9.96(*9.92, s, 1H. C-NH-C), 8.31 (*7.97, s, 1H. N=CH-) 7.61-6.73 (m, 7Harom), 5.05 (s, 1H. O-CH2-C=O), 4.58 (s, 1H. O-CH2-C=O), 2.85-2.81 (m, 2H. O=C-CH2-), 2.57 (t, J = 7.5 Hz, 2H. O=C-CH2-CH2-), 2.43 2.36 (m, 2H. =C-CH2-CH2), 1.62-1.56 (m, 2H. CH2-CH3), 0.88 (t, J = 8.6 Hz, 3H. CH3). (* refer to the rotameric peak).128.80, 127.12, 126.90, 124.75, 115.68, 114.12, 113.05, 65.05, 37.10, 30.36, 25.09,23.92, 13.59.

[0236] Synthesis of (E)-N'-(cyclohexylmethylene)-2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetohydrazide (TR-G029)

[0237]

[0238] Starting from 6-hydroxy-3,4-dihydroquinolin-2(1H)-one, compound 2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetohydrazide (TR-G019) was prepared through couple of steps following procedures A and C respectively. After that following procedure D,180 mg of TR-G019 (0.765 mmol) was allowed to stir under refluxed with 0.112 ml of cyclohexanecarbaldehyde (0.918 mmol) in ethanol and 3 drops of acetic acid. After workup by extracting with DCM and water obtained 200 mg (79.3%) of TR-G029 as white powder. LCMS / MS: m / z 329.99 [M+H]+

[0239] 1H NMR (500 MHz, DMSO- -NH-N=), 9.94(*9.90, s, 1H. C-NH-C), 7.52 (*7.21, s, 1H. N=CH-) 6.82-6.65 (m, 3Harom), 4.86 (s,67 1H. O-CH2-C=O), 4.47 (s, 1H. O-CH2-C=O), 2.84-2.80 (m, 2H. O=C-CH2-), 2.41-2.37 (m, 2H. O=C-CH2-CH2-), 2.21 2.15 (m, 1H. =CH-CH<), 1.76-1.60 (m,5HCycloHexane), 1.31-1.13 (m, 5HCycloHexane). (* refer to the rotameric peak). 1124.73, 115.66, 114.04, 112.99, 64.89, 30.34, 30.29, 29.60, 29.53, 25.50, 25.08, 24.96, 24.95.

[0240] Synthesis of 6-((4-(tert-butyl)benzyl)oxy)-3,4-dihydroquinolin-2(1H)-one(TR-G030)

[0242] Following procedure A, 250 mg of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.5 mmol) was stirred with 317.61 mg of the base K2CO3 (2.3 mmol) for 1 h. in . in THF and drops of DMF, then 0.16 ml of 1-(tert-butyl)-4-(chloromethyl)benzene (1.99 mmol) was added slowly to the reaction at room temperature. The reaction wasscreened by TLC and after workup by ice water the final product was filtered andobtained 380 mg (80%) of TR-G030 as white powder. LCMS / MS: m / z 310.33 [M+H]+

[0243] 1H NMR (500 MHz, DMSO- -H), 7.40-6.76 (m, 7Harom), 4.98 (s, 2H. O-CH2-), 2.82 (t, J = 7.5 Hz, 2H. O=C-CH2-), 2.39 (m, 2H.O=C-CH2-CH2-), 1.27 (s, 9H. CH3). 13150.19, 134.27, 131.88, 127.52 (2C), 125.13 (2C), 124.86, 115.73, 114.34, 113.18, 69.22, 34.28, 31.14 (3C), 30.35, 25.11.

[0244] Synthesis of 6-((6-((tetrahydro-2H-pyran-2-yl)oxy)hexyl)oxy)-3,4-dihydroquinolin-2(1H)-one (TR-G031)

[0246] Following procedure A, 250 mg of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.5 mmol) was stirred with 317.61 mg of the base K2CO3 (2.3 mmol) for 1 h. in68 THF and drops of DMF, then 394 µL of 2-(6-chlorohexyloxy)tetrahydro-2H-pyran (1.84 mmol) was added slowly to the reaction at room temperature. The reaction was screened by TLC and after workup by ice water the final product was filtered and obtained 320 mg (60%) of TR-G031. LCMS / MS: m / z 348.22 [M+H]+

[0247] 1H NMR (500 MHz, DMSO- N-H), 6.75-6.68 (m,3Harom), 4.52 (t, J = 3.4 Hz, 1H. CHpyran) 3.87 (t, 2H. J = 5 Hz O-CH2).3.74 -3.70 (m, 2H. O-CH2pyran), 3.40 (t, 2H. J = 5 Hz CH2-O), 2.81 (t, J = 5 Hz, 2H. CH2CH2- C=O), 2.38 (t, J = 5 Hz, 2H. CH2C=O), 1.73-1.56 (m, 6H. CH2pyran), 1.45 -1.36 (m,8H. -CH2 Alphatic). 1C NMR (126 MHz, DMSO) 170.16 (NH-C=O), 154.31, 132.08,125.24, 116.19, 114.40, 113.34, 98.37, 68.03, 67.00, 61.71, 30.84, 30.80, 29.66, (29.20 2C), 26.01, 25.85, 25.57, 25.54.

[0248] Synthesis of Ethyl 2-(4-(((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)acetate (TR-G033)

[0250] Compound TR-G033 has been prepared according to procedure A and E.In the first step, ethyl 2-azidoacetate was prepared starting from 500 µL of ethyl bromoacetate (4.94 mmol) which were refluxed with 641 mg of sodium azide salt (9.87 mmol) for 2 hours in ethanol / water (2:1). After that, the mixture was cooled to room temperature and filtered. Secondly, 6-(prop-2-yn-1-yloxy)-3,4- dihydroquinolin-2(1H)-one TR-G006 was prepared according to procedure A as mentioned before. In the last step, a mixture of -(prop-2-yn-1-yloxy)-3,4- dihydroquinolin-2(1H)-one TR-G006 (250 mg, 1.24 mmol), 29.74 mg of copper sulfate (0.186 mmol) and 12 mg of sodium ascorbate (0.062 mmol) in EtOH was added to the ethyl 2-azidoacetate solution and stirred for 8 h. After that, the ethanol was evaporated. The residue was dissolved in water and the mixture was extractedwith DCM (3 × 50 ml), dried over anhydrous magnesium sulfate MgSO4 and thesolvent was evaporated under vacuum. Finally, the product was purified using flash chromatography (Hexane:EtOAc:TEA) (40:60:1%) to obtain 230 mg (52%) of compound TR-G033 as crystals. LCMS / MS: m / z 331.42 [M+H]+69

[0251] 1H NMR (500 MHz, DMSO- -H), 8.20 (s, 1HTraizole),6.90-6.76 (m, 3Harom), 5.40 (S, 2H), 5.10 (S, 2H), 4.18 (q, J = 7.1 Hz, 2H CH2-CH3), 2.83 (t, J = 7.5 Hz, 2H. CH2CH2-C=O) 2.40 (m, 2H. CH2-C=O) 1.22 (t, J = 7.1 Hz,3H. CH3). 13 -C=O), 167.69 (C=O), 153.62(Ctraizole), 143.35, 132.54, 126.34, 125.33, 116.19, 114.84, 113.72, 61.97, 61.74, 50.84, 30.79, 25.57, 14.44.

[0252] Synthesis of (E)-N'-benzylidene-2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetohydrazide (TR-G035)

[0253]

[0254] Starting from 6-hydroxy-3,4-dihydroquinolin-2(1H)-one, compound 2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetohydrazide (TR-G019) was prepared through couple of steps following procedures A and C respectively. After that following procedure D, 200 mg of TR-G019 (0.850 mmol) was refluxed with 95 µL of benzaldehyde (0.935 mmol) were refluxed in ethanol and drops of acetic acid for 6 h. After completing the reaction, the precipitate was filtered out of the hot ethanol,washed with hot ethanol and dried to obtain 220 mg (80%) of the final product aswhite powder. LCMS / MS: m / z 324.11 [M+H]+

[0255] 1H NMR (500 MHz, DMSO- -NH-N=), 9.96(*9.92, s, 1H. C-NH-C), 8.34 (*8.01, s, 1H. N=CH-) 7.70-6.74 (m, 8Harom), 5.07 (s, 1H. O-CH2-C=O), 4.60 (s, 1H. O-CH2-C=O), 2.86-2.81 (m, 2H. O=C-CH2-CH2-),2.43-2.38 (m, 2H. O=C-CH2-CH2-). (* refer to the rotameric peak).NMR (126-NH=N-), 153.88, 148.39, 144.21 (N=CH-), 134.41, 132.44, 130.41, 129.30, 127.37 (2C), 125.23, 116.15, 114.59, 113.51, 65.51, 30.80, 25.54.

[0256] Synthesis of 2-oxo-1,2,3,4-tetrahydroquinolin-6-yl 2-fluoro-5-(trifluoromethyl)benzoate (TR-G036)

[0257] 70

[0258] Following procedure B, 200 mg of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.23 mmol) was stirred with 254 mg of the base K2CO3 (1.84 mmol) for 30 min in THF and drops of DMF, then 222 µL of 2-fluoro-5-(trifluoromethyl)benzoyl chloride (1.47 mmol) was slowly added to the reaction mixture and stirred for 16 h. After completing the reaction, the solvent was evaporated and the residue washed with distilled water, filtered and air-dried and then recrystallized in ethanol to obtain370 mg of the product. LCMS / MS: m / z 354.21 [M+H]+

[0259] Synthesis of 2-oxo-1,2,3,4-tetrahydroquinolin-6-ylethyl(methyl)carbamate (TR-G037)

[0261] Following procedure B, 200 mg of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.23 mmol) was stirred with 254 mg of the base K2CO3 (1.84 mmol) for 30 min in THF and drops of DMF, then 163 µL of ethyl(methyl)carbamic chloride (1.47 mmol) was slowly added to the reaction mixture and stirred for 12 h. After completing the reaction, the solvent was evaporated and the residue washed with distilled water, filtered and air-dried and then recrystallized in ethanol to obtain 210 mg (69%) of the product as crystals. LCMS / MS: m / z 249.23 [M+H]+

[0262] Synthesis of (Z)-2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)-N'-(2-oxoindolin-3-ylidene)acetohydrazide (TR-G038)

[0263]

[0264] Starting from hydroxy-3,4-dihydroquinolin-2(1H)-one, TR-G038 wasprepared through three steps following procedure A,C and D. In the first and second steps compounds TR-G012 and TR-G019 were obtained as previously mentioned. In the third step, 250 mg of 2-((2-oxo-1,2,3,4-tetrahydroquinolin-6- yl)oxy)acetohydrazide TR-G019 (1.06 mmol) was refluxed with 156 mg of isatin (1.06 mmol) in ethanol and 3 drops of acetic acid for 5 hours. After completing the71 reaction, the product was filtered out the hot ethanol to obtain 335 mg of the final product as yellow powder with a yield of 86%. LCMS / MS: m / z 363.34 [M-H]-

[0265] 1H- -NH-), 11.25 (s, 1H .C=N-NH-), 9.97 (s, 1H .N=N=CH-), 7.58-6.81 (m, 6Harom.), 4.78 (s, 2H. O-CH2-), 2.89- 2.84 (m, 2H. O=C-CH2-), 2.41 (t, J = 3 Hz, 2H. O=CH2-CH2-).13C-NMR (126 MHz, 119.71, 115.84 (2C), 114.48, 113.47, 111.22 (2C), 67.45, 30.26, 25.06

[0266] Synthesis of 2-oxo-1,2,3,4-tetrahydroquinolin-6-yl acrylate (TR-G039)

[0267]

[0268] Following procedure B, 200 mg of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.23 mmol) was stirred with 265 µL of the base TEA (1.84 mmol) for 30 min DMF, then 119 µL of acroyl chloride (1.47 mmol) was slowly added to the reaction mixture and stirred for 6 h. After completing the reaction, and the final product was obtained by extraction in DCM / water system (25ml x3), dried over anhydrous magnesium sulfate MgSO4 and the solvent was evaporated under vacuum. Finally, the product was purified using flash chromatography (Hexane:EtOAc:TEA) (40:60:1%) to obtain 201 mg (75%) of compound TR-G039 as light white powder. LCMS / MS: m / z 218.21 [M+H]+

[0269] 1H NMR (500 MHz, DMSO- N-H), 7.01-6.86 (m,3Harom), 6.53 -6.41 (m, 2H. CH2=C) 6.39-6.11 (m, 1H. CH=CH2), 2.87 (t, J = 5 Hz,2H. CH2CH2-C=O), 2.45 (t, J = 5 Hz, 2H. CH2C=O). 13C NMR (126 MHz, DMSO)170.50 (NH-C=O), 164.89, 145.14, 136.62, 133.87, 128.17, 125.20, 121.46, 120.61, 115.95, 30.50, 25.13.

[0270] Synthesis of N-acryloyl-N'-(2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetyl)acrylohydrazide (TR-G040)

[0271] 72

[0272] TR-G040 have synthesized according to procedure A and B. In the firstand second steps compounds TR-G012 and TR-G019 have been synthesized respectively. After that, 200 mg of TR-G019 (0.85 mmol) was stirred with 368 µL ofthe base TEA in DMF for 15 min then 171 µL of acroyl chloride (2.55 mmol) wasslowly added to the reaction mixture and stirred for 6 h. After completing the reaction, and the final product was obtained by extraction in DCM / water system (25ml X 3), dried over anhydrous magnesium sulfate MgSO4 and the solvent wasevaporated under vacuum. Finally, the product was purified using flashchromatography (Hexane:EtOAc:TEA) (40:60:1%) to obtain 198 mg (67%) of compound TR-G040 as white powder. LCMS / MS: m / z 342.21 [M+H]+

[0273] Synthesis of 6-((4-methylbenzyl)oxy)-3,4-dihydroquinolin-2(1H)-one(TR-G041)

[0274]

[0275] Following procedure A, 250 mg of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.5 mmol) was stirred with 600 mg of the base Cs2CO3 (1.84 mmol) for 2 h. in THF and drops of DMF, then 295 mg of 1-(bromomethyl)-4-methylbenzene (1.59 mmol) was added slowly to the reaction at room temperature. The reaction was tested until finished by TLC and after workup and column chromatography (Hexan:EtOAc) (60:40), the final product was filtered and obtained 209 mg (64%) of TR-G041 as milky white crystals. LCMS / MS: m / z 268.44 [M+H]+

[0276] 1H NMR (500 MHz, DMSO- -H), 7.31-6.74 (m, 7Harom), 4.97 (s, 2H O-CH2-), 2.81 (t, J = 7.5 Hz, 2H. O=C-CH2-CH2-), 2.39 (m, 2H.O=C-CH2-), 2.29 (s, 3H. - CH3). 13153.53, 136.95, 134.23, 131.89, 128.94 (2C), 127.71 (2C), 124.83, 115.72, 114.40, 113.28, 69.35, 30.35, 25.11, 20.78.

[0277] Synthesis of 2-oxo-1,2,3,4-tetrahydroquinolin-6-yl 2,3-dichlorobenzenesulfonate (TR-G042)73

[0279] Following procedure A, 250 mg of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.5 mmol) was stirred with 317.6 mg of the base K2CO3(2.3 mmol) for 30 min in THF and drops of DMF, then 2,3-dichlorobenzenesulfonyl chloride (1.5 mmol) was added slowly to the reaction at room temperature. The product precipitated in ice water the final product filtered and recrystallized by EtOH and obtained 483.00 mg (84.7%) of TR-G042 as white powder. LCMS / MS: m / z 373.11 [M+H]+

[0280] 1H NMR (500 MHz, DMSO- N-H), 8.11-7.57 (m,3Harom), 7.03-6.78 (m, 3Harom), 2.84 (t, J = 7.6 Hz, 2H. O=C-CH2-CH2-), 2.41 (m, 2H. O=C-CH2-).13-O-S), 137.81, 136.82, 135.07, 134.49, 131.09, 130.02, 129.03, 125.50, 121.30, 120.22, 115.92, 29.73, 24.49.

[0281] Synthesis of N-(4-(4-methylpiperazin-1-yl)phenyl)-2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetamide (TR-G043)

[0282]

[0283] Following procedure B, the intermediate 2-chloro- N-(4-(4-methylpiperazin-1-yl)phenylacetamide was prepared by dissolving 300 mg of 4-(4- methylpiperazin-1-yl )aniline (1.57 mmol) with 340 µLTEA (2.35 mmol) in THF, then152µL of chloroacetyl chloride (1.88 mmol) was added, drop wisely to the reactionmixture in ice bath (0-5 °C). After completing the reaction, the solvent was evaporated under vacuum, and the residue was washed with distilled water, filtered, and dried. The second step was according to procedure A, 200 mg of 6-hydroxy-3,4- dihydroquinolin-2(1H)-one (1.23 mmol) was stirred with 254 mg of the base K2CO3(1.84 mmol) for 15 min in DMF after that 328 mg of 2-chloro- N-(4-(4-methylpiperazin-1-yl)phenylacetamide (1.23 mmol) was added to the reaction mixture and stirred for 24h. After that, the product was precipitated in ice water and74 brine, filtered and air-dried. The product was recrystallized in ethanol to obtain 385 mg (79%) as brown powder. LCMS / MS: m / z 395.41 [M+H]+

[0284] Synthesis of 2-oxo-1,2,3,4-tetrahydroquinolin-6-yl naphthalene-1-sulfonate (TR-G045)

[0285]

[0286] Following procedure H, In round bottom flask, 250 mg of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.53 mmol) was stirred with 317.6 mg of the base K2CO3 (2.3 mmol) for 1 hours min in THF and drops of DMF, then 416.74 mg of 1- naphthalenesulfonyl chloride (1.84 mmol) was added to the reaction at room temperature. The product was precipitated in iced water, washed with distilled water, filtered, dried under vacuum, and then recrystallized by EtOH to obtain 462.00 mg (85%) of TR-G045 as off-white powder. LCMS / MS: m / z 354.21 [M+H]+

[0287] 1H NMR (500 MHz, DMSO- -H), 10.14 (s, 1H), 8.667.63 (m, 7Harom. (Naph).), 6.85 6.50 (m, 3Harom), 2.75 (t, J = 7.6 Hz, 2H. O=C-CH2-CH2-), 2.37 2.34 (m, 2H. O=C-CH2-). 13(>C=O), 143.29 (C-O-S), 137.51, 136.31, 133.76, 131.32, 129.80, 129.44, 129.32, 127.65, 127.59, 125.21, 124.61, 124.15, 121.30, 120.10, 115.69, 29.74, 24.52.

[0288] Synthesis of 2-oxo-1,2,3,4-tetrahydroquinolin-6-yl 4-nitrobenzenesulfonate (TR-G046)

[0290] Following procedure H, 250 mg of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.5 mmol) was stirred with 317.6 mg of the base K2CO3 (2.3 mmol) for 30 min in THF and drops of DMF, then 332.43 mg of 4-nitrobenzenesulfonyl chloride (1.5 mmol) was added to the reaction at room temperature. The product was precipitated in iced water, washed with distilled water, filtered, dried under vacuum and then recrystallized by EtOH to obtain 462.00 mg (87%) of the product TR-G046 as white powder. LCMS / MS: m / z 348.95 [M+H]+75

[0291] 1H NMR (500 MHz, DMSO-d6 -H), 8.46-8.12 (m, 4Harom.O2N-Ph-SO3), 7.02-6.73 (m, 3Harom.), 2.83 (t, J = 7.6 Hz, 2H. O=C-CH2-), 2.41 (m,2H. O=C-CH2-CH2-).13-NO2), 143.03 (C-O-S), 139.58 (C-SO3), 137.80, 130.01(2C.), 125.45, 125.00 (2C.), 121.58, 120.58, 115.80, 29.74, 24.48.

[0292] Synthesis of (Z)-N'-(5-fluoro-1-methyl-2-oxoindolin-3-ylidene)-2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetohydrazide (TR-G047)

[0293]

[0294] Starting from 6-hydroxy-3,4-dihydroquinolin-2(1H)-one, compound 2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetohydrazide (TR-G019) was prepared through couple of steps following procedures A and C respectively. Later, 5-fluoro-1- methyl-2-indolin-2,3-dione was prepared according to procedure A by reacting 5- fluoruisatin with methyl iodide under basic condition of K2CO3 at room temperature. After that following procedure D, 200 mg of TR-G019 (0.850 mmol) was refluxed with 152 mg of 5-fluoro-1-methyl-2-indolin-2,3-dione (0.850 mmol) were refluxed in ethanol and drops of acetic acid for 10 h. After completing the reaction, the precipitate was filtered out of the hot ethanol, washed with hot ethanol, and dried to obtain 275 mg (81%) of the final product as white powder. LCMS / MS: m / z 397.12 [M+H]+

[0295] 1H-NMR (500 MHz, DMSO- -NH-), 11.35 (s, 1H.C=N-NH-), 7.51-6.78 (m, 6Harom.), 4.80 (s, 2H. O-CH2-), 3.38 (s, 3H. -CH3), 2.89-2.86 (m, 2H. O=C-CH2-), 2.48 (t, J = 3 Hz, 2H. O=CH2-CH2-). 13C-NMR (126 MHz,116.28, 114.88, 113.89, 112.81, 112.74, 108.72, 108.50, 56.49, 30.72, 27.48, 25.51.

[0296] Synthesis of 2-oxo-1,2,3,4-tetrahydroquinolin-6-yl 4-bromobenzenesulfonate (TR-G048)

[0297] 76

[0298] Following procedure H, 250 mg of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.5 mmol) was stirred with 317.6 mg of the base K2CO3 (2.3 mmol) for 30 min in THF and drops of DMF, then 391 mg of 4-bromobenzenesulfonyl chloride (1.5 mmol) was added to the reaction at room temperature and stirred for 18h. The product was precipitated in iced water, washed with distilled water, filtered, dried under vacuum, and then recrystallized by EtOH to obtain 470 mg (80%) of theproduct TR-G048 as crystals. LCMS / MS: m / z 383.8 [M+H]+

[0299] 1H NMR (500 MHz, DMSO-d6 N-H), 8.04-6.76 (m,7Harom), 2.82 (t, J = 5 Hz, 2H. CH2CH2-C=O) 2.41 (NMR (126 MHz, DMSO) 170.45 (NH-C=O), 143.55, 138.32, 138.13, 136.68, 132.38, 130.76, 127.80, 125.76, 122.98, 122.06, 121.09, 116.20, 30.25, 25.00.

[0300] Synthesis of 2-(3-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)propyl)isoindoline-1,3-dione (TR-G049)

[0301]

[0302] Following procedure A, 250 mg of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.5 mmol) was stirred with 317.6 mg of the base K2CO3 (2.3 mmol) for 30 min in THF and drops of DMF, then 402 mg of N-(3-bromopropyl) phthalimide (1.5mmol) was added to the reaction at room temperature. After that, the product wasprecipitated in ice water, filtered, and dried. Then purified using flash chromatography (Hexane:EtOAc:TEA) (40:60:1%) to obtain 430 mg (81%) as light- yellow powder. LCMS / MS: m / z 350.2 [M+H]+

[0303] 1H NMR (500 MHz, DMSO-d6 -H), 7.88-7.80 (m, 4HArom.Isoindoline), 6.71-6.56 (m, 3Harom.), 3.94 (t, J = 5.8 Hz, 2H. -CH2-O-), 3.74 (t, J = 6.7 Hz,2H. -CH2-N-), 2.76 (t, J = 7.5 Hz, 2H. O=C-CH2-), 2.37 (m, 2H. O=C-CH2-CH2-), 2.02(m, 2H. -O-CH2-CH2-).13(2C), 134.26 (2C), 131.76 (2C), 124.71, 122.99 (2C), 115.65, 113.99, 112.78, 65.79, 35.14, 30.32, 27.57, 25.08.

[0304] Synthesis of (Z)-N'-(5-fluoro-2-oxoindolin-3-ylidene)-2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetohydrazide (TR-G050)77

[0305]

[0306] Starting from hydroxy-3,4-dihydroquinolin-2(1H)-one, TR-G050 wasprepared through three steps following procedure A, C and D. In the first and second steps compounds TR-G012 and TR-G019 were obtained as previously mentioned. In the third step, 250 mg of 2-((2-oxo-1,2,3,4-tetrahydroquinolin-6- yl)oxy)acetohydrazide TR-G019 (1.06 mmol) was refluxed with 175 mg of 5- flouroisatin (1.06 mmol) in ethanol and 3 drops of acetic acid for 9hours. After completing the reaction, the product was filtered out the hot ethanol to obtain 321 mg of the final product as yellow powder with a yield of 79%. LCMS / MS: m / z 381.10 [M- H]-

[0307] 1H-NMR (500 MHz, DMSO- -NH-), 11.28 (s, 1H.C=N-NH-), 9.97 (s, 1H .N=N=CH-), 7.40-6.81 (m, 6Harom.), 4.80 (s, 2H. O-CH2-),2.87-2.84 (m, 2H. O=C-CH2-), 2.41 (t, J = 3 Hz, 2H. O=CH2-CH2-). 13C-NMR (126116.28, 114.88, 113.89, 112.81, 112.74, 108.72, 108.50, 56.49, 30.72, 25.51.

[0308] Synthesis of 6-((3-(4-fluorophenyl)-4,5-dihydroisoxazol-5-yl)methoxy)-3,4-dihydroquinolin-2(1H)-one (TR-G051)

[0310] Compound TR-G051 has been prepared according to procedure A and F.Firstly, TR-G014 was prepared according to procedure A as previously mentioned. After that, a solution of 700 mg of 4-fluorobenzaldehyde (5.64 mmol), 784 mg of hydroxylamine hydrochloride (11.28 mmol) and 948 mg of NaHCO3 in ethanol were refluxed for 3h to prepare the corresponding oxime. The reaction was monitored by TLC until completing reaction. After that, the product was filtered, washed and dried. In cyclization step, 250 mg of TR-G014 (1.23 mmol) and 205 mg of 4-78 flourobenzaldehyde oxime (1.48 mmol) were dissolved in chloroform then catalytic amount of calcium hypochlorite was added to the mixture in ice bath 0 °C for 8 h, then water was added,and the product was extracted with chloroform (3x 30 mL). Organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under vacuum. The crude was purified using flash chromatography (Hexane:EtOAc) (60:40) to afford 210 mg (50%) of the final product. LCMS / MS: m / z 341.43 [M+H]+.

[0311] 1H NMR (500 MHz, DMSO-d6 -H), 7.60-6.88 (m, 7Harom),5.18-5.12 (qui,H oxazol), 4,17 -4.07 (m, 2H .CH2), 3,55 -3.22 (m, 2H .CH2oxazol), 2.91- 2.89 (t, 2H. J = 5Hz .CH2CH2-C=O) 2.47-2.445 (m, 2H. J = 5Hz .CH2C=O).13C NMR -C=O), 161.54, 159.32, 153.98, 151.14, 133.78, 132.86, 129.34, 128.44, 126.46, 119.81, 118.08, 115.62, 114.22, 113.67, 79.33, 69.78, 30.84, 26.09.

[0312]

[0313] Synthesis of 6-((1-isopentyl-1H-1,2,3-triazol-4-yl)methoxy)-3,4-dihydroquinolin-2(1H)-one (TR-G052)

[0314]

[0316] Compound TR-G052 has been prepared according to procedure A and E.In the first step, 1-azido-3-methylbutne was prepared starting from 500 µL of 1- bromo-3-methylbutane (4.17 mmol) which were refluxed with 542 mg of sodium azide salt (8.34 mmol) for 2 hours in ethanol / water (2:1). After that, the mixture was cooled to room temperature and filtered. Secondly, 6-(prop-2-yn-1-yloxy)-3,4- dihydroquinolin-2(1H)-one TR-G006 was prepared according to procedure A as mentioned before. In the last step, a mixture of -(prop-2-yn-1-yloxy)-3,4- dihydroquinolin-2(1H)-one TR-G006 (250 mg, 1.24 mmol), 29.74 mg of copper sulfate (0.186 mmol) and 12 mg of sodium ascorbate (0.062 mmol) in EtOH was added to the 1-azido-3-methylbutne solution and stirred for 12 h. After that, the79 ethanol was evaporated. Residue was dissolved in water and the mixture wasextracted with DCM (3 × 50 ml), dried over anhydrous magnesium sulfate MgSO4 andthe solvent was evaporated under vacuum. Finally, the product was purified using flash chromatography (Hexane:EtOAc:TEA) (40:60:1%) to obtain 218 mg (52%) of compound TR-G052 as crystals. LCMS / MS: m / z 315.61 [M+H]+

[0317] 1H NMR (500 MHz, DMSO-d6 -H), 8.21 (s, 1HTraizole),6.88-6.76 (m, 3Harom), 5.05 (S, 2H), 4.37(t, J = 5 Hz. 2H. N-CH2), 2.82 (t, J = 5 Hz,2H. CH2CH2-C=O) 2.40 (t, 2H. J = 5 Hz. CH2-C=O) 1.73-1.69 (m, 2H. -CH2-), 1.48-1.42 (m, 1H. >CH-), 0.90 (m, 3H. -CH3), 0.90 (-C=O), 153.64 (Ctraizole), 143.22, 132.51, 125.30, 124.71, 116.18, 114.85, 113.77, 61.93, 48.20, 38.97, 30.80, 25.56, 25.37, 22.49 (2C).

[0318] Synthesis of 6-((4-vinylbenzyl)oxy)-3,4-dihydroquinolin-2(1H)-one (TR-G053)

[0320] Following procedure A, 250 mg of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.53 mmol) was stirred with 749 mg Cs2CO3 (2.3 mmol) for 30 min in THF and drops of DMF, then 274 µL of 4-Vinylbenzyl chloride (1.84 mmol) was added slowly to the reaction at room temperature. After that, the product was precipitated in ice water, filtered and dried. Then purified using flash chromatography (Hexane:EtOAc:TEA) (40:60:1%) to obtain 360 mg (85%) as crystals. LCMS / MS: m / z 280.01 [M+H]+

[0321] 1H NMR (500 MHz, DMSO-d6 N-H), 7.50-7.37 (m, 4Harom.),6.87-6.76 (m, 3Harom), 6.75 6.69 (m, 1H. CH2=CH-), 5.85-5.82 (m, 1H. CH2=CH-), 5.27-5.25 (m, 1H. CH2=CH-), 5.02 (s, 2H. -O-CH2-), 2.82 (t, J = 7.5 Hz, 2H. O=C- CH2-CH2-), 2.42 2.36 (m, 2H. O=C-CH2-).13153.91, 137.42, 137.05, 136.76 (2C), 132.43, 128.32 (2C), 126.62 (2C), 125.32, 116.20, 114.89, 113.77, 69.64, 30.80, 25.57.80

[0322] Synthesis of N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetamide (TR-G054)

[0324] Following procedure B, the intermediate 2-chloro- N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenylacetamide was prepared by dissolving 400 mg of 3-(4-methyl-1H-imidazol-1-yl)aniline (1.66 mmol) with 360 µL TEA (2.49 mmol) in THF, then 160 µL of chloroacetyl chloride (1.99 mmol) was added, drop wisely to the reaction mixture in ice bath (0-5 °C). After completing the reaction, the solvent was evaporated under vacuum, and the residue was washed with distilled water, filtered and dried. The second step was according to procedure A, 200 mg of 6- hydroxy-3,4-dihydroquinolin-2(1H)-one (1.23 mmol) was stirred with 254 mg of thebase K2CO3 (1.48 mmol) for 15 min in DMF after that 389 mg of 2-chloro- N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenylacetamide (1.23 mmol) was added to the reaction mixture and stirred for 24h. After that, the product was precipitated in ice water and brine, filtered and air-dried. Then purified using flash chromatography (Hexane:EtOAc:TEA) (40:60:1%) to obtain 420 mg (77%) as white powder. LCMS / MS: m / z 445.04 [M+H]

[0325] 1H NMR (500 MHz, DMSO-d6 -H), 10.00 (s, 1H. N-H),8.24-8.12 (m, 3Harom), 7.71 (S, 1HImidazol), 7.46 (S, 1HImidazol), 6.91-6.81 (m, 3Harom), 4.76 (s, 2H), 2.84 (t, J = 7.6 Hz, 2H. O=C-CH2-CH2-), 2.41 (t, J = 7.6 Hz, 2H. CH2- C=O), 2.17 (153.34, 141.21, 139.34, 138.36, 135.41, 132.89, 131.47, 131.21, 125.34, 116.23, 114.91, 114.69, 114.60, 113.99, 113.66, 112.00, 67.78, 30.75, 25.52, 14.01.

[0326] Synthesis of (E)-N'-(4-nitrobenzylidene)-2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetohydrazide (TR-G055)81

[0327]

[0328] Starting from 6-hydroxy-3,4-dihydroquinolin-2(1H)-one, compound 2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetohydrazide (TR-G019) was prepared through couple of steps following procedures A and C respectively. After that following procedure D, 200 mg of TR-G019 (0.850 mmol) was refluxed with 151 mg of 4-nitrobenzaldehyde (0.850 mmol) were refluxed in ethanol and drops of acetic acid for 6 h. After completing the reaction, the precipitate was filtered out of the hot ethanol, washed with hot ethanol and dried to obtain 271 mg (86%) of the final product as white powder. LCMS / MS: m / z 367.21 [M-H]-

[0329] 1H NMR (500 MHz, DMSO-d6 -NH-N=), 9.97(*9.93, s, 1H. C-NH-C), 8.45 (*8.25, s, 1H. N=CH-) 8.30-8.25 (m, 2Harom), 7.98-6.77 (m, 5Harom), 5.12 (s, 1H. O-CH2-C=O), 4.65 (s, 1H. O-CH2-C=O), 2.85-2.82 (m, 2H. O=C-CH2-CH2-), 2.42-2.39 (m, 2H. O=C-CH2-CH2-). (* refer to the rotameric peak).13-NH=N-), 153.81, 148.17, 145.89, 141.80, 140.72, 132.51, 128.32 (2C), 124.43 (2C), 116.14, 114.61, 113.52, 65.52 (O-CH2-C=O), 30.80, 25.54.

[0330] Synthesis of (Z)-N'-(5-nitro-2-oxoindolin-3-ylidene)-2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetohydrazide (TR-G056)

[0331]

[0332] Starting from hydroxy-3,4-dihydroquinolin-2(1H)-one, TR-G056 wasprepared through three steps following procedure A, C and D. In the first and second steps compounds TR-G012 and TR-G019 were obtained as previously mentioned. In the third step, 250 mg of 2-((2-oxo-1,2,3,4-tetrahydroquinolin-6- yl)oxy)acetohydrazide TR-G019 (1.06 mmol) was refluxed with 204 mg of 5- nitroisatin (1.06 mmol) in ethanol and 3 drops of acetic acid for 9 hours. After completing the reaction, the product was filtered out the hot ethanol to obtain 38782 mg of the final product as yellow powder with a yield of 86%. LCMS / MS: m / z 408.26 [M-H]-

[0333] 1H-NMR (500 MHz, DMSO- -NH-), 11.30 (s, 1H.C=N-NH-), 10.02 (s, 1H. O=C-NHIndol), 7.43-6.84 (m, 6Harom.), 4.81 (s, 2H. O-CH2-), 2.88-2.86 (m, 2H. O=C-CH2-), 2.42 (t, J = 3 Hz, 2H. O=CH2-CH2-).13C-NMR (126 117.23, 117.88, 115.89, 114.81, 113.74, 109.72, 109.50, 57.49, 29.72, 26.51.

[0334] Synthesis of 2-oxo-1,2,3,4-tetrahydroquinolin-6-yl methanesulfonate(TR-G057)

[0336] Following procedure H, 250 mg of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.5 mmol) was stirred with 317.6 mg of the base K2CO3 (2.3 mmol) for 30 min in in THF and drops of DMF, then 145 µL of methanesulfonyl chloride (1.84 mmol) was added slowly to the reaction at room temperature. After completing the reaction, the final product was obtained by extraction in DCM / water system three times. The product was purified using flash chromatography (Hexane:EtOAc) (50:50) to obtain 320 mg (86%) of the product as white powder. LCMS / MS: m / z 242.21 [M+H]+

[0337] 1H NMR (500 MHz, DMSO-d6 -H), 7.21 6.88 (m,3Harom.), 3.34 (s, 3H. CH3), 2.90 (t, J = 7.6 Hz, 2H. O=C-CH2-), 2.46 (m, 2H. O=C-CH2-CH2-).13121.66, 120.96, 115.84, 37.15 (-CH3), 29.88, 24.64.

[0338] Synthesis of (3R,4R)-2-(acetoxymethyl)-5-(4-(((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)tetrahydrofuran-3,4-diyl diacetate (TR-G058)

[0339] 83

[0340] Starting from D-ribofuranose, tetraacetate the intermediate (3R,4R)-2-(acetoxymethyl)-5-azidotetrahydrofuran-3,4-diyl diacetate have been synthesized by reacting 700 mg of D-ribofuranose, tetraacetate (2.20 mmol), 506 mg oftrimethylsilyl azide (1.40 mmol) and 62 mg of boron trifluoride etherate (0.439mmol) in DCM for 1 hour at room temperature. After that. Water was added to the reaction mixture and the product was extracted in DCM / water system and the organic phase was dried over anhydrous magnesium sulfate (3x 30mL). In the next step, a mixture of -(prop-2-yn-1-yloxy)-3,4-dihydroquinolin-2(1H)-one TR-G006 (250 mg, 1.24 mmol), 29.74 mg of copper sulfate (0.186 mmol) and 12 mg of sodium ascorbate (0.062 mmol) in EtOH was added to 3R,4R)-2-(acetoxymethyl)-5- azidotetrahydrofuran-3,4-diyl diacetate solution and stirred for 12 h. After that, waterwas added, and the mixture was extracted with DCM (3 × 50 ml), the organic phasedried over anhydrous magnesium sulfate MgSO4 and the solvent was evaporated under vacuum to obtain (TR-G058) as liquid. LCMS / MS: m / z 503.51 [M+H]+.

[0341] 1H NMR (500 MHz, Chloroform-d 8.09 (s, 1H. N-H), 7.81 (s, 1HTriazol),6.83-6.68 (m, 3Harom.), 6.16 (d, J = 4 Hz, 1H), 5.86-5.81 (m, 1H), 5.61 (m, 1H), 5.18 (s,2H. -O-CH2-CTriazol), 4.50-4.47 (m, 1H. -O-CH2-CHTHF), 4.43-4.20 (m, 2H. -O-CH2-CTHF), 2.93 (t, J = 7.5 Hz, 2H), 2.62-2.59 (m, 2H), 2.127 (s, 3H. -CH3), 2.126 (s, 3H. -CH3), 2.06 (s, 3H. -CH3). 13C NMR (126 MHz, CDCl3 171.28, 170.50, 169.60, 169.44,154.20, 144.79, 131.51, 125.36, 122.04, 116.26, 114.95, 113.66, 90.29, 81.04, 74.54, 70.75, 62.92, 62.48, 30.69, 25.83, 20.82, 20.64, 20.59.

[0342] Synthesis of (E)-2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)-N'-(pyridin-2-ylmethylene)acetohydrazide (TR-G059)

[0344] Starting from 6-hydroxy-3,4-dihydroquinolin-2(1H)-one, compound 2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetohydrazide (TR-G019) was prepared through couple of steps following procedures A and C respectively. After that following procedure D, 200 mg of TR-G019 (0.850 mmol) was refluxed with 88 µL of 2-pyridinecarboxaldehyde (0.935 mmol) were refluxed in ethanol and drops of acetic acid for 6 h. After completing the reaction, the precipitate was filtered out of the hot84 ethanol, washed with hot ethanol, and dried to obtain 220 mg (80%) of the final product as beige powder. LCMS / MS: m / z 325.2 [M+H]+.

[0345] 1H-NMR (500 MHz, DMSO-d6 -NH-N=), 9.97 (*9.93, s,1H. C-NH-C), 8.59 (*8.37, s, 1H. N=CH-) 8.05-6.74 (m, 7Harom), 5.09 (s, 1H. O-CH2- C=O), 4.64 (s, 1H. O-CH2-C=O), 2.84-2.81 (m, 2H. O=C-CH2-CH2-), 2.41-2.38 (m, 2H. O=C-CH2-CH2-). (* refer to the rotameric peak).13C- 169.91, 153.44, 152.88, 149.52, 144.25, 136.88, 132.07, 124.85, 124.40, 119.91, 115.77, 114.46, 114.20, 113.13, 65.08, 30.34, 25.13.

[0346] Synthesis of 2-oxo-1,2,3,4-tetrahydroquinolin-6-yl 4-cyanobenzoate (TR-G060)

[0348] Following procedure B, 250 mg of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.5 mmol) was stirred with 317.6 mg of the base K2CO3 (2.3 mmol) for 2 h. in in THF and drops of DMF, then 329.78 mg of 4-cyanobenzoyl chloride (1.99 mmol) was added slowly to the reaction at room temperature. The product precipitated in ice water the final product filtered and recrystallized by EtOH and obtained 410 mg (91.6%) of TR-G060 as white powder. LCMS / MS: m / z 263.22 [M+H]+

[0349] 1H NMR (500 MHz, DMSO-d6 -8.06 (m, 4Harom),7.15-6.90 (m, 3Harom.), 2.89 (t, J = 7.5 Hz, 2H. O=C-CH2-), 2.49-2.43 (m, 2H. O=C-CH2-CH2-).13-C=O), 144.83, 136.43, 133.02, 132.96 (2C), 130.35 (2C), 124.82, 121.04, 120.21, 118.01, 115.98, 115.54, 30.04, 24.72.

[0350] Synthesis of 2-oxo-1,2,3,4-tetrahydroquinolin-6-yl pyrrolidine-1-carboxylate (TR-G061)

[0351] 85

[0352] Following procedure B, 250 mg of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.5 mmol) was stirred with 317.6 mg of the base K2CO3 (2.3 mmol) for 30 min in in THF and drops of DMF, then 200 µL of 1-pyrrolidinecarbonyl chloride (1.8 mmol) was added slowly to the reaction at room temperature. After completing the reaction, the product was extracted in DCM three times from water to obtain 280 mg of TR- G061 as crystal. LCMS / MS: m / z 261.07 [M+H]+

[0353] 1H NMR (500 MHz, DMSO-d6 N-H), 6.95 6.78 (m,3Harom), 3.46 (t, J = 6.6 Hz, 2H. N-CH2), 3.31 (t, J = 6.6 Hz, 2H. N-CH2-CH2-), 2.85(t, J = 7.5 Hz, 2H. O=C-CH2-), 2.46 2.40 (m, 2H. O=C-CH2-CH2-), 1.91-1.81 (m, 4H.-CH2-CH2- Pyrolidine). 13 -C=O), 152.55 (O-C=O),145.73 (O-C=C), 135.41, 124.38, 121.36, 120.40, 115.25, 46.24, 45.99, 30.14, 25.35, 24.72, 24.48.

[0354] Synthesis of 2-oxo-1,2,3,4-tetrahydroquinolin-6-yl 2-propylpentanoate(TR-G062)

[0356] Following procedure B, 250 mg of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.5 mmol) was stirred with 317.6 mg of the base K2CO3 (2.3 mmol) for 30 min in in THF and drops of DMF, then 322 µL of 2-propylvaleryl chloride (1.7 mmol) was added slowly to the reaction in ice bath 0-5 °C and stirred for 6 h. After that, THF was evaporated, the residue was dissolved in water and the product was extracted in DCM(3 × 50 ml), dried over anhydrous magnesium sulfate MgSO4 and the solvent wasevaporated under vacuum to obtain 342 mg of TR-G062 (77%) as crystal. LCMS / MS: m / z 290.20 [M+H]+

[0357] 1H NMR (500 MHz, DMSO-d6 N-H), 6.95-6.84 (m,3Harom), 2.89 - 2.86 (t, 2H. J = 5Hz. CH2-CH2-C=O), 2.45-2.42 (t, 2H. J = 5 Hz .CH2-C=O), 1.65-1.51 (m, 1H. O=C-CH<), 1.47-1.39 (m, 4H- CH2-CH2-), 1.37-1.34 (m, 4H. -CH2-CH2-), 0.93-0.91 (t, J = 5Hz, 3H. -CH3), 0.87-0.84 (t, J = 5Hz, 3H. CH3).13C NMR (126 MHz, DMSO) (177.50 NH-C=O), (175.00 C=O), 170.47, 145.31, 136.51, 125.24, 121.41, 120.58, 115.98, 44.92, 44.87, 34.62, 30.51, 25.09, 20.60, 14.36 (2C).86

[0358] Synthesis of 2-oxo-1,2,3,4-tetrahydroquinolin-6-yl 4-bromo-2-fluorobenzenesulfonate (TR-G063)

[0360] Following procedure H, 200 mg of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.23 mmol) was stirred with 203.2 mg of the base K2CO3 (1.47 mmol) for 2 h. in THF and drops of DMF, then 4-bromo-2-fluorobenzenesulfonyl chloride (1.47 mmol) was added slowly to the reaction at room temperature. The product precipitated in ice water the final product filtered and recrystallized by EtOH and obtained 483.0 mg (84.7%) of TR-G063 as white powder. LCMS / MS: m / z 261.07 [M+H]+

[0361] 1H NMR (500 MHz, DMSO-d6 1H. N-H), 8.07-7.64 (m, 3H),7.03-6.79 (m, 3H), 2.84 (t, J = 7.6 Hz, 2H. O=C-CH2-CH2-), 2.43-2.40 (m, 2H. O=C- CH2-).13-C), 142.97, 137.84, 132.29, 130.62, 128.88, 125.47, 121.81, 121.70, 121.35, 120.29, 115.88, 29.74, 24.48.

[0362] Synthesis of N-(4-acetylphenyl)-2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetamide (TR-G064)

[0364] Following procedure B, the intermediate N-(4-acetylphenyl)-2--aminoacetophenone (2.59 mmol) with 561 µLTEA (3.88 mmol) in THF, then 250 µL of chloroacetyl chloride (3.11 mmol) was added, drop wisely to the reaction mixture in ice bath (0-5 °C). After completing the reaction, the solvent was evaporated under vacuum, and the residue was washed with distilled water, filtered and dried. The second step was according to procedure A, 200 mg of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.23 mmol) was stirred with 254 mg of the base K2CO3 (1.84 mmol) for 15 min in DMF after that 259 mg of N-(4-acetylphenyl)-2-chloroacetamide (1.23 mmol) was added to the reaction mixture and stirred for 24h. After that, the product was precipitated in87 ice water and brine, filtered, air-dried then purified using flash chromatography (Hexane:EtOAc:TEA) (40:60:1%) to obtain 259 mg (71%) as crystals. LCMS / MS: m / z 339.42 [M+H]+

[0365] 1H NMR (500 MHz, DMSO-d6 -H), 9.95 (s, 1H.N-H),7.95-6.77 (m, 7Harom), 4.67 (s, 2H), 2.85 -2.82 (t, J = 5Hz, 2H. CH2-CH2-C=O), 2.53 (s, 3H), 2.42-2.39 (t, J = 5 Hz, 2H. CH2-C=O).13NH-C=O), (170.23 NH-C=O), (167.81 C=O), 153.37, 143.20, 132.90 (2C), 132.51 (2C), 129.90, 125.34, 119.34, 116.18, 114.89, 113.69, 68.02, 30.76, 26.94, 25.54.

[0366] Synthesis of 2-oxo-1,2,3,4-tetrahydroquinolin-6-yl 4-(chloromethyl)benzoate (TR-G065)

[0368] Following procedure B, 250 mg of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.5 mmol) was stirred with 317.6 mg of the base K2CO3 (2.3 mmol) for 30 min in in THF and drops of DMF, then 289 mg of 4-(chloromethyl)benzoyl chloride (1.5 mmol) was added to the reaction at room temperature and stirred for 10h. After that, THF was evaporated, the residue was dissolved in water and the product wasextracted in ethyl acetate (3 × 50 ml), dried over anhydrous magnesium sulfateMgSO4 and the solvent was evaporated under vacuum to obtain 380 mg (78%) of TR-G065 as brown powder. LCMS / MS: m / z 316.01 [M+H]+

[0369] 1H NMR (500 MHz, DMSO-d6 -H), 8.12-6.90 (m, 7Harom),4.88 (S, 2H), 2.89 (t, J = 5Hz, 2H. CH2CH2-C=O), 2.48-2.45 (-C=O), (164.91, C=O), 145.47, 144.01, 136.70, 130.56, 129.72 (2C), 129.22 (2C), 125.24, 121.63, 120.77, 115.99, 45.63, 30.53, 25.17.

[0370] Synthesis of (E)-N'-((2-(4-chlorophenyl)pyrimidin-5-yl)methylene)-2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetohydrazide (TR-G066)88

[0371]

[0372] Starting from 6-hydroxy-3,4-dihydroquinolin-2(1H)-one, TR-G066 wasprepared through 3 steps following procedures A, C and D respectively. Starting from 6-hydroxy-3,4-dihydroquinolin-2(1H)-one. Firstly, 300 mg of 6-hydroxy-3,4- dihydroquinolin-2(1H)-one (1.84 mmol) was stirred with 381 mg K2CO3 (2.76 mmol) for 15 min in THF and drops of DMF, then 244 µL of ethyl 2-bromoacetate (2.21 mmol, d= 1.51 g / mL) was added slowly to the reaction mixture. After the completing of reaction, the solvent was evaporated and the residue was washed with water, filtered and air-dried to obtain ethyl 2-((2-oxo-1,2,3,4-tetrahydroquinolin-6- yl)oxy)acetate (TR-G012) which was further refluxed with 156 µL hydrazine hydrate 99% (4.81 mmol) for 5 hours then it was cooled to room temperature, filtered out of ethanol and dried to obtain 2-((2-oxo-1,2,3,4-tetrahydroquinolin-6- yl)oxy)acetohydrazide. Later, 200 mg of 2-((2-oxo-1,2,3,4-tetrahydroquinolin-6- yl)oxy)acetohydrazide (TR-G019) (0.850 mmol) was refluxed with 278.83 mg of 2-(4- chlorophenyl)pyrimidine-5-carbaldehyde (1.28 mmol) in ethanol and drops of acetic acid for 6 hours. After filtration, the product was obtained as pure white powder. LCMS / MS: m / z 436.81 [M+H]+

[0373] 1H NMR (500 MHz, DMSO-d6 -NH-N=), 9.96(*9.92, s, 1H. C-NH-C), 9.20-9.13 (m, 2Hpyrimidine), 8.42-8.39 (m, 2Harom), 8.07 (*8.04, s, 1H. N=CH-) 7.60-6.74 (m, 5Harom), 5.07 (s, 1H. O-CH2-C=O), 4.60 (s, 1H. O-CH2- C=O), 2.86-2.81 (m, 2H. O=C-CH2-CH2-), 2.43-2.38 (m, 2H. O=C-CH2-CH2-). (* refer to the rotameric peak).1155.66, 153.38, 152.87, 142.62, 138.08, 136.12, 135.52, 132.51, 132.02, 129.56, 128.96, 126.30, 124.76, 115.68, 114.15, 113.11, 65.10, 30.36, 25.10.

[0374] Synthesis of 6-propoxy-3,4-dihydroquinolin-2(1H)-one (TR-G068)

[0375] 89

[0376] Following procedure A, 250 mg of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.5 mmol) was stirred with 317.6 mg of the base K2CO3 (2.3 mmol) for 30 min in THF and drops of DMF, then 167 µL of 1-bromopropane (1.84 mmol) was added, slowly to the reaction mixture at room temperature. After completing the reaction, the solvent was evaporated and the product was washed with distilled water, filtered, and dried. The purification was done using flash chromatography (Hexan:EtOAc)(60:40) to obtain 240 mg of the final product as crystals. LCMS / MS: m / z 206.02 [M+H]+

[0377] 1H NMR (500 MHz, DMSO-d6 N-H), 6.77-6.69 (m, 3Harom),3.86 -4.83 (t, J=5 Hz.2H. O-CH2), 2.84-2.81 (m, 2H. CH2-), 2.41 -2.38 (t, 2H. J =5 Hz, 2H. CH2-CH2-C=O), 1.72 -1.65 (m, 2H. -CH2-) 0.97-0.974(t, J = 5 Hz.3H.).13C NMR (126 MHz, DMSO) (170.24, NH-C=O), 154.31, 132.06, 125.29, 116.22, 114.44, 113.38, 69.63, 30.82, 25.55, 22.57, 10.88.

[0378] Synthesis of 2-oxo-1,2,3,4-tetrahydroquinolin-6-yl 5-bromo-2-methylbenzenesulfonate (TR-G069)

[0379]

[0380] Following procedure H, 200 mg of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.23 mmol) was stirred with 254 mg of the base K2CO3 (1.84 mmol) for 30 min in THF and drops of DMF, then 0.17 mL of 5-bromo-2-methylbenzenesulfonyl chloride (1.84 mmol) was added, after workup and column chromatography (Hexane:EtOAc) (60:40) then afford 260 mg (72%) of TR-G069 as white powder. LCMS / MS: m / z 367.44 [M+H]+

[0381] 1H NMR (500 MHz, DMSO-d6 N-H), 7.92-7.55 (m, 3Harom),6.96-6.76 (m, 3H), 2.82 (t, J = 7.6 Hz, 2H. O=C-CH2-CH2-), 2.64 (s, 3H. -CH3), 2.42(d, J = 7.9 Hz, 2H. O=C-CH2-). 13 -S-O-C), 137.68 (S-C), 137.57, 135.21, 134.95, 131.71, 125.37, 121.40, 120.32, 118.90, 115.79 (Br-C), 29.76, 24.51, 19.41 (CH3).

[0382] Synthesis of 6-((3-(4-chlorophenyl)-4,5-dihydroisoxazol-5-yl)methoxy)-3,4-dihydroquinolin-2(1H)-one (TR-G070)90

[0384] Compound TR-G070 has been prepared according to procedure A and F.Firstly, TR-G014 was prepared according to procedure A as previously mentioned. After that, a solution of 700 mg of 4-chlorobenzaldehyde (4.98 mmol), 692 mg of hydroxylamine hydrochloride (9.96 mmol) and 836 mg of NaHCO3 in ethanol were refluxed for 3h to prepare the corresponding oxime. The reaction was monitored by TLC until the completion of reaction after that the product was filtered, washed and dried. In cyclization step, 250 mg of TR-G014 (1.23 mmol) and 231 mg of 4- chlorobenzaldehyde oxime (1.48 mmol) were dissolved in chloroform then catalytic amount of calcium hypochlorite was added slowly to the mixture in ice bath 0 °C for 8 h, then water was added, and the product was extracted with chloroform (3x 30 mL). Organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under vacuum. The crude was purified using combiflash chromatography Hexane:EtOAc) (60:40) to afford 220 mg (50%) of the final product. LCMS / MS: m / z 357.04 [M+H]+.

[0385] 1H NMR (500 MHz, DMSO-d6 -H), 7.71-6.74 (m, 7Harom),5.01-5.02 (qui,Hoxazol), 4,08 -4.02 (m, 2H .CH2), 3,59 -3.29 (m, 2H, CH2Oxazol), 2.81 (t,J = 7.5 Hz, 2H. CH2CH2-C=O) 2.40-2.37 (m, 2H. CH2C=O).

[0386] 13 -C=O), 156.25, 153.88, 135.10,132.58, 129.37, 128.81, 128.67, 125.34, 116.21, 114.70 (2C), 113.64 (2C), 79.66, 69.73, 36.91, 30.78, 25.51.

[0387] Synthesis of Allyl 2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetate(TR-G071)

[0389] Following procedure A, 250 mg of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.5 mmol) was stirred with 317.6 mg of the base K2CO3 (2.3 mmol) for 3 hours in THF and drops of DMF, then 214 µL (247.39 mg, d=1.16 g / mL) of allyl chloroacetate91 (1.84 mmol) was added slowly to the reaction at room temperature. After that, the product was precipitated in ice water, filtered, and dried. Then purified using flash chromatography (Hexane:EtOAc:TEA) (40:60:1%) to obtain 316 mg (79%) as crystals. LCMS / MS: m / z 262.02 [M+H]+

[0390] 1H NMR (500 MHz, DMSO-d6 N-H), 6.82 6.71 (m,3Harom), 5.92 (m, 1H), 5.34-5.22 (m, 2H. C=CH2), 4.76 (s, 2H. O-CH2-C=O), 4.65 (d, J= 5.4 Hz, 2H. O-CH2-CH=), 2.82 (t, J = 7.5 Hz, 2H. O=C-CH2-), 2.43 2.36 (m, 2H.O=C-CH2-CH2-).13-N), 168.61 (O=C-O-), 152.74 (C=C-O), 132.40, 132.28, 124.87, 118.09, 115.71, 114.21, 113.06, 64.92(O-C- C=O), 64.85 (O=C-O-C-C), 30.29, 25.05.

[0391] Synthesis of 2-oxo-1,2,3,4-tetrahydroquinolin-6-ylmethyl(phenyl)carbamate (TR-G072)

[0393] Following procedure B, 250 mg of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.5 mmol) was stirred with 317.6 mg of the base K2CO3 (2.3 mmol) for 30 min in in THF and drops of DMF, then 260 mg of N-methyl-N-phenylcarbamoyl chloride (1.5 mmol) was added to the reaction at room temperature and stirred for 12h. After that, THF was evaporated, the residue was dissolved in water and the product wasextracted in ethyl acetate (3 × 50 ml), dried over anhydrous magnesium sulfateMgSO4 and the solvent was evaporated under vacuum to obtain 320 mg (70%) of TR-G072 as white powder. LCMS / MS: m / z 297.03 [M+H]+

[0394] 1H NMR (500 MHz, DMSO-d6 -H), 7.45-6.81 (m, 8Harom),3.18 (s, 3H), 2.86 -2.83 (t, J = 5Hz, 2H. CH2-CH2-C=O), 2.44-2.41 (t, J = 5 Hz, 2H.88, C=O), 146.06, 143.30, 136.10, 129.41, 126.36, 124.97, 121.67 (2C), 120.74 (2C), 115.74, 49.06, 40.08, 30.53, 25.12.

[0395] Synthesis of 2-oxo-1,2,3,4-tetrahydroquinolin-6-yl 4-(trifluoromethyl)benzenesulfonate (TR-G073)92

[0396]

[0397] Following procedure H, 200 mg of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.23 mmol) was stirred with 254 mg of the base K2CO3 (1.84 mmol) for 1h. in acetone, then 299.81 mg of 4-(trifluoromethyl)benzene sulfonyl chloride (1.23 mmol) was added, after workup and column chromatography (Hexane:EtOAc) (60:40) then afford 405 mg (89%) of TR-G073 as white powder. LCMS / MS: m / z 372.39 [M+H]+

[0398] 1H NMR (500 MHz, DMSO-d6 N-H), 8.10-8.05 (m,4Harom), 6.99-6.74 (m, 3Harom), 2.82 (t, J = 7.6 Hz, 2H), 2.44-2.39 (m, 2H).1C NMR -O-S), 138.31, 137.73, 134.37, 134.11, 129.35, 127.01, 125.38, 124.27, 122.09, 121.59, 120.57, 115.77, 29.75, 24.50.

[0399] Synthesis of 6-(3-bromopropoxy)-3,4-dihydroquinolin-2(1H)-one (TR-G074)

[0401] Following procedure B, 250 mg of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.5 mmol) was stirred with 317.6 mg of the base K2CO3 (2.3 mmol) for 30 min in in THF and drops of DMF, then 187 µL of 1,3-dibromopropane (1.84 mmol) was added to the reaction at room temperature and stirred for 10h. After that, THF was evaporated, the residue was dissolved in water and the product was extracted in ethylacetate (3 × 50 ml), dried over anhydrous magnesium sulfate MgSO4 and the solventwas evaporated under vacuum to obtain 341 mg (70%) of TR-G074 as white powder. LCMS / MS: m / z 285.08 [M+H]+

[0402] Synthesis of N-(3-chloro-4-fluorophenyl)-2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetamide (TR-G075)

[0403] 93

[0404] Following procedure B, the intermediate 2-chloro- N-(3-chloro-4-fluorophenyl)acetamide was prepared by dissolving 300 mg of 3-chloro-4- fluoroaniline (2.06 mmol) with 447 µLTEA (3.09 mmol) in THF, then 200 µL of chloroacetyl chloride (2.47 mmol) was added, drop wisely to the reaction mixture in ice bath (0-5 °C). After completing the reaction, the solvent was evaporated under vacuum, and the residue was washed with distilled water, filtered and dried. Thesecond step was according to procedure A, 200 mg of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.23 mmol) was stirred with 254 mg of the base K2CO3(1.84 mmol) for 15 min in DMF after that 272 mg of 2-chloro- N-(3-chloro-4-fluorophenyl)-acetamide (1.23 mmol) was added to the reaction mixture and stirred for 24h. After that, the product was precipitated in ice water and brine, filtered and air-dried then purified using column chromatography (Hexane:EtOAc) (60:40) to afford 385 mg (84%) of the product as white powder. LCMS / MS: m / z 347.11 [M-H]-

[0405] 1H NMR (500 MHz, DMSO-d6 -H), 9.93 (s, 1H. N-H),7.93-6.75 (m, 6Harom), 4.61(S, 2H), 2.82 (t, J = 7.5 Hz, 2H. CH2CH2-C=O), 2.40-2.37 (t, 2H. J = 7.5Hz .CH2-C=O).13-C=O), (167.57, C=O), 154.77, 153.31, 136.08, 132.95, 125.34, 121.69, 120.55, 119.46, 117.47, 116.19, 114.95, 113.75, 68.02, 30.75, 25.54.

[0406] Synthesis of (E)-N'-((2-aminopyrimidin-5-yl)methylene)-2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetohydrazide (TR-G076)

[0408] Starting from 6-hydroxy-3,4-dihydroquinolin-2(1H)-one, compound 2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetohydrazide (TR-G019) was prepared through couple of steps following procedures A and C respectively. After that following procedure D, 200 mg of TR-G019 (0.850 mmol) was refluxed with 105 mg of 2-pyridinecarboxaldehyde (0.850 mmol) were refluxed in ethanol and drops of acetic acid for 6 h. After completing the reaction, the precipitate was filtered out of the hot ethanol, washed with hot ethanol and dried to obtain 231 mg (79%) of the final product as white powder. LCMS / MS: m / z 339.21 [M-H]-94

[0409] 1H-NMR (500 MHz, DMSO- -NH-N=), 9.95(*9.90, s, 1H. C-NH-C), 8.55 (s, 1H. -NH2), 8.51 (s, 1H. -NH2), 8.16 (*7.82, s, 1H. N=CH-), 7.17-6.71 (m, 5Harom), 5.02 (s, 1H. O-CH2-C=O), 4.55 (s, 1H. O-CH2-C=O), 2.84-2.81 (m, 2H. O=C-CH2-CH2-), 2.42-2.37 (m, 2H. O=C-CH2-CH2-). (*refer to the rotameric peak).13C- 144.36, 139.97, 132.44, 131.94, 124.87, 116.91, 115.67, 114.11, 113.08, 65.05, 30.31, 25.10.

[0410] Synthesis of N-(3,4-dimethoxyphenyl)-2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetamide (TR-G077)

[0412] Following procedure B, the intermediate 2-chloro- N-(3,4-dimethoxyphenyl)acetamide was prepared by dissolving 300 mg of 3,4- dimethoxyaniline (1.96 mmol) with 424 µLTEA (2.94 mmol) in THF, then 190 µL of chloroacetyl chloride (2.35 mmol) was added, drop wisely to the reaction mixture in ice bath (0-5 °C). After completing the reaction, the solvent was evaporated under vacuum, and the residue was washed with distilled water, filtered, and dried. The second step was according to procedure A, 200 mg of 6-hydroxy-3,4- dihydroquinolin-2(1H)-one (1.23 mmol) was stirred with 254 mg of the base K2CO3(1.84 mmol) for 15 min in DMF after that 282 mg of 2-chloro- N-(3,4-dimethoxyphenyl)acetamide (1.23 mmol) was added to the reaction mixture and stirred for 24h. After that, the product was precipitated in ice water and brine, filtered and air-dried then purified using column chromatography (Hexane:EtOAc) (60:40) to afford 359 mg (82%) of the product as beige powder. LCMS / MS: m / z 355.17 [M-H]-

[0413] 1H NMR (500 MHz, DMSO-d6 -H), 9.85 (s, 1H. N-H),7.34-6.77 (m, 6Harom), 4.58 (s, 2H), 3.72 (s, 6H. -CH3), 2.86 -2.83 (t, 2H. J = 5 Hz. CH2-CH2-C=O J), 2.42-2.39 (-C=O), (166.69 C=O), 153.42, 148.93, 145.57, 132.85, 132.36, 125.31,95 116.17, 114.93, 113.72, 112.37, 112.14, 105.34, 68.10, (56.15 -CH3), (55.84 -CH3), 30.77, 25.56.

[0414] Synthesis of 6-((1-(1H-indazol-4-yl)-1H-1,2,3-triazol-4-yl)methoxy)-3,4-dihydroquinolin-2(1H)-one (TR-G078)

[0415]

[0416] Compound TR-G078 has been prepared according to procedure A and E.In the first step, 4-azido-1H-indazole was prepared starting from 700 mg of 1H-indazol-4-amine (5.2 mmol) which was dissolved in 5 mL of HCl (2.5 mL of HCl 37%+ 2.5 mL H2O) at 0 °C and 535 mg of NaNO3 (7.77 mmol) dissolved in 12.5 mL of H2O was added dropwise to the reaction and stirred for 4 h at 0 °C. The mixture was extracted with EtOAc (3x 50mL) and dried over anhydrous magnesium sulfate.

[0417] Secondly, 6-(prop-2-yn-1-yloxy)-3,4-dihydroquinolin-2(1H)-one (TR-G006) was prepared according to procedure A as mentioned before. In the last step,a mixture of 6-(prop-2-yn-1-yloxy)-3,4-dihydroquinolin-2(1H)-one (TR-G006) (250mg, 1.24 mmol), 29.74 mg of copper sulfate (0.186 mmol) and 12 mg of sodium ascorbate (0.062 mmol) in DMF / water (3:1) was added to 4-azido-1H-indazole andstirred for 24 h. After that, the mixture was extracted with DCM (3×50 ml), theorganic layer was dried over anhydrous MgSO4 and the solvent was evaporated under vacuum. Finally, the product was purified using flash chromatography (Hexane:EtOAc:TEA) (40:60:1%) to obtain 320 mg (65%) of compound TR-G078. LCMS / MS: m / z 361.21 [M+H]+.

[0418] 1H NMR (500 MHz, DMSO-d6 -H), 9.96 (s, 1H. N-H),8.91 (s, 1HTraizole), 8.28-6.80 (m, 7Harom), 5.18 (S, 2H), 2.87-2.84 (t, 2H. J = 5 Hz CH2CH2-C=O) 2.42 -2.43 (t, 2H. J = 7.5 Hz. CH2-C=O).

[0419] 13 traizole), 144.30,139.72, 134.95, 132.62, 130.68, 125.38, 123.64, 123.09, 120.20, 116.24, 114.86, 113.79, 112.90, 111.96, 61.84, 30.80, 25.57.

[0420] Synthesis of ethyl 3-(4-(((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)propanoate (TR-G079)96

[0422] Compound TR-G079 has been prepared according to procedure A and E.In the first step, ethyl 3-azidopropanoate was prepared starting from ethyl 3-chloropropanoate (1 eq.) which were refluxed with sodium azide salt (2 eq.) for 12hours in ethanol / water (2:1). After that, the mixture was cooled to room temperature and filtered. Secondly, 6-(prop-2-yn-1-yloxy)-3,4-dihydroquinolin-2(1H)-one TR-G006 was prepared according to procedure A as mentioned before. In the last step, amixture of 6-(prop-2-yn-1-yloxy)-3,4-dihydroquinolin-2(1H)-one TR-G006 (250 mg, 1.24 mmol), 29.74 mg of copper sulfate (0.186 mmol) and 12 mg of sodium ascorbate(0.062 mmol) in EtOH was added to the ethyl 3-azidopropanoate solution and stirredfor 6 h. After that, the ethanol was evaporated. The residue was dissolved in waterand the mixture was extracted with DCM (3 × 50 ml), dried over anhydrousmagnesium sulfate MgSO4 and the solvent was evaporated under vacuum. Finally, the product was purified using flash chromatography (Hexane:EtOAc:TEA) (40:60:1%) to obtain 350 mg (81%) of compound TR-G079 as crystals. LCMS / MS: m / z 345.12 [M+H]+.

[0423] -H), 8.19 (s, 1HTraizole),6.88-6.77 (m, 3Harom), 5.06 (S, 2H), 4.62- 4.59 (t, 2H. CH2 J = 7.5 Hz.), 4.07- 4.03(q, 2H. CH3CH2), 2.99- 2.597 (t, 2H. CH2 J = 7.5 Hz.), 2.85-2.82 (t, 2H. J = 5 HzCH2CH2-C=O) 2.42 -2.39 (t, 2H. J = 5 Hz. CH2-C=O) 1.16-1.13(t, 3H J = 5 Hz. CH3).

[0424] 13C NMR -C=O), (170.24 C=O), (153.65CTraizole), 143.20, 132.51, 125.32, 125.10, 116.20, 114.79, 113.69, 61.81, 60.79, 45.72, 34.40, 30.79, 25.56, 14.42.

[0425] Synthesis of 6-((1-(2-(benzyloxy)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)-3,4-dihydroquinolin-2(1H)-one (TR-G080)97

[0427] Compound TR-G080 has been prepared according to procedure A and E.In the first step, ((2-azidoethoxy)methyl)benzene was prepared starting from 700 µL of ((2-chloroethoxy)methyl)benzene (4.64 mmol) which were refluxed with 602 mg of sodium azide salt (9.27 mmol) for 2 hours in ethanol / water (2:1). After that, the mixture was cooled to room temperature and filtered. Secondly, 6-(prop-2-yn-1- yloxy)-3,4-dihydroquinolin-2(1H)-one TR-G006 was prepared according to procedure A as mentioned before. In the last step, a mixture of TR-G006 (250 mg, 1.24 mmol), 29.74 mg of copper sulfate (0.186 mmol) and 12 mg of sodium ascorbate(0.062 mmol) in EtOH was added to the ((2-azidoethoxy)methyl)benzene solutionand stirred for 12 h. After that, the ethanol was evaporated. The residue was dissolvedin water and the mixture was extracted with ethyl acetate (3 × 50 ml), dried overanhydrous magnesium sulfate MgSO4 and the solvent was evaporated under vacuum. Finally, the product was purified using flash chromatography (Hexane:EtOAc:TEA) (40:60:1%) to obtain 261 mg (52%) of compound TR-G080 as beige powder. LCMS / MS: m / z 379.32 [M+H]+.

[0428] 1H NMR (500 MHz, DMSO-d6 -H), 8.18 (s, 1HTraizole),7.31-6.78 (m, 8Harom), 5.09 (S, 2H), 4.60- 4.58 (t, 2H. CH2 J = 7.5 Hz), 4.47 (S, 2H),3.84- 3.82 (t, 2H. CH2 J = 7.5 Hz.), 2.85-2.81 (t, 2H. J = 5 Hz CH2CH2-C=O) 2.41 -2.36 (m, 2H. CH2-C=O).

[0429] 13 (170.24 NH-C=O), 153.68, 152.82, 143.22,138.37, 132.50, 130.72, 128.71, 127.89, 125.30, 116.21, (114.802C), (113.712C), 72.20, 68.45, 61.84, 49.93, 30.79, 25.56.

[0430] Synthesis of 2-oxo-1,2,3,4-tetrahydroquinolin-6-yl 3-nitrobenzoate (TR-G081)

[0431]

[0432] Following procedure B, 250 mg of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.5 mmol) was stirred with 317.6 mg of the base K2CO3 (2.3 mmol) for 30 min in in THF and drops of DMF, then 284 mg of 3-nitrobenzoyl chloride was added to the reaction at room temperature and stirred for 9h. After that, THF was evaporated, theresidue was dissolved in water and the product was extracted in DCM (3 × 50 ml),98 dried over anhydrous magnesium sulfate MgSO4 and the solvent was evaporated under vacuum to obtain 365 mg (76%) of TR-G081 as white powder. LCMS / MS: m / z 313.00 [M+H]+.

[0433] 1H NMR (500 MHz, DMSO-d6 N-H), 8.76-6.91 (m, 7Harom),2.92 -2.89 (t, J = 5 Hz, 2H. CH2-CH2-C=O), 2.49-2.46 (t, J = 5 Hz, 2H. CH2-C=O).13C NMR (126 MHz, DMSO) (170.52 NH-C=O), (163.67 C=O), 148.45, 145.25, 136.95, 136.22, 131.40, 131.13, 128.80, 125.31, 124.57, 121.53, 120.70, 116.02, 30.50, 25.18.

[0434] Synthesis of 6-((1-propyl-1H-1,2,3-triazol-4-yl)methoxy)-3,4-dihydroquinolin-2(1H)-one (TR-G082)

[0436] Compound TR-G082 has been prepared according to procedure A and E.In the first step, 1-azidopropane was prepared starting from 200 µL of 1- brompropane (3.17 mmol) which were refluxed with 412 mg of sodium azide salt (6.34 mmol) for 2 hours in ethanol / water (2:1). After that, the mixture was cooled to room temperature and filtered. Secondly, 6-(prop-2-yn-1-yloxy)-3,4- dihydroquinolin-2(1H)-one TR-G006 was prepared according to procedure A as mentioned before. In the last step, a mixture of -(prop-2-yn-1-yloxy)-3,4- dihydroquinolin-2(1H)-one TR-G006 (250 mg, 1.24 mmol), 29.74 mg of copper sulfate (0.186 mmol) and 12 mg of sodium ascorbate (0.062 mmol) in EtOH was added to the azidopropane solution and stirred for 6 h. After that, the ethanol was evaporated. the residue was dissolved in water and the mixture was extracted withethyl acetate (3 × 50 ml), dried over anhydrous magnesium sulfate MgSO4 and thesolvent was evaporated under vacuum. Finally, the product was purified using flash chromatography (Hexane:EtOAc:TEA) (40:60:1%) to obtain 210 mg (59%) of compound TR-G082 as light yellow powder. LCMS / MS: m / z 287.10 [M+H]+

[0437] 1H NMR (500 MHz, DMSO-d6 -H), 8.20 (s, 1HTraizole),6.77-6.88 (m, 3Harom), 5.07 (S, 2H), 4.31-4.34 (t, J = 5 Hz, 2H. N-CH2), 2.85-2.82 (t, 2H. J = 5 Hz CH2CH2-C=O) 2.42 -2.39 (t, 2H. J = 5 Hz. CH2-C=O) 1.92-1.81 (m, 2H.), 0.85-0.82 (t, 3H J = 5 Hz. CH3).13-C=O),99 (153.67, Ctraizole), 143.22, 132.51, 125.31, 124.74, 116.19, 114.84, 113.74, 61.93, 51.39, 30.79, 25.56, 23.63, 11.25.

[0438] Synthesis of 6-((3-(4-chlorophenyl)isoxazol-5-yl)methoxy)-3,4-dihydroquinolin-2(1H)-one (TR-G084)

[0440] Compound TR-G084 has been prepared according to procedure A and F.Firstly, TR-G006 was prepared according to procedure A as previously mentioned. After that, a solution of 700 mg of 4-chlorobenzaldehyde (4.98 mmol), 692 mg of hydroxylamine hydrochloride (9.96 mmol) and 836 mg of NaHCO3 in ethanol were refluxed for 3h to prepare the corresponding oxime. The reaction was monitored by TLC until the reaction complete after that the product was filtered, washed, anddried. In cyclization step, 250 mg of TR-G006 (1.24 mmol) and 231 mg of 4-chlorobenzaldehyde oxime (1.49 mmol) were dissolved in chloroform then catalytic amount of calcium hypochlorite was added to the mixture in ice bath 0 °C for 8 h, then water was added, and the product was extracted with chloroform (3x 30 mL). Organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under vacuum. The crude was purified using flash chromatography (Hexane:EtOAc) (60:40) to afford 231 mg (52%) of the final product. LCMS / MS: m / z 355.81 [M+H]+

[0441] 1H NMR (500 MHz, DMSO-d6 -H), 7.89-7.09 (m, 7Harom),6.99 (s, 1HOxazole), 5.33 (S, 2H), 2.92 -2.89 (t, J = 5Hz, 2H. CH2-CH2-C=O), 2.48-2.45 (t, J = 5 Hz.2H. CH2-C=O)13(170.49 NH-C=O), 168.81, 162.41, 153.14, 130.84, 129.84, 129.63, 128.71, 128.50, 127.12, 119.82, 114.58 (2C), 114.06 (2C), (102.87oxazole), 61.44, 30.79, 26.07.

[0442] Synthesis of 2-oxo-1,2,3,4-tetrahydroquinolin-6-yl 3,4-dimethoxybenzenesulfonate (TR-G085)100

[0444] Following procedure H, 200 mg of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.23 mmol) was stirred with 254 mg of the base K2CO3 (1.84 mmol) for 1h. in acetone, then 291 mg of 3,4-dimethoxybenzenesulfonyl chloride (1.23 mmol) was added. After workup, column chromatography (Hexane:EtOAc) (60:40) was done to afford 380 mg (85%) of TR-G085 as beige powder. LCMS / MS: m / z 364.41 [M+H]+

[0445] 1H NMR (500 MHz, DMSO-d6 -H), 7.38 6.71 (m,6Harom), 3.86 (s, 3H. O-CH3), 3.81 (s, 3H. O-CH3), 2.82 (t, J = 7.6 Hz, 2H. O=C-CH2-),2.43 2.39 (m, 2H. O=C-CH2-CH2-).13153.81, 148.96, 143.51, 137.35, 125.37, 125.09, 122.76, 121.68, 120.73, 115.63, 111.31, 110.12, 56.04, 55.98, 29.85, 24.57.

[0446] Synthesis of 6-((1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)-3,4-dihydroquinolin-2(1H)-one (TR-G086)

[0447]

[0448] Compound TR-G086 has been prepared according to procedure A and E.In the first step, 1-(azidomethyl)-4-fluorobenzene was prepared starting from 700 µL of 4-fluorbenzyl chloride (6.49 mmol) which were refluxed with 843 mg of sodium azide salt (12.98 mmol) for 2 hours in ethanol / water (2:1). After that, the mixture was cooled to room temperature and filtered. Secondly, 6-(prop-2-yn-1-yloxy)-3,4- dihydroquinolin-2(1H)-one TR-G006 was prepared according to procedure A as mentioned before. In the last step, a mixture of 6-(prop-2-yn-1-yloxy)-3,4- dihydroquinolin-2(1H)-one TR-G006 (250 mg, 1.24 mmol), 29.74 mg of copper sulfate (0.186 mmol) and 12 mg of sodium ascorbate (0.062 mmol) in EtOH wasadded to the 1-(azidomethyl)-4-fluorobenzene solution and stirred for 6 h. After that,the ethanol was evaporated. The residue was dissolved in water and the mixture wasextracted with ethyl acetate (3 × 50 ml), dried over anhydrous magnesium sulfateMgSO4 and the solvent was evaporated under vacuum. Finally, the product was purified using flash chromatography (Hexane:EtOAc:TEA) (40:60:1%) to obtain 230 mg (68%) of compound TR-G086 as yellow powder. LCMS / MS: m / z 353.19 [M+H]+.101

[0449] 1H NMR (500 MHz, DMSO-d6 -H), 8.25 (s, 1HTraizole), 7.4 -6.75 (m, 7Harom), 5.60 (S, 2H), 5.06 (S, 2H), 2.83-2.80 (t, 2H. J = 7.5 Hz CH2CH2- C=O) 2.41 -2.38(m, 2H. CH2-C=O).

[0450] .61,143.67, 132.54, 130.79, 130.72, 124.94, 116.18, 115.98, (114.842C), (113.772C), 61.85, 52.47, 31.17, 30.79, 25.55.

[0451] Synthesis of 6-(2-oxo-2-(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)ethoxy)-3,4-dihydroquinolin-2(1H)-one (TR-G087)

[0452]

[0453] Following procedure B, the intermediate 2-chloro-1-(4-(4-trifluoromethyl)phenyl)piprazin-1-yl)ethan-1-one was prepared by dissolving 350 mgof 1-(4-(trifluoromethyl)phenyl)piprazine (1.52 mmol) with 329 µL TEA (2.28 mmol)in THF, then 147 µL of chloroacetyl chloride (1.82 mmol) was added, drop wisely to the reaction mixture in ice bath (0-5 °C). After the reaction complete, the solvent was evaporated under vacuum, and the residue was washed with distilled water, filtered and dried. The second step was according to procedure A, 200 mg of 6-hydroxy-3,4- dihydroquinolin-2(1H)-one (1.23 mmol) was stirred with 254 mg of the base K2CO3 (1.84 mmol) for 15 min in DMF after that 272 mg of 2-chloro-1-(4-(4- trifluoromethyl)phenyl)piprazin-1-yl)ethan-1-one (1.23 mmol) was added to the reaction mixture and stirred for 24h. After that, the product was precipitated in ice water and brine, filtered and air-dried then purified using column chromatography (Hexane:EtOAc) (60:40) to afford 410 mg (77%) of the product as white powder. LCMS / MS: m / z 434.2 [M+H]+

[0454] 1H NMR (500 MHz, DMSO-d6 -H), 7.54-6.75 (m,7Harom), 4.79 (S, 2H.), 3.62 (m, 4Hpiprazin), 3.37-3.30 (m, 4Hpiprazin), 2.84-2.81 (t, J = 5Hz, 2H. CH2-CH2-C=O), 2.41-2.38 (t, J = 5Hz, 2H. CH2-C=O).13C NMR (126 MHz, -C=O), (166.60, C=O), 153.62, 153.38, 132.60, 126.67, 125.22, 116.11, 114.87 (2C), 114.69 (2C), 113.62, 66.84, 47.54, 47.22, 44.15 (2C), 41.23 (2C), 30.79, 25.56.102

[0455] Synthesis of 2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)-N-(quinolin-6-yl)acetamide (TR-G089)

[0457] Following procedure B, the intermediate 2-chloro-N-6-quinolinylacetamide was prepared by dissolving 350 mg of 6-aminoquinoline (2.42 mmol) with 520 µLTEA (3.64 mmol) in THF, then 134 µL of chloroacetyl chloride (2.90 mmol) was added, drop wisely to the reaction mixture in ice bath (0-5 °C). After the reaction complete, the solvent was evaporated under vacuum, and the residue was washed with distilled water, filtered, and dried. The second step was according to procedure A, 250 mg of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.5 mmol) was stirred with 317.6 mg of the base K2CO3 (2.3 mmol) for 15 min in DMF after that, 330 mg of the intermediate 2-chloro-N-6-quinolinylacetamide (1.5 mmol) was added, . After TLC control, the product was added, onto iced water and precipitated in brine water then filtered and dried. The product was purified using flash chromatography (Hexan:EtOAc) (50:50) to obtain 400 mg (76%) as brownish powder. LCMS / MS: m / z 348.1 [M+H]+

[0458] 1H NMR (500 MHz, DMSO-d6 -H), 9.96 (s, 1H. N-H),6.81-8.81 (m, 9Harom), 4.71 (S, 2H), 2.87-2.84 (t, J = 5 Hz, 2H. CH2-CH2-C=O), 2.43-2.40 (t, J = 5 Hz, 2H. CH2-C=O). 13 -C=O),(167.69, -O-CH2-C=O), 153.44, 149.71, 145.30, 136.76, 136.02, 132.89, 129.96, 128.67, 125.35, 124.12 (2C), 122.28, 116.20, 114.94, 113.74, 68.11, 30.77, 25.56.

[0459] Synthesis of N-(3,5-dimethoxyphenyl)-2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetamide (TR-G091)103

[0461] Following procedure B, the intermediate 2-chloro- N-(3,5-dimethoxyphenyl)acetamide was prepared by dissolving 300 mg of 3,5- dimethoxyaniline (1.96 mmol) with 424 µL TEA (2.94 mmol) in THF, then 190 µL of chloroacetyl chloride (2.35 mmol) was added drop wisely to the reaction mixture in ice bath (0-5 °C). After the reaction was completed, the solvent was evaporated under vacuum, and the residue was washed with distilled water, filtered, and dried.The second step was performed according to procedure A, 200 mg of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.23 mmol) was stirred with 254 mg of the base K2CO3(1.84 mmol) for 2 hours in DMF. After that, 338 mg of 2-chloro- N-(3,5-dimethoxyphenyl)acetamide (1.47 mmol) was added to the reaction mixture and stirred for 24 h. After that, the product was precipitated in ice water and brine, filtered and air-dried then purified using column chromatography (Hexane:EtOAc) (60:40) to afford 332 mg (76%) of the product as beige powder. LCMS / MS: m / z 357.63 [M+H]+

[0462] 1H NMR (500 MHz, DMSO-d6 -H), 6.92-6.24 (m, 6Harom),4.60 (s, 2H), 3.71 (s, 6H), 2.85 -2.82 (t, J = 5 Hz, 2H. CH2-CH2-C=O), 2.41(t, J = 5-C=O), 167.23 (C=O), 160.91, 153.39, 140.50, 132.86, 125.32, 116.17, 114.89, 113.68, 98.39 (2C), (96.092C), 68.03, 55.57, 30 (2C).76, 25.55.

[0463] Synthesis of 6-((3-cyclohexylisoxazol-5-yl)methoxy)-3,4-dihydroquinolin-2(1H)-one (TR-G092)

[0465] Compound TR-G092 has been prepared according to procedure A and F.Firstly, TR-G006 was prepared according to procedure A as previously mentioned. After that, a solution of 700 µL of cyclohexancarbaldehyde (5.74 mmol), 789 mg of hydroxylamine hydrochloride (11.48 mmol) and 964 mg of NaHCO3 (11.48 mmol) in ethanol were refluxed for 3h to prepare the corresponding oxime. The reaction was monitored by TLC until the reaction complete after that the product was filtered, washed, and dried. In cyclization step, 250 mg of TR-G006 (1.23 mmol) and 185 mg of the oxime (1.48 mmol) were dissolved in chloroform then catalytic amount of104 calcium hypochlorite was added to the mixture in ice bath 0 °C for 8 h, then water was added, and the product was extracted with chloroform (3x 30 mL). The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under vacuum. The crude was purified using combi flash chromatography (Hexane:EtOAc) (60:40) to afford 241 mg (59%) of the final product. LCMS / MS: m / z 329.41 [M+H]+.

[0466] 1H NMR (500 MHz, DMSO-d6 -H), 7.04-6.94 (m, 3Harom),6.55 (s,H oxazol), 5,19 (s, 2H .CH2), 2.91-2.88 (t, 2H. J = 5Hz .CH2CH2-C=O), 2.73-2.68(qui, Hcycohexan). 2.47-2.44 (m, 2H. J = 5Hz .CH2C=O). ), 1.88-1.23 (m, 10H cyclohexan).

[0467] 168.34, 167.24, 153.21,129.72, 128.44, 119.79, 114.49, 113.90, 103.23, 61.37, (35.562c), (31.812c), 30.80, 30.28, 26.06, 25.82.

[0468] Synthesis of 6-((1-(4-acetylphenyl)-1H-1,2,3-triazol-4-yl)methoxy)-3,4-dihydroquinolin-2(1H)-one (TR-G093)

[0469]

[0470] Compound TR-G093 has been prepared according to procedure A and E.In the first step, 1-(4-azidophenyl)ethane-1-one was prepared starting from 700 mg of 1-(4-aminophenyl)ethan-1-one (5.18 mmol) which wa dissolved in 5 mL of HCl (2.5 mL of HCl 37% + 2.5 mL H2O) at 0 °C and 535 mg of NaNO3 (7.77 mmol) dissolved in 12.5 mL of H2O was added, dropwise to the reaction and stirred for 4 h at 0 °C. The mixture was extracted with EtOAc (3x 50mL) and dried over anhydrous magnesium sulfate.

[0471] Secondly, 6-(prop-2-yn-1-yloxy)-3,4-dihydroquinolin-2(1H)-one TR-G006was prepared according to procedure A as mentioned before. In the last step, a mixture of 6-(prop-2-yn-1-yloxy)-3,4-dihydroquinolin-2(1H)-one TR-G006 (250 mg, 1.24 mmol), 29.74 mg of copper sulfate (0.186 mmol) and 12 mg of sodium ascorbate (0.062 mmol) in DMF / water (3:1) was added, to the 1-(4-azidophenyl)ethane-1-oneand stirred for 24 h. After that, the mixture was extracted with DCM (3 × 50 ml), theorganic layer was dried over anhydrous magnesium sulfate MgSO4 and the solvent was evaporated under vacuum. Finally, the product was purified using flash105 chromatography (Hexane:EtOAc:TEA) (40:60:1%) to obtain 320 mg (66%) of compound TR-G093 as crystals. LCMS / MS: m / z 363.45 [M+H]+

[0472] 1H NMR (500 MHz, DMSO-d6 -H), 9.08 (s, 1HTraizole),8.19-6.79 (m, 7Harom), 5.19 (S, 2H), 2.87 -2.84 (t, J = 5 Hz, 2H. CH2-CH2-C=O), 2.65 (s, 3H), 2.50-2.40 (t, J = 5 Hz, 2H. CH2-C=O).13O=C-CH3), (170.22 NH-C=O), (153.56traizol), 144.92, 139.99, 136.88, 132.69, 130.56 (2C), 125.39 (2C), 123.36, 120.28, 116.24, 114.88, 113.81, 61.78, 30.78, 27.34, 25.56.

[0473] Synthesis of 2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)-N-(3,4,5-trimethoxyphenyl)acetamide (TR-G094)

[0474]

[0475] Following procedure B, the intermediate 2-chloro-N-3,4,5-trimethoxyphenylacetamide was prepared by dissolving 350 mg of 3,4,5- trimethoxyaniline (1.91 mmol) with 414 µLTEA (2.87 mmol) in THF, then 184 µL of chloroacetyl chloride (2.29 mmol) was added, drop wisely to the reaction mixture in ice bath (0-5 °C). After completing the reaction, the solvent was evaporated under vacuum, and the residue was washed with distilled water, filtered, and dried. The second step was according to procedure A, 250 mg of 6-hydroxy-3,4- dihydroquinolin-2(1H)-one (1.53 mmol) was stirred with 317.6 mg of the base K2CO3 (2.3 mmol) for 15 min in DMF after that 397 mg of 2-chloro-N-3,4,5- trimethoxyphenylacetamide (1.53 mmol) was added to the reaction mixture and stirred for 24h. After that, the product was precipitated in ice water and brine, filtered and air-dried. The product was purified using flash chromatography (Hexane:EtOAc) (60:40) to obtain 480 mg (81%) as white powder. LCMS / MS: m / z 387.42 [M+H]+

[0476] 1H NMR (500 MHz, DMSO-d6 -H), 9.98 (s, 1H. N-H),7.12-6.81 (m, 5Harom), 4.63 (S, 2H. O-CH2-C=O), 3.73 (S, 6H), 3.62 (S, 3H), 2.85-2.82 (t, J = 5Hz, 2H.CH2CH2-C=O), 2.42 -2.39 (-C=O), (167.03, NH-C=O), 153.43, 153.09, 135.123,106 134.03, 132.82, 125.31, 116.20 (2C), 114.88 (2C), 113.64 (2C), 97.82, 67.95, 60.56, 56.17, 30.77, 25.55.

[0477] Synthesis of 6-(but-3-en-2-yloxy)-3,4-dihydroquinolin-2(1H)-one (TR-G095)

[0479] Following procedure A, 250 mg of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.5 mmol) was stirred with 317.6 mg of the base K2CO3 (2.3 mmol) for 30 min in THF and drops of DMF, then 185 µL of 3-chloro-1-butene (1.8 mmol) was added, slowly to the reaction at room temperature. After that, the product was precipitated in ice water, filtered, and dried. Then purified using flash chromatography (Hexane:EtOAc:TEA) (40:60:1%) to obtain 281 mg (84%). LCMS / MS: m / z 274.21 [M+H]+

[0480] Synthesis of 2-oxo-1,2,3,4-tetrahydroquinolin-6-yl (2-chlorophenyl)carbamate (TR-G096)

[0482] 250 mg of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.5 mmol) wasstirred with 265 µL of the TEA (1.84 mmol) for 1 h in THF and drops of DMF, then 214 µL of 2-chlorophenyl isocyanate (1.84 mmol) was added, to the reaction mixture and stirred for 2h at room temperature. After that, the product was precipitated in ice, filtered and air-dried. Finally, the product was purified using flash chromatography (Hexane:EtOAc) (40:60) to obtain 360 mg (74%) of the final product. LCMS / MS: m / z 317.44 [M+H]+

[0483] Synthesis of 2-oxo-1,2,3,4-tetrahydroquinolin-6-yl (5-fluoro-2-methylphenyl)carbamate (TR-G097)

[0484] 107

[0485] 250 mg of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.53 mmol) wasstirred with 265 µL of the TEA (1.84 mmol) for 1 h in THF and drops of DMF, then 240 µL of 2-fluoro-5-methylphenyl isocyanate (1.84 mmol) was added, to the reaction mixture and stirred for 2h at room temperature. After that, the product was precipitated in ice, filtered and air-dried. Finally, the product was purified using flash chromatography (Hexane:EtOAc:TEA) (40:60:1%) to obtain 360 mg (75%) of the final product. LCMS / MS: m / z 315.66 [M+H]+

[0486] 1H NMR (500 MHz, CDCL3-d6 -H), 7.92 (s, H. N-H), 7.18-6.96 (m, 6Harom), 2.99-2.96 (t, J = 5 Hz, 2H. CH2-CH2-C=O), 2.66-2.63 (m, 2H. CH2-C=O), 2.31 (C=O), 144.75, 134.03, 133.45, 133.42, 124.25, 123.79, 123.25, 120.35, 119.57, 115.01, 113.56, 113.40, 29.29, 24.37, 20.22

[0487] Synthesis of 6-(4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy)-1-isopentyl-3,4-dihydroquinolin-2(1H)-one (TR-G101)

[0488]

[0489] Following procedure A, 250 mg of 6-(3-(1-cyclohexyl-1H-tetrazol-5-yl)propoxy)-3,4-dihydroquinolin-2(1H)-one (0.676 mmol) was stirred with 330 mg of the base Cs2CO3 (1.01 mmol) for 1 h in THF and drops of DMF, then 98 µL of 1- bromo-3-methylbutane (0.812 mmol) was added, to the reaction mixture and stirred for 12h at room temperature. After that, the solvent was evaporated and the product was extracted in DCM / water system, the organic layer was dried over anhydrous magnesium sulfate MgSO4 and the solvent was evaporated under vacuum. Finally, the product was purified using flash chromatography (Hexane:EtOAc:TEA) (40:60:1%) to obtain 198 mg (67%) of the final product. LCMS / MS: m / z 440.29 [M+H]+

[0490] 1H NMR (500 MHz, DMSO-d6 -6.80 (m, 3Harom), 4.43-3.38 (qui,2H cyclohexan), 4.01-3.98 (t, 2H.. J = 5Hz. N-CH2), 3.87-3.84 (t, 2H.. J = 5Hz. CH2-O), 2,99-2.96 (t, 2H. J = 5Hz CH2-N-C-CH2), 2.78 (t, 2H. J = 5Hz. CH2-CH2-C=O), 2.48-2.45(t, 2H. J=5Hz. CH2-C=O), 1.97-1.87 (m, 4HCyclohexan), 1.84-1.78(m, 4H Cyclohexan),1081.76-1.56(m, 2HCyclohexan), 1.55-1.42(m, 2H. CH2), 1.39-1.36 (m, 2H , CH2). 1.36-1.26(m, 2H. CH2), 1.24-1.06 (m, 1H. >CH-), 0.91 (S, 3H. -CH3) 0.90114.80 (2C), 113.12 (2C), 67.54, 56.51, 36.10, 32.93, 31.87, 28.46, 26.05, 25.49 (2C), 25.06, 25.03, 23.74, 22.92, 22.25 (2C).

[0491] Synthesis of ethyl 2-(6-(4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetate (TR-G102)

[0493] Following procedure A, 250 mg of 6-(3-(1-cyclohexyl-1H-tetrazol-5-yl)propoxy)-3,4-dihydroquinolin-2(1H)-one (0.703 mmol) was stirred with 145.81 mg of the base Cs2CO3 (1.06 mmol) for 2 h. in THF and drops of DMF, then 129.29 mg of ethyl 2-chloroacetate (1.06 mmol) was added, slowly to the reaction at room temperature. The reaction was tested until finished by TLC and after workup and flash chromatography (Hexan:EtOAc:MeOH) (50:50:3), the final product was filtered and obtained 279 mg (87%) of TR-G102 as milky white crystals. LCMS / MS: m / z 456.2 [M+H]+

[0494] 1H NMR (500 MHz, DMSO-d6 6.77 (m, 3Harom.), 4.61 (s, 2H. >N-CH2-C=O), 4.45 4.38 (m, 1H. >N-CH<), 4.13 (q, J = 7.1 Hz, 2H. -O-CH2-CH3), 4.00(t, J = 6.1 Hz, 2H. O-CH2-CH2-), 2.99 (t, J = 7.5 Hz, 2H. -CH2-CH2-C=O), 2.88 2.82(m, 2H. N=CH-CH2-CH2), 2.57 2.51 (m, 2H. CH2-CH2-C=O), 1.98-1.95 (m, 2H. - CH2-CH2-CH2-O-), 1.92 1.73 (m, 8H.6HCyclohexane, O-CH2-CH2), 1.70-1.65 (m,1HCyclohexane), 1.48-1.38 (m, 2HCyclohexane), 1.31 1.23 (m, 1HCyclohexane), 1.20 (t, J = 7.1Hz, 3H. -CH3). 13C NMR (12 -C=O), 168.69 (O-C=O),154.18 (CTetrazole), 154.08 (O-Carom)., 132.96, 127.58, 115.77, 114.22, 112.53, 67.15, 60.76, 56.05, 44.09, 32.46 (2CCyclohexane), 30.94, 28.01, 24.86, 24.60 (2CCyclohexane), 24.57, 23.27, 21.82, 14.01 (-CH3).

[0495] Synthesis of 1-allyl-6-(4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one (TR-G103)109

[0496]

[0497] Following procedure A, 250 mg of 6-(3-(1-cyclohexyl-1H-tetrazol-5-yl)propoxy)-3,4-dihydroquinolin-2(1H)-one (0.676 mmol) was stirred with 330 mg of the base Cs2CO3 (1.01 mmol) for 1 h in THF and drops of DMF, then 70 µL of allyl bromide (0.812 mmol) was added, to the reaction mixture and stirred for 8h at room temperature. After that, the solvent was evaporated and the product was extracted inDCM / water system, the organic layer was dried over anhydrous magnesium sulfateMgSO4 and the solvent was evaporated under vacuum. Finally, the product was purified using flash chromatography (Hexane:EtOAc) (40:60) to obtain 195 mg (70%) of the final product. LCMS / MS: m / z 410.68 [M+H]+.

[0498] Synthesis of 6-(4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy)-1-(4-methylbenzyl)-3,4-dihydroquinolin-2(1H)-one (TR-G104)

[0499]

[0500] Following procedure A, 250 mg of 6-(3-(1-cyclohexyl-1H-tetrazol-5-yl)propoxy)-3,4-dihydroquinolin-2(1H)-one (0.676 mmol) was stirred with 330 mg of the base Cs2CO3 (1.01 mmol) for 1 h in THF and drops of DMF, then 108 µL of 4- methylbenzyl chloride (0.812 mmol) was added, to the reaction mixture and stirred for 10h at room temperature. After that, the product was precipitated in water. Filtered and air-dried. Finally, the product was purified using flash chromatography (Hexane:EtOAc) (40:60) to obtain 210 mg (66%) of the final product as beige powder. LCMS / MS: m / z 474.87 [M+H]+

[0501] Synthesis of 6-(4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy)-1-propyl-3,4-dihydroquinolin-2(1H)-one (TR-G105)110

[0503] Following procedure A, 250 mg of 6-(3-(1-cyclohexyl-1H-tetrazol-5-yl)propoxy)-3,4-dihydroquinolin-2(1H)-one (0.676 mmol) was stirred with 330 mg of the base Cs2CO3 (1.01 mmol) for 1 h in THF and drops of DMF, then 74 µL of 1- bromopropane (0.812 mmol) was added, to the reaction mixture and stirred for 14h at room temperature. After that, the solvent was evaporated and the product was extracted in DCM / water system, the organic layer was dried over anhydrous magnesium sulfate MgSO4 and the solvent was evaporated under vacuum. Finally, the product was purified using flash chromatography (Hexane:EtOAc:TEA) (40:60:1%) to obtain 210 mg (75%) of the final product as light yellow powder. LCMS / MS: m / z 412.82 [M+H]+

[0504] 1H NMR (500 MHz, DMSO-d6 -6.79 (m, 3Harom), 4.43-3.38 (m, 2HCyclohexan), 4.01-3.98 (t, J = 5Hz. 2H. N-CH2), 3.82-3.79 (t, J = 5Hz, 2H. CH2-O), 2.98(t, J = 5Hz, 2H. CH2-N-C-CH2), 2.81-2.78 (t, 2H. J = 5Hz. CH2-CH2-C=O), 2.50-2.47(t, J=5Hz, 2H.CH2-C=O), 2.02-1.89 (m, 2H Cyclohexan), 1.87-1.76 (m, 4H Cyclohexan), 1.75-1.66 (m, 4H Cyclohexan), 1.41-1.24(m, 4H , CH2CH2), 0.86-0.83 (t, J = 5Hz. 3H. CH3). 13C114.75, 113.11(2C), 67.55, 56.52, 42.90, 32.93 (2C), 31.85, 28.47, 25.51, 25.06 (2C), 23.74, 22.26, 20.44, 11.46.

[0505] Synthesis of 6-(4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy)-1-(3-phenylpropyl)-3,4-dihydroquinolin-2(1H)-one (TR-G106)

[0506]

[0507] Following procedure A, 250 mg of 6-(3-(1-cyclohexyl-1H-tetrazol-5-yl)propoxy)-3,4-dihydroquinolin-2(1H)-one (0.676 mmol) was stirred with 330 mg of the base Cs2CO3 (1.01 mmol) for 1 h in THF and drops of DMF, then 124 µL of (3-111 broopropyl)benzene (0.812 mmol) was added, to the reaction mixture and stirred for 16h at room temperature. After that, the solvent was evaporated and the product was extracted in DCM / water system, the organic layer was dried over anhydrous magnesium sulfate MgSO4 and the solvent was evaporated under vacuum. Finally, the product was purified using flash chromatography (Hexane:EtOAc:TEA) (40:60:1%) to obtain 276 mg (83%) of the final product as beige powder. LCMS / MS: m / z 488.81 [M+H]+.

[0508] 1H NMR (500 MHz, DMSO-d6 -6.71 (m, 8Harom), 4.43-3.37 (qui, 2Hcyclohexan), 4.01-3.98 (t, 2H. J = 5Hz..N-CH2), 3.89-3.86 (t, 2H.. J = 5Hz. CH2-O), 2,99- 2.96 (t, 2H. J = 5Hz CH2-N-C-CH2), 2.80-2.77 (t, 2H. J = 5Hz. CH2-CH2-C=O), 2.63- 2.59 (t, 2H. J = 5Hz CH2-Ph), 2.48-2.46(t, 2H. J=5Hz CH2-C=O), 2.09-1.95 (m, 2Hcyclohexan), 1.92-1.86 (m, 4H cyclohexan), 1.83-1.80 (m, 4H cyclohexan), 1.76-1.65(m, 2H. CH2),1.47-1.41 (m, 2H. CH2).1.30-1.21 ((C=O), 154.57, 154.32, 141.91, 132.97, 128.66, 128.49, 126.26, 116.22, 114.78 (2C),113.04 (2C), 67.54, 56.52, 41.21, 32.92, 32.83, 31.84, 28.97, 28.46, 25.46 (2C), 25.05 (2C), 23.74, 22.26.

[0509] Synthesis of 6-(4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy)-1-(4-vinylbenzyl)-3,4-dihydroquinolin-2(1H)-one (TR-G107)

[0510]

[0511] Following procedure A, 250 mg of 6-(3-(1-cyclohexyl-1H-tetrazol-5-yl)propoxy)-3,4-dihydroquinolin-2(1H)-one (0.676 mmol) was stirred with 330 mg of the base Cs2CO3 (1.01 mmol) for 1 h in THF and drops of DMF, then 115 µL of 4- vinylbenzyl chloride (0.812 mmol) was added, to the reaction mixture and stirred for 15h at room temperature. After that, the product was precipitated in water. Filtered and air-dried. Finally, the product was purified using flash chromatography (Hexane:EtOAc) (40:60) to obtain 264 mg (80%) of the final product. LCMS / MS: m / z 486.77 [M+H]+.

[0512] Synthesis of 1-benzyl-6-(4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one (TR-G110)112

[0513]

[0514] Following procedure A, 250 mg of 6-(3-(1-cyclohexyl-1H-tetrazol-5-yl)propoxy)-3,4-dihydroquinolin-2(1H)-one (0.676 mmol) was stirred with 330 mg of the base Cs2CO3 (1.01 mmol) for 1 h in THF and drops of DMF, then 94 µL of benzyl chloride (0.812 mmol) was added, to the reaction mixture and stirred for 10h at room temperature. After that, the product was precipitated in water. Filtered and air- dried. Finally, the product was purified using flash chromatography (Hexane:EtOAc) (40:60) to obtain 240 mg (77%) of the final product as brown powder. LCMS / MS: m / z 460.32 [M+H]+.

[0515] 1H NMR (500 MHz, DMSO-d6) 7.24-6.53 (m, 8Harom), 5.08(S, 2H), 4.07-4.01 (qui, H cyclohexan), 3.89-3.86 (t, 2H. J = 6Hz. CH2-O), 2.88-2.85 (t, 2H. J = 7.6 - CH2), 2.84-2.81 (t, 2H. J = 7.6Hz .CH2-CH2-C=O), 2.71-2.68 (m, 2H.CH2-C=O), 1.95- 1.78(m, 10H cyclohexan), 1.33-1.18 (m, 4H, CH2. aliphatic).

[0516] 13 (169.07 C=O), 153.43, 152.46, 136.01,132.43, 127.67, 126.89, 126.00, 125.34, 115.49, 113.40, 111.42, 66.33, 56.56, 45.16, 31.86 (2C), 30.82 (2C), 27.47, 24.81, 24.28, 23.76 (2C), 22.96 (2C), 21.97.

[0517] Synthesis of 1-(4-chlorobenzyl)-6-(4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one (TR-G111)

[0518]

[0519] Following procedure A, 400 mg of 6-(3-(1-cyclohexyl-1H-tetrazol-5-yl)propoxy)-3,4-dihydroquinolin-2(1H)-one (1.08 mmol) was stirred with 529 mg of Cs2CO3 (1.62 mmol) for 2h in THF and drops of DMF, then 174 mg of 4-chlorobenzyl chloride (1.08 mmol) was added, to the reaction mixture and stirred for 24h. After completing the reaction, the solvent was evaporated and the crude product was washed with ice water, filtered, and dried. The final product was purified using flash113 chromatography (Hexane:EtOAc:) (50:50) to obtain 420 mg (78%) as white powder. LCMS / MS: m / z 495.31 [M+H]+.

[0520] Synthesis of 6-(4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy)-1-(4-fluorobenzyl)-3,4-dihydroquinolin-2(1H)-one (TR-G112)

[0521]

[0522] Following procedure A, 250 mg of 6-(3-(1-cyclohexyl-1H-tetrazol-5-yl)propoxy)-3,4-dihydroquinolin-2(1H)-one (0.676 mmol) was stirred with 330 mg of the base Cs2CO3 (1.01 mmol) for 1 h in THF and drops of DMF, then 94 µL of 4- flourobenzyl chloride (0.812 mmol) was added, to the reaction mixture and stirred for 12h at room temperature. After that, the product was precipitated in water. Filtered and air-dried. Finally, the product was purified using flash chromatography (Hexane:EtOAc) (40:60) to obtain 258 mg (79%) of the final product as beige powder. LCMS / MS: m / z 478.66 [M+H]+.

[0523] 1H NMR (500 MHz, DMSO-d6 -6.68 (m, 7Harom),5.10 (S, 2H), 4.41-3.36 (qui, 2H cyclohexan), 3.97-3.94 (t, 2H. J = 5Hz. CH2-O), 2.95 (t, J = 5Hz, 2H. CH2), 2,90 (t, J = 5Hz, 2H. CH2-CH2-C=O), 2.64 (t, 2H. J = 5Hz. CH2-C=O), 2.09-1.85 (m,4H cyclohexan), 1.83-1.79(m, 4H Cyclohexan), 1.77-1.67(m, 2H Cyclohexan), 1.65-1.39 (m, 2H,CH2), 1.28-1.22 (m, 2H. CH2). 13160.59, 154.50, 134.03, 132.95, 128.84, 128.37, 116.69, 115.81, 115.64 (2C), 114.77 (2C), 112.90, 67.52, 56.50, 44.24, 32.91, 31.67, 28.42, 25.39, 25.04 (2C), 23.71 (2C), 22.23.

[0524] Synthesis of Allyl 6-(4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (TR-G114)

[0525] 114

[0526] Following procedure A, 250 mg of 6-(3-(1-cyclohexyl-1H-tetrazol-5-yl)propoxy)-3,4-dihydroquinolin-2(1H)-one (0.676 mmol) was stirred with 330 mg of the base Cs2CO3 (1.01 mmol) for 1 h in THF and drops of DMF, then 84 µL of allyl chloroacetate (0.812 mmol) was added to the reaction mixture and stirred for 13h at room temperature. After that, the product was precipitated in water. Filtered and air-dried. Finally, the product was purified using flash chromatography (Hexane:EtOAc)(40:60) to obtain 238 mg (77%) of the final product. LCMS / MS: m / z 454.72[M+H]+.

[0527] Synthesis of 4-(6-(4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)butyl benzoate (TR-G115)

[0529] Following procedure A, 250 mg of 6-(3-(1-cyclohexyl-1H-tetrazol-5-yl)propoxy)-3,4-dihydroquinolin-2(1H)-one (0.676 mmol) was stirred with 330 mg of the base Cs2CO3 (1.01 mmol) for 1 h in THF and drops of DMF, then 152 µL of 4- chlorobutyl benzoate (0.812 mmol) was added to the reaction mixture and stirred for 18h at room temperature. After that, the product was precipitated in water. Filteredand air-dried. Finally, the product was purified using flash chromatography(Hexane:EtOAc) (40:60) to obtain 245 mg (66%) of the final product. LCMS / MS: m / z 446.90 [M+H]+.

[0530] Synthesis of 6-((3-(2-chloro-6-fluorophenyl)isoxazol-5-yl)methoxy)-3,4-dihydroquinolin-2(1H)-one (TR-G116)

[0531]

[0532] Compound TR-G116 has been prepared according to procedure A and F.Firstly, TR-G006 was prepared according to procedure A as previously mentioned.115 After that, a solution of 700 mg of 2-chloro-6-fluorobenzaldehyde (4.14 mmol), 614 mg of hydroxylamine hydrochloride (8.83 mmol) and 742 mg of NaHCO3 in ethanol were refluxed for 3h to prepare the corresponding oxime. The reaction was monitored by TLC until compliting reaction. Then the product was filtered, washed and dried. In cyclization step, 250 mg of TR-G006 (1.24 mmol) and 259 mg of 2-chloro-6- fluorobenzaldehyde oxime (1.49 mmol) were dissolved in chloroform then catalytic amount of calcium hypochlorite was added to the mixture in ice bath 0 °C for 8 h, then water was added, and the product was extracted with chloroform (3x 30 mL). The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under vacuum. The crude was purified using combiflash chromatography (Hexane:EtOAc) (60:40) to afford 256 mg (55%) of the final product. LCMS / MS: m / z 373.90 [M+H]+.

[0533] 1H NMR (500 MHz, DMSO-d6 -H), 7.93-6.97 (m, 6Harom),7.09 (s, 1HOxazole), 5.33 (S, 2H), 2.92 -2.89 (t, 2H. J = 7.5Hz. CH2-CH2-C=O), 2.48- 2.45 (m, 2H. CH2-C=O).

[0534] 13 -C=O), 169.11, 161.51, 153.11,135.53, 129.86, 129.73, 128.93, 128.50, 127.58, 119.82, 114.58 (2C), 114.06 (2C),(102.87 oxazole), 61.42, 30.79, 26.06.

[0535] Synthesis of 2-(3-(4-(((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)propyl)isoindoline-1,3-dione (TR-G117)

[0537] Compound TR-G117 has been prepared according to procedure A and E. Inthe first step, 2-(3-azidopropyl)isoindoline-1,3-dione was prepared starting from 700 mg of 2-(3-chloropropyl)isoindoline-1,3-dione (4.10 mmol) which were refluxed with 534 mg of sodium azide salt (8.20 mmol) for 2 hours in ethanol / water (2:1). After that, the mixture was cooled to room temperature and filtered. Secondly, 6-(prop-2- yn-1-yloxy)-3,4-dihydroquinolin-2(1H)-one TR-G006 was prepared according to procedure A as mentioned before. In the last step, a mixture of 6-(prop-2-yn-1-116 yloxy)-3,4-dihydroquinolin-2(1H)-one TR-G006 (250 mg, 1.24 mmol), 29.74 mg of copper sulfate (0.186 mmol) and 12 mg of sodium ascorbate (0.062 mmol) in EtOH was added to the 2-(3-azidopropyl)isoindoline-1,3-dione solution and stirred for 18 h. After that, the ethanol was evaporated. The residue was dissolved in water and themixture was extracted with ethyl acetate (3 × 50 ml), dried over anhydrousmagnesium sulfate MgSO4 and the solvent was evaporated under vacuum. Finally, the product was purified using flash chromatography (Hexane:EtOAc:TEA) (40:60:1%) to obtain 259 mg (45%) of compound TR-G117. LCMS / MS: m / z 432.10 [M+H]+.

[0538] 1H NMR (500 MHz, DMSO-d6 N-H), 8.20 (s, 1HTraizole),6.86-6.76 (m, 7Harom), 5.04 (S, 2H), 4.45- 4.42 (t, 2H. CH2 J = 7.5 Hz.), 3.64- 3.61 (t,2H. CH2 J = 7.5 Hz.), 2.85-2.82 (t, 2H. J = 5 Hz CH2CH2-C=O) 2.41 -2.38 (t, 2H. J = 5 Hz. CH2-C=O) 2.21-2.16(m, 2H. CH2).13-C=O), (168.422C=O), 153.66, 143.17, 134.76, 132.52, 132.21, 125.31, (124.94, 2C),(123.452C), (116.202C), 114.83, 113.74, 61.92, 47.72, 35.37, 30.79, 29.16, 25.56.

[0539]

[0540] Synthesis of N-(4-morpholinophenyl)-2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetamide (TR-G120)

[0541]

[0542] Following procedure B, the intermediate 2-chloro- N-(-(4-morpholinophenyl)acetamide was prepared by dissolving 300 mg of 4- morpholinoaniline (1.68 mmol) with 365 µLTEA (2.52 mmol) in THF, then 163 µL of chloroacetyl chloride (2.02 mmol) was added drop wisely to the reaction mixture in ice bath (0-5 °C). After completing the reaction, the solvent was evaporated under vacuum, and the residue was washed with distilled water, filtered and dried. The second step was according to procedure A, 200 mg of 6-hydroxy-3,4- dihydroquinolin-2(1H)-one (1.23 mmol) was stirred with 254 mg of the base K2CO3(1.84 mmol) for 15 min in DMF after that 312 mg of 2-chloro- N-(-(4-morpholinophenyl)acetamide (1.23 mmol) was added to the reaction mixture and117 stirred for 24h. After that, the product was precipitated in ice water and brine, filtered and air-dried then purified using column chromatography (Hexane:EtOAc) (60:40) to afford 400 mg (85%) of the product as brown powder. LCMS / MS: m / z 382.11 [M+H]+.

[0543] 1H NMR (500 MHz, DMSO-d6 N-H), 90.82 (s, 1H. N-H),7.51-6.77(m, 7Harom), 4.58 (S, 2H.), 3.73-3.71 (t, J = 5Hz .4Hmorphline), 3.05-3.03 (t, J = 5Hz.4HMorphline), 2.85-2.82 (t, J = 7.6 Hz, 2H. CH2-CH2-C=O), 2.42-2.39 (t, J = 7.6 Hz, 2H. CH2-C=O).13-C=O), (166.51 -C=O), 153.45, 148.00, 132.82, 130.99, 125.30, 121.36, 116.17 (2C), 115.77 (2C), 114.91, 113.72, 68.11, 66.56 (2C), 49.30 (2C), 30.77, 25.56.

[0544] Synthesis of N-(2-chloropyridin-4-yl)-2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-6-yl)oxy)Acetamide (TR-G121)

[0546] Following procedure B, the intermediate 2-chloro- N-(2-chloropyridin-4-yl)acetamide was prepared by dissolving 300 mg of 2-chloropyridin-4-amine (2.33 mmol) with 506 µLTEA (2.5 mmol) in THF, then 266 µL of chloroacetyl chloride (2.80 mmol) was added drop wisely to the reaction mixture in ice bath (0-5 °C). After completing the reaction, the solvent was evaporated under vacuum, and the residue was washed with distilled water, filtered and dried. The second step was according to procedure A, 200 mg of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.23 mmol) was stirred with 254 mg of the base K2CO3 (1.84 mmol) for 15 min in DMF after that 251mg of 2-chloro- N-(2-chloropyridin-4-yl)acetamide (1.23 mmol) was added to thereaction mixture and stirred for 24h. After that, the product was precipitated in ice water and brine, filtered and air-dried then purified using column chromatography (Hexane:EtOAc) (60:40) to afford 325 mg (80%) of the product as beige powder. LCMS / MS: m / z 373.90 [M+H]+.

[0547] Synthesis of N-(5-nitropyridin-2-yl)-2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetamide (TR-G122)118

[0549] Following procedure B, the intermediate 2-chloro-N-(5-nitropyridin-2-yl)acetamide was prepared by dissolving 320 mg of 5-nitropyridin-2-amine (2.30 mmol) with 481 µL TEA (3.45 mmol, d=0.726 g / mL) in THF, then 220 µL of chloroacetyl chloride (2.76 mmol, d=1.42 g / mL) was added drop wisely to the reaction mixture in ice bath (0-5 °C). After the reaction complete, the solvent was evaporated under vacuum, and the residue was washed with distilled water, filtered, and dried. The second step was according to procedure A, 250 mg of 6-hydroxy-3,4- dihydroquinolin-2(1H)-one (1.35 mmol) was stirred with 280 mg of the base K2CO3 (2.02 mmol) for 3 hours in DMF. After that, 348 mg of 2-chloro-N-(5-nitropyridin-2- yl)acetamide (1.62 mmol) was added to the reaction mixture and stirred for 24 h. After that, the product was precipitated in ice water and brine, filtered and air-dried then purified using column chromatography (Hexane:EtOAc) (50:50) to afford 390 mg (78%) of the product as white powder. LCMS / MS: m / z 343.22 [M+H]+.

[0550] 1H NMR (500 MHz, DMSO-d6 -8.39 (m, 3Hpyridine),7.39-6.78 (m, 3Harom), 4.77 (s, 2H), 2.93-2.87 (m, 2H), 2.65-2.50124.67, 119.38, 115.51, 115.29, 112.87, 66.90, 31.01, 27.81.

[0551] Synthesis of 2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)-N-4-bromophenyl)acetamide (TR-G123)

[0552]

[0553] Following procedure B, the intermediate 2-chloro- N-(4-bromophenyl)acetamide was prepared by dissolving 300 mg of 4-bromoaniline (1.74 mmol) with 378 µLTEA (2.62 mmol) in THF, then 169 µL of chloroacetyl chloride (2.09 mmol) was added drop wisely to the reaction mixture in ice bath (0-5 °C). After completing the reaction, the solvent was evaporated under vacuum, and the residue was washed with distilled water, filtered, and dried. The second step was according to119 procedure A, 200 mg of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.23 mmol) was stirred with 254 mg of the base K2CO3 (1.84 mmol) for 15 min in DMF after that 305mg of 2-chloro- N-(4-bromophenyl)acetamide (1.23 mmol) was added to the reactionmixture and stirred for 24h. After that, the product was precipitated in ice water and brine, filtered and air-dried then purified using column chromatography (Hexane:EtOAc) (60:40) to afford 377 mg (81%) of the product. LCMS / MS: m / z 375.01 [M+H]+.

[0554] Synthesis of 6-((1-hexyl-1H-1,2,3-triazol-4-yl)methoxy)-3,4-dihydroquinolin-2(1H)-one (TR-G125)

[0556] Compound TR-G125 has been prepared according to procedure A and E.In the first step, 1-azidohexane was prepared starting from 500 µL of 1-bromhexane (3.57 mmol) which were refluxed with 464 mg of sodium azide salt (7.15 mmol) for 2hours in ethanol / water (2:1). After that, the mixture was cooled to room temperatureand filtered. Secondly, 200 mg of 6-(prop-2-yn-1-yloxy)-3,4-dihydroquinolin-2(1H)- one TR-G006 was prepared according to procedure A as mentioned before. In the last step, a mixture of -(prop-2-yn-1-yloxy)-3,4-dihydroquinolin-2(1H)-one TR-G006 (200 mg, 1 mmol), 23.79 mg of copper sulfate (0.149 mmol) and 8 mg of sodium ascorbate (0.049 mmol) in EtOH was added to the azidohexane solution and stirred for 24 h. After that, the ethanol was evaporated. The residue was dissolved in waterand the mixture was extracted with ethyl acetate (3 × 50 ml), dried over anhydrousmagnesium sulfate MgSO4 and the solvent was evaporated under vacuum. Finally, the product was purified using flash chromatography (Hexane:EtOAc:TEA) (40:60:1%) to obtain 310 mg (68%) of compound TR-G125 as brown powder. LCMS / MS: m / z 329.41 [M+H]+.

[0557] 1H NMR (500 MHz, DMSO-d6 -H), 8.19 (s, 1HTraizole),6.88-6.76 (m, 3Harom), 5.06 (S, 2H), 4.36-4.33 (t, 2H. J = 5Hz. N-CH2), 2.85-2.82 (t,2H J = 5Hz.CH2- CH2-C=O) 2.42 -2.39 (t, 2H. J = 5Hz. CH2-C=O), 1.83-1.77 (q, 2H),1.25-1.19 (m, 6H.), 0.85-0.82 (t, 3H. J = 5 Hz. CH3).13120 (170.22, NH-C=O), (153.64, Ctraizole), 143.21, 132.50, 125.30, 124.72, 116.19, 114.84, 113.74, 61.90, 49.81, 31.03, 30.79, 30.11, 25.94, 25.56, 22.39, 14.30.

[0558] Synthesis of 2-(2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)ethoxy)acetamide (TR-G126)

[0559]

[0560] Following procedure A, 250 mg of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.5 mmol) was stirred with 317.6 mg of the base K2CO3 (2.3 mmol) for 30 min in THF and drops of DMF, then 214 µL of 2-(2-chloroethoxy)acetamide (1.84 mmol) was added slowly to the reaction mixture at room temperature and stirred for 18 h. After completing the reaction, the product was precipitated in water, filtered and air- dried. After that, the purification was carried out using flash chromatography(Hexane:EtOAc) (40:60) to obtain 318 mg as beige powder. LCMS / MS: m / z 265.27[M+H]+.

[0561] 1H NMR (500 MHz, DMSO-d6 -H), 7.30 (s, 1H. N-H), 7.18(s, 1H. N-H) 6.80-6.73 (m, 3Harom), 4.08-4.087 (t, 2H J =5 Hz. O-CH2), 3.88 (S, 2H- CH2-C=O) 3.77 -3.75 (t, 2H. J = 5Hz. CH2-O), 2.84-2.81 (t, 2H. J =5 Hz .CH2 CH2- C=O), 2.41 -2.38 (NH-C=O), (170.23, C=O-NH2), 153.98, 132.35, 125.33, 116.23, 114.52, 113.48, 70.34, 69.91, 67.65, 30.80, 25.55.

[0562] Synthesis of (E)-N'-(4-fluorobenzylidene)-2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetohydrazide (TR-G128)

[0564] Starting from 6-hydroxy-3,4-dihydroquinolin-2(1H)-one, compound 2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetohydrazide (TR-G019) was prepared through couple of steps following procedures A and C respectively. After that following procedure D, 200 mg of TR-G019 (0.850 mmol) was refluxed with 100 µL of 4-flourobenzaldehyde (0.935 mmol) were refluxed in ethanol and drops of acetic acid for 6 h. After completing the reaction, the precipitate was filtered out of the hot121 ethanol, washed with hot ethanol and dried to obtain 250 mg (86%) of the final product as white powder. LCMS / MS: m / z 342.22 [M+H]+.

[0565] 1H NMR (500 MHz, DMSO- -NH-N=), 9.97(*9.93, s, 1H. C-NH-C), 8.35 (*8.01, s, 1H. N=CH-) 7.79-6.73 (m, 7Harom), 5.08 (s, 1H. O-CH2-C=O), 4.61 (s, 1H. O-CH2-C=O), 2.87-2.82 (m, 2H. O=C-CH2-CH2-), 2.43-2.39

[0568] Following procedure B, 250 mg of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.5 mmol) was stirred with 317.6 mg of the base K2CO3 (2.3 mmol) for 30 min in in THF and drops of DMF, then 250 mg of diisopropylcarbamic chloride(1.5 mmol) was added to the reaction and stirred for 16h at room temperature. After that, THF was evaporated, the residue was dissolved in water and the product was extracted inDCM (3 × 50 ml), dried over anhydrous magnesium sulfate MgSO4 and the solventwas evaporated under vacuum to obtain 320 mg (71%) of TR-G129. LCMS / MS: m / z 291.41 [M+H]+.

[0569] Synthesis of 2-oxo-1,2,3,4-tetrahydroquinolin-6-yl phenylcarbamate (TR-G131)

[0570]

[0571] 250 mg of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.5 mmol) wasstirred with 265 µL of the TEA (1.84 mmol) for 1 h in THF and drops of DMF, then 201 µL of phenyl isocyanate (1.84 mmol) was added to the reaction mixture and stirred for 2h at room temperature. After that, the product was precipitated in ice, filtered, and air-dried. Finally, the product was purified using flash chromatography122 (Hexane:EtOAc) (40:60) to obtain 350 mg (81%) of the final product. LCMS / MS: m / z 283.11 [M+H]+.

[0572] 1H NMR (500 MHz, DMSO-d6 -H), 10.13 (s, 1H. N-H),7.52-6.87(m, 8Harom), 2.90 -2.87 (t, J = 5 Hz, 2H .CH2-CH2-C=O) 2.47-2.44 (t, J =5 Hz, 2H. CH2-C=O)13-C=O), (152.49 NH- C=O), 145.46, 139.13, 136.24, 129.33, 125.10, 123.36, 121.83, 120.94, 118.82, 115.90, 114.31, 113.88, 30.56, 25.18.

[0573] Synthesis of 2-oxo-1,2,3,4-tetrahydroquinolin-6-yl (2-methoxyphenyl)carbamate (TR-G132)

[0574]

[0575] 250 mg of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.5 mmol) wasstirred with 265 µL of the TEA (1.84 mmol) for 1 h in THF and drops of DMF, then 244 µL of 2-methoxyphenyl isocyanate (1.84 mmol) was added to the reaction mixture and stirred for 2h at room temperature. After that, the product was precipitated in ice, filtered and air-dried. Finally, the product was purified using flash chromatography (Hexane:EtOAc) (40:60) to obtain 371 mg (77%) of the final product. LCMS / MS: m / z 313.33 [M+H]+.

[0576] 1H NMR (500 MHz, DMSO-d6 -H), 9.90 (s, 1H. N-H),7.12-6.57(m, 8Harom), 2.90 -2.86 (t, J=7.2Hz, 2H. -CH2-CH2-C=O), 2.46-2.47(m, 2H. CH2-C=O), 2.09 (S, 3H).13-C=O), (170.10 NH-C=O), 152.81, 145.68, 136.13, 127.00, 125.02, 121.74, 120.77, 116.27, 115.84, 115.00, 113.88, 111.88, 56.12, 49.06, 25.17.

[0577] Synthesis of 2-oxo-1,2,3,4-tetrahydroquinolin-6-yl (4-nitrophenyl)carbamate (TR-G133)

[0578] 123

[0579] 250 mg of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.5 mmol) wasstirred with 265 µL of the TEA (1.84 mmol) for 1h in THF and drops of DMF, then 201µL of 4-nitrophenyl isocyanate (1.84 mmol) was added to the reaction mixture and stirred for 2h at room temperature. After that, the product was precipitated in ice, filtered, and air-dried. Finally, the product was purified using flash chromatography (Hexane:EtOAc) (40:60) to obtain 402 mg (80%) of the final product. LCMS / MS: m / z 328.44 [M+H]+.

[0580] Synthesis of 2-oxo-1,2,3,4-tetrahydroquinolin-6-yl-o-tolylcarbamate (TR-G134)

[0581]

[0582] 250 mg of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.5 mmol) wasstirred with 265 µL of the TEA (1.84 mmol) for 1 h in THF and drops of DMF, then 228 µL of o-tolyl isocyanate (1.84 mmol) was added to the reaction mixture and stirred for 2h at room temperature. After that, the product was precipitated in ice, filtered and air-dried. Finally, the product was purified using flash chromatography (Hexane:EtOAc) (40:60) to obtain 375 mg (82%) of the final product. LCMS / MS: m / z 297.44 [M+H]+.

[0583] Synthesis of 2-oxo-1,2,3,4-tetrahydroquinolin-6-yl naphthalene-1-ylcarbamate (TR-G135)

[0584]

[0585] 250 mg of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.5 mmol) wasstirred with 265 µL of the TEA (1.84 mmol) for 1h in THF and drops of DMF, then 263 µL of 1-naphthyl isocyanate (1.84 mmol) was added to the reaction mixture and stirred for 2h at room temperature. After that, the product was precipitated in ice, filtered, and air-dried. Finally, the product was purified using flash chromatography (Hexane:EtOAc) (40:60) to obtain 368 mg (72%) of the final product. LCMS / MS: m / z 333.53 [M+H]+.124

[0586] Synthesis of 2-oxo-1,2,3,4-tetrahydroquinolin-6-yl (2-bromophenyl)carbamate (TR-G136)

[0588] 250 mg of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.5 mmol) wasstirred with 265 µL of the TEA (1.84 mmol) for 1 h in THF and drops of DMF, then 228 µL of 2-bromophenyl isocyanate (1.84 mmol) was added to the reaction mixture and stirred for 2h at room temperature. After that, the product was precipitated in ice, filtered, and air-dried. Finally, the product was purified using flash chromatography (Hexane:EtOAc) (40:60) to obtain 415 mg (75%) of the final product. LCMS / MS: m / z 362.44 [M+H]+.

[0589] Synthesis of 2-oxo-1,2,3,4-tetrahydroquinolin-6-yl (2-(trifluoromethyl)phenyl)carbamate (TR-G137)

[0590]

[0591] 250 mg of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.5 mmol) wasstirred with 265 µL of the TEA (1.84 mmol) for 1 h in THF and drops of DMF, then 277 µL of 2-(trifluoromethyl)phenyl isocyanate (1.84 mmol) was added to the reaction mixture and stirred for 2h at room temperature. After that, the product was precipitated in ice, filtered, and air-dried. Finally, the product was purified using flash chromatography (Hexane:EtOAc) (40:60) to obtain 391 mg (73%) of the final product. LCMS / MS: m / z 351.33 [M+H]+.

[0592] Synthesis of (E)-N'-(3-(4-chlorophenoxy)benzylidene)-2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetohydrazide (TR-G138)

[0593] 125

[0594] Starting from 6-hydroxy-3,4-dihydroquinolin-2(1H)-one, compound 2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetohydrazide (TR-G019) was prepared through couple of steps following procedures A and C respectively. After that following procedure D, 200 mg of TR-G019 (0.850 mmol) was refluxed with 198 mg of 3-(4-chlorophenoxy)benzaldehyde (0.850 mmol) were refluxed in ethanol and drops of acetic acid for 6 h. After completing the reaction, the precipitate was filtered out of the hot ethanol, washed with hot ethanol and dried to obtain 320 mg (83%) of the final product as white powder. LCMS / MS: m / z 450.92 [M+H]+.

[0595] 1H-NMR (500 MHz, DMSO-d -NH-N=), 9.96(*9.92, s, 1H. C-NH-C), 8.32 (*7.98, s, 1H. N=CH-) 7.49-6.70 (m, 11Harom), 5.03 (s, 1H. O-CH2-C=O), 4.59 (s, 1H. O-CH2-C=O), 2.83-2.80 (m, 2H. O=C-CH2-CH2-), 2.41- 2.37 (m, 2H. O=C-CH2-CH2-). (*refer to the rotameric peak).13C-NMR (126 MHz, 132.47, 132.00, 130.71, 129.94, 127.39, 124.74, 122.72, 120.28, 116.74, 115.74, 114.13, 113.03, 65.03, 30.36, 25.10.

[0596] Synthesis of 2-oxo-1,2,3,4-tetrahydroquinolin-6-yl 3-flurobenzoate (TR-G139)

[0598] Following procedure B, 250 mg of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.5 mmol) was stirred with 317.6 mg of the base K2CO3 (2.3 mmol) for 30 min in in THF and drops of DMF, then 224 µL of 3-fluorobenzoyl chloride was added slowly to the reaction at room temperature and stirred for 7h. After that, THF was evaporated, the residue was dissolved in water and the product was extracted in DCM(3 × 50 ml), dried over anhydrous magnesium sulfate MgSO4 and the solvent wasevaporated under vacuum to obtain 332 mg of TR-G139 (76%) as white powder. LCMS / MS: m / z 286.33 [M+H]+.

[0599] Synthesis of 2-oxo-1,2,3,4-tetrahydroquinolin-6-yl (4-fluorophenyl)carbamate (TR-G140)126

[0600]

[0601] 250 mg of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.5 mmol) wasstirred with 265 µL of the TEA (1.84 mmol) for 1 h in THF and drops of DMF, then 210 µL of 4-fluorophenyl isocyanate (1.84 mmol) was added to the reaction mixture and stirred for 2h at room temperature. After that, the product was precipitated in ice, filtered and air-dried. Finally, the product was purified using flash chromatography (Hexane:EtOAc) (40:60) to obtain 378 mg (82%) of the final product. LCMS / MS: m / z 301.11 [M+H]+.

[0602] 1H NMR (500 MHz, Chloroform-d -O-CO-NH-), 8.10 (s, 1H.O=C-NH), 7.21-6.77 (m, 7H), 3.01-2.96 (m, 2H. -CH2-CH2-C=O), 2.65 (m, 2H. -CH2- C=O).13C NMR (126 MHz, CDCl3 -Cph), 145.88, 135.19, 125.04, 124.92, 124.89, 121.63 (2C), 121.59, 120.77 (2C), 116.04 (2C), 30.47, 25.58.

[0603] Synthesis of (E)-N'-(naphthalen-1-ylmethylene)-2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetohydrazide (TR-G141)

[0604]

[0605] Starting from 6-hydroxy-3,4-dihydroquinolin-2(1H)-one, compound 2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetohydrazide (TR-G019) was prepared through couple of steps following procedures A and C respectively. After that following procedure D, 200 mg of TR-G019 (0.850 mmol) was refluxed with 125 µL of 1-naphthaldehyde (0.935 mmol) were refluxed in ethanol and drops of acetic acid for 6 h. After completing the reaction, the precipitate was filtered out of the hot ethanol, washed with hot ethanol, and dried to obtain 231 mg (72%) of the final product as white powder. LCMS / MS: m / z 374.28 [M+H]+.

[0606] 1H-NMR (500 MHz, DMSO-d -NH-N=), 9.97(*9.93, s, 1H. C-NH-C), 9.02 (*8.68, s, 1H. N=CH-) 8.81-6.75 (m, 10Harom), 5.15 (s, 1H. O-CH2-C=O), 4.66 (s, 1H. O-CH2-C=O), 2.87-2.82 (m, 2H. O=C-CH2-CH2-), 2.43- 2.38 (m, 2H. O=C-CH2-CH2-). (*refer to the rotameric peak).13C-NMR (126 MHz,127 129.22, 128.85, 127.39, 126.30, 125.56, 124.78, 123.75, 115.72, 114.49, 113.07, 65.24, 54.94, 30.31, 25.11.

[0607] Synthesis of 6-((3-(4-fluorophenyl)isoxazol-5-yl)methoxy)-3,4-dihydroquinolin-2(1H)-one (TR-G142)

[0609] Compound TR-G142 has been prepared according to procedure A and F.Firstly, TR-G006 was prepared according to procedure A as previously mentioned. After that, a solution of 700 mg of 4-fluorobenzaldehyde (5.64 mmol), 784 mg of hydroxylamine hydrochloride (11.28 mmol) and 948 mg of NaHCO3 in ethanol were refluxed for 3h to prepare the corresponding oxime. The reaction was monitored by TLC until the completion of reaction. After that, the product was filtered, washed, anddried. In cyclization step, 250 mg of TR-G006 (1.24 mmol) and 229 mg of 4-flourobenzaldehyde oxime (1.49 mmol) were dissolved in chloroform then 184 µL of Calcium hypochlorite (12-16 grade) (2.48 mmol) were added slowly to the mixture in ice bath 0 °C for 8 h, then water was added, and the product was extracted with chloroform (3x 30 mL). The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under vacuum. The crude was purified using combiflash chromatography (Hexane:EtOAc) (60:40) to afford 196 mg (46%) of the final product. LCMS / MS: m / z 339.29 [M+H]+.

[0610] 1H NMR (500 MHz, CDCL3-d -H), 7.62-6.69 (m, 7Harom),6.54 (s, 1HOxazole), 5.09 (S, 2H),2.92 -2.89 (t, 2H. J = 6.7Hz. CH2-CH2-C=O), 2.58- 2.55 (m, 2H. CH2-C=O).

[0611] NMR (126 MHz, -C=O), 166.96, 160.63, 152.20,127.79, 127.73, 125.57, 123.76, 118.98, 115.20 (2C), 115.02(2C), 112.93, 112.90, 100.41, 60.91, 29.36, 25.12.

[0612] Synthesis of N-((1,1`-biphenyl)-4-yl)-2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetamide (TR-G143)128

[0614] Following procedure B, the intermediate N-((1,1`-biphenyl)-4-yl)-2--biphenyl)-4-amine (2.07 mmol) with 448 µLTEA (3.10 mmol) in THF, then 200 µL of chloroacetyl chloride (2.48 mmol) was added drop wisely to the reaction mixture in ice bath (0-5 °C). After completing the reaction, the solvent was evaporated under vacuum, and the residue was washed with distilled water, filtered, and dried. The second step was according to procedure A, 200 mg of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.23 mmol) was stirred with 254 mg of the base K2CO3 (1.84 mmol) for 15 min in DMF after that 282 mg of N-((1,1`-biphenyl)-4-yl)-2-chloroacetamide (1.23 mmol) was added to the reaction mixture and stirred for 24h. After that, the product was precipitated in ice water and brine, filtered and air-dried then purified using column chromatography (Hexane:EtOAc) (60:40) to afford 397 mg (83%) of the product. LCMS / MS: m / z 373.92 [M+H]+.

[0615] Synthesis of 6-(pent-4-en-1-yloxy)-3,4-dihydroquinolin-2(1H)-one (TR-G144)

[0617] Following procedure A, a mixture of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.23 mmol, 200 mg) and K2CO3 (1.84 mmol, 254.09 mg) was stirred for 30 min in THF and drops of DMF. After that, 5-bromopent-1-ene (1.47 mmol, 219.20 mg) 0.174 ml was added to the solution at room temperature. After workup and column chromatography (Hexane:EtOAc) (50:50), 219 mg of TR-G144 (77%) was obtained as off-white crystals. LCMS / MS: m / z 232.44 [M+H]+.

[0618] 1H NMR (500 MHz, CDCL3-d -H), 6.74-6.69 (m, 3Harom),5.89-5.81 (m, H .C=H), 5.08-4.99 (m, 2H .CH2=C), 3.94 -3.91 (t, 2H. J = 6.4 Hz. O- CH2), 2.94 -2.91 (t, 2H. J = 6.6Hz. CH2-CH2-C=O), 2.62-2.59 (m, 2H. CH2-C=O), 2.25 -2.21 (q, 2H. J = 7 Hz. CH=CH2-CH2), 1.89 -1.83 (m, 2H. CH2-CH2-CH2).129

[0619] 13C NMR -C=O), 154.01, 136.75, 129.69,123.93, 115.19, 114.18, 113.45, 112.10, 66.56, 29.61, 29.06, 27.42, 24.67.

[0620] Synthesis of (E)-N'-([1,1'-biphenyl]-4-ylmethylene)-2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetohydrazide (TR-G145)

[0621]

[0622] According to procedure A, C and D starting from 6-hydroxy-3,4-dihydroquinolin-2(1H)-one. Firstly, 300 mg of 6-hydroxy-3,4-dihydroquinolin- 2(1H)-one (1.84 mmol) was stirred with 381 mg of the base K2CO3 (2.76 mmol) for 15 min in THF and drops of DMF, then 244 µL of ethyl 2-bromoacetate (2.21 mmol, d= 1.51 g / mL) was added slowly to the reaction mixture. After the completing of reaction, the solvent was evaporated and the residue was washed with water, filtered and air-dried to obtain ethyl 2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetate (TR-G012) which was further refluxed with 241 µL hydrazine hydrate 99% (4.81 mmol) for 5 hours then it was cooled to room temperature, filtered out of ethanol and dried to obtain 2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetohydrazide (TR- G019). Later, 210 mg of (TR-G019) (0.892 mmol) was refluxed with 211.47 mg of [1,1'-biphenyl]-4-carbaldehyde (1.16 mmol) in ethanol and drops of acetic acid for 6 hours. After that the precipitate was filtered out of ethanol to obtain 283 mg of the final product as white powder with a yield of 79%. LCMS / MS: m / z 400.59 [M+H]+.

[0623] 1H-NMR (500 MHz, DMSO-d -NH-N=), 9.97 (*9.93, s,1H. C-NH-C), 8.39 (*8.05, s, 1H. N=CH-) 7.79-6.76 (m, 12Harom), 5.10 (s, 1H. O-CH2- C=O), 4.61 (s, 1H. O-CH2-C=O), 2.84-2.81 (m, 2H. O=C-CH2-CH2-), 2.42-2.38 (m, 2H. O=C-CH2-CH2-). (* refer to the rotameric peak).13C- 169.79 (O=C<), 164.43 (O=C-NH=N-), 153.45, 147.49, 143.35, 141.42, 139.32, 133.09, 132.48, 132.02, 129.04 (2C), 127.75, 127.06, 126.68 (2C), 124.78, 115.77, 115.71, 114.15, 113.08, 65.09, 30.31, 25.11.

[0624] Synthesis of (E)-N'-((4'-chloro-[1,1'-biphenyl]-4-yl)methylene)-2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetohydrazide (TR-G146)130

[0626] Starting from 6-hydroxy-3,4-dihydroquinolin-2(1H)-one, TR-G146 wasprepared through 3 steps following procedures A, C and D respectively.200 mg of TR-G019 (0.850 mmol) was refluxed with 221 mg of 4'-chloro-[1,1'-biphenyl]-4-carbaldehyde (1.02 mmol) in ethanol and drops of acetic acid. After filtration, theproduct was obtained as pure off-white powder with yield of 84% (310 mg). LCMS / MS: m / z 434.97 [M+H]+.

[0627] 1H-NMR (500 MHz, DMSO-d -NH-N=), 9.96 (*9.92, s,1H. C-NH-C), 8.38 (*8.04, s, 1H. N=CH-) 7.79-6.73 (m, 11Harom), 5.09 (s, 1H. O-CH2- C=O), 4.61 (s, 1H. O-CH2-C=O), 2.86-2.81 (m, 2H. O=C-CH2-CH2-), 2.42-2.38 (m, 2H. O=C-CH2-CH2-). (* refer to the rotameric peak).13C- 169.77 (O=C<), 164.45 (O=C-NH=N-), 153.43, 147.33, 143.20, 140.00, 138.11, 133.43, 132.75, 132.47, 132.01, 128.98, 128.45, 128.44 (2C), 127.58, 126.96, 124.76, 115.69, 114.14, 113.07, 65.08 (O-CH2-C=O), 30.36, 25.10.

[0628] Synthesis of 6-((1-(3-oxobutyl)-1H-1,2,3-triazol-4-yl)methoxy)-3,4-dihydroquinolin-2(1H)-one (TR-G147)

[0630] Compound TR-G147 has been prepared according to procedure A and E.In the first step, 4-azidobutan-2-one was prepared starting from 600 µL of 4- chlorobutan-2-one (5.63 mmol) which were refluxed with 732 mg of sodium azide salt (11.26mmol) for 2 hours in ethanol / water (2:1). After that, the mixture was cooled to room temperature and filtered. Secondly, 200 mg of 6-(prop-2-yn-1-yloxy)- 3,4-dihydroquinolin-2(1H)-one TR-G006 was prepared according to procedure A asmentioned before. In the last step, a mixture of -(prop-2-yn-1-yloxy)-3,4-dihydroquinolin-2(1H)-one TR-G006 (200 mg, 1 mmol), 23.79 mg of copper sulfate (0.149 mmol) and 8 mg of sodium ascorbate (0.049 mmol) in EtOH was added to the131 azidohexane solution and stirred for 12 h. After that, the ethanol was evaporated. The residue was dissolved in water and the mixture was extracted with ethyl acetate(3 × 50 ml), dried over anhydrous magnesium sulfate MgSO4 and the solvent wasevaporated under vacuum. Finally, the product was purified using flash chromatography (Hexane:EtOAc:TEA) (40:60:1%) to obtain 240 mg (76%) of compound TR-G147 as brown powder. LCMS / MS: m / z 315.51 [M+H]+.

[0631] 1H NMR (500 MHz, DMSO-d6 N-H), 8.15 (s, 1HTraizole),6.88-6.76 (m, 3Harom), 5.04 (S, 2H), 4.54-4.151 (t, 2H. J = 7.5 Hz. C=OCH2CH2), 3.15-3.12 (t, 2H. J = 7.5 Hz. C=OCH2CH2), 2.85-2.82 (t, 2H. J = 5 Hz CH2CH2-C=O) 2.42 -2.39 (t, 2H. J = 5 Hz. CH2-C=O) 2.12(S, 3H. CH3).Ctraizole), 143.14, 132.49, 125.33, 125.08, 116.20, 114.79, 113.70, 61.82, 44.78, 42.72, 30.78, 30.22, 25.55.

[0633] Synthesis of 6-((3-(2-chloro-6-fluorophenyl)-4,5-dihydroisoxazol-5-yl)methoxy)-3,4-dihydroquinolin-2(1H)-one (TR-G150)

[0634]

[0635] Compound TR-G150 has been prepared according to procedure A and F.Firstly, TR-G014 was prepared according to procedure A as previously mentioned. After that, a solution of 700 mg of 2-chloro-6-fluorobenzaldehyde (4.41mmol), 583 mg of hydroxylamine hydrochloride (17.66 mmol) and 800 mg of NaHCO3 in ethanol were refluxed for 3h to prepare the corresponding oxime. The reaction was monitored by TLC until the completion of reaction after that the product was filtered, washed and dried. In cyclization step, 300 mg of TR-G014 (2.21 mmol) and 384 mg of 2- chloro-6-fluorobenzaldehyde oxime (2.21mmol) were dissolved in chloroform then catalytic amount of calcium hypochlorite was added to the mixture in ice bath 0 °C for 8 h, then water was added, and the product was extracted with chloroform (3x 30 mL). The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under vacuum. The crude was purified using flash chromatography132 (Hexane:EtOAc) (60:40) to afford 360 mg (65%) of the final product as yellow powder. LCMS / MS: m / z 375.32 [M+H]+.

[0636] 1H NMR (500 MHz, DMSO-d6 -H), 7.50-6.69 (m, 6Harom.),5.01 (tt, J = 6.8, 5.5 Hz, 1H. CHOxazol), 4.22-4.17 (m, 2H), 3.62 (m, 1H. CH2Oxazol), 3.23 (m, 1H. CH2Oxazol), 2.95-2.85 (m, 2H), 2.67-2.53d6130.70 : Coupled with fluorine), (130.47, 130.41 : Coupled with fluorine), 125.14, 125.12 : Coupled with fluorine), 124.44, (119.74, 119.58 : Coupled with fluorine), 119.48, 115.72, 115.48, (114.46, 114.30 : Coupled with fluorine), 77.81, 67.92, (37.87, 37.84 : Coupled with fluorine), 30.95, 27.47.

[0637] Synthesis of 6-((4-(trifluoromethyl)benzyl)oxy)-3,4-dihydroquinolin-2(1H)-one (TR-G161)

[0638]

[0639] Following procedure A, 250 mg of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.5 mmol) was stirred with 600 mg of the base Cs2CO3 (1.84 mmol) for 2 h. in THF and drops of DMF, then 366 mg of 1-(bromomethyl)-4-(trifluoromethyl)benzene (1.5 mmol) was added slowly to the reaction at room temperature. The reaction was tested until finished by TLC and after workup and column chromatography (Hexan:EtOAc) (60:40), the final product was filtered and obtained 360 mg (73%) of TR-G161. LCMS / MS: m / z 321.93 [M+H]+.

[0640] Synthesis of 6-(2-((3-chloro-4-fluorophenyl)amino)ethoxy)-3,4-dihydroquinolin-2(1H)-one (TR-G171)

[0641] 133

[0642] According to procedure A, 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.23mmol, 200 mg) was dissolved in THF and drops of DMF. K2CO3 (1.84 mmol, 254 mg) was added and the mixture was allowed to stir for 2 h. After that, 1,2-dibromoethane (1.59 mmol, 0.137 mL, d: 2.18 g / ml) was added to the mixture at room temperature. After workup and column chromatography (Hexane:EtOAc) (1:1), 251 mg of TR-G017 (94.25%) was obtained as light yellow crystals. In the second step, 3-chloro-4- fluoroaniline (687.00µmol, 100 mg) was dissolved in THF and stirred with K2CO3 (1 mmol, 138 mg) for 2 h at room tempereture. Then, 6-(2-bromoethoxy)-3,4- dihydroquinolin-2(1H)-one ( 687.00 µmol, 185.5 mg) was added to the reaction mixture with contious stirring for 24 h at room temperature. After workup and column chromatography (Hexane:EtOAc:MeOH) (49:50:1), 200 mg of TR-G171 (86.96%) was obtained. LCMS / MS: m / z 334.99 [M+H]+.

[0643] Synthesis of 6-(4,4,4-trifluoro-3-(trifluoromethyl)butoxy)quinolin-2(1H)-one (TR-G172)

[0644]

[0645] Following procedure A, a mixture of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (0. 319 mmol, 52 mg) and K2CO3 (0.478 mmol, 66.09 mg) was stirred for30 min in THF and drops of DMF. After that, 4-bromo-1,1,1-trifluoro-2-(trifluoromethyl)butane (0.382mmol, 99 mg) was added to the solution at roomtemperature. After workup and column chromatography (Hexane:EtOAc) (1:1), 92mg of TR-G172 (77%) was obtained as yellowish white crystals. LCMS / MS: m / z340.34 [M+H]+.

[0646] Synthesis of 6-((1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-4-yl)methoxy)-3,4-dihydroquinolin-2(1H)-one (TR-G174)134

[0648] Compound TR-G0174 has been prepared according to procedure A and E.In the first step, 5-azido-1,2,3-trimethoxybenzene was prepared starting from 275 mg of 3,4,5-trimethoxyaniline (1.5 mmol) which were refluxed with 195 mg of sodiumazide salt (3 mmol) for 2 hours in ethanol / water (2:1). After that, the mixture wascooled to room temperature and filtered. Secondly, 6-(prop-2-yn-1-yloxy)-3,4- dihydroquinolin-2(1H)-one TR-G006 was prepared according to procedure A as mentioned before. In the last step, a mixture of 6-(prop-2-yn-1-yloxy)-3,4- dihydroquinolin-2(1H)-one TR-G006 (250 mg, 1.24 mmol), 29.74 mg of copper sulfate (0.186 mmol) and 12 mg of sodium ascorbate (0.062 mmol) in EtOH was added to the 5-azido-1,2,3-trimethoxybenzene solution and stirred for 6 h. After that, the ethanol was evaporated. The residue was dissolved in water and the mixture was extracted with ethyl acetate (3 × 50 ml), dried over anhydrous magnesium sulfate MgSO4 and the solvent was evaporated under vacuum. Finally, the product was purified using flash chromatography (Hexane:EtOAc:TEA) (40:60:1%) to obtain 266mg (65%) of compound TR-G174. LCMS / MS: m / z 411.02 [M+H]+.

[0649] Synthesis of 6-((4-chloro-2,6-difluorobenzyl)oxy)-3,4-dihydroquinolin-2(1H)-one (TR-G181)

[0650]

[0651] Following procedure A, 250 mg of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.5 mmol) was stirred with 600 mg of the base Cs2CO3 (1.84 mmol) for 2 h. inTHF and drops of DMF, then 294 mg of 5-chloro-2-(chloromethyl)-1,3-difluorobenzene (1.5 mmol) was added slowly to the reaction at room temperature. The reaction was tested until finished by TLC and after workup and column chromatography (Hexan:EtOAc) (60:40), the final product was filtered and obtained320 mg (64.5%) of TR-G181. LCMS / MS: m / z 323.92 [M+H]+.

[0652] Synthesis of 6-((4-(methylsulfonyl)benzyl)oxy)-3,4-dihydroquinolin-2(1H)-one (TR-G182)135

[0653]

[0654] Following procedure A, 250 mg of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.5 mmol) was stirred with 600 mg of the base Cs2CO3 (1.84 mmol) for 2 h. inTHF and drops of DMF, then 382 mg of 1-(bromomethyl)-4-(methylsulfonyl)benzene(1.5 mmol) was added slowly to the reaction at room temperature. The reaction was tested until finished by TLC and after workup and column chromatography(Hexan:EtOAc) (60:40), the final product was filtered and obtained 410 mg (80.75%)of TR-G182. LCMS / MS: m / z 331.95 [M+H]+.

[0655] Synthesis of 6-((3,3-difluorocyclobutyl)methoxy)-3,4-dihydroquinolin-2(1H)-one (TR-G193)

[0657] Following procedure A, 6-hydroxy-3,4-dihydroquinolin-2(1H)-one 200 mg(1.23 mmol) was stirred with 254.1 mg of the base K2CO3 (1.84mmol) for 1 h. in THFand drops of DMF. Then 294.79 mg of 3-(bromomethyl)-1,1-difluorocyclobutane(1.59 mmol) was added, after workup and column chromatography (Hexane:EtOAc)(2:1) then afford 245 mg (74.8%) of TR-G193 as white crystals. LCMS / MS: m / z268.60 [M+H]+.

[0658] 1H NMR (500 MHz, DMSO-d6) 9.71 (s, 1H), 7.43 (d, J = 8.4 Hz, 1H), 6.79(dd, J = 8.4, 2.0 Hz, 1H), 6.73 (m, 1H), 4.05 3.97 (m, 2H), 3.04 2.84 (m, 2H),2.64 2.50 (m, 2H), 2.46 2.26(m,NMR (125 MHz, DMSO-d6 170.16,153.56, 134.56, 124.59, , 119.22, 116.29, 115.79, 115.40, 71.07 (t, ³J(C(36.02, 35.80, 35.58) C -difluorocyclobutyl), 27.62.136

[0659] Synthesis of 6-((3,3-difluorocyclobutyl)methoxy)-3,4-dihydroquinolin-2(1H)-one (TR-G194)

[0661] According to procedure A, 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.23mmol, 200 mg) was dissolved in THF and drops of DMF. K2CO3 (1.84 mmol, 254 mg)was added and the mixture was allowed to stir for 1.5 h. After that, 3-(bromomethyl)-1,1-dimethylcyclobutane (1.47 mmol, 0.211 mL, d: 1.23 g / ml) was added to themixture at room temperature. After workup and column chromatography(Hexane:EtOAc) (2:1), 291 mg of TR-G194 (91.5%) was obtained as white powder.LCMS / MS: m / z 260.12 [M+H]+.

[0662] 1H NMR (500 MHz, DMSO-d6) -H), 7.41 6.74 (m, 3H),3.95 (d, J = 6.7 Hz, 2H), 2.95 2.85 (m, 2H), 2.64 2.50 (m, 2H), 2.24 (m, 1H), 1.85(dd, J = 11.1, 7.6 Hz, 2H), 1.75 (dd, J = 10.8, 7.5 Hz, 2H), 0.97 (s, 6H). 1C NMR (125MHz, DMSO-d6 170.16, 153.50, 134.56, 124.58, 119.22, 115.79, 115.40, 71.71, 42.18, 34.39, 31.02, 30.58, 28.51, 27.62.

[0663] Synthesis of 6-(isopentyloxy)quinolin-2(1H)-one (TR-G201)

[0665] According to procedure A, 6-hydroxyquinolin-2(1H)-one (1.24 mmol, 200mg) was dissolved in N,N-Dimethylacetamide in ice bath. NaH (1.86 mmol, 44.67mg)was added, and the mixture was allowed to stir for 2 h. After that, 1-bromo-3-methylbutane (1.49 mmol, 0.178 mL, d: 1.26g / mL) was added to the mixture at 0°Cfor 6h., after workup and column chromatography (Hexane:EtOAc) (1:1), 200 mg(70%) of TR-G201 was obtained as off-white powder. LCMS / MS: m / z 233.41[M+H]+.

[0666] 1H NMR (500 MHz, DMSO-d6 7.90 7.33 (m, 3Harom),7.01 6.75 (m, 2Harom), 4.10 (t, J = 6.7 Hz, 2H), 1.82 1.73 (m, 1H), 1.60 (q, J = 6.9137 Hz, 2H), 0.91 (d, J = 6.7 Hz, 6H).13161.91, 153.80, 146.21, 133.67, 122.22, 120.13, 118.59, 118.53, 111.92, 66.80, 39.02, 26.50, 23.53.

[0667] Synthesis of 6-((tetrahydro-2H-pyran-4-yl)methoxy)quinolin-2(1H)-one(TR-G202)

[0669] Following procedure A, a mixture of 6-hydroxyquinolin-2(1H)-one (1.24mmol, 200 mg) and K2CO3 (0.478 mmol, 66.09 mg) was stirred for 30 min in THFand drops of DMF. After that, 4-(iodomethyl)tetrahydro-2H-pyran (1.49 mmol,336.65 mg) 0.204 ml, d:1.65 g / mL was added to the solution at room temperature.After workup and column chromatography (Hexane:EtOAc) (2:1), 195 mg of TR-G202 (61%) was obtained as yellowish white crystals. LCMS / MS: m / z 260.21[M+H]+.

[0670] 1H NMR (500 MHz, DMSO-d6 7.82 6.81 (m, 5H), 3.94 (d, J = 6.4 Hz,2H), 3.75 (m, , 2H), 3.52 (m, 2H), 1.84 (h, J = 6.2 Hz, 1H), 1.78 1.61 (m, 4H). 1NMR (125 MHz, DMSO-d6 163.10, 155.29, 145.20, 133.83, 123.17, 121.14, 118.50, 117.93, 112.68, 71.80, 70.40 (2C), 33.52, 29.41 (2C).

[0671] Synthesis of 6-((4-(trifluoromethyl)benzyl)oxy)quinolin-2(1H)-one (TR-G203)

[0672]

[0673] 100 mg of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (0.620 mmol) wasstirred with 266 mg of the base TEA (1.84 mmol) for 30 min in THF and drops ofDMF, then 178 mg of 1-(bromomethyl)-4-(trifluoromethyl)benzene (0.744 mmol)was added, . After workup and column chromatography (Hexane:EtOAc) (70:30) 170mg (85%) of TR-G203 was obtained as white powder. LCMS / MS: m / z 320.36[M+H]+.138

[0674] Synthesis of 6-((1-(4-(trifluoromethyl)benzyl)-1H-1,2,3-triazol-4-yl)methoxy)-3,4-dihydroquinolin-2(1H)-one (TR-G305)

[0675]

[0676] Compound TR-G0305 has been prepared according to procedure A and E.In the first step, 1-(azidomethyl)-4-(trifluoromethyl)benzene was prepared startingfrom 700 µL of 4-trifluorbenzyl chloride (4.8 mmol) which were refluxed with 843mg of sodium azide salt (12.98 mmol) for 2 hours in ethanol / water (2:1). After that, the mixture was cooled to room temperature and filtered. Secondly, 6-(prop-2-yn-1-yloxy)-3,4- dihydroquinolin-2(1H)-one TR-G006 was prepared according toprocedure A as mentioned before. In the last step, a mixture of 6-(prop-2-yn-1-yloxy)-3,4- dihydroquinolin-2(1H)-one TR-G006 (250 mg, 1.24 mmol), 29.74 mg ofcopper sulfate (0.186 mmol) and 12 mg of sodium ascorbate (0.062 mmol) in EtOH was added to the 1-(azidomethyl)-4-trifluorobenzene solution and stirred for 6 h. After that, the ethanol was evaporated. The residue was dissolved in water and the mixture was extracted with ethyl acetate (3 × 50 ml), dried over anhydrous magnesium sulfate MgSO4 and the solvent was evaporated under vacuum. Finally, the product was purified using flash chromatography (Hexane:EtOAc:TEA)(40:60:1%) to obtain 250 mg (50%) of compound TR-G305. LCMS / MS: m / z 402.99[M+H]+.

[0677] 1H NMR (500 MHz, DMSO-d6 -H) , 8.28 (s, 1HTraizole),7.56 6.74 (m, 7Harom), 5.37 (t, J = 1.0 Hz, 2H), 5.19 (s, 2H), 2.96 2.82 (m, 2H. CH2-CH2-C=O), 2.66 2.52 (170.24 (NH-C=O), 151.23, 145.91(Ctraizol), 136.23, 134.59, (129.20, 129.18, 129.16, 129.15 J3C-F coupling), (128.99, 128.74, 128.48, 128.23 C-CF3 coupling), (127.61, 125.47, 123.32, 121.18 C-F3 coupling) 126.06, 126.03, 126.00, 125.97, 124.63, 123.32, 119.45, 119.07, 115.43, 115.02, 58.27, 53.04, 30.95, 27.57.139 Methods In Vitro study

[0678] Cell Proliferation Analysis

[0679] U87-MG,U138-MG and KALS1 cells, were incubated with 10% fetal bovineserum (FBS) (Gibco, 10500-064), 1% L-glutamine (Gibco, 25030-024), in ahumidified incubator with 5% CO2 at 37 °C. The cells were contained in DMEM HighGlucose (Gibco, 41966-029) supplemented with 1% penicillin-streptomycin (P / S)(Gibco 15140-122) solution. The cytotoxic effects of the target compounds on U87-MG and U138-MG cell lines were assessed using the MTT (Thiazolyl Blue Tetrazolium Bromide) method.7x103 cells were seeded into a 96-well plate in 100 µlDMEM High Glucose 10% FBS and 1% P / S. 24 hours after cell incubation, each targetcompound was added at a dose of 10 µM and the drug treatment was carried out fortwo days. After the incubation period, 10 µL of MTT solution was added to each well (5 mg / ml in PBS). After 2 hours, MTT solutions were removed from the wells. Then, 100 µl DMSO was added, and mixed to dissolve the formazan crystals. Cellproliferation was analysed by measuring the absorbance of dissolved formazan at awavelength of 570 nm.

[0680] IC50 values were determined using the same method as above wherein thecells were treated with the target compounds at different doses.

[0681] Permeability study

[0682] PAMPA assay (BioAssay System, PMBBB-096, USA) has been used forassessing the permeability rates of the target compounds through the BBB mimickingmembrane and the gastrointestinal mimicking membrane. Permeability assay andpermeability and low permeability standards, drugs (500 µM) and equilibrium standards (200 µM) were prepared. After the loading of lipid solutions into the pores, all drug solutions and the permeability controls were put onto the lipid membrane indonor wells. The permeability assay was performed for 18 hours at 37 °C incubator.All samples were collected from acceptor wells after the incubation period was finished and the absorbance values were measured with equilibrium standards for normalization.140 In Vivo study

[0683] An in Vivo study was performed to assess the therapeutic potential of TR-G002, TR-G045, TR-G053, TR-G066, TR-G071 and TR-G091 in the GBM xenograft rat model when administered orally by gavage for five consecutive days.152 female rats of the Sprague Dawley strain were allocated to the study. Six groups of sixteen females were given dose of 30 mg / kg of the respective target compounds. Temozolomide (TMZ, a known drug for treatment of GBM) was used as a positivecontrol, and sixteen females were given 30 mg / kg of TMZ. The study design can beseen in Fig. 11 and Table 10.

[0684] Table 10 shows the study design with details on groups and dosing.

[0685] This study has been approved by Ethics Committee of Laboratory Animals(HADYEK), Atatürk University (E-75296309-050.01.04-2300011862; 10.01.2023; Decision Number: 2023 / 01 / 02).

[0686] All efforts were made to decrease suffering and possible stress for theanimals and performed in accordance with the Directive 2010 / 63 / EU of the European Parliament and of the Council of 22 September 2010 on the protection of animals used for scientific purposes.

[0687] The method of blind research was applied at all stages.141

[0688] The animals were included in the study if their tumor implantation wassuccessfully defined by a tumor size greater than 80 mm3 with MRI and the animalswere having alterations in motor functions. The animals were excluded if they were unable to continue their life functions (agony).

[0689] Animals, animal care and husbandrySpecies RatStrain RjHan: SDSupplier ATADEM, Erzurum, TurkeyAge 5 weeks on arrival, approximately 8 weeks at start ofdosing Number and sex 152 femalesBody weight at start of dosing 255-310 gAnimal identification Each animal was uniquely identified within the study by an animal reference number and ear notching. Acclimatisation At least 14 days before start of dosing.Housing, water and diet Animals were group-housed under standardconditions. Animal had free access to water from the site drinking water supply and standard rodent diet supplied by Bayramoglu Feed Factory, Erzurum, Turkey. Environmental conditions, Animal rooms were air-conditioned. The air was temperature and humidity changed about 15 times per hour via a centrally placed air intake and peripheral ventilator. Target values for temperature and humidity were 20-26 Cand 40-70%, respectively. Light cycle 12 hours light; 12 hours dark.

[0690] DosingRoute of administration Oral gavage with soft tube.142 Frequency and duration of Once daily for 5 consecutive days. administrationTime of dosing In the morning

[0691] Cell culture

[0692] U87-MG human glioma cells (American Type Culture Collection,Manassas, VA) were grown in DMEM medium (Thermo Fisher Scientific, Waltham,MA) containing 10% fetal bovine serum and 1% P / S. All cells were grown at 37 °C in a5% CO2 incubator.

[0693] In vivo GBM rat model

[0694] Female Sprague Dawley rats (age: 6 8 weeks; weight: 255 310 g;ATADEM, Erzurum, Turkey) were utilized in the study. Rats underwent anaesthesia with 5% isoflurane, maintained at 2% isoflurane (1 L / min oxygen), and were positioned in a stereotactic frame for cell implantation (Stoelting Co., IL). The fur on the superior side of the head was removed to expose the skin, and the bregma was marked after incision. A burr hole was drilled 1-mm anterior and 3-mm lateral to the right bregma. A microsyringe (Hamilton 1700 series) containing 5x104 U87-MG cells °C was advanced to a depth of 4 mm into the brain. The cells were hole to prevent cell suspension reflux. The incision was sutured, and 1 mL of Meloxicam (5 mg / mL; Metacam, Boehringer Ingelheim Vetmedica, Ingelheim, Germany) was administered via a subcutaneous injection.

[0695] Fourteen days after inoculation, tumor development in rats was visualizedand confirmed through magnetic resonance imaging (MRI). Rats confirmed to have developed tumors were then distributed into six different groups for treatment. Ratswere treated with the test compounds (target compounds and TMZ) for 5 days. 9 daysafter the final treatment dose, the rats underwent another MRI scan and blood and brain samples were taken under anaesthesia.

[0696] A check of animal health and welfare status was done at least once onworking days and weekend days.

[0697] Magnetic resonance imaging (MRI)143

[0698] The anaesthetic was administered via an intraperitoneal route on animalsfixed in the supine position with parallel hind limbs. MRI was performed using a 3 Tesla clinical scanner (Magnetom Skyra; Siemens Healthineers, Erlangen, Germany). Rats were placed in the prone position. T2-SPACE (sampling perfection with application-optimized contrast using different flip angle Evolution) sequence was obtained to view the brain in coronal and transverse planes. (TR: 6000 ms, TE: 100 ms, voxel size: 0.5 × 0.5 × 1 mm, 34 slices, slice thickness: 2 mm, slice spacing: 0.6mm). The volume measurements of brain tumors were performed manually. Oneradiologist calculated the tumour volume manually measuring tumour length (L), width (W), and height (H) and then calculated the tumour volume using the formula 0.5236 × L × W × H (Stuppner S et al., 2020).

[0699] Blood samplingAnimals that were bled All animals.Blood sampling time Blood for scheduled hematology and plasmachemistry were taken at necropsy. Blood sample volume and Plasma chemistry: 0.6 mL (lithium heparin) per anticoagulant animal. Haematology: 0.5 mL (K2 EDTA) per animal. Sample analyses Blood and plasma were analysed using BS-200Automatic Biochemistry Analyzer (Mindary Co., Ltd.) and automated hematology system analyzer (Archem, BM240, Istanbul, Turkey) Hematology sample Blood was analyzed within 60 minutes of sampling. procedures On the morning of analysis, the automated hematology system analysis (Archem, BM240,Istanbul, Turkey) was checked against a reference sample provided by the manufacturer, and a control sample analysis cycle was performed. For each study sample, Animal ID, Sample number was manually entered on the analyzer. The analyzer was set to automatic print-out and144 each individual sample print-out was collected and saved in the study folder. Plasma chemistry sample Blood samples were kept in room temperature procedures (approx. 20 °C) after collection and mixing. The blood samples were analysed as whole blood within 60 minutes of collection. BS-200 Automatic Biochemistry Analyzer (Mindary Co., Ltd.) was calibrated with calibration samples with known plasma levels of each parameter before start of analysis, occasionally during the analysis period of study samples and after completed analyses. For each study sample, Animal ID, Sample number was manually entered on the analyzer. The analyzer was set to automatic print-out and each individual sample print-out was collected and saved in the study folder.

[0700] The parameters that were analysed can be seen in Table 11.

[0701] Table 11 shows the haematology and plasma chemistry parameters thatwere analysed in the in Vivo study.145

[0702] Histopathological Examinations

[0703] Brain tissue samples were fixed in a 10% buffered formaldehyde solution.After fixation, the tissues were processed through graded alcohol and xylene series and embedded in paraffin blocks. Sections of 5 µm thickness were taken from the paraffin blocks at intervals of 50-100 µm. Hematoxylin and eosin staining was performed on these sections to evaluate histopathological changes. Histopathological findings included tumor focus size, necrotic area, vascular proliferation, and cellular proliferation patterns. Tumor focus size was categorized as follows based on the diameter measured with a 4X objective on the microscope: >3500 µm was considered very severe, 3499-2000 µm severe, 1999-1000 µm moderate, 999-500 µm mild, and <500 µm very mild. Necrotic area size was classified based on the diameter of necrosis: >1500 µm as very severe, 1499-1000 µm severe, 999-500 µm moderate, 499-200 µm mild, and <199 µm very mild.

[0704] Immunohistochemical Examinations

[0705] For immunohistochemical examinations, primary antibodies (Ki67 Cat no:ab15580 dilution ratio: 1 / 100; CMPK2 Cat no: PA5-34461, dilution ratio: 1 / 100, GFAP Cat no: ab6842 dilution ratio: 1 / 100) were used.3- were examined under a light microscope (Zeiss AXIO, Germany).146

[0706] Double Immunofluorescence Examination

[0707] In immunofluorescence examinations, primary antibody (NOP10 Cat no:ab134902 dilution ratio: 1 / 100) was applied to tissues and incubated according to the instructions. A fluorescent secondary antibody (FITC Cat No: ab6785 dilution Ratio: 1 / 1000 UK) was then applied and incubated in the dark for 45 minutes. Afterward, a second primary antibody (H2A.X Cat no: sc-517336 dilution ratio: 1 / 100) was applied and incubated according to the instructions. A different fluorescent secondary antibody (Texas Red Cat No: ab6719 dilution Ratio: 1 / 1000 UK) was applied and incubated in the dark for 45 minutes. Finally, DAPI (Cat no: D1306 dilution ratio: 1 / 200 UK) was applied to the sections for 5 minutes in the dark, followed by covering the tissues with coverslips. The stained tissues were examined under a fluorescence attachment-equipped microscope (Zeiss AXIO, Germany).

[0708] Peripheral blood micronucleus assay

[0709] Blood smears were made on clean microscope slides, allowed to air-dry,treated with methanol for fixation, and then stained with Giemsa (10% in 0.1 mM of sodium phosphate buffer, pH 6.8) for 10 min. After washing with PBS, the slides were examined under a light microscope. The frequencies of micronuclei (MN) were calculated by evaluating 1000 cells per animal.

[0710] Calculations and statistical analysis

[0711] Individual body weights were manually calculated. Group mean bodyweights; group mean body weight changes and organ weights were also manually calculated without statistical analysis. To determine the density of positive staining from immunohistochemical and immunofluorescence staining images, five randomly selected areas were evaluated using ZEISS Zen Imaging Software. Data were statistically defined as mean and standard deviation (mean ± SD) for the percentage of the area. One-way ANOVA followed by the Tukey test was performed to compare immunoreactive cells and immune-positive stained areas with healthy controls. GraphPad Prism software was used for analysis. Results In Vitro study

[0712] Cell proliferation147

[0713] U87-MG and U138-MG glioma cell lines were used to evaluate the effect ofthe treatment with the target compounds on glioblastoma in vitro. The effectivenessof the treatment with the target compounds was evaluated on cell proliferation, seeTables 12-14. Cilostazol and TMZ were used as reference drugs. Cilostazol is known topass the blood-brain barrier and TMZ is a known drug for treatment of GBM.

[0714] Table 12 shows the cell proliferation and inhibition of U87-MG and U138-MG cells when treated with reference drugs Cilostazol and TMZ.

[0715] Table 13 shows the cell proliferation and inhibition of U87-MG cells whentreated with the target compounds.148149150151

[0716] Treatment of U87-MG cells with 90 of the 130 synthesized targetcompounds, resulted in a reduction of cell proliferation with at least 20 % compared to non-treated cells. This means that treatment with 90 of the target compoundsexhibited the same or lower cell proliferation than the known GBM drug TMZ, seeTables 12-13. Treatment with 50 of the target compounds resulted in a reduction ofcell proliferation of at least 30 % compared to non-treated cells. Treatment of U87-MG cells with 80 of the target compounds exhibited the same or lower cellproliferation than the known drug Cilostazol. The top 5 target compounds whosetreatment resulted in the lowest proliferation of U87-MG cells were TR-G053, TR-G078, TR-G103, TR-G1013A and TR-G107 wherein treatment with TR-G053 resulted in the lowest cell proliferation, 42 %.

[0717] Table 14 shows the cell proliferation and inhibition of U138-MG cells whentreated with the target compounds.152153154155156

[0718] Treatment of U138-MG cells with 78 of the 130 synthesized targetcompounds, resulted in a reduction of cell proliferation with at least 20 % compared to non-treated cells. Treatment with 68 of the target compounds exhibited the sameor lower cell proliferation as the known GBM drug TMZ, see Tables 12 and 14.Treatment with 44 of the target compounds resulted in a reduction of cellproliferation of at least 30 % compared to non-treated cells. Treatment of U138-MGwith 101 of the target compounds exhibited the same or lower cell proliferation as theknown drug Cilostazol. The top 5 target compounds whose treatment resulted in thelowest cell proliferation of U138-MG cells were TR-G066, TR-G112, TR-G143, TR-G102 and TR-G014 wherein treatment with TR-G066 resulted in the lowest cell proliferation, 39 %.

[0719] IC50 values were determined for some of the target compounds, see Fig. 12-16. IC50 values in U87-MG cells varied from 4.6-16.3 µM while the IC50 values inU138-MG cells varied from 4.2-13.6 µM.

[0720] Furthermore, KALS1 cells were treated with some of the synthesizedcompounds, see Table 16 and Fig.38-40.

[0721] Table 15 shows the cell proliferation and inhibition of KALS1 cells whentreated with the target compounds.157158

[0722] Treatment of KALS1 cells with 30 synthesized target compounds resultedin a reduction of cell proliferation by at least 20% compared to non-treated cells. Treatment with 22 of the target compounds exhibited the same or lower cellproliferation as the known GBM drug TMZ (cell viability: 91%), see Table 15.Treatment with 17 of the target compounds resulted in a reduction of cell proliferation by at least 30% compared to non-treated cells. Moreover, treatment of KALS1 cells with 26 of the target compounds exhibited the same or lower cell proliferation as the known drug Cilostazol (cell viability: 73%). The top 5 target compounds whose treatment resulted in the lowest cell proliferation of KALS1 cells were TR-G194, TR-G193, TR-G201, TR-G002, and TR-G172, with treatment with TR- G194 resulting in the lowest cell proliferation value (cell viability: 29.78%).

[0723] Permeability study

[0724] A permeability study using the PAMPA assay was conducted for some ofthe target compounds, see Fig.17-22. The permeability rate of the target compoundsthrough a blood-brain barrier and gastrointestinal mimicking membrane weredetermined.

[0725] The permeability results through the blood-brain barrier mimickingmembrane showed that TR-G097, TR-G144, TR-G014 and TR-G095 are highlypermeable while TR-G002, TR-G035, TR-G103, TR-G029 and TR-G025 have middlepermeability and the rest of the tested compounds have lower permeability.

[0726] The permeability results through the gastrointestinal mimickingmembrane showed that TR-G024, TR-G128, TR-G097, TR-G072, TR-G014, TR-G095, TR-G006 and TR-G092 are highly permeable, while the other testedcompounds had a lower permeability.In Vivo study

[0727] Body weight159

[0728] The untreated GBM rats (induced GBM after 14 days) exhibited a decreasein body weight compared to the healthy control group. No significant change in bodyweight was observed in GBM rats treated with TMZ and the target compoundscompared to the GBM rats.

[0729] Evaluation of survival

[0730] Overall survival was assessed from the end of tumor induction (14th day)until death or end of experiment (28thday) and the results can be seen in Fig.23. Treatment with all tested target compounds and TMZ prolonged the survival of thetreated rats compared to GBM rats. GBM rats treated with TR-G066, TR-G002, TR-G045 and TMZ exhibited significantly improved survival compared to untreatedGBM rats, wherein the TR-G066 treated GBM rats exhibited the highest survival.

[0731] MRI analysis of tumor volumes

[0732] Tumor volumes were determined 14 days after tumor implantation in theanimals using MRI, see Fig. 24-33. Rats having a tumor volume of 80 mm3 and abovewere included in the experiments.6 different target compounds were administered along with TMZ as reference drug to animals with confirmed tumor formation.

[0733] Treatment with all the target compounds and TMZ resulted in adeceleration in tumor size compared to the control group, see Fig.24-25. Treatment with TR-G002 resulted in a small increase in tumor size, similar to the increaseobtained after treatment with TMZ. Treatment with TR-G045 and TR-G066 resultedin a decrease in tumor size.

[0734] The antitumor activities of tested compounds were in the following order:TR-G066> TR-G045> TR-G002>TMZ> TR-G091> TR-G053> TR-G071.

[0735] Histopathological findings

[0736] In the GBM rats, histopathological examination of brain tissues revealedextensive tumor foci containing grey and white matter, see Fig. 34-35. In the centralportions of the tumor foci, large areas of necrosis, intense vascular proliferation, and cells with a high level of mitotic figures and hyperchromatic cells were identified, particularly around blood vessels, see Fig.34-35.

[0737] In the TMZ treated GBM rats, histopathological examination of braintissues showed a reduction in the diameter of the tumor focus, with very few cells160 exhibiting mitosis and no observed necrotic cells. Mild levels of vascular proliferation and cell proliferation were observed, see Fig.34-35.

[0738] In the TR-G002 treated group, histopathological examination of braintissues revealed a significantly reduced tumor focus with mild levels of vascular and cellular proliferation, see Fig.34-35.

[0739] In the TR-G045 treated GBM rats, histopathological examination of braintissues classified the tumor focus as moderate. Necrotic cells were present in the central regions, along with moderate mitosis, atypical hyperchromatic tumor cells, and vascular proliferation in the vicinity of healthy tissue, see Fig.34-35.

[0740] In the TR-G053 treated GBM rats, histopathological examination of braintissues showed a tumor focus including both grey and white matter. Severe necrosisin the inner parts of the tumor focus, intense mitosis around blood vessels, and hyperchromatic cells near healthy tissue were identified, see Fig.34-35.

[0741] In the TR-G066 treated GBM rats, histopathological examination of braintissues revealed few tumor cells, particularly around blood vessels, rather than a distinct tumor focus shape, see Fig.34-35.

[0742] In the TR-G071 group, histopathological examination of brain tissuesindicated an expanded tumor focus with moderate necrotic cells in the central part and moderate levels of mitosis and vascular proliferation, see Fig.34-35.

[0743] In the TR-G091 treated group, histopathological examination of braintissues revealed an extended tumor focus encompassing both grey and white matter.Moderate necrosis, mitotic figures, and atypical cells were observed in the central part of the tumor focus, see Fig.24-35.

[0744] Immunohistochemical and immunofluorescence findings

[0745] In the GBM rats, immunohistochemical and immunofluorescence stainingof brain tissues revealed intense cytoplasmic expression of Ki67 in cells around blood vessels and near healthy tissue, severe cytoplasmic expression of CMPK2 in tumor cells, and mild GFAP expression in astrocytes in non-tumor regions, see Fig.34. In brain tissues, severe cytoplasmic expressions of Nop10 and H2AX were observed in the vicinity of tumor tissue, see Fig.36-37.161

[0746] In the TMZ treated GBM rats, immunohistochemical andimmunofluorescence staining of brain tissues showed mild cytoplasmic expression of Ki67 and CMPK2 in tumor cells around blood vessels, and severe GFAP expression in astrocytes around the tumor, see Fig.34. In these brain tissues, mild expressions of Nop10 and H2AX were observed in neurons around tumor tissue, see Fig.36-37.

[0747] In the TR-G002 treated GBM rats, immunohistochemical andimmunofluorescence staining of brain tissues revealed mild cytoplasmic expression of Ki67 and CMPK2 in tumor cells around blood vessels, and severe GFAP expression in astrocytes around the tumor, see Fig.34. In TR-G002 treated brain tissues, mild expressions of Nop10 and H2AX were observed in neurons around tumor tissue, see Fig.36-37.

[0748] In the TR-G045 treated GBM rats, immunohistochemical andimmunofluorescence staining of brain tissues showed moderate cytoplasmic expression of Ki67 and CMPK2 in tumor cells, and moderate GFAP expression in astrocytes around the tumor, see Fig.34. In the TR-G045 treated brain tissues, moderate cytoplasmic expressions of Nop10 and H2AX were observed in neurons, see Fig.36-37.

[0749] In the TR-G071 treated GBM rats, immunohistochemical andimmunofluorescence staining of brain tissues revealed moderate Ki67 and CMPK2 expression in tumor cells, and moderate GFAP expression in astrocytes around thetumor, see Fig. 34. In the TR-G071 treated brain tissues, moderate expressions ofNop10 and H2AX were detected in neurons, see Fig.36-37.

[0750] In the TR-G091 treated group, immunohistochemical andimmunofluorescence staining of brain tissues showed moderate cytoplasmic Ki67 expression, particularly around normal tissue and blood vessels, and moderate CMPK2 expression in tumor cells throughout the focus. Moderate GFAP expression in astrocytes around the tumor was observed, see Fig.34. In the TR-G091 treated brain tissues, moderate cytoplasmic expressions of Nop10 and H2AX were noted in neurons, especially around the tumor focus, see Fig.36-37.

[0751] In the TR-G053 treated group, immunohistochemical andimmunofluorescence staining of brain tissues revealed severe cytoplasmic expression of Ki67 and CMPK2 in tumor cells, and mild GFAP expression in astrocytes around162the tumor mass, see Fig. 34. In TR-G053 treated brain tissues, severe cytoplasmicexpressions of Nop10 and H2AX were observed in neurons around the tumor tissue,see Fig. 36-37.

[0752] In the TR-G066 treated group, immunohistochemical andimmunofluorescence staining of brain tissues showed very mild cytoplasmic expression of Ki67 and CMPK2 in tumor cells around blood vessels, and very severe GFAP expression in astrocytes around the tumor, see Fig.34. In TR-G066 treated brain tissues, very mild cytoplasmic expressions of Nop10 and H2AX were observed in neurons around tumor tissue, see Fig.36-37.

[0753] Haematological parameters

[0754] When haematological parameters were examined, no significant changeswere observed in parameters other than WBC, HCT, and PLT values. As compared to the corresponding heathy group, slightly elevated levels WBC were noted in GBMrats. Treatment with TMZ and target compounds did not cause any significantchanges in WBC level compared to the GBM rats. The PLT level was significantlyincreased in the GBM rats when compared to corresponding heathy group. In TMZand target compounds treated GBM rats, no significant changes were found in PLTlevels compared to GBM rats, see Table 16.

[0755] Table 16 shows the haematological parameters.163

[00756] Plasma chemistry parameters

[0757] Table 17 shows the levels of AST, ALT and LDH in the healthy andexperimental rats. GBM rats showed significantly greater levels of all of these enzyme activities than healthy rats. Treating GBM rats with TR-G045, TR-G053, and TR- G066, respectively, significantly decreased these levels in comparison to the levels inuntreated GBM rats.

[00758] Table 17 shows plasma chemistry parameters.UAmmol / l1.741.691.671.711.61.641.71.691.7

[00759] Genotoxicity evaluation by micronucleus assay

[0760] The micronuclei (MN) frequency was increased in GBM rats and thetreated GBM rats compared to the healthy control, see Table 18. The highest observedMN frequency was obtained after treatment with TMZ while all the groups treatedwith the target compounds exhibited a lower MN frequency than both GBM rats andTMZ treated GBM rats. The lowest MN frequency was obtained for the TR-G053treated GBM rats.

[00761] Table 18 shows the MN frequencies of healthy rats, GBM rats before andafter treatment with TMZ and the target compounds.164

[0762] The results obtained in the Examples section provide evidence thattreatment with a compound according to formula (I) reduced the proliferation ofglioblastoma cells. Furthermore, it was shown in an animal model that treating ratswith induced GBM with compounds according to formula (I), specifically TR-G002,TR-G045, TR-G053, TR-G066, TR-G071 and TR-G091, resulted in a prolongedsurvival, decreased tumor volume, decelerated tumor growth and in some cases(treatment with TR-G046 and TR-G066) reduced the tumor size, and decreased thevascular and cellular proliferation. These results indicate that compounds accordingto formula (I) are well-suited for treatment of glioblastoma, such as GBM.References

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Claims

169 CLAIMS1. A compound according to formula (I)or a pharmaceutically acceptable salt or prodrug thereof; wherein R1 is selected from optionally branched C3-C7 alkyl, optionally branched C2-170is independently a single bond or a double bond;W is independently selected from carbon and nitrogen;R3 is selected from optionally substituted naphthalene,A is selected from H, X and OMe ; D is selected from H, X , OMe and CX3;Q is selected from H, X and OMe;X is a halogen;171R5 is selected fromR6 is selected from H, X, C3 alkyl, -R7 is selected from H, Me; R8 is selected from H and X;R10 is selected from X, CX3 and acetyl; R11 is selected from a phenyl, C1-C3 alkyl and isopropyl; R12 is selected from H and OMe;R13 is selected from OMe, phenyl, acetyl, morpholine and N-methyl piperazine;R14 is selected from H and OMe provided that when R12 is H, R13 and / or R14 isalso H;R15 is selected from H, X, Me, OMe and CF3;172R16 is selected from H and X;R17 is selected from H and X;R18 is selected from H, X and OMe;R19 is selected from H, NO2, OMe and X;R20 is selected fromHand X;R22 is selected from X and NO2;R2 is selected from H, optionally branched C3-C7 alkyl,,R23 is selected from C1-C4 alkyl and C3-C4 alkenyl;R24 is selected from, F, phenyl and C2-C4 alkyl; andR25 is selected from Me and X , provided that R1 is notwhen R2 is H . 2.

3. The compound according to claim 2, wherein R2 is H.173The compound according to claim 2 or 3, wherein R1 is.

6. The compound according to claim 5, wherein R4 is selected from174.

7. The compound according to claim 2 or 3, wherein R1 is a substituted benzyl,8.

9. The compound according to claim 2 or 3, wherein R1 is a branched C3-C7 alkyl,preferably a branched C4-C7 alkyl, more preferably.17510. The compound according to claim 2 or 3, wherein R1 is.The compound according to claim 2 or 3, wherein R1 is12. The compound according to claim 2 or 3, wherein R1 is17613. The compound according to claim 2 or 3, wherein R1 is14. The compound according to claim 2 or 3, wherein R1 is , preferably15..17716. The compound according to claim 2 or 3, whereinpreferably17. The compound according to claim 2 or 3, wherein R1 is.

18. The compound according to claim 1, where the compound is a compoundaccording to formula (III)19. The compound according to claim 18, wherein R2 is H.

20. The compound according to claim 18 or 19, wherein R1 is selected fromoptionally branched C3-C7 alkyl, substituted benzyl or21. The compound according to claim 20, wherein R1 selected from22. A pharmaceutical composition comprising a compound according to any one ofclaims 1-21.

23. A compound or a pharmaceutical composition according to any one of theprevious claims, for use as a medicament.

24. A compound or a pharmaceutical composition according to any one of claims 1-22, for use in a method of treatment of glioma, such as glioblastoma, such asglioblastoma multiforme.

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