DNA topoisomerase iiß inhibitors

Abstract

The present disclosure provides in one embodiment compounds of formula (I) that are DNA topoisomerase inhibitors useful in treating and / or preventing cardiotoxicity and cardiomyopathy in patients undergoing cardiotoxic chemotherapy, for example, with anthracycline drugs such as doxorubicin.

Description

[0001] DNA TOPOISOMERASE Up INHIBITORS

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Application Serial No.

[0004] 63 / 534,074, filed August 22, 2023. The disclosure of the prior application is considered part of the disclosure of this application, and is incorporated in its entirety into this application.

[0005] TECHNICAL FIELD

[0006] The present disclosure provides chromen-2-one compounds that are useful, e.g., in preventing and / or treating cardiotoxicity and cardiomyopathy in patients undergoing cardiotoxic chemotherapy.

[0007] BACKGROUND

[0008] Anthracycline (“ANT”) drugs, such as doxorubicin (“DOX”), daunorubicin (“DAU”), epirubicin, or idarubicin, belong to highly effective and widely used class of chemotherapeutics indicated for a number of hematological malignancies as well as solid tumors. See, e.g., Cortes-Funes et al., Cardiovasc Toxicol, 2007, 7, 56-60; Lenneman et al., Circulation research, 2016, 118, 1008-1020. However, clinical use of ANT agents in the chemotherapy of cancer is complicated and frequently also limited by these drugs’ toxic effects on the myocardium.

[0009] SUMMARY

[0010] The present disclosure is based, at least in part, on a realization that chromen-2-one compounds disclosed herein are selective DNA topoisomerase lip inhibitors capable of protecting primary cardiomyocytes against ANT toxicity. Further, these compounds do not interfere with anticancer therapeutic effect of ANTs and are highly efficacious as cardioprotectants at low doses against chronic cumulative ANT cardiotoxicity.

[0011] In one general aspect, the present disclosure provides a compound of Formula (I):

[0012] or a pharmaceutically acceptable salt thereof, wherein R1and R2are as described herein.

[0013] In one general aspect, the present disclosure provides a compound of Formula (II): or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, and Y are as described herein.

[0014] In one general aspect, the present disclosure provides a compound of Formula (III): or a pharmaceutically acceptable salt thereof, wherein R2, R3, R4, Y, Z, q, and A, are as described herein. In another general aspect, the present disclosure provides a pharmaceutical composition comprising a compound of Formula (I) as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0015] In another general aspect, the present disclosure provides a pharmaceutical composition comprising a compound of Formula (II) as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0016] In another general aspect, the present disclosure provides a pharmaceutical composition comprising a compound of Formula (III) as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0017] In yet another general aspect, the present disclosure provides a method of treating or preventing a disease or condition associated with topoisomerase 110, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same.

[0018] In yet another general aspect, the present disclosure provides a method of treating cancer in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of an ANT chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a compound of Formula (I) as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same. In some embodiments, the subject does not develop a cardiotoxicity or a cardiomyopathy associated with the administration of the ANT chemotherapeutic agent.

[0019] In yet another general aspect, the present disclosure provides a method of treating cancer in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of etoposide, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a compound of Formula (I) as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same. In some embodiments, the subject does not develop a cardiotoxicity or a cardiomyopathy associated with the administration of etoposide.

[0020] In yet another general aspect, the present disclosure provides a method of treating cancer in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of mAMSA, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a compound of Formula (I) as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same. In some embodiments, the subject does not develop a cardiotoxicity or a cardiomyopathy associated with the administration of mAMSA.

[0021] In yet another general aspect, the present disclosure provides a method of treating or preventing a disease or condition in which activity of a topoisomerase lip enzyme is implicated in the pathology of the disease or condition, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (II) as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same.

[0022] In yet another general aspect, the present disclosure provides a method of treating cancer in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of an ANT chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a compound of Formula (II) as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same. In some embodiments, the subject does not develop a cardiotoxicity or a cardiomyopathy associated with the administration of the ANT chemotherapeutic agent.

[0023] In yet another general aspect, the present disclosure provides a method of treating cancer in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of etoposide, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a compound of Formula (II) as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same. In some embodiments, the subject does not develop a cardiotoxicity or a cardiomyopathy associated with the administration of etoposide.

[0024] In yet another general aspect, the present disclosure provides a method of treating cancer in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of mAMSA, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a compound of Formula (II) as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same. In some embodiments, the subject does not develop a cardiotoxicity or a cardiomyopathy associated with the administration of mAMSA.

[0025] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present application belongs. Methods and materials are described herein for use in the present application; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

[0026] In yet another general aspect, the present disclosure provides a method of treating or preventing a disease or condition in which activity of a topoisomerase lip enzyme is implicated in the pathology of the disease or condition, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (III) as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same.

[0027] In yet another general aspect, the present disclosure provides a method of treating cancer in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of an ANT chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a compound of Formula (III) as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same. In some embodiments, the subject does not develop a cardiotoxicity or a cardiomyopathy associated with the administration of the ANT chemotherapeutic agent.

[0028] In yet another general aspect, the present disclosure provides a method of treating cancer in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of etoposide, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a compound of Formula (III) as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same. In some embodiments, the subject does not develop a cardiotoxicity or a cardiomyopathy associated with the administration of etoposide. In yet another general aspect, the present disclosure provides a method of treating cancer in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of mAMSA, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a compound of Formula (III) as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same. In some embodiments, the subject does not develop a cardiotoxicity or a cardiomyopathy associated with the administration of mAMSA.

[0029] Other features and advantages of the present application will be apparent from the following detailed description and figures, and from the claims.

[0030] DESCRIPTION OF DRAWINGS

[0031] FIG. 1 is a bar graph showing protective effect of compound 3 against DAU- induced cytotoxicity in primary cultures of rat cardiomyocytes indicated by LDH release.

[0032] FIG. 2 is a bar graph showing protective effect of compound 7 against DAU- induced cytotoxicity in primary cultures of rat cardiomyocytes indicated by LDH release.

[0033] FIG. 3 is a bar graph showing protective effect of compound 8 against DAU- induced cytotoxicity in primary cultures of rat cardiomyocytes indicated by LDH release.

[0034] FIG. 4 is a bar graph showing protective effect of compound 9 against DAU- induced cytotoxicity in primary cultures of rat cardiomyocytes indicated by LDH release.

[0035] FIG. 5 is a bar graph showing protective effect of compound 10 against DAU- induced cytotoxicity in primary cultures of rat cardiomyocytes indicated by LDH release.

[0036] FIG. 6 is a bar graph showing protective effect of compound 13 against DAU- induced cytotoxicity in primary cultures of rat cardiomyocytes indicated by LDH release.

[0037] FIG. 7 is a bar graph showing protective effect of compound 14 against DAU- induced cytotoxicity in primary cultures of rat cardiomyocytes indicated by LDH release.

[0038] FIG. 8 is a bar graph showing protective effect of compound 15 against DAU- induced cytotoxicity in primary cultures of rat cardiomyocytes indicated by LDH release.

[0039] FIG. 9 is a bar graph showing protective effect of compound 18 against DAU- induced cytotoxicity in primary cultures of rat cardiomyocytes indicated by LDH release.

[0040] FIG. 10 is a bar graph showing protective effect of compound 19 against DAU- induced cytotoxicity in primary cultures of rat cardiomyocytes indicated by LDH release. FIG. 11 is a bar graph showing protective effect of compound 20 against DAU- induced cytotoxicity in primary cultures of rat cardiomyocytes indicated by LDH release.

[0041] FIG. 12 is a bar graph showing antiproliferative activity of compound 15 and its effect on antiproliferative activity of DAU on HL-60 promyelocytic cell line.

[0042] FIG. 13 is a bar graph showing antiproliferative activity of compound 17 and its effect on antiproliferative activity of DAU on HL-60 promyelocytic cell line.

[0043] FIG. 14 is a bar graph showing antiproliferative activity of compound 18 and its effect on antiproliferative activity of DAU on HL-60 promyelocytic cell line.

[0044] FIG. 15 is a bar graph showing antiproliferative activity of compound 19 and its effect on antiproliferative activity of DAU on HL-60 promyelocytic cell line.

[0045] FIG. 16 is a bar graph showing antiproliferative activity of compound 20 and its effect on antiproliferative activity of DAU on HL-60 promyelocytic cell line.

[0046] FIG. 17A Cardioprotective effects of the compound 20 against chronic ANT cardiotoxicity induced by DAU in vivo in rabbits. BW gain - relative change of animal body weight in the study (end vs begging of the study, in %).

[0047] FIG. 17B Cardioprotective effects of the compound 20 against chronic ANT cardiotoxicity induced by DAU in vivo in rabbits. cTnT - cardiac troponin T in plasma at the end of the study (LMV - last measured values).

[0048] FIG. 17C Cardioprotective effects of the compound 20 against chronic ANT cardiotoxicity induced by DAU in vivo in rabbits. LV FS - left ventricular fractional shortening determined by echocardiography at the end of the study (last measured values).

[0049] FIG. 17D Cardioprotective effects of the compound 20 against chronic ANT cardiotoxicity induced by DAU in vivo in rabbits. A LV FS - total change in the LV FS found in this study (beginning vs end) in individual animals.

[0050] FIG. 17E Cardioprotective effects of the compound 20 against chronic ANT cardiotoxicity induced by DAU in vivo in rabbits. LV dP / dtmax- an index of left ventricular systolic function determined at the scheduled end of the study via LV catheterization in surgical anesthesia.

[0051] FIG. 17F Cardioprotective effects of the compound 20 against chronic ANT cardiotoxicity induced by DAU in vivo in rabbits. Gene expression of atrial natriuretic peptide (ANP ) in the LV myocardium of individual animals. Data are presented as medians (means are shown as “+”) with boxes and whiskers representing the interquartile range and 5th-95th percentile. Statistical significance (p > 0.05) as determined by SigmaPlot 14.0 software using one-way ANOVA / Kruskal-Wallis ANOVA on ranks with Holm-Sidak’s / Dunn’s post-hoc test. Referring to Figures 17A-17F, “CTR” - the control group (the Group 1) receiving volume-matched saline, “DAU” - the DAU alone group (3 mg / kg, i.v., the Group 3), “20” is a substance 20 administered at 10 mg / kg i.v. via 20 min infusion alone (the Group 2) or in the combination with DAU (“20+DAU”, the Group 4), 60 min before DAU (3 mg / kg, i.v.). All drugs were administered once weekly for 10 weeks, and the experiment was finished 1 week after the last dose.

[0052] FIG. 18 shows inhibition of enzymatic activity of TOP2a and TOP2P by compound 20.

[0053] Fig. 19 shows a 1 ,5A resolution structure of the ATPase domain of TOP2B bound to an ATP analog (AMPPNP) and compound 20 (purple), determined using X-ray crystallography. Each individual chain of the TOP2B dimer is colored separately (gray, light yellow). The binding site for compounds of Formula (I), (II) and (III) is located near the center of the ATPase domain.

[0054] Fig. 20 shows how catalytic inhibitors of TOP2 block the ATP hydrolysis step of the TOP2 reaction cycle. Alignment of the TOP2B-ATP-compound 20 structure (gray, purple) with the previously reported TOP2B-ADP structure (PDB entry 7QFN; blue) reveals that the conformational change (red arrows) normally associated with hydrolysis of ATP to ADP plus phosphate is blocked by a steric clash with compounds of Formula (I), Formula (II) or Formula (III).

[0055] Fig. 21 shows a 1.5A resolution crystal structures of compound 20 bound to the ATPase domain of TOP2A and the same of TOP2B. A composite omit map (green mesh) reveals the location and conformation of compound 20 in each TOP2 isoform.

[0056] Fig. 22 shows the alignment of the structures of TOP2A and TOP2B containing compound 20, revealing that residues that differ between the two isozymes (S320 / T336, Y72 / C88) alter the conformation of compound 20 (red arrows) by altering the position of the chromene and R2 functional groups. Fig. 23 shows compounds of Formula (I), Formula (IT) or Formula (TIT) containing an amide bond between the chromene and tetrahydroquinoline rings that is a nearly planar bond (1.7° dihedral angle) in the crystal structure of free compound 20 (right). The amide bond is only slightly strained upon binding to TOP2B (4.4° dihedral angle), but highly strained upon binding to TOP2A (14.3° dihedral angle) indicating disfavorable binding to this isozyme.

[0057] Fig. 24 shows the levels of TOP2A and TOP2B measured in the ovarian cancer cell line OVCAR5 after 24 hours treatment with the indicated concentration of compound 20 by western blotting with antibodies specific to each isozyme. Degradation of the TOP2B isozyme is evident at concentrations as low as 0.063 micromolar, while TOP2A is unaffected in all concentrations assayed indicating specific targeting of TOP2B by compound 20 in cultured cells.

[0058] Fig. 25 shows fluorescence Recovery After Photobleaching (FRAP) analysis. HEK293F cells that express yellow-fluorescent protein (YFP)-TOP2A or YFP-TOP2B were pre-incubated with or without compound 20 (cpd 20) for 15 minutes prior to FRAP analysis. YFP-TOP2 in the bleached area (purple box) rapidly mixes throughout the nucleus and the bleached area is no longer visible after 20 seconds in untreated cells. In the presence of 0.25 micromolar compound 20 the bleached area is still visible after 20 seconds for YFP-TOP2B, but not YFP-TOP2A, indicating compound 20 can specifically inhibit the TOP2B isozyme and impair diffusion throughout the cell.

[0059] DETAILED DESCRIPTION

[0060] Chronic forms of cardiotoxicity are clinically significant. These toxicities develop after the administration of multiple chemotherapeutic cycles comprising ANTs (i.e., after repeated exposure of myocardium to ANTs), and the risk primarily depends on the total cumulative dose of ANTs (Gharib at el, European journal of heart failure 2002, 4, 235- 242; Allen, Seminars in oncology 1992, 79, 529; and Kantrowitz et al, Progress in cardiovascular diseases 1984, 27, 195-200). Chronic forms of cardiotoxicity are associated with the development of cardiomyopathy (most frequently of the dilatation type) and progressive heart failure. The chronic cardiotoxicity is clinically manifested in the course of months or years after completion of a therapy comprising ANTs (i.e., with an early or delayed onset of toxicity, respectively) ( Bloom et al., Circulation: Heart Failure 2016, 9, e002661). Chronic ANT cardiotoxicity is considered to be largely irreversible and difficult to treat, which can principally affect morbidity, mortality and quality of life of cancer survivors who received ANTs as a part of cancer therapy. Thus, it is important to treat and / or prevent the onset of damage to the myocardium. This requirement may be particularly urgent in patients with pre-existent major morphological or functional damage to the myocardium (Zamorano et al., European Heart Journal 2016, 37, 2768-2801).

[0061] Historically, the first and only drug that has been approved as a cardioprotective drug for clinical use in prevention of chronic cumulative cardiotoxicity caused by ANT therapy is dexrazoxane (DEX, dextrorotatory enantiomer (+)-(5)-4,4'-(propane-l,2- diyl)bis(piperazine-2, 6-dione) (Reichardt et al., Future Oncology 2018, 14, 2663-2676). Chemical structure of cardioprotective drug dexrazoxane is shown below.

[0062] O

[0063] O

[0064] DEX efficiency has been repeatedly proved in experimental models (with the use of various laboratory animals and also with various ANTs) (Herman et al., Progress in Pediatric Cardiology 2014, 36, 33-38; Jirkovsky et al., Toxicology 2013, 311, 191-204) and especially in randomized controlled clinical studies with more than 1000 patients (van Dalen etal., Cochrane Database of Systematic Reviews 2011). Though the cardioprotective effect of DEX has been proved beyond all doubt, its clinical use is limited - especially due to concerns about possible negative impact on outcomes of ANT anticancer therapy (Swain et al., Journal of Clinical Oncology 1997, 15, 1318-1332) or about possible increased incidence of secondary malignancies (Tebbi et al., Journal of Clinical Oncology 2007, 25, 493-500). In addition, DEX may worsen myelosuppression induced by ANTs. Recent studies ascribe the cardioprotective effect of DEX to its interaction with topoisomerase Ilbeta (Top2b) (Lyu et al., Cancer research 2007, 67, 8839-8846; Lencova-Popelova et al., Journal of molecular and cellular cardiology 2016, 91, 92-103). This hypothesis is in line with the results of experiments with conditional knockout of Top2b in the myocardium (Zhang et al., Nature medicine 2012, 18, 1639; Vejpongsa et el, Clinical Pharmacology & Therapeutics 2014, 95, 45-52) and with the thorough structure-activity relationship studies of DEX and its metabolite ADR-925, where only analogs of DEX that efficiently inhibited Top2b protected cardiomyocytes against ANT toxicity in vitro and protected heart against chronic cumulative cardiotoxicity caused by repeated administration of ANT in vivo (P. Kollarova-Brazdova etal., Journal of Pharmacology and Experimental Therapeutics 2020, 373(3), 402-415; A. Jirkovska et al., Journal of Medicinal Chemistry 2021, 64, 3997-4019; P. Kollarova-Brazdova el al., Clinical Science 2021, 135, 1897-1914; E. Jirkovsky et al., Circulation Heart Failure 2021; 14, e008209). However, DEX is a non-selective inhibitor of topoisomerases II, i.e. it similarly inhibits both topoisomerase Ila (“TOP2A”) and TOP2B isoforms. Anti-tumor effects of ANTs are mediated primarily via TOP2A (see Burgess DJ, Doles J, Zender L, Xue W, Ma B, McCombie WR, Hannon GJ, Lowe SW, Hemann MT. Topoisomerase levels determine chemotherapy response in vitro and in vivo. Proc Natl Acad Sci U S A. 2008 Jul l;105(26):9053-8. doi: 10.1073 / pnas.0803513105. Epub 2008 Jun 23. PMID: 18574145; PMCID: PMC2435590; Faratian D, Bartlett J. Predictive markers in breast cancer-the future. Histopathology. 2008 Jan;52(l):91-8. doi: 10.1111 / j. 1365-2559.2007.02896.X. PMID: 18171420), which led to the suspicion that DEX may interfere with other TOP2A inhibitors such as ANTs and influence their anticancer effect and / or to worsen myelosuppression induced by ANT. Therefore, inhibiting TOP2A is undesirable for any agent used to mitigate ANT cardiotoxicity.

[0065] The compounds described herein show inhibitory activity to Top2 in some examples with high selectivity to the TOP2B isoform (See Table 2). The selectivity of compounds to TOP2B isoform was explained using X-ray crystallography that showed novel inhibitor binding pocket of the compounds of this disclosure with more beneficial interactions with TOP2B than that with TOP2A. The compounds were able to protect primary cardiomyocytes against ANT toxicity in vitro and were not toxic when administered alone (See Table 1). Moreover, the compounds of Formula (I), Formula (II) or Formula (III) did not interfere with the antiproliferative activity of ANT in vitro in HL 60 cell line (See Table 3).

[0066] Finally, the exemplified compounds showed excellent efficacy as a cardioprotectant at low doses against chronic cumulative ANT cardiotoxicity induced by repeated (10-week) administration of a clinically relevant dose of DAU (once weekly i.v. at a dose of 3 mg / kg DAU) in a rabbit model (Fig.17). This model shows functional, biochemical and morphological similarities to chronic ANT cardiotoxicity observed in the clinical practice. Moreover, the cardioprotective effect of DEX, the approved drug with demonstrated cardioprotective efficacy in the clinical practice, was repeatedly shown in this model (Jirkovský et al., Toxicology 2013, 311, 191-204; Popelová et al., British journal of cancer 2009, 101, 792; E. Jirkovský et al., Circulation Heart Failure 2021; 14, e008209). Compounds In some embodiments, the present application provides a compound of Formula (I): (I), or a pharmaceutically acceptable salt thereof, wherein: R1is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, CH2OH, CORe1, ORa1, and SRa1; R2is selected from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C(O)-C1-6 alkyl, C(O)-C1-6 haloalkyl, C(O)-C2-6 alkenyl, C(O)-C2-6 alkynyl, and C(O)-C3-6cycloalkyl, wherein each of said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C(O)-C1-6 alkyl, C(O)-C1-6 haloalkyl, C(O)-C2-6 alkenyl, C(O)-C2-6 alkynyl, and C(O)-C3-6 cycloalkyl is optionally substituted with a substituent elected from ORa2and NRc2Rd2; Re1is selected from H, OH, C1-3alkoxy, NH2, C1-3alkylamino, and di(C1-3alkyl)amino; Ra1is selected from C1-6 alkyl and C1-6 haloalkyl; Ra2, Rc2, and Rd2are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C(=O)ORa1, C(O)-C1-6 alkyl, C(O)-C2-6 alkenyl, and C(O)-C1-6 haloalkyl, wherein said C1-6 alkyl, C(O)-C1-6 alkyl, and C(O)-C1-6 haloalkyl, is optionally independently substituted with 1, 2, or 3 substituents independently selected from Rb2; or Rc2and Rd2together with the N atom to which they are attached form 4 to 7- membered heterocyclic ring, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rb3; each Rb2is independently selected from CN, OH, NO2, OCN, SCN, SeCN, N3, C1-3 alkoxy, C1-3 haloalkoxy, NH2, C1-3 alkylamino, di(C1-3 alkyl)amino, C1-6 alkoxycarbonyl, (C1-6 alkoxycarbonyl)amino, and Cy1; each Rb3is independently selected from C1-6alkyl and Rb2, wherein said C1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from Rb2; each Cy1is independently selected from C6-10 aryl and 5-10 membered heteroaryl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy1; and each RCy1is independently selected from C1-3 alkyl, C1-3 haloalkyl, halo, CN, NO2, OCN, SCN, SeCN, N3, OH, C1-3alkoxy, C1-3haloalkoxy, NH2, C1-3alkylamino, di(C1-3alkyl)amino, tri(C1-3alkyl)amino, C(=O)OH, C(=O)(C1-6alkoxy), C(=O)H, and C(=O)(C1-6 alkyl). In some embodiments, R1is H. In some embodiments, R1is C1-6 alkyl. In some embodiments, R1is C1-6haloalkyl. In some embodiments, R1is C3-6cycloalkyl. In some embodiments, R1is selected from C1-3 alkoxy and C1-3 haloalkoxy. In some embodiments, R1is CH2OH. In some embodiments, R1is CHO. In some embodiments, R1is COOH. In some embodiments, R1is CO(NH2). In some embodiments, R1is CO(C1-3alkylamino). In some embodiments, R1is CO(di(C1-3alkyl)amino). In some embodiments, R2is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6alkynyl, and C3-6cycloalkyl, wherein each of said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C3-6cycloalkyl is optionally substituted with a substituent elected from ORa2and NRc2Rd2. In some embodiments, R2is H. In some embodiments, R2is C1-6 alkyl. In some embodiments, R2is C1-6haloalkyl. In some embodiments, R2is C1-6alkyl-ORa2. In some embodiments, R2is C1-6alkyl-OH. In some embodiments, R2is C1-6alkyl substituted with C1-3 alkoxy or C1-3 haloalkoxy. In some embodiments, R2is C1-6 alkyl-NRc2Rd2. In some embodiments, R2is C1-6 alkyl-NH2. In some embodiments, R2is C1-6 alkyl- NHC(=O)ORa1. In some embodiments, R2is C1-6alkyl-NH(C1-6alkyl).In some embodiments, R2is C1-6alkyl-N(C1-6alkyl)2. In some embodiments, R2is C(O)-C1-6alkyl. In some embodiments, R2is C(O)-C1-6 haloalkyl. In some embodiments, R2is C(O)-C3-6cycloalkyl. In some embodiments, Rc2and Rd2together with the N atom to which they are attached form 4 to 7-membered heterocyclic ring, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rb3. In some embodiments, the heterocyclic ring has formula: , wherein: m is 1 or 2; and X is selected from CH2, CHRb3, O, S, NH, and NRb3. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, the heterocyclic ring has formula: . In some embodiments, the heterocyclic ring has formula: . In some embodiments, the heterocyclic ring has formula: . In some embodiments, the heterocyclic ring has formula: . In some embodiments, Rb3is C1-6alkyl In some embodiments, Rb3is C1-6alkoxycarbonyl. In some embodiments, Rb3is C1-6 alkyl substituted with Cy1. In some embodiments, Cy1is phenyl. In some embodiments, Cy1is pyridinyl. In some embodiments, Ra2, Rc2, and Rd2are each independently selected from H, C1-6alkyl, C1-6haloalkyl, and C(=O)ORa1, wherein said C1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from Rb2;; or Rc2and Rd2together with the N atom to which they are attached form 4 to 7- membered heterocyclic ring, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rb3. In some embodiments, each of Ra2, Rc2, and Rd2is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, and C(=O)ORa1. In some embodiments, each of Ra2, Rc2, and Rd2is independently selected from C(O)-C1-6 alkyl, C(O)-C2-6 alkenyl, and C(O)-C1-6 haloalkyl. In some embodiments, each of Ra2, Rc2, and Rd2is C(O)-C1-6alkyl that is optionally independently substituted with 1, 2, or 3 substituents independently selected from Rb2. In some embodiments, each Rb2is independently selected from CN, OH, NO2, OCN, SCN, SeCN, N3, C1-3 alkoxy, C1-3 haloalkoxy, NH2, C1-3 alkylamino, di(C1-3 alkyl)amino, C1-6 alkoxycarbonyl, (C1-6 alkoxycarbonyl)amino,.and Cy1. In some embodiments, each Rb2is independently selected from CN, OH, NO2, OCN, SCN, SeCN, N3, C1-3alkoxy, C1-3haloalkoxy, NH2, C1-3alkylamino, di(C1-3alkyl)amino, and Cy1. In one general aspect, the present disclosure provides a compound of Formula (II): (II), or a pharmaceutically acceptable salt thereof, wherein R3and R4are each independently selected from H, C1-6 alkyl optionally substituted with COOH, halogen, CN, OH, NO2, OCN, SCN, SeCN, N3, C1-3alkoxy, C1-3haloalkoxy, NH2, C1-3 alkylamino, di(C1-3 alkyl)amino, and Cy1; Y = O, S, CH2, or NRb3;and R1and R2are each as described herein for Formula (I); or R1and R3taken together with the atoms connecting them form a five, six, or seven-membered carbocyclic ring, a six-membered aromatic ring, a five, six, or seven- membered heterocyclic ring containing one or more heteroatoms independently selected from O and NR5, or a five or six-membered heteroaromatic ring containing one or more heteroatoms independently selected from O, N and NR5, wherein each R5is independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C(O)-C1-6 alkyl, C(O)-C2-6 alkenyl, C(O)-C2-6 alkynyl, C(O)-C3-6 cycloalkyl, and C(O)- C1-6 alkoxy. In some embodiments of Formula (II), R1is H. In some embodiments of Formula (II), R1is C1-6alkyl. In some embodiments, R1is C1-6haloalkyl. In some embodiments, R1is C3-6 cycloalkyl. In some embodiments, R1is selected from C1-3 alkoxy and C1-3 haloalkoxy. In some embodiments, R1is CH2OH. In some embodiments, R1is CHO. In some embodiments, R1is COOH. In some embodiments, R1is CO(NH2). In some embodiments, R1is CO(C1-3 alkylamino). In some embodiments, R1is CO(di(C1-3 alkyl)amino). In some embodiments of Formula (II), R2is H. In some embodiments, R2is C1-6alkyl. In some embodiments, R2is C1-6 haloalkyl. In some embodiments, R2is C1-6 alkyl- ORa2. In some embodiments, R2is C1-6alkyl-OH. In some embodiments, R2is C1-6alkyl substituted with C1.3 alkoxy or C1-3 haloalkoxy. In some embodiments, R2is C1-6 alkyl- NRc2Rd2. In some embodiments, R2is C1-6 alkyl-NH2. In some embodiments, R2is C1-6 alkyl-NHC(=O)ORal. In some embodiments, R2is C1-6 alkyl-NH(C1-6 alkyl). In some embodiments, R2is C1-6 alkyl-N( C1-6 alkyl)2. In some embodiments, R2is C(O)-C1-6 alkyl. In some embodiments, R2is C(O)-C1-6 haloalkyl. In some embodiments, R2is C(O)-C2-6 alkenyl. In some embodiments, R2is C(O)-C2-6 alkynyl. In some embodiments, R2is C(O)-C3-6 cycloalkyl.

[0067] In some embodiments of Formula (II), Rc2and Rd2together with the N atom to which they are attached form 4 to 7-membered heterocyclic ring, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rb3.

[0068] In some embodiments of Formula (II), the heterocyclic ring has formula: 4~N / X wherein: m is 1 or 2; and

[0069] X is selected from CH2, CHRb3, O, S, NH, and NRb3.

[0070] In some embodiments of Formula (II), m is 1. In some embodiments, m is 2.

[0071] In some embodiments of Formula (II), the heterocyclic ring has formula: 4-r / X3

[0072] In some embodiments of Formula (II), the heterocyclic ring has formula:

[0073] In some embodiments of Formula (II), the heterocyclic ring has formula:

[0074] 4~N N-Rb3

[0075] In some embodiments of Formula (II), the heterocyclic ring has formula: 4'N7N-Cy1

[0076] In some embodiments of Formula (II), Rb3is C1-6 alkyl.

[0077] In some embodiments, Rb3is C1-6 alkoxycarbonyl.

[0078] In some embodiments of Formula (II), Rb3is C1-6 alkyl substituted with Cy1.

[0079] In some embodiments of Formula (II), Cy1is phenyl. In some embodiments, Cy1is pyridinyl.

[0080] In some embodiments of Formula (II), R3is H. In some embodiments, R3is C1-6 alkyl. In some embodiments, R3is halogen. In some embodiments, R3is CN. In some embodiments, R3is OH. In some embodiments, R3is NO2. In some embodiments, R3is OCN. In some embodiments, R3is SCN. In some embodiments, R3is SeCN. In some embodiments, R3is N In some embodiments, R3is C1-3 alkoxy. In some embodiments, R3is C1-3 haloalkoxy. In some embodiments, R3is NH2. In some embodiments, R3is C1-3 alkylamino. In some embodiments, R3is di(C1-3 alkyl)amino. In some embodiments, R3is Cy1.

[0081] In some embodiments of Formula (II), R4is H. In some embodiments, R4is C1-6 alkyl. In some embodiments, R4is halogen. In some embodiments, R4is CN. In some embodiments, R4is OH. In some embodiments, R4is NO2. In some embodiments, R4is OCN. In some embodiments, R4is SCN. In some embodiments, R4is SeCN. In some embodiments, R4is N In some embodiments, R4is C1-3 alkoxy. In some embodiments, R4is C1-3 haloalkoxy. In some embodiments, R4is NH2. In some embodiments, R4is C1-3 alkylamino. In some embodiments, R4is di(C1-3 alkyl)amino. In some embodiments, R4is and Cy1.

[0082] In some embodiments of Formula (II), R1and R3taken together with the atoms connecting them form a five, six, or seven-membered carbocyclic ring. In some embodiments, R1and R3taken together with the atoms connecting them form a five- membered carbocyclic ring. In some embodiments, R1and R3taken together with the atoms connecting them form a six-membered carbocyclic ring. In some embodiments, R1and R3taken together with the atoms connecting them form a seven-membered carbocyclic ring. In some embodiments of Formula (II), R1and R3taken together with the atoms connecting them form a five, six, or seven-membered heterocyclic ring containing one or more heteroatoms independently selected from O and NR5, wherein each R5is independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C(O)-C1-6alkyl, C(O)-C2-6alkenyl, C(O)-C2-6alkynyl, C(O)-C3-6cycloalkyl, and C(O)- C1-6 alkoxy. In some embodiments, R1and R3taken together with the atoms connecting them form a five-membered heterocyclic ring containing one or more heteroatoms independently selected from O and NR5. In some embodiments, R1and R3taken together with the atoms connecting them form a six-membered heterocyclic ring containing one or more heteroatoms independently selected from O and NR5. In some embodiments, R1and R3taken together with the atoms connecting them form a seven-membered heterocyclic ring containing one or more heteroatoms independently selected from O and NR5. In some embodiments, R5is H. In some embodiments, R5is C1-6 alkyl. In some embodiments, R5is C3-6cycloalkyl. In some embodiments, R5is C(O)-C1-6alkyl. In some embodiments, R5is C(O)-C3-6 cycloalkyl. In some embodiments, R5is C(O)-C1-6 alkoxy. In some embodiments, R1and R3taken together with the atoms connecting them form a six-membered aromatic ring. In some embodiments, R1and R3taken together with the atoms connecting them form a five or six-membered heteroaromatic ring containing one or more heteroatoms independently selected from O, N and NR5, wherein each R5is independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C(O)-C1-6 alkyl, C(O)-C2-6 alkenyl, C(O)-C2-6 alkynyl, C(O)-C3-6 cycloalkyl, and C(O)- C1-6 alkoxy. In some embodiments of Formula (II), Y = O. In some embodiments of Formula (II), Y =S. In some embodiments of Formula (II), Y = CH2. In some embodiments of Formula (II), Y = NRb3. In one general aspect, the present disclosure provides a compound of Formula (III): (III), or a pharmaceutically acceptable salt thereof, wherein R3and R4are each independently selected from H, C1-6 alkyl optionally substituted with COOH, halogen, CN, OH, NO2, OCN, SCN, SeCN, N3, C1-3alkoxy, C1-3haloalkoxy, NH2, C1-3 alkylamino, di(C1-3 alkyl)amino, and Cy1; Y = O, S, CH2, or NRb3 ;Z = N or CR1; A = NH or O; q = 0 or 1; and R1and R2are each as described herein for Formula (I); or R1and R3taken together with the atoms connecting them form a five, six, or seven-membered carbocyclic ring, a six-membered aromatic ring, a five, six, or seven- membered heterocyclic ring containing one or more heteroatoms independently selected from O and NR5, or a five or six-membered heteroaromatic ring containing one or more heteroatoms independently selected from O, N and NR5, wherein each R5is independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C(O)-C1-6 alkyl, C(O)-C2-6 alkenyl, C(O)-C2-6 alkynyl, C(O)-C3-6 cycloalkyl, and C(O)- C1-6 alkoxy. In some embodiments of Formula (III), R1is H. In some embodiments of Formula (III), R1is C1-6 alkyl. In some embodiments, R1is C1-6 haloalkyl. In some embodiments, R1is C3-6cycloalkyl. In some embodiments, R1is selected from C1-3alkoxy and C1-3haloalkoxy. In some embodiments, R1is CH2OH. In some embodiments, R1is CHO. In some embodiments, R1is COOH. In some embodiments, R1is CO(NH2). In some embodiments, R1is CO(C1-3alkylamino). In some embodiments, R1is CO(di(C1-3alkyl)amino). In some embodiments of Formula (III), R2is H. In some embodiments, R2is C1-6 alkyl. In some embodiments, R2is C1-6haloalkyl. In some embodiments, R2is C1-6alkyl- ORa2. In some embodiments, R2is C1-6alkyl-OH. In some embodiments, R2is C1-6alkyl substituted with C1-3 alkoxy or C1-3 haloalkoxy. In some embodiments, R2is C1-6 alkyl- NRc2Rd2. In some embodiments, R2is C1-6alkyl-NH2. In some embodiments, R2is C1-6alkyl-NHC(=O)ORa1. In some embodiments, R2is C1-6alkyl-NH(C1-6alkyl).In some embodiments, R2is C1-6 alkyl-N(C1-6 alkyl)2. In some embodiments, R2is C(O)-C1-6 alkyl. In some embodiments, R2is C(O)-C1-6 haloalkyl. In some embodiments, R2is C(O)-C2-6alkenyl. In some embodiments, R2is C(O)-C2-6alkynyl. In some embodiments, R2is C(O)-C3-6 cycloalkyl. In some embodiments of Formula (III), Z = N. In some embodiments of Formula (III), Z = CR1. In some embodiments of Formula (III), A = NH. In some embodiments of Formula (III), A = O. In some embodiments of Formula (III), q = 0. In some embodiments of Formula (III), q = 1. In some embodiments of Formula (III), Rc2and Rd2together with the N atom to which they are attached form 4 to 7-membered heterocyclic ring, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rb3. In some embodiments of Formula (III), the heterocyclic ring has formula: , wherein: m is 1 or 2; and X is selected from CH2, CHRb3, O, S, NH, and NRb3. In some embodiments of Formula (III), m is 1. In some embodiments, m is 2. In some embodiments of Formula (III), the heterocyclic ring has formula: . In some embodiments of Formula (III), the heterocyclic ring has formula: . In some embodiments of Formula (III), the heterocyclic ring has formula: . In some embodiments of Formula (III), the heterocyclic ring has formula: . In some embodiments of Formula (III), Rb3is C1-6 alkyl. In some embodiments, Rb3is C1-6alkoxycarbonyl. In some embodiments of Formula (III), Rb3is C1-6 alkyl substituted with Cy1. In some embodiments of Formula (III), Cy1is phenyl. In some embodiments, Cy1is pyridinyl. In some embodiments of Formula (III), R3is H. In some embodiments, R3is C1-6 alkyl. In some embodiments, R3is halogen. In some embodiments, R3is CN. In some embodiments, R3is OH. In some embodiments, R3is NO2. In some embodiments, R3is OCN. In some embodiments, R3is SCN. In some embodiments, R3is SeCN. In some embodiments, R3is N. In some embodiments, R3is C1-3 alkoxy. In some embodiments, R3is C1-3haloalkoxy. In some embodiments, R3is NH2. In some embodiments, R3is C1-3alkylamino. In some embodiments, R3is di(C1-3alkyl)amino. In some embodiments, R3is Cy1. In some embodiments of Formula (III), R4is H. In some embodiments, R4is C1-6 alkyl. In some embodiments, R4is halogen. In some embodiments, R4is CN. In some embodiments, R4is OH. In some embodiments, R4is NO2. In some embodiments, R4is OCN. In some embodiments, R4is SCN. In some embodiments, R4is SeCN. In some embodiments, R4is N.In some embodiments, R4is C1-3alkoxy. In some embodiments, R4 is C1-3haloalkoxy. In some embodiments, R4is NH2. In some embodiments, R4is C1-3alkylamino. In some embodiments, R4is di(C1-3 alkyl)amino. In some embodiments, R4is and Cy1. In some embodiments of Formula (III), R1and R3taken together with the atoms connecting them form a five, six, or seven-membered carbocyclic ring. In some embodiments, R1and R3taken together with the atoms connecting them form a five- membered carbocyclic ring. In some embodiments, R1and R3taken together with the atoms connecting them form a six-membered carbocyclic ring. In some embodiments, R1and R3taken together with the atoms connecting them form a seven-membered carbocyclic ring. In some embodiments of Formula (III), R1and R3taken together with the atoms connecting them form a five, six, or seven-membered heterocyclic ring containing one or more heteroatoms independently selected from O and NR5, wherein each R5is independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C(O)-C1-6 alkyl, C(O)-C2-6 alkenyl, C(O)-C2-6 alkynyl, C(O)-C3-6 cycloalkyl, and C(O)- C1-6 alkoxy. In some embodiments, R1and R3taken together with the atoms connecting them form a five-membered heterocyclic ring containing one or more heteroatoms independently selected from O and NR5. In some embodiments, R1and R3taken together with the atoms connecting them form a six-membered heterocyclic ring containing one or more heteroatoms independently selected from O and NR5. In some embodiments, R1and R3taken together with the atoms connecting them form a seven-membered heterocyclic ring containing one or more heteroatoms independently selected from O and NR5. In some embodiments, R5is H. In some embodiments, R5is C1-6 alkyl. In some embodiments, R5is C3-6cycloalkyl. In some embodiments, R5is C(O)-C1-6alkyl. In some embodiments, R5is C(O)-C3-6cycloalkyl. In some embodiments, R5is C(O)-C1-6alkoxy. In some embodiments, R1and R3taken together with the atoms connecting them form a six-membered aromatic ring. In some embodiments, R1and R3taken together with the atoms connecting them form a five or six-membered heteroaromatic ring containing one or more heteroatoms independently selected from O, N and NR5, wherein each R5is independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C(O)-C1-6alkyl, C(O)-C2-6alkenyl, C(O)-C2-6alkynyl, C(O)-C3-6cycloalkyl, and C(O)- C1-6 alkoxy. In some embodiments of Formula (III), Y = O. In some embodiments of Formula (III), Y =S. In some embodiments of Formula (III), Y = CH2. In some embodiments of Formula (III), Y = NRb3. In some embodiments of Formula (III), the compound is a compound of Formula (IIIA): (IIIA), or a pharmaceutically acceptable salt thereof, wherein R2, R3and R4are each as described herein for Formula (III). In some embodiments of Formula (III), the compound is a compound of Formula (IIIB): (IIIB), or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3and R4are each as described herein for Formula (III). In some embodiments of Formula (III), the compound is a compound of Formula (IIIC): (IIIC), or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3and R4are each as described herein for Formula (III). In some embodiments of Formula (III), the compound is a compound of Formula (IIID): (IIID), or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3and R4are each as described herein for Formula (III). In some embodiments, the compound of Formula (I), Formula (II) or Formula (III) is selected from any one of the following compounds: 1

[0083] HO^^O

[0084] JI I 1

[0085]

[0086] or a pharmaceutically acceptable salt thereof.

[0087] In some embodiments, the compound of Formula (II) is selected from any one of the following compounds:

[0088]

[0089] or a pharmaceutically acceptable salt thereof.

[0090] In some embodiments, the compound of Formula (III) is selected from any one of the following compounds:

[0091] 73

[0092] 74

[0093] 75

[0094] 77 or a pharmaceutically acceptable salt thereof.

[0095] Pharmaceutically acceptable salts

[0096] In some embodiments, a salt of a compound of Formula (I), Formula (II) or Formula (III) is formed between an acid and a basic group of the compound, such as an amino functional group, or a base and an acidic group of the compound, such as a carboxyl functional group. According to another embodiment, the compound is a pharmaceutically acceptable acid addition salt.

[0097] In some embodiments, acids commonly employed to form pharmaceutically acceptable salts of the compounds of Formula (I), Formula (II) or Formula (III) include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, as well as organic acids such as para- toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid, as well as related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne- 1,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylene sulfonate, phenyl acetate, phenylpropionate, phenylbutyrate, citrate, lactate, P-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene- 1 -sulfonate, naphthal ene-2- sulfonate, mandelate and other salts. In one embodiment, pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and especially those formed with organic acids such as maleic acid.

[0098] In some embodiments, bases commonly employed to form pharmaceutically acceptable salts of the compounds of Formula (I), Formula (II) or Formula (III) include hydroxides of alkali metals, including sodium, potassium, and lithium; hydroxides of alkaline earth metals such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, organic amines such as unsubstituted or hydroxyl- substituted mono-, di-, or tri-alkylamines, dicyclohexylamine; tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-OH-(Cl- C6)-alkylamine), such as N,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2- hydroxyethyl)amine; N-methyl-D-glucamine; morpholine; thiomorpholine; piperidine; pyrrolidine; and amino acids such as arginine, lysine, and the like.

[0099] In some embodiments, the compounds of Formula (I), Formula (II) or Formula (III), or pharmaceutically acceptable salts thereof, are substantially isolated.

[0100] Methods of use

[0101] Topoisomerase II (TOP2) is an enzyme that alters the topology of DNA; it is intensively studied for its essential role in DNA replication and transcription and represents an attractive target for anticancer drugs. TOP2 is found in two isoforms in the human body, alpha (TOP2A), characteristic of dividing cells, including cancer cells, and beta (TOP2B), also expressed in terminally differentiated cells. The high structural similarity of the two isoforms is behind the severe side effects of ANTs (e.g. doxorubicin, daunorubicin, epirubicin), very potent anticancer drugs from the group of so-called “TOP2 poisons”. Although they have been used in the clinic for many decades, ANTs still represent an important component of anticancer therapy for many serious hematological and solid tumors, even for children. Inhibition of TOP2 by ANTs leads to cytotoxic DNA damage, which is a desirable effect in cancer cells via TOP2A inhibition, but has a fundamentally negative impact on healthy non-dividing cells via TOP2B inhibition. Clinically, the most notable impact of TOP2B inhibition is chronic ANT cardiotoxicity leading to the development of chronic heart failure. It has been shown that catalytic inhibition of TOP2B can prevent DNA damage by ANTs and thus protect cardiac cells from ANT cardiotoxicity. The only cardioprotective drug currently proven to be effective and in clinical use is the non-selective TOP2 catalytic inhibitor dexrazoxane (as discussed above), but its use is very limited due to concerns about its side effects and interference with the antitumor effect of ANTs through interaction with T0P2A. The compounds of this disclosure are uniquely selective to TOP2B due to interaction with a previously undescribed TOP2 binding site that differs in structure between the T0P2A and TOP2B isoforms.

[0102] Cardiovascular disease and cancer are two of the leading causes of death in Western countries. Unfortunately, successful cancer treatment often entails toxicity to healthy (non-tumor) tissues. Due to its minimal regenerative capacity, myocardial damage is one of the most serious side effects of anticancer chemotherapy and is often characterised by permanent consequences. Thus, cardiotoxicity of anticancer therapy can have a significant impact on morbidity and mortality of patients surviving long-term after successful cancer treatment. The increase in the number of these patients (approximately 16.9 million in the USA alone) and the understanding of the urgency of the problem has also given rise to a relatively new field - cardio-oncology. Damage to the myocardium by anticancer treatment can be the cause of chronic heart failure, which can develop during or shortly after the end of treatment, but also many years later. For example, long-term survivors of childhood malignancies have a 15-fold higher risk of developing chronic heart failure than the general population (Oeffinger et al. 2006; PMID: 17035650. Patients treated with ANT chemotherapeutic agents (which include, for example, DOX, DAU or epirubicin) have the highest risk of ChSS, despite measures aimed at reducing their cardiotoxicity. ANTs have been widely used for decades in children and adults for the treatment of a wide range of cancers (e.g., hematological malignancies, lymphomas, breast tumors and sarcomas). They are often essential for treatment success and are therefore indispensable in many treatment protocols. However, epidemiological studies suggest that toxic myocardial damage from ANTs may be a significant contributor to the epidemic increase in CVD in the 21st century. In the last decade, topoisomerase II (TOP2), has been identified as an important common denominator for successful anticancer therapy and the development of toxic myocardial injury. The former effect is associated with DNA damage induced by inhibition of the alpha isoform (TOP2A) in tumor cells by ANTs, whereas the cardiotoxicity of ANTs is associated with inhibition of the beta isoform (TOP2B) in cardiomyocytes. Dexrazoxane (DEX) is a clinically approved cardioprotective drug for which it has been relatively recently established that its mechanism of action is precisely through interaction with TOP2B, which prevents ANT-induced DNA damage in cardiomyocytes and their irreversible damage. However, the non- selectivity of DEX against TOP2 isoforms is a source of adverse effects, which fundamentally limits its clinical use. For this reason, DEX is only used in patients with higher cumulative doses of ANT where a risk-benefit analysis speaks for its use. Although DEX is clearly cardioprotective, according to current recommendations, most patients undergo ANT therapy without active myocardial protection for safety reasons.

[0103] In a general aspect, the present disclosure provides a method of treating and / or preventing cardiotoxicity (or cardiomyopathy) in a subject, the method comprising administering to the subject (e.g., subject in need of such treatment or prevention) a therapeutically effective amount of a compound of Formula (I), Formula (II) or Formula (III), or a pharmaceutically acceptable salt thereof.

[0104] In some embodiments, the cardiotoxicity (or cardiomyopathy) in the subject is induced by administration to the subject an amount of an ANT chemotherapeutic agent. In some embodiments, the amount of the ANT chemotherapeutic agent is sufficient to induce apoptosis in a cancer cell. In some embodiments, the ANT chemotherapeutic agent is selected from DOX, DAU, epirubicin, and idarubicin, or a pharmaceutically acceptable salt thereof.

[0105] In any of the methods herein, administration of a compound of Formula (I), Formula (II) or Formula (III) , or a pharmaceutically acceptable salt thereof, may be simultaneous with, subsequent to, or prior to the administration of the ANT chemotherapeutic agent.

[0106] In some embodiments, the cardiotoxicity (or cardiomyopathy) is grade 2 toxicity or higher according to NCI nomenclature. For example, cardiotoxicity is moderate (grade 2), severe (grade 3), or life-threatening (grade 4). In some embodiments, the cardiotoxicity is characterized by cardiotoxic events such as pericardial edema, impaired cardiac contractility, decreased blood flow through the vasculature, left ventricular ejection fraction (LVEF) of less than 55 % (e.g., less than 50%), congestive heart failure (e.g., irreversible CHF), abnormal heartbeat, impaired myocardial function, fractional shortening in cardiomyocytes, reduction of strain rate in cardiomyocytes. Cardiotoxicity can also be diagnosed based on abnormal markers of cardiac injury (e.g., troponin) or a decline in strain / strain rate on echocardiography. Suitable examples of cardiomyopathies include hypertrophic cardiomyopathy, dilated cardiomyopathy, restrictive cardiomyopathy, arrhythmogenic right ventricular dysplasia, and broken heart syndrome. In hypertrophic cardiomyopathy, the heart muscle enlarges and thickens. In dilated cardiomyopathy, the ventricles enlarge and weaken. In restrictive cardiomyopathy, the ventricle stiffens. In some embodiments, the method of treating cardiotoxicity (or cardiomyopathy) in the subject includes ameliorating symptoms of cardiotoxicity such as shortness of breath, feeling tired, swelling of the legs, heart failure, abnormal heartbeat, chest discomfort, fainting and fatigue.

[0107] In some embodiments of any of the foregoing methods, an ANT chemotherapeutic agent (e.g., DOX) is administered to the subject at a maximum safe dosage tolerated in cancer treatment. The maximum safe dosage may be approximately 400-500 mg / m2or any suitable dosage greater than 400 mg / m2, based on factors related to each individual patient's disease state.

[0108] In a general aspect, the present disclosure provides a method of treating or preventing cardiotoxicity in a subject receiving cardiotoxic chemotherapy, comprising administering to the subject (e.g., in need thereof) a therapeutically effective amount of a compound of Formula (I), Formula (II) or Formula (III), or a pharmaceutically acceptable salt thereof. In one example, the cardiotoxic chemotherapy includes administering to the subject a therapeutically effective amount of ANT chemotherapeutic agent (e.g., DOX). In some embodiments, the compound of Formula (I), Formula (II) or Formula (III), or a pharmaceutically acceptable salt thereof, is administered to the subject prior to cardiotoxic chemotherapy. For example, the compound of Formula (I), Formula (II) or Formula (III), or a pharmaceutically acceptable salt thereof, may be administered to the subject at least 5 min, at least 15 min, at least 30 min, at least 24 hours or at least 3 days, or at least 1 week prior to cardiotoxic chemotherapy. In certain embodiments, the compound of Formula (I), Formula (II) or Formula (III), or a pharmaceutically acceptable salt thereof, may be administered to the subject at least 5 min, at least 15 min, at least 30 min, or at least 60 min after administration of cardiotoxic chemotherapy. In yet other embodiments, the compound of Formula (I), Formula (II) or Formula (III), or a pharmaceutically acceptable salt thereof, may be administered to the subject simultaneously with cardiotoxic chemotherapy, for example, in a single dosage form with a cardiotoxic chemotherapeutic agent (e.g., doxorubicin).

[0109] In a general aspect, the present application provides a method of enhancing antitumor effect of an ANT chemotherapeutic agent (such as DOX), comprising administering to the subject (e g., in need thereof) a therapeutically effective amount of a compound of Formula (I), Formula (II) or Formula (III), or a pharmaceutically acceptable salt thereof. In some embodiments, the application is directed to a method of providing cardioprotection to a subject, comprising administering a therapeutically effective amount of a compound of Formula (I), Formula (II) or Formula (III), or a pharmaceutically acceptable salt thereof, to the subject. In a more particular embodiment, provided herein is a method of treating cancer in a subject, the method comprising administering an ANT chemotherapeutic agent (ANT) to a subject who is administered a therapeutically effective amount of a compound of Formula (I), Formula (II) or Formula (III), or a pharmaceutically acceptable salt thereof, wherein the method comprises administering a higher cumulative dose of ANT than the cumulative dose of ANT administered to a subject who is not administered a therapeutically effective amount of a compound of Formula (I), Formula (II) or Formula (III), or a pharmaceutically acceptable salt thereof. In this example, the subject’s chance of survival may be increased by using a higher dose of doxorubicin to treat cancer in the subject, with the reduced risk of cardiotoxic adverse events associated with doxorubicin therapy.

[0110] In a general aspect, the present application provides a method of treating extravasation, such as extravasation in a subject receiving chemotherapy, such as chemotherapy with an ANT chemotherapeutic agent (such as DOX), comprising administering to the subject (e g., in need thereof) a therapeutically effective amount of a compound of Formula (I), Formula (IT) or Formula (TIT), or a pharmaceutically acceptable salt thereof.

[0111] In some embodiments, a compound provided herein (e.g., Examples 79 and 81-83 herein) can be cysteine-reactive with TOP2B. In some cases, a compound provided herein (e.g., Examples 79 and 81-83 herein) can covalently bind to TOP2B and inhibit TOP2B activity. In some cases, a compound provided herein can non-covalently bind to TOP2B and inhibit TOP2B activity.

[0112] In some embodiments, the compound of Formula (I), Formula (II) or Formula (III), or a pharmaceutically acceptable salt thereof, may be administered to the subject in combination with another cardioprotective therapeutic agent. Suitable examples of cardioprotective agents include cardioprotective drugs (e.g., dexrazoxane, ACE- inhibitors, diuretics, cardiac glycosides), cholesterol lowering drugs, revascularization drugs, anti-inflammatory drugs, cardioprotective diets, cardioprotective nutrients, cardioprotective herbs, cardioprotective vitamins (e.g., folic acid, B vitamin family), beta-blockers (e.g., acebutolol, atenolol, bisoprolol, carvedilol, metoprolol, nadolol, nebivolol, or propranolol), angiotensin receptor blockers (also called ARBs or angiotensin II inhibitors) (e.g., azilsartan, candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, or valsartan), and cardioprotective hormone treatments. In some embodiments, a therapeutically effective amount of the compound of Formula (I), Formula (II) or Formula (III), or a pharmaceutically acceptable salt thereof, may be administered to the subject in combination with a therapeutically effective amount of dexrazoxane, or a pharmaceutically acceptable salt thereof.

[0113] Cancer treatment

[0114] In a general aspect, the present disclosure provides a method of treating cancer in a subject, comprising administering to the subject (e.g., subject in need of cancer treatment) a therapeutically effective amount of a compound of Formula (I), Formula (II) or Formula (III), or a pharmaceutically acceptable salt thereof, and an ANT chemotherapeutic agent, or a pharmaceutically acceptable salt thereof.

[0115] In some embodiments, cancer is selected from the group selected from sarcoma, angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyoma, fibroma, lipoma, teratoma, lung cancer, breast cancer, bronchogenic carcinoma squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma, alveolar bronchiolar carcinoma, bronchial adenoma, lymphoma, chondromatous hamartoma, mesothelioma, gastrointestinal cancer, cancer of the esophagus, squamous cell carcinoma, leiomyosarcoma, lymphoma, cancer of the stomach, carcinoma, cancer of the pancreas, ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, vipoma, cancer of the small bowel, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, neurofibroma, cancer of the large bowel or colon, tubular adenoma, villous adenoma, hamartoma, genitourinary tract cancer, cancer of the kidney, Wilm's tumor (nephroblastoma), leukemia, cancer of the bladder, cancer of the urethra, transitional cell carcinoma, cancer of the prostate, cancer of the testis, seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, interstitial cell carcinoma, fibroadenoma, adenomatoid tumors, liver cancer, hepatoma hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, hepatocellular adenoma, hemangioma, bone cancer, osteogenic sarcoma (osteosarcoma), malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochrondroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma giant cell tumor, nervous system cancer, cancer of the skull, osteoma, hemangioma, granuloma, xanthoma, osteitis deformans, cancer of the meninges meningioma, meningiosarcoma, gliomatosis, cancer of the brain, astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, cancer of the spinal cord, meningioma, gynecological cancer, cancer of the uterus, endometrial carcinoma, cancer of the cervix, cervical carcinoma, pre tumor cervical dysplasia, cancer of the ovaries, ovarian carcinoma, serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma, granulosa-theca cell tumor, Sertoli Leydig cell tumor, dysgerminoma, malignant teratoma, cancer of the vulva, intraepithelial carcinoma, melanoma, cancer of the vagina, clear cell carcinoma, botryoid sarcoma, embryonal rhabdomyosarcoma, cancer of the fallopian tubes, hematologic cancer, cancer of the blood, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, myelodysplastic syndrome, Hodgkin's lymphoma, non-Hodgkin's lymphoma (malignant lymphoma), Waldenstrom's macroglobulinemia, skin cancer, malignant melanoma, basal cell carcinoma, moles dysplastic nevi, angioma, dermatofibroma, keloids, adrenal gland cancer, and neuroblastoma.

[0116] In the method of treating cancer, the compound of Formula (I), Formula (II) or Formula (III) and the ANT chemotherapeutic agent may be administered to the subject simultaneously (e.g., in the same dosage form or in separate dosage forms), or consecutively (e.g., ANT chemotherapeutic agent may be administered before or after the compound of Formula (I), Formula (II) or Formula (III)).

[0117] In some embodiments, the subject of the combination cancer treatment as described herein does not develop a cardiotoxicity or a cardiomyopathy associated with the administration of the ANT chemotherapeutic agent. In such embodiments, the cardiotoxicity or the cardiomyopathy may be characterized by any one of cardiotoxic events of symptoms described herein.

[0118] In some embodiments, the method of treating cancer in a subject comprises administering to the subject a total cumulative dose of about 200 mg / m2to about 500 mg / m2of doxorubicin, or a pharmaceutically acceptable salt thereof, and from about 0.1 mg / kg to about 2 mg / kg of the compound of Formula (I), Formula (II) or Formula (III), or a pharmaceutically acceptable salt thereof. In some aspects of these embodiments, the total cumulative dose of doxorubicin is from about 220 mg / m2to about 500 mg / m2, about 240 mg / m2to about 500 mg / m2, or about 240 mg / m2to about 300 mg / m2. In some embodiments, e.g., when the cancer is breast cancer, the total ANT dose may be about 240 mg / m2or less. In some embodiments, the total ANT dose if less than about 200 mg / m2. In other embodiments, the total ANT dose is greater than about 500 mg / m2.

[0119] In some embodiments, the method of treating cancer in a subject comprises administering to the subject a total cumulative dose of about 300 mg / m2to about 500 mg / m2of doxorubicin, or a pharmaceutically acceptable salt thereof, and from about 0.001-100 mg / kg, such as 0.1 mg / kg to about 2 mg / kg, of the compound of Formula (I), Formula (II) or Formula (III), or a pharmaceutically acceptable salt thereof. In some aspects of these embodiments, the compound of Formula (I), Formula (II) or Formula (III), or a pharmaceutically acceptable salt thereof, is administered once daily, twice daily, thrice daily, every other day, every two days, every three days, once weekly, twice weekly, once every two weeks, or once a month, and the doxorubicin, or a pharmaceutically acceptable salt thereof, is administered according to the regimen described in the FDA-approved drug label (e.g., NDA050629). In other aspects of these embodiments, doxorubicin, or a pharmaceutically acceptable salt thereof, is administered to the subject by parenteral injection (e.g., infusion), and the compound of Formula (I), Formula (II) or Formula (III), or a pharmaceutically acceptable salt thereof, is administered to the subject orally. In yet other aspects of these embodiments, doxorubicin, or a pharmaceutically acceptable salt thereof, and the compound of Formula (I), Formula (II) or Formula (III), or a pharmaceutically acceptable salt thereof, are both administered by parenteral injection (e.g., infusion).

[0120] In some embodiments, the method of treating cancer in a subject further comprises administering to the subject an additional therapeutic agent, or pharmaceutically acceptable salt thereof. Suitable examples of additional therapeutic agents include an anti-HER2 agent (e.g., trastuzumab, pertuzumab, lapatinib), a pain relief agent (e.g., a nonsteroidal anti-inflammatory drug such as celecoxib or rofecoxib), an antinausea agent, or an additional anticancer agent (e.g., paclitaxel, docetaxel, DAU, epirubicin, fluorouracil, melphalan, cis-platin, carboplatin, cyclophosphamide, mitomycin, methotrexate, mitoxantrone, vinblastine, vincristine, ifosfamide, teniposide, etoposide, bleomycin, leucovorin, taxol, trastuzumab, bevacizumab, cytarabine, dactinomycin, interferon alpha, streptozocin, prednisolone, irinotecan, sulindac, 5- fluorouracil, capecitabine, oxaliplatin / 5 FU, abiraterone, letrozole, 5-aza / romidepsin, or procarbazine). In certain embodiments, the anticancer agent is paclitaxel or docetaxel. In other embodiments, the anticancer agent is cisplatin or irinotecan. In some embodiments, the method of treating cancer in a subject further comprises administering to the subject a cell carcinoma treatment. Examples of additional optional renal cell carcinoma treatments include, without limitation, treatment with Nexavar® (sorafenib), Sutent® (sunitinib), Torisel® (temsirolimus), Afinitor® (everolimus), axitinib, pazopanib, levatinib, interleukin-2, and combinations thereof. In some embodiments, the method of treating cancer in a subject further comprises administering to the subject a proteasome inhibitor. Exemplary proteasome inhibitors include lactacystin, bortezomib, dislfiram, salinosporamide A, carfilzomib, ONX0912, CEP-18770, MLN9708, epoxomicin, and MG132). Non-limiting examples of proteasome inhibitors include marizomib (NPI- 0052), bortezomib (Velcade®), and carfilzomib (Kyprolis®). In some embodiments, the method of treating cancer in a subject also comprises administering to the subject a therapeutically effective amount of an additional cardioprotective therapeutic agent. Suitable examples of such agents are described herein.

[0121] Compositions, formulations, and routes of administration

[0122] The present application also provides pharmaceutical compositions comprising an effective amount of a compound of Formula (I), Formula (II), or Formula (III) disclosed herein, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. The pharmaceutical composition may also comprise any one of the additional therapeutic agents described herein (e.g., doxorubicin or an additional cardioprotective agent). In certain embodiments, the application also provides pharmaceutical compositions and dosage forms comprising any one the additional therapeutic agents described herein. The carrier(s) are “acceptable” in the sense of being compatible with the other ingredients of the formulation and, in the case of a pharmaceutically acceptable carrier, not deleterious to the recipient thereof in an amount used in the medicament.

[0123] Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of the present application include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

[0124] The compositions or dosage forms may contain any one of the compounds and therapeutic agents described herein in the range of 0.005% to 100% with the balance made up from the suitable pharmaceutically acceptable excipients. The contemplated compositions may contain 0.001%-100% of any one of the compounds and therapeutic agents provided herein, in one embodiment 0.1-95%, in another embodiment 75-85%, in a further embodiment 20-80%, wherein the balance may be made up of any pharmaceutically acceptable excipient described herein, or any combination of these excipients.

[0125] Routes of administration and dosage forms

[0126] The pharmaceutical compositions of the present application include those suitable for any acceptable route of administration. Acceptable routes of administration include, but are not limited to, buccal, cutaneous, endocervical, endosinusial, endotracheal, enteral, epidural, interstitial, intra-abdominal, intra-arterial, intrabronchial, intrabursal, intracerebral, intraci sternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intranasal, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasy novi al, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, nasal, nasogastric, oral, parenteral, percutaneous, peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral and vaginal.

[0127] Compositions and formulations described herein may conveniently be presented in a unit dosage form, e.g., tablets, sustained release capsules, and in liposomes, and may be prepared by any methods well known in the art of pharmacy. See, for example, Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, Baltimore, MD (20th ed. 2000). Such preparative methods include the step of bringing into association with the molecule to be administered ingredients such as the carrier that constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers, liposomes or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0128] In some embodiments, any one of the compounds and therapeutic agents disclosed herein are administered orally. Compositions of the present application suitable for oral administration may be presented as discrete units such as capsules, sachets, granules or tablets each containing a predetermined amount (e.g., effective amount) of the active ingredient; a powder or granules; a solution or a suspension in an aqueous liquid or a non-aqueous liquid; an oil-in-water liquid emulsion; a water-in-oil liquid emulsion; packed in liposomes; or as a bolus, etc. Soft gelatin capsules can be useful for containing such suspensions, which may beneficially increase the rate of compound absorption. In the case of tablets for oral use, carriers that are commonly used include lactose, sucrose, glucose, mannitol, and silicic acid and starches. Other acceptable excipients may include: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and / or flavoring and / or coloring agents may be added. Compositions suitable for oral administration include lozenges comprising the ingredients in a flavored basis, usually sucrose and acacia or tragacanth; and pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia.

[0129] Compositions suitable for parenteral administration include aqueous and non- aqueous sterile injection solutions or infusion solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, saline (e.g., 0.9% saline solution) or 5% dextrose solution, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets. The injection solutions may be in the form, for example, of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3 -butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long- chain alcohol diluent or dispersant.

[0130] The pharmaceutical compositions of the present application may be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of the present application with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycols.

[0131] The pharmaceutical compositions of the present application may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art. See, for example, U.S. Patent No. 6,803,031. Additional formulations and methods for intranasal administration are found in Ilium, L., J Pharm Pharmacol, 56:3-17, 2004 and Ilium, L., Eur J Pharm Set 11 : 1-18, 2000.

[0132] The topical compositions of the present disclosure can be prepared and used in the form of an aerosol spray, cream, emulsion, solid, liquid, dispersion, foam, oil, gel, hydrogel, lotion, mousse, ointment, powder, patch, pomade, solution, pump spray, stick, towelette, soap, or other forms commonly employed in the art of topical administration and / or cosmetic and skin care formulation. The topical compositions can be in an emulsion form. Topical administration of the pharmaceutical compositions of the present application is especially useful when the desired treatment involves areas or organs readily accessible by topical application. In some embodiments, the topical composition comprises a combination of any one of the compounds and therapeutic agents disclosed herein, and one or more additional ingredients, carriers, excipients, or diluents including, but not limited to, absorbents, anti-irritants, anti-acne agents, preservatives, antioxidants, coloring agents / pigments, emollients (moisturizers), emulsifiers, film-forming / holding agents, fragrances, leave-on exfoliants, prescription drugs, preservatives, scrub agents, silicones, skin-identical / repairing agents, slip agents, sunscreen actives, surfactants / detergent cleansing agents, penetration enhancers, and thickeners.

[0133] Dosages and regimens

[0134] In the pharmaceutical compositions of the present application, a compound of any one of Formula (I), Formula (II) or Formula (III) is present in an effective amount (e g., a therapeutically effective amount). Effective doses may vary, depending on the diseases treated, the severity of the disease, the route of administration, the sex, age and general health condition of the subject, excipient usage, the possibility of co-usage with other therapeutic treatments such as use of other agents and the judgment of the treating physician. In some embodiments, an effective amount of a compound of any one of Formula (I), Formula (II) or Formula (III) can range, for example, from about 0.001 mg / kg to about 500 mg / kg (e.g., from about 0.001 mg / kg to about 200 mg / kg; from about 0.01 mg / kg to about 200 mg / kg; from about 0.01 mg / kg to about 150 mg / kg; from about 0.01 mg / kg to about 100 mg / kg; from about 0.01 mg / kg to about 50 mg / kg; from about 0.01 mg / kg to about 10 mg / kg; from about 0.01 mg / kg to about 5 mg / kg; from about 0.01 mg / kg to about 1 mg / kg; from about 0.01 mg / kg to about 0.5 mg / kg; from about 0.01 mg / kg to about 0.1 mg / kg; from about 0. 1 mg / kg to about 200 mg / kg; from about 0. 1 mg / kg to about 150 mg / kg; from about 0. 1 mg / kg to about 100 mg / kg; from about 0.1 mg / kg to about 50 mg / kg; from about 0. 1 mg / kg to about 10 mg / kg; from about 0.1 mg / kg to about 5 mg / kg; from about 0.1 mg / kg to about 2 mg / kg; from about 0.1 mg / kg to about 1 mg / kg; or from about 0.1 mg / kg to about 0.5 mg / kg). In some embodiments, an effective amount of a compound of any one of Formula (I), Formula (II) or Formula (III) is about 0.1 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 2 mg / kg, or about 5 mg / kg. The foregoing dosages can be administered on a daily basis (e.g., as a single dose or as two or more divided doses, e.g., once daily, twice daily, thrice daily) or non-daily basis (e.g., every other day, every two days, every three days, once weekly, twice weekly, once every two weeks, once a month).

[0135] Definitions

[0136] As used herein, the term "about" means "approximately" (e g., plus or minus approximately 10% of the indicated value).

[0137] At various places in the present specification, substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges. For example, the term “C1-6 alkyl” is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and Ce alkyl.

[0138] At various places in the present specification various aryl, heteroaryl, cycloalkyl, and heterocycloalkyl rings are described. Unless otherwise specified, these rings can be attached to the rest of the molecule at any ring member as permitted by valency. For example, the term “a pyridine ring” or “pyridinyl” may refer to a pyridin-2-yl, pyri din-3 - yl, or pyridin-4-yl ring.

[0139] It is further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

[0140] The term “aromatic” refers to a carbocycle or heterocycle having one or more polyunsaturated rings having aromatic character (i.e., having (4n + 2) delocalized n (pi) electrons where n is an integer).

[0141] The term “heteroaromatic” refers to a heterocycle having one or more polyunsaturated rings having aromatic character (i.e., having (4n + 2) delocalized it (pi) electrons where n is an integer) and containing one or more heteroatoms independently selected from O, N and S. The term “n-membered” where n is an integer typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is n. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group. As used herein, the phrase “optionally substituted” means unsubstituted or substituted. The substituents are independently selected, and substitution may be at any chemically accessible position. As used herein, the term “substituted” means that a hydrogen atom is removed and replaced by a substituent. A single divalent substituent, e.g., oxo, can replace two hydrogen atoms. It is to be understood that substitution at a given atom is limited by valency. Throughout the definitions, the term “Cn-m” indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons. Examples include C1-4, C1-6, and the like. As used herein, the term “Cn-m alkyl”, employed alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chain or branched, having n to m carbons. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; higher homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n- hexyl, 1,2,2-trimethylpropyl, and the like. In some embodiments, the alkyl group contains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, or 1 to 2 carbon atoms. As used herein, the term “Cn-mhaloalkyl”, employed alone or in combination with other terms, refers to an alkyl group having from one halogen atom to 2s+1 halogen atoms which may be the same or different, where “s” is the number of carbon atoms in the alkyl group, wherein the alkyl group has n to m carbon atoms. In some embodiments, the haloalkyl group is fluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, “Cn-m alkenyl” refers to an alkyl group having one or more double carbon-carbon bonds and having n to m carbons. Example alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like. In some embodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. As used herein, “Cn-m alkynyl” refers to an alkyl group having one or more triple carbon-carbon bonds and having n to m carbons. Example alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, and the like. In some embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. As used herein, the term “Cn-malkoxy”, employed alone or in combination with other terms, refers to a group of formula -O-alkyl, wherein the alkyl group has n to m carbons. Example alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), butoxy (e.g., n-butoxy and tert-butoxy), and the like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, “Cn-m haloalkoxy” refers to a group of formula –O-haloalkyl having n to m carbon atoms. An example haloalkoxy group is OCF3. In some embodiments, the haloalkoxy group is fluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term “amino” refers to a group of formula –NH2. As used herein, the term “Cn-malkylamino” refers to a group of formula -NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkylamino groups include, but are not limited to, N-methylamino, N-ethylamino, N- propylamino (e.g., N-(n-propyl)amino and N-isopropylamino), N-butylamino (e.g., N-(n- butyl)amino and N-(tert-butyl)amino), and the like. As used herein, “CO(C1-3 alkylamino)” has the same meaning as”CON(H)C1-3 alkyl”. As used herein, the term “di(Cn-m-alkyl)amino” refers to a group of formula - N(alkyl)2, wherein the two alkyl groups each has, independently, n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, ”CO(di(C1-3alkyl)amino)” has the same meaning as”CON(C1-3alkyl)2”. As used herein, “halo” refers to F, Cl, Br, or I. In some embodiments, a halo is F, Cl, or Br. As used herein, the term "aryl," employed alone or in combination with other terms, refers to an aromatic hydrocarbon group, which may be monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings). The term "Cn-maryl" refers to an aryl group having from n to m ring carbon atoms. Aryl groups include, e.g., phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and the like. In some embodiments, aryl groups have from 6 to 10 carbon atoms. In some embodiments, the aryl group is phenyl or naphtyl.

[0142] As used herein, “carbocyclic” refers to non-aromatic cyclic hydrocarbon groups including cyclized alkyl and / or alkenyl groups. Carbocyclic groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) groups and spirocycles. Ring-forming carbon atoms of a carbocyclic group can be optionally substituted by 1 or 2 independently selected oxo or sulfide groups (e.g., C(O) or C(S)). Also included in the definition of carbocyclic are moi eties that have one or more aromatic rings fused (i.e., having a bond in common with) to the carbocyclic ring, for example, benzo or thienyl derivatives of cyclopentane, cyclohexane, and the like. A carbocyclic group containing a fused aromatic ring can be attached through any ring-forming atom including a ring- forming atom of the fused aromatic ring. Carbocyclic groups can have 3, 4, 5, 6, 7, 8, 9, or 10 ring-forming carbons (C3-10). In some embodiments, the carbocyclic is a C3-10 monocyclic or bicyclic carbocyclic. In some embodiments, the carbocyclic is a C3-7 monocyclic carbocyclic. Example carbocyclic groups include three-, four-, five-, six-, or seven-membered saturated or unsaturated monocyclic groups; six-, seven-, eight-, nine-, or ten-membered saturated or unsaturated monocyclic groups; and the like.

[0143] As used herein, “cycloalkyl” refers to non-aromatic cyclic hydrocarbons including cyclized alkyl and / or alkenyl groups. Cycloalkyl groups can include mono- or polycyclic (e g., having 2, 3 or 4 fused rings) groups and spirocycles. Ring-forming carbon atoms of a cycloalkyl group can be optionally substituted by 1 or 2 independently selected oxo or sulfide groups (e.g., C(O) or C(S)). Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of cyclopentane, cyclohexane, and the like. A cycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9, or 10 ring-forming carbons (C3-10). In some embodiments, the cycloalkyl is a C3-10 monocyclic or bicyclic cycloalkyl. In some embodiments, the cycloalkyl is a C3-7 monocyclic cyclocalkyl. Example cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, adamantyl, and the like. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0144] As used herein, “heteroaryl” refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from sulfur, oxygen, and nitrogen. In some embodiments, the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, any ring-forming N in a heteroaryl moiety can be an N-oxide. In some embodiments, the heteroaryl is a 5-10 membered monocyclic or bicyclic heteroaryl having 1, 2, 3 or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl is a 5-6 monocyclic heteroaryl having 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl is a five-membered or six-membereted heteroaryl ring. A five-membered heteroaryl ring is a heteroaryl with a ring having five ring atoms wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary five-membered ring heteroaryls are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3- thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl. A six-membered heteroaryl ring is a heteroaryl with a ring having six ring atoms wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.

[0145] As used herein, “heterocyclic” refers to non-aromatic monocyclic or polycyclic groups having one or more ring -forming heteroatoms selected from O, N, or S. Included in “heterocyclic” are monocyclic 4-, 5-, 6-, 7-, 8-, 9- or 10-membered groups. Heterocyclic groups can also include spirocycles. Example heterocyclic groups include pyrrolidin-2-one, l,3-isoxazolidin-2-one, pyran, tetrahydropyran, oxetane, azetidine, morpholino, thiomorpholino, piperazine, tetrahydrofuran, tetrahydrothiene, piperidine, pyrrolidine, isoxazolidine, isothiazolidine, pyrazolidine, oxazolidine, thiazolidine, imidazolidine, azepan, benzazapene, and the like. Ring-forming carbon atoms and heteroatoms of a heterocyclic group can be optionally substituted by 1 or 2 independently selected oxo or sulfido groups (e.g., C(O), S(O), C(S), or S(O)2, etc.). The heterocyclic group can be attached through a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocyclic group contains 0 to 3 double bonds. In some embodiments, the heterocyclic group contains 0 to 2 double bonds. Also included in the definition of “heterocyclic" are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the heterocyclic ring, for example, benzo or thienyl derivatives of piperidine, morpholine, azepine, etc. A heterocyclic group containing a fused aromatic ring can be attached through any ring-forming atom including a ring- forming atom of the fused aromatic ring. In some embodiments, the heterocyclic is a monocyclic 4-6 membered heterocyclic having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members. In some embodiments, the heterocyclic is a monocyclic or bicyclic 4-10 membered heterocyclic having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur and optionally having one or more oxidized ring members.

[0146] As used herein, “heterocycloalkyl” refers to non-aromatic monocyclic or polycyclic heterocycles having one or more ring-forming heteroatoms selected from O, N, or S. Included in heterocycloalkyl are monocyclic 4-, 5-, 6-, 7-, 8-, 9- or 10- membered heterocycloalkyl groups. Heterocycloalkyl groups can also include spirocycles. Example heterocycloalkyl groups include pyrrolidin-2-one, 1,3-isoxazolidin- 2-one, pyranyl, tetrahydropuran, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, benzazapene, and the like. Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally substituted by 1 or 2 independently selected oxo or sulfido groups (e.g., C(O), S(O), C(S), or S(O)2, etc.). The heterocycloalkyl group can be attached through a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are moi eties that have one or more aromatic rings fused (z.e., having a bond in common with) to the heterocycloalkyl ring, for example, benzo or thienyl derivatives of piperidine, morpholine, azepine, etc. A heterocycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring. In some embodiments, the heterocycloalkyl is a monocyclic 4-6 membered heterocycloalkyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members. In some embodiments, the heterocycloalkyl is a monocyclic or bicyclic 4-10 membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur and optionally having one or more oxidized ring members.

[0147] At certain places, the definitions or embodiments refer to specific rings (e g., an azetidine ring, a pyridine ring, etc.). Unless otherwise indicated, these rings can be attached to any ring member provided that the valency of the atom is not exceeded. For example, an azetidine ring may be attached at any position of the ring, whereas a pyridin- 3-yl ring is attached at the 3-position.

[0148] The term “compound” as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.

[0149] The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, N=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. In some embodiments, the compound has the ^-configuration. In some embodiments, the compound has the (S)- configuration.

[0150] Compounds provided herein also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H- imidazole, 1H-, 2H- and 4H- 1,2,4-triazole, 1H- and 2H- isoindole, and 1H- and 2H- pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.

[0151] As used herein, the following abbreviations are used interchangeably for topoisomerase II and its isoforms: topoisomerase II: TOP2, Top2; topoisomerase Ila: TOP2A, TOP2a, Top2A, Top2a, TOP2a, Top2a; topoisomerase lip: TOP2B, TOP2b, Top2B, Top2b, TOP20, Top2p. As used herein, the term “individual”, “patient”, or “subject” used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.

[0152] As used herein, the phrase “effective amount” or “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.

[0153] As used herein the term “treating” or “treatment” refers to 1) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder ( / .<?.. arresting further development of the pathology and / or symptomatology), or 2) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and / or symptomatology).

[0154] As used herein, the term “preventing” or “prevention” of a disease, condition or disorder refers to decreasing the risk of occurrence of the disease, condition or disorder in a subject or group of subjects (e.g., a subject or group of subjects predisposed to or susceptible to the disease, condition or disorder). In some embodiments, preventing a disease, condition or disorder refers to decreasing the possibility of acquiring the disease, condition or disorder and / or its associated symptoms. In some embodiments, preventing a disease, condition or disorder refers to completely or almost completely stopping the disease, condition or disorder from occurring.

[0155] Example methods of making compounds

[0156] Generally, the compounds described herein are available by well-known organic synthesis procedures. To synthesize 4-substituted 7-alkoxy-8-(l,2,3,4-tetrahydroquinolin- l-carbonyl)-2Z / -chromen-2-ones, methods according to the following publications may be used: Morrison, R et al,. Enzyme Inhib. Med. C / vcw.2016, 31, 86-95 (Scheme la); Wang, A., et al., Eur. J. Med. Chem. 2021, 222, 113591 (Scheme lb); Abdelnaby, R. M., et. al., Pharmaceuticals 2022, 15 (4), 428; Nemecek, J., et. al., Eur. J. Med. Chem. 2017, 130, 419-432 (Scheme 1). 4-Alkyl-7-hydroxy-2-oxo-27 / -chromen-8-carboxylic acids of general formula IV may be synthesized via cyclization reaction of commercially available 2,6-dihydroxybenzoic acid with ethyl esters of aliphatic 3 -oxocarboxylic acids in sulfuric acid (Morrison, R. et al., Journal of Enzyme Inhibition and Medicinal Chemistry, 2016, 31, 86-95) (Scheme 1). The reaction of 4-alkyl-7-hydroxy-2-oxo-2Z7- chromen-8-carboxylic acids of general formula IV with 1,2,3,4-tetrahydroquinoline and EDOHCl at the presence of dimethylaminopyridine (DMAP) in CH2CI2 led to formation of amides of general formula (la) (Wang, A., et al., European Journal of Medicinal Chemistry, 2021, 222, 113591) (Scheme 1). To obtain the final products, the following procedures may be used (Abdelnaby R.M., etal., Pharmaceuticals, 2022, 75(4), 428; Nemecek, J., et al., European Journal of Medicinal Chemistry, 2017, 130, 419-432). The reactions of the appropriate intermediate compounds with the corresponding alkylating agents may be performed in the presence of potassium carbonate as a base and in acetone at reflux or DMF with heating to about 75-130 °C (Scheme 1). Scheme 1

[0157] Referring to Scheme 1, synthesis of final 4-alkyl-7-substituted-8-(l,2,3,4- tetrahydroquinolin- 1 -carbonyl )-2 / / -chromen-2-ones of general formula (I) (e.g., wherein R1and R2are as defined herein). Example reaction conditions: a) methyl or ethyl ester of aliphatic 3 -oxocarboxylic acid, H2SO4, about 75 °C, about 2-5 h; b) EDC*HC1, 1,2, 3, 4- tetrahydroquinoline, DMAP, CH2CI2, about rt, about 48 h; c) alkylating or acylating agent, K2CO3, acetone (reflux) or DMF (about 75-130 °C).

[0158] In addition, the following procedures may be used (Qi, L., et al.: Journal of Medicinal Chemistry 2005, 48, 7389-7399 (Scheme 2a); Qi, B., et al.: Bioorganic and Medicinal Chemistry 2019, 27, 2127-2139 (Scheme 2b). The compounds of general formula (lb) (as shown in Scheme 2) may be converted to corresponding bromides with general formula (Ic) by their reaction with tetrabromomethane and triphenylphosphine in CH3CN. Bromo derivatives (Ic) (as shown in Scheme 2) may be converted to compounds of general formula (Id) (as shown in Scheme 2) by the reaction with corresponding amine at the presence of potassium carbonate as a base in DMF and heating to about 60 °C (Scheme 2).

[0159] Scheme 2

[0160] Referring to Scheme 2, n is selected from 1, 2, 3, 4, 5 and 6, and R1, m, X, Rc2and Rd2are as defined herein. Example reaction conditions for the synthesis of final compounds of general formula (lb), (Ic), and (Id) (as shown in Scheme 2): a) CBn, PPh.3, CH3CN, about rt; b) corresponding amine, K2CO3, DMF, about 60 °C.

[0161] Scheme 3 shows the preparation of a compound of Formula (II), which can be made in a manner analogous to a compound of Formula (I):

[0162] Scheme 3

[0163] Referring to Scheme 3, R1, R2, R3, R4and Y are as defined herein. Example reaction conditions: a) methyl or ethyl ester of substituted aliphatic 3 -oxocarboxylic acid, H2SO4, about 75 °C, about 2-5 h; b) EDCxHCl, 1,2,3,4-tetrahydroquinoline or its Y-containing analog, DMAP, CH2CI2, about rt, about 48 h; c) alkylating or acylating agent, K2CO3, acetone (reflux) or DMF (about 75-130 °C).

[0164] In addition, the following procedures may be used (Qi, L., et al.: Journal of Medicinal Chemistry 2005, 48, 7389-7399 (Scheme 4a); Qi, B., et al.: Bioorganic and Medicinal Chemistry 2019, 27, 2127-2139 (Scheme 4b). The compounds of general formula (Hb) (as shown in Scheme 4) may be converted to corresponding bromides with general formula (lie) by their reaction with tetrabromomethane or N-bromosuccinimide (NBS) and triphenylphosphine in CH3CN. Bromo derivatives (lie) (as shown in Scheme 4) may be converted to compounds of general formula (lid) (as shown in Scheme 4) by the reaction with corresponding amine at the presence of potassium carbonate as a base in DMF and heating to about 60 °C (Scheme 4).

[0165] Scheme 4

[0166] Referring to Scheme 4, n is selected from 1, 2, 3, 4, 5 and 6, and R1, R2, R3, R4, Y, Rc2and Rd2are as defined herein. Example reaction conditions for the synthesis of final compounds of general formula (lib), (lie), and (lid) (as shown in Scheme 4): a) CBn or NBS, PPhs, CH3CN, about rt; b) corresponding amine, K2CO3, DMF, about 60 °C.

[0167] Scheme 5 shows the example methods of the preparation of compounds of general formula (III). Compounds of general formula (Illb) and (IIIc) can be made in a manner analogous to a compound of Formula (I). Intermediate compound of general formula (V) can be prepared from substituted 2-amino-3 -nitrobenzoic acid by its reaction with 1, 2,3,4- tetrahydroquinoline or its analog and EDC*HC1 at the presence of dimethylaminopyridine (DMAP) in THF followed by the reduction with H2 on palladium. Final compounds of general formula Illa can be prepared by the reaction of intermediate compound of general formula (V) with methyl or ethyl ester of substituted aliphatic 2-oxocarboxylic acid.

[0168] Scheme 5

[0169] (lllb) (Illc)

[0170] Referring to Scheme 5, R1, R2, R3, R4and Y and q are as defined herein. Example reaction conditions for the synthesis of final compounds of general formula (Illa) (as shown in Scheme 5): a) 1,2,3,4-tetrahydroquinoline or its analog, EDCxHCl, DMAP, THF, about rt, about 24h b) H2, Pd / C, MeOH, about rt, about 3h; c) methyl or ethyl ester of substituted aliphatic 2-oxocarboxylic acid, MeOH, about rt, about 18 h. Example reaction conditions for the synthesis of final compounds of general formula (lllb) and (IIIc) (as shown in Scheme 5): d) methyl or ethyl ester of substituted aliphatic 3 -oxocarb oxy lie acid, H2SO4, about 75 °C, about 2-5 h; e) EDCxHCl, 1,2,3,4-tetrahydroquinoline or its analog, DMAP, CH2CI2, about rt, about 48 h; f) alkylating or acylating agent, K2CO3, acetone (reflux) or DMF (about 75-130 °C).

[0171] EXAMPLES

[0172] EXAMPLE 1: 7-Hydroxy-4-methyl-2-oxo-2 / f-chromene-8-carboxylic acid (IVa)

[0173] (intermediate compound) Attorney Docket No. 07039.2229WO1 / 2023-174 The product was prepared according to Scheme 1. Ethyl ester of 3-oxobutyric acid (1.9 g, 1.85 mL, 14.6 mmol) was added dropwise to a suspension of 2,6- dihydroxybenzoic acid (1.5 g, 9.73 mmol) in conc. H2SO4 (4.6 g, 2.5 mL, 45 mmol). The reaction mixture was heated to 75 °C for 2 hours. After cooling to rt, the reaction mixture was poured into ice water (150 mL) and a precipitation was filtered off, washed with water to neutral pH and dried over P2O5.7-Hydroxy-4-methyl-2-oxo-2H-chromene-8- carboxylic acid (IVa) was obtained in 70 % yield as a white solid; mp 255-257 °C (lit mp 266 °C).1H NMR (500 MHz, DMSO) ? 7.66 (d, J = 8.7 Hz, 1H), 6.90 (d, J = 8.8 Hz, 1H), 6.18 (d, J = 1.3 Hz, 1H), 2.37 (d, J = 1.2 Hz, 3H).13C NMR (126 MHz, DMSO) ? 166.26, 159.81, 158.56, 153.86, 151.42, 127.58, 112.93, 112.03, 110.76, 110.70, 18.49. Elem. Anal. Calcd. for C11H8O5: C, 60.01; H, 3.66. Found: C, 59.62; H, 3.82 EXAMPLE 2: 4-Ethyl-7-hydroxy-2-oxo-2H-chromene-8-carboxylic acid (IVb) (intermediate compound) The product was prepared according to Scheme 1. Ethyl ester of 3-oxovaleric acid (2.1 g, 2.08 mL, 14.6 mmol) was added dropwise to a suspension of 2,6-dihydroxybenzoic acid (1.5 g, 9.73 mmol) in conc. H2SO4 (4.6 g, 2.5 mL, 45 mmol). The reaction mixture was heated to 75 °C for 2 hours and then was worked up according to the above-mentioned procedure.4-Ethyl-7-hydroxy-2-oxo-2H-chromene-8-carboxylic acid (IVb) was obtained in 61 % yield as a white solid; mp 234-236 °C.1H NMR (500 MHz, DMSO) δ 11.05 (s, 1H), 7.70 (d, J = 8.8 Hz, 1H), 6.90 (d, J = 8.8 Hz, 1H), 6.13 (d, J = 1.4 Hz, 1H), 2.77 (qd, J = 7.4, 1.2 Hz, 2H), 1.20 (t, J = 7.4 Hz, 3H).13C NMR (126 MHz, DMSO) δ 166.16, 160.00, 158.59, 158.34, 151.51, 127.06, 112.88, 111.12, 110.92, 108.88, 24.35, 12.54. Elem. Anal. Calcd. for C12H10O5: C, 61.54; H, 4.30. Found: C, 61.16; H, 4.14. EXAMPLE 3: 7-Hydroxy-4-propyl-2-oxo-2H-chromene-8-carboxylic acid (IVc) (intermediate compound) The product was prepared according to Scheme 1. Ethyl ester of 3-oxohexanoic acid (2.31 g, 2.33 mL, 14.6 mmol) was added dropwise to a suspension of 2,6- dihydroxybenzoic acid (1.5 g, 9.73 mmol) in conc. H2SO4 (4.6 g, 2.5 mL, 45 mmol). The reaction mixture was heated to 75 °C for 5 hours and then was worked up according to the above-mentioned procedure.7-Hydroxy-4-propyl-2-oxo-2H-chromene-8-carboxylic acid (IVc) was obtained in 51 % yield as a white solid; mp 210-212 °C.1H NMR (500 MHz, DMSO) ? 7.71 (d, J = 8.8 Hz, 1H), 6.90 (d, J = 8.8 Hz, 1H), 6.13 (s, 1H), 2.71 (t, J = 7.6 Hz, 2H), 1.61 (h, J = 7.4 Hz, 2H), 0.95 (t, J = 7.3 Hz, 3H).13C NMR (126 MHz, DMSO) ? 166.13, 159.85, 158.36, 157.11, 151.63, 127.24, 112.94, 111.16, 110.96, 109.83, 33.11, 21.56, 13.81. Elem. Anal. Calcd. for C13H12O5: C, 62.9; H, 4.87. Found: C, 62.92; H, 4.81. EXAMPLE 4: 4-Butyl-7-hydroxy-2-oxo-2H-chromene-8-carboxylic acid (IVd) (intermediate compound) The product was prepared according to Scheme 1. Methyl ester of 3-oxoheptanoic acid (2.31 g, 14.6 mmol) was added dropwise to a suspension of 2,6-dihydroxybenzoic acid (1.5 g, 9.73 mmol) in conc. H2SO4(4.6 g, 2.5 mL, 45 mmol). The reaction mixture was heated to 75 °C for 3 hours and then was worked up according to the above- mentioned procedure.4-Butyl-7-hydroxy-2-oxo-2H-chromene-8-carboxylic acid (IVd) was obtained in 73 % yield as a white solid; mp 179-181 °C.1H NMR (600 MHz, DMSO-D6)δ 7.67 (d, J = 8.9 Hz, 1H), 6.87 (d, J = 8.8 Hz, 1H), 6.10 (s, 1H), 2.73 – 2.64 (m, 2H), 1.58 – 1.48 (m, 2H), 1.37 – 1.31 (m, 2H), 0.87 (t, J = 7.4 Hz, 3H).13C NMR Attorney Docket No. 07039.2229WO1 / 2023-174 (151 MHz, DMSO-D6) ? 166.50, 160.22, 158.77, 157.73, 152.01, 127.58, 113.33, 111.48, 111.30, 110.09, 31.30, 30.75, 22.43, 14.20. Elem. Anal. Calcd. for C14H14O5: C, 64.12; H, 5.38. Found: C, 64.08; H, 5.48. EXAMPLE 5: 3-Bromo-7-hydroxy-2-oxo-4-propyl-2H-chromene-8-carboxylic acid (IVe) (intermediate compound) The solution of bromine (0.64 g, 0.21 mL, 4 mmol) in chloroform (20 mL) was added dropwise to a suspension of 7-hydroxy-2-oxo-4-propyl-2H-chromene-8-carboxylic acid IVc (1.00 g, 4 mmol) in chloroform (50 mL). The reaction mixture was heated to reflux overnight. After cooling to rt, a precipitation was filtered and dried over P2O5.3- Bromo-7-hydroxy-2-oxo-4-propyl-2H-chromene-8-carboxylic acid (IVe) was obtained in 53 % yield as a light pink solid; mp 231-233 °C.1H NMR (600 MHz, DMSO)δ 7.77 (d, J = 9.1 Hz, 1H), 6.92 (d, J = 8.9 Hz, 1H), 2.92-2.98 (m, 2H), 1.59-1.51 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H).13C NMR (151 MHz, DMSO) ? 166.16, 159.13, 156.63, 155.85, 150.48, 128.42, 114.10, 111.37, 111.09, 108.16, 34.58, 21.90, 14.44. Elem. Anal. Calcd for C13H11BrO5: C, 47.73; H, 3.39. Found: C, 47.69; H, 3.34. EXAMPLE 6: 3-Ethyl-7-hydroxy-4-methyl-2-oxo-2H-chromene-8-carboxylic acid (IVf) (intermediate compound) The compound was synthesized according to Scheme 3. Ethyl 2-ethylacetoacetate (3.85 g, 3.92 mL, 24.33 mmol) was added dropwise to a suspension of 2,6- dihydroxybenzoic acid (2.5 g, 16.22 mmol) in conc. H2SO4 (8.31 g, 4.5 mL, 81.1 mmol). The reaction mixture was heated to 75 °C for 7 hours and after cooling to rt it was poured Attorney Docket No. 07039.2229WO1 / 2023-174 into ice water (250 mL). The formed suspension was extracted with EtOAc (2 × 100 mL). The organic phase was washed with water (2 × 100 mL) and brine (1 × 100 mL), dried over anhydrous sodium sulfate and concentrated. The product was purified using column chromatography (mobile phase: hexane / EtOAc / acetic acid, 10:20:1).3-Ethyl-7-hydroxy- 4-methyl-2-oxo-2H-chromene-8-carboxylic acid IVf was obtained in 13 % yield (0.51 g) as a while solid; mp 240-242 °C.1H NMR (600 MHz, DMSO-d6) ? 7.64 (d, J = 8.9 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 2.50 (q, J = 7.5 Hz, 2H), 2.32 (s, 3H), 0.99 (t, J = 7.5 Hz, 3H).13C NMR (151 MHz, DMSO-d6) ? 166.78, 160.80, 158.19, 150.28, 147.18, 127.83, 123.67, 113.23, 112.84, 110.43, 20.69, 14.95, 13.47. Elem. Anal. Calcd for C13H12O5: C, 62.90; H, 4.87. Found: C, 62.52; H, 4.98. EXAMPLE 7: 7-Hydroxy-4-oxo-1,2,3,4-tetrahydrocyclopenta[c]chromene-6- carboxylic acid (IVg) (intermediate compound) The compound was synthesized according to Scheme 3. Ethyl 2- oxocyclopentanecarboxylate (1.52 g, 1.44 mL, 9.73 mmol) was added dropwise to a suspension of 2,6-dihydroxybenzoic acid (1 g, 6.49 mmol) in conc. H2SO4(3.31 g, 1.8 mL, 32.4 mmol). The reaction mixture was heated to 75 °C for 3 hours. After cooling to rt, the reaction mixture was poured into ice water (150 mL) and a precipitation was filtered off, washed with water to neutral pH and dried over P2O5. The product was additionally purified using column chromatography (mobile phase: hexane / EtOAc / acetic acid, 10:30:1). 7- Hydroxy-4-oxo-1,2,3,4-tetrahydrocyclopenta[c]chromene-6-carboxylic acid IVg was obtained in 22 % yield as beige solid; mp 250-252 °C.1H NMR (600 MHz, DMSO-d6) δ 7.42 (d, J = 8.5 Hz, 1H), 6.84 (d, J = 8.6 Hz, 1H), 2.97 (t, J = 7.7 Hz, 2H), 2.67 (t, J = 7.6 Hz, 2H), 2.09 – 2.00 (m, 2H).13C NMR (151 MHz, DMSO-d6)δ 166.92, 159.20, 158.68, 157.21, 152.27, 127.93, 123.24, 113.30, 111.02, 110.52, 32.25, 30.49, 22.44. Elem. Anal. Calcd for C13H10O5: C, 63.42; H, 4.09. Found: C, 63.03; H, 4.38. EXAMPLE 8: 3-hydroxy-6-oxo-7,8,9,10-tetrahydro-6H-benzo[c]chromene-4- carboxylic acid (IVh) (intermediate compound) The compound was synthesized according to Scheme 3. Ethyl 2- oxocyclohexanecarboxylate (2.48 g, 2.33 mL, 14.6 mmol) was added dropwise to a suspension of 2,6-dihydroxybenzoic acid (1.5 g, 9.73 mmol) in conc. H2SO4 (4.6 g, 2.5 mL, 45 mmol). The reaction mixture was heated to 75 °C for 3 hours. After cooling to rt, the reaction mixture was poured into ice water (150 mL) and a precipitation was filtered off, washed with water to neutral pH and dried over P2O5. 3-Hydroxy-6-oxo-7,8,9,10- tetrahydro-6H-benzo[c]chromene-4-carboxylic acid IVh was obtained in 57 % yield as a beige solid; mp 238-240 °C.1H NMR (600 MHz, DMSO-d6) δ 7.54 (d, J = 8.8 Hz, 1H), 6.83 (d, J = 8.7 Hz, 1H), 2.68 (t, J = 6.2 Hz, 2H), 2.33 (t, J = 6.2 Hz, 2H), 1.73 – 1.61 (m, 4H).13C NMR (151 MHz, DMSO-d6) ? 166.91, 160.87, 158.00, 150.13, 148.20, 126.50, 119.40, 113.14, 112.31, 110.33, 25.21, 23.96, 21.66, 21.35. Elem. Anal. Calcd for C14H12O5: C, 64.61; H, 4.65. Found: C, 64.29; H, 4.90. EXAMPLE 9: 3-Hydroxy-6-oxo-6,7,8,9,10,11-hexahydrocyclohepta[c] chromene-4-carboxylic acid (IVi) (intermediate compound) The compound was synthesized according to Scheme 3. Ethyl 2- oxocycloheptanecarboxylate (1 g, 5.43 mmol) was added dropwise to a suspension of 2,6- dihydroxybenzoic acid (0.56 g, 3.63 mmol) in conc. H2SO4 (1.86 g, 1 mL,18.2 mmol). The reaction mixture was heated to 75 °C for 6 hours and then was worked up according to the above-mentioned procedure. The product was additionally purified by column chromatography (mobile phase: hexane / EtOAc / acetic acid, 10:20:1). 3-Hydroxy-6-oxo- 6,7,8,9,10,11-hexahydrocyclohepta[c]chromene-4-carboxylic acid IVi was obtained in 4 % yield as a white solid; mp 220-222 °C.1H NMR (600 MHz, DMSO-d6) δ 7.72 (d, J = 9.1 Hz, 1H), 6.80 (d, J = 8.9 Hz, 1H), 2.92 – 2.82 (m, 2H), 2.77 – 2.67 (m, 2H), 1.57 – 1.41 (m, 6H).13C NMR (151 MHz, DMSO-d6) ? 167.01, 161.46, 160.46, 154.97, 151.46, 127.29, 123.62, 113.63, 111.47, 110.24, 31.94, 27.96, 26.41, 26.06, 25.36. EXAMPLE 10: 7-Hydroxy-4-isobutyl-2-oxo-2H-chromene-8-carboxylic acid (IVj) (intermediate compound) The compound was synthesized according to Scheme 1. Methyl 5-methyl-3- oxohexanoate (2.31 g, 14.6 mmol) was added dropwise to a suspension of 2,6- dihydroxybenzoic acid (1.5 g, 9.73 mmol) in conc. H2SO4(4.6 g, 2.5 mL, 45 mmol). The reaction mixture was heated to 75 °C for 3 hours and then was worked up according to the above-mentioned procedure.7-Hydroxy-4-isobutyl-2-oxo-2H-chromene-8-carboxylic acid IVj was obtained in 13 % yield as a white solid; mp 184-186 °C.1H NMR (600 MHz, DMSO-d6) ? 7.68 (d, J = 9.0 Hz, 1H), 6.87 (d, J = 8.8 Hz, 1H), 6.08 (s, 1H), 2.57 (d, J = 7.1 Hz, 2H), 1.88 (dt, J = 13.5, 6.7 Hz, 1H), 0.89 (d, J = 6.6 Hz, 6H).13C NMR (151 MHz, DMSO-d6)δ 166.47, 160.08, 158.75, 156.54, 152.07, 127.87, 113.28, 111.67, 111.36, 111.19, 40.65, 28.27, 22.81. Elem. Anal. Calcd for C14H14O5: C, 64.12; H, 5.38. Found: C, 63.75; H, 5.52. EXAMPLE 11: 7-Hydroxy-4-methyl-8-(1,2,3,4-tetrahydroquinoline-1-carbonyl)- 2H-chromen-2-one (1) 7-Hydroxy-4-methyl-8-(1,2,3,4-tetrahydroquinoline-1-carbonyl)-2H-chromen-2- one (1) was synthesized according to Scheme 1b by reaction of 7-hydroxy-4-methyl-2- oxo-2H-chromen-8-carboxylic acid IVa (0.94 g, 4.27 mmol) with 1,2,3,4- tetrahydroquinoline (2.16 g, 2.04 mL, 16.2 mmol) and EDC×HCl (1.88 g, 9.83 mmol) in CH2Cl2(50 mL) at the presence of DMAP (26 mg, 0.214 mmol). The reaction mixture was stirred at rt for 48 hours. Then, the reaction mixture was washed with water (1 × 50 mL), 1N HCl (2 × 50 mL), water (2 × 50 mL), and brine (1 × 50 mL). Organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Product was purified by column chromatography (mobile phase: hexane / EtOAc / acetic acid, 20:20:1).7-Hydroxy-4-methyl-8-(1,2,3,4-tetrahydroquinoline-1-carbonyl)-2H-chromen- 2-one (1) was obtained in 64 % yield (0.92 g) as a white solid; mp 241-243 °C as a mixture of two rotamers in a ratio 2.2:1. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR.1H NMR (500 MHz, DMSO)δ 11.02 (1H, bs, OH, A, 1H, bs, OH, B), 8.11 (1H, d, J = 8.3 Hz, CH, B), 7.67 (1H, d, J = 8.3 Hz, CH, B), 7.50 (1H, d, J = 8.8 Hz, CH, A), 7.23-7.18 (2H, m, CH, B), 7.13-7.06 (1H, m, CH, A, 1H, m, CH, B), 6.95 (1H, d, J = 8.8 Hz, CH, B), 6.90 (1H, t, J = 7.3 Hz, CH, A), 6.76 (1H, d, J = 8.8 Hz, CH, A), 6.73 (1H, t, J = 7.3 Hz, CH, A), 6.66 (1H, d, J = 7.3 Hz, CH, A), 6.19 (1H, s, CH, B), 6.03 (1H, s, CH, A), 4.14-4.04 (1H, m, CH2, A), 3.71-3.61 (1H, m, CH2, A), 3.50-3.42 (2H, m, CH2, B), 2.91-2.68 (2H, m, CH2, A, 2H, m, CH2, B), 2.40 (3H, s, CH3, B), 2.28 (3H, s, CH3, A), 2.20-2.09 (1H, m, CH2, A), 1.99-1.81 (1H, m, CH2, A, 2H, m, CH2, B). Isomer A:13C NMR (125 MHz, DMSO) ? 163.8, 159.5, 158.2, 153.7, 150.8, 138.5, 133.3, 128.1, 126.7, 125.4, 125.3, 122.8, 113.5, 112.5, 111.5, 110.3, 42.5, 26.2, 23.6, 18.3. Isomer B:13C NMR (125 MHz, DMSO) ? 163.6, 159.9, 157.2, 153.9, 150.7, 137.7, 129.8, 129.3, 126.7, 125.5, 124.6, 124.2, 113.2, 112.9, 112.2, 110.7, 46.5, 26.6, 23.4, 18.4. Elem. Anal. Calcd for C20H17NO4: C, 71.63; H, 5.11; N, 4.18. Found: C, 71.38; H, 5.18; N, 4.31. EXAMPLE 12: 4-Ethyl-7-hydroxy-8-(1,2,3,4-tetrahydroquinolin-1-carbonyl)- 2H-chromen-2-one (2) 4-Ethyl-7-hydroxy-8-(1,2,3,4-tetrahydroquinolin-1-carbonyl)-2H-chromen-2-on (2) was synthesized according to Scheme 1 by reaction of 4-ethyl-7-hydroxy-2-oxo-2H- chromen-8-carboxylic acid IVb (1 g, 4.27 mmol) with 1,2,3,4-tetrahydroquinoline (2.16 g, 2.04 mL, 16.2 mmol) and EDC×HCl (1.88 g, 9.83 mmol) in CH2Cl2(50 mL) at the presence of DMAP (26 mg, 0.214 mmol). The reaction mixture was stirred at rt for 72 hours and then was worked up according to the above-mentioned procedure.4-Ethyl-7- hydroxy-8-(1,2,3,4-tetrahydroquinolin-1-carbonyl)-2H-chromen-2-one (2) was obtained in 64 % yield (0.95 g) as a white solid; mp 218-219 °C as a mixture of two rotamers in a ratio 2:1. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR.1H NMR (500 MHz, DMSO)δ 10.96 (1H, bs, OH, B), 10.87 (1H, bs, OH, A), 8.11 (1H, d, J = 8.3 Hz, CH, B), 7.72 (1H, d, J = 8.3 Hz, CH, B), 7.55 (1H, d, J = 8.8 Hz, CH, A), 7.23-7.17 (2H, m, CH, B), 7.13-7.05 (1H, m, CH, A, 1H, m, CH, B), 6.96 (1H, d, J = 8.8 Hz, CH, B), 6.90 (1H, dt, J = 7.6 Hz, J = 1.0 Hz, CH, A), 6.77 (1H, d, J = 8.8 Hz, CH, A), 6.73 (1H, t, J = 7.6 Hz, CH, A), 6.65 (1H, d, J = 7.6 Hz, CH, A), 6.15 (1H, s, CH, B) 5.98 (1H, s, CH, A), 4.13-4.06 (1H, m, CH2, A), 3.69- 3.62 (1H, m, CH2, A), 3.49-3.43 (2H, m, CH2, B), 2.95-2.60 (4H, m, CH2, A, 4H, m, CH2, B), 2.20-2.09 (1H, m, CH2, A), 1.98-1,82 (1H, m, CH2, A, 2H, m, CH2, B), 1.23 (3H, t, J = 7.3 Hz, CH3, B), 1.14 (3H, t, J = 7.3 Hz, CH3, A). Isomer A:13C NMR (125 MHz, DMSO) ? 163.8, 159.7, 158.4, 157.9, 150.9, 138.5, 133.3, 128.0, 126.3, 125.3, 125.3, 122.7, 113.6, 112.5, 110.8, 108.4, 42.5, 26.2, 24.1, 23.5, 12.2. Isomer B:13C NMR (125 MHz, DMSO) ? 163.5, 160.1, 158.6, 156.9, 150.8, 137.7, 129.8, 129.3, 126.3, 125.5, 124.6, 124.1, 113.4, 112.8, 111.4, 109.0, 46.5, 26.6, 24.3, 23.4, 12.5. Elem. Anal. Calcd for C21H19NO4: C, 72.19; H, 5.48; N, 4.01. Found: C, 72.32; H, 5.39; N, 3.91. EXAMPLE 13: 7-Hydroxy-4-propyl-8-(1,2,3,4-tetrahydroquinolin-1-carbonyl)- 2H-chromen-2-one (3) 7-Hydroxy-4-propyl-8-(1,2,3,4-tetrahydroquinolin-1-carbonyl)-2H-chromen-2- one (3) was synthesized according to Scheme 1 by reaction of 7-hydroxy-4-propyl-2- oxo-2H-chromen-8-carboxylic acid IVc (1.1 g, 4.27 mmol) with 1,2,3,4- tetrahydroquinoline (2.16 g, 2.04 mL, 16.2 mmol) and EDC×HCl (1.88 g, 9.83 mmol) in CH2Cl2 (50 mL) at the presence of DMAP (26 mg, 0.214 mmol). The reaction mixture was stirred at rt for 72 hours and then was worked up according to the above-mentioned procedure.7-Hydroxy-4-propyl-8-(1,2,3,4-tetrahydroquinolin-1-carbonyl)-2H-chromen- 2-one (3) was obtained in 64 % yield (1 g) as a white solid; mp 184-185 °C as a mixture of two rotamers in a ratio 2:1. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR.1H NMR (500 MHz, DMSO)δ 10.60 (1H, bs, OH, A , 1H, bs, OH, B), 8.11 (1H, d, J = 8.6 Hz, CH, B), 7.71 (1H, d, J = 8.6 Hz, CH, B), 7.55 (1H, d, J = 8.8 Hz, CH, A), 7.23-7.18 (2H, m, CH, B), 7.13-7.06 (1H, m, CH, A, 1H, m, CH, B), 6.94 (1H, d, J = 8.8 Hz, CH, B), 6.90 (1H, t, J = 7.6 Hz, CH, A), 6.75 (1H, d, J = 8.8 Hz, CH, A), 6.72 (1H, t, J = 7.6 Hz, CH, A), 6.65 (1H, d, J = 7.6 Hz, CH, A), 6.14 (1H, s, CH, B), 5.97 (1H, s, CH, A), 4.13-4.06 (1H, m, CH2, A), 3.68-3.61 (1H, m, CH2, A), 3.46 (2H, t, J = 5.6 Hz, CH2, B), 2.91-2.52 (4H, m, CH2, A, 4H, m, CH2, B), 2.20-2.09 (1H, m, CH2, A), 1.97-1.83 (1H, m, CH2, A, 2H, m, CH2, B), 1.71-1.46 (2H, m, CH2, A, 2H, m, CH2, B), 0.98 (3H, t, J = 7.3 Hz, CH3, B), 0.89 (3H, t, J = 7.3 Hz, CH3, A). Isomer A:13C NMR (125 MHz, DMSO) ? 163.9, 159.6, 158.1, 157.0, 151.1, 138.5, 133.3, 128.0, 126.4, 125.3, 125.3, 122.7, 113.6, 112.5, 110.7, 109.3, 42.4, 32.9, 26.2, 23.5, 21.4, 13.7. Isomer B:13C NMR (125 MHz, DMSO) ? 163.6, 160.0, 158.1, 157.2, 151.0, 137.7, 129.8, 129.3, 126.4, 125.5, 124.5, 124.1, 113.4, 112.9, 111.3, 109.7, 46.5, 33.1, 26.6, 23.4, 21.5, 13.9. Elem. Anal. Calcd for C22H21NO4: C, 72.71; H, 5.82; N, 3.85. Found: C, 72.33; H, 5.87; N 3.77. EXAMPLE 14: 4-Butyl-7-hydroxy-8-(1,2,3,4-tetrahydroquinolin-1-carbonyl)- 2H-chromen-2-one (4) HO O O O N 4-Butyl-7-hydroxy-8-(1,2,3,4-tetrahydroquinolin-1-carbonyl)-2H-chromen-2-one (4) was synthesized according to Scheme 1 by reaction of 4-butyl-7-hydroxy-2-oxo-2H- chromen-8-carboxylic acid IVd (1.12 g, 4.27 mmol) with 1,2,3,4-tetrahydroquinoline (2.16 g, 2.04 mL, 16.2 mmol) and EDC×HCl (1.88 g, 9.83 mmol) in CH2Cl2 (50 mL) at the presence of DMAP (26 mg, 0.214 mmol). The reaction mixture was stirred at rt for 48 hours and then was worked up according to the above-mentioned procedure.4-Butyl-7- hydroxy-8-(1,2,3,4-tetrahydroquinolin-1-carbonyl)-2H-chromen-2-one (4) was obtained in 46 % yield (0.74 g) as a beige solid; mp 133-135 °C as a mixture of two rotamers in a ratio 2:1. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR.1H NMR (500 MHz, DMSO)δ 10.98 (1H, bs, OH, A, 1H, bs, OH, B), 8.11 (1H, d, J = 8.3 Hz, CH, B), 7.72 (1H, d, J = 8.3 Hz, CH, B), 7.56 (1H, d, J = 8.7 Hz, CH, A), 7.23-7.18 (2H, m, CH, B), 7.13-7.05 (1H, m, CH, A, 1H, m, CH, B), 6.95 (1H, d, J = 8.7 Hz, CH, B), 6.90 (1H, t, J = 7.7 Hz, CH, A), 6.76 (1H, d, J = 8.7 Hz, CH, A), 6.72 (1H, t, J = 7.7 Hz, CH, A), 6.64 (1H, d, J = 7.7 Hz, CH, A), 6.14 (1H, s, CH, B), 5.97 (1H, s, CH, A), 4.14-4.04 (1H, m, CH2, A), 3.69-3.59 (1H, m, CH2, A), 3.48-3.44 (2H, m, CH2, B), 2.90-2.55 (4H, m, CH2, A, 4H, m, CH2, B), 2.20-2.09 (1H, m, CH2, A), 1.98-1.83 (1H, m, CH2, A, 2H, m, CH2, B), 1.65-1.55 (2H, m, CH2, B), 1.55-1.45 (2H, m, CH2, A), 1.45-1.37 (2H, m, CH2, B), 1.36-1.25 (2H, m, CH2, A) 0.93 (3H, t, J = 7.5 Hz, CH3, B), 0.87 (3H, t, J = 7.3 Hz, CH3, A). Isomer A:13C NMR (125 MHz, DMSO) ? 163.9, 159.6, 158.0, 157.3, 151.1, 138.5, 133.3, 128.0, 126.5, 125.3, 125.3, 122.8, 113.7, 112.5, 110.7, 109.3, 42.5, 30.8, 30.2, 26.2, 23.6, 20.0, 13.9. Isomer B:13C NMR (125 MHz, DMSO)δ 163.6, 160.0, 157.5, 157.1, 151.0, 137.7, 129.8, 129.3, 126.5, 125.5, 124.6, 124.1, 113.5, 112.9, 111.4, 109.7, 46.5, 31.0, 30.4, 26.6, 23.4, 22.2, 13.9. Elem. Anal. Calcd for C23H23NO4: C, 73.19; H, 6.14; N, 3.71. Found: C, 72.81; H 6.05; N 3.62. EXAMPLE 15: 7-Methoxy-4-methyl-8-(1,2,3,4-tetrahydroquinolin-1-carbonyl)- 2H-chromen-2-one (5) 7-Methoxy-4-methyl-8-(1,2,3,4-tetrahydroquinolin-1-carbonyl)-2H-chromen-2- one (5) was synthesized according to Scheme 1 by reaction of 7-hydroxy-4-methyl-8- (1,2,3,4-tetrahydroquinolin-1-carbonyl)-2H-chromen-2-one 1 (0.3 g, 0.9 mmol) with dimethyl sulfate (0.23 g, 0.17 mL, 1.8 mmol) and K2CO3 (0.25 g, 1.8 mmol) in acetone (30 mL). The reaction mixture was refluxed for 6 hours. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with water (2 × 40 mL) and brine (1 × 30 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Product 5 was suspended with EtOAc (5 mL), filtered off and obtained in high quality without additional purification.7-Methoxy-4-methyl-8-(1,2,3,4-tetrahydroquinolin-1- carbonyl)-2H-chromen-2-one (5) was obtained in 97 % yield (0.3 g) as a beige solid; mp 170-171 °C as a mixture of two rotamers in a ratio 2.5:1. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR.1H NMR (500 MHz, DMSO)δ 8.12-8.08 (1H, m, CH, B), 7.84 (1H, d, J = 8.8 Hz, CH, B), 7.67 (1H, d, J = 8.8 Hz, CH, A), 7.23-7.18 (3H, m, CH, B), 7.14-7.07 (1H, m, CH, A, 1H, m, CH, B), 7.00 (1H, d, J = 8.8 Hz, CH, A), 6.91 (1H, dt, J = 7.5 Hz, J = 1.0 Hz, CH, A), 6.70 (1H, t, J = 7.5 Hz, CH, A), 6.53 (1H, d, J = 7.5 Hz, CH, A), 6.28 (1H, s, CH, B), 6.13 (1H, s, CH, A), 4.05-3.96 (1H, m, CH2, A), 3.93 (3H, s, CH3, B), 3.77 (3H, s, CH3, A), 3.78-3.70 (1H, m, CH2, A), 3.45-3.38 (2H, m, CH2, B), 2.91-2.78 (1H, m, CH2, A, 2H, m, CH2, B), 2.78-2.69 (1H, m, CH2, A), 2.44 (3H, s CH3, B), 2.33 (3H, s CH3, A), 2.16-2.06 (1H, m, CH2, A), 2.00-1.82 (1H, m, CH2, A, 2H, m, CH2, B). Isomer A:13C NMR (125 MHz, DMSO)δ 163.3, 159.3, 158.6, 153.5, 150.1, 138.3, 133.4, 128.0, 127.3, 125.5, 125.4, 122.8, 114.6, 113.2, 111.5, 108.2, 56.5, 42.5, 26.1, 23.5, 18.3. Isomer B:13C NMR (125 MHz, DMSO) ? 163.0, 159.6, 157.9, 153.7, 149.9, 137.5, 129.9, 129.4, 127.2, 125.6, 124.7, 124.1, 114.4, 113.9, 111.9, 108.5, 56.8, 46.5, 26.5, 23.3, 18.4. Elem. Ananl. Calcd for C21H19NO4: C, 72.19; H, 5.48; N, 4.01. Found: C, 71.58; H, 5.49; N, 3.89. EXAMPLE 16: 4-Ethyl-7-methoxy-8-(1,2,3,4-tetrahydroquinolin-1-carbonyl)- 2H-chromen-2-one (6) 4-Ethyl-7-methoxy-8- rbonyl)-2H-chromen-2-one (6) was synthesized according to Scheme 1 by reaction of 4-ethyl-7-hydroxy-8-(1,2,3,4- tetrahydroquinolin-1-carbonyl)-2H-chromen-2-one 2 (0.32 g, 0.9 mmol) with dimethyl sulfate (0.23 g, 0.17 mL, 1.8 mmol) and K2CO3(0.25 g, 1.8 mmol) in acetone (30 mL). The reaction mixture was refluxed for 6 hours and then worked up according to above- mentioned procedure.4-Ethyl-7-methoxy-8-(1,2,3,4-tetrahydroquinolin-1-carbonyl)-2H- chromen-2-one (6) was obtained in 86 % yield (0.28 g) as a white solid; mp 218-220 °C as a mixture of two rotamers in a ratio 2.4:1. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR.1H NMR (500 MHz, DMSO)δ 8.10 (1H, d, J = 8.6 Hz, CH, B), 7.89 (1H, d, J = 8.6 Hz, CH, B), 7.72 (1H, d, J = 8.8 Hz, CH, A), 7.24-7.18 (3H, m, CH, B), 7.14-7.06 (1H, m, CH, A, 1H, m, CH, B), 6.99 (1H, d, J = 8.8 Hz, CH, A), 6.91 (1H, t, J = 7.4 Hz, CH, A), 6.70 (1H, t, J = 7.4 Hz, CH, A), 6.53 (1H, d, J = 7.4 Hz, CH, A), 6.22 (1H, s, CH, B), 6.07 (1H, s, CH, A), 4.06-3.96 (1H, m, CH2, A), 3.93 (3H, s, CH3, B), 3.77 (3H, s, CH3, A), 3.80-3.69 (1H, m, CH2, A), 3.46-3.37 (2H, m, CH2, B), 2.92-2.66 (4H, m, CH2, A, 4H, m, CH2, B), 2.16-2.06 (1H, m, CH2, A), 2.01-1.83 (1H, m, CH2, A, 2H, m, CH2, B), 1.24 (3H, t, J = 7.4 Hz, CH3, B), 1.15 (3H, t, J = 7.2 Hz, CH3, A). Isomer A:13C NMR (125 MHz, DMSO) ? 163.3, 159.6, 158.5, 158.2, 150.3, 138.3, 133.4, 128.0, 126.8, 125.5, 125.4, 122.8, 114.8, 112.4, 109.6, 108.2, 56.5, 42.5, 26.1, 24.1, 23.5, 12.2. Isomer B:13C NMR (125 MHz, DMSO)δ 163.0, 159.9, 158.4, 157.7, 150.0, 137.5, 129.9, 129.4, 126.8, 125.6, 124.7, 124.1, 114.5, 113.0, 110.1, 108.6, 56.8, 46.6, 26.5, 24.3, 23.3, 12.5. Elem. Ananl. Calcd for C22H21NO4: C, 72.71; H, 5.82; N, 3.85. Found: C, 72.32; H, 5.89; N, 3.69. EXAMPLE 17: 7-Methoxy-4-propyl-8-(1,2,3,4-tetrahydroquinolin-1-carbonyl)- 2H-chromen-2-one (7) 7-Methoxy-4-propyl-8-(1,2,3,4-tetrahydroquinolin-1-carbonyl)-2H-chromen-2- one (7) was synthesized according to Scheme 1 by reaction of 7-hydroxy-4-propyl-8- (1,2,3,4-tetrahydroquinolin-1-carbonyl)-2H-chromen-2-one 3 (0.33 g, 0.9 mmol) with dimethyl sulfate (0.23 g, 0.17 mL, 1.8 mmol) and K2CO3 (0.25 g, 1.8 mmol) in acetone (30 mL). The reaction mixture was refluxed for 12 hours and then worked up according to above-mentioned procedure.7-Methoxy-4-propyl-8-(1,2,3,4- tetrahydroquinolin-1-carbonyl)-2H-chromen-2-one (7) was obtained in 80 % yield (0.27 g) as a white solid; mp 200-202 °C as a mixture of two rotamers in a ratio 2.4:1. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR.1H NMR (500 MHz, DMSO)δ 8.10 (1H, d, J = 8.2 Hz, CH, B), 7.90 (1H, d, J = 8.2 Hz, CH, B), 7.73 (1H, d, J = 8.9 Hz, CH, A), 7.23-7.18 (3H, m, CH, B), 7.14-7.07 (1H, m, CH, A, 1H, m, CH, B), 6.99 (1H, d, J = 8.9 Hz, CH, A), 6.90 (1H, dt, J = 7.3 Hz, J = 1.4 Hz, CH, A), 6.69 (1H, t, J = 7.3 Hz, CH, A), 6.52 (1H, d, J = 7.3 Hz, CH, A), 6.23 (1H, s, CH, B), 6.07 (1H, s, CH, A), 4.06-3.97 (1H, m, CH2, A), 3.93 (3H, s, CH3, B), 3.77 (3H, s, CH3, A), 3.78-3.70 (1H, m, CH2, A), 3.46-3.39 (2H, m, CH2, B), 2.91-2.59 (4H, m, CH2, A, 4H, m, CH2, B), 2.16-2.06 (1H, m, CH2, A), 2.00- 1.84 (1H, m, CH2, A, 2H, m, CH2, B), 1.75-1.49 (2H, m, CH2, A, 2H, m, CH2, B), 0.99 (3H, t, J = 7.3 Hz, CH3, B), 0.91 (3H, t, J = 7.5 Hz, CH3, A). Isomer A:13C NMR (125 MHz, DMSO) ? 163.3, 159.4, 158.5, 156.8, 150.4, 138.3, 133.4, 128.0, 127.0, 125.5, 125.3, 122.8, 114.8, 112.4, 110.6, 108.2, 56.5, 42.5, 32.8, 26.1, 24.5, 21.3, 13.7. Isomer B:13C NMR (125 MHz, DMSO)δ 163.0, 159.7, 157.7, 156.9, 150.1, 137.5, 129.9, 129.4, 127.0, 125.6, 124.7, 124.1, 114.6, 113.1, 111.0, 108.6, 56.8, 46.5, 33.0, 26.5, 24.3, 21.5, 13.9. Elem. Anal. Calcd for C23H23NO4: C, 73.19; H, 6.14; N, 3.71. Found: C, 72.8; H, 6.10; N, 3.58. EXAMPLE 18: 4-Butyl-7-methoxy-8-(1,2,3,4-tetrahydroquinolin-1-carbonyl)- 2H-chromen-2-one (8) 4-Butyl-7-methoxy-8-(1,2,3,4-tetrahydroquinolin-1-carbonyl)-2H-chromen-2-one (8) was synthesized according to Scheme 1 by reaction of 4-butyl-7-hydroxy-8-(1,2,3,4- tetrahydroquinolin-1-carbonyl)-2H-chromen-2-one 4 (0.34 g, 0.9 mmol) with dimethyl sulfate (0.23 g, 0.17 mL, 1.8 mmol) and K2CO3 (0.25 g, 1.8 mmol) in acetone (30 mL). The reaction mixture was refluxed for 12 hours and then worked up according to above- mentioned procedure.4-Butyl-7-methoxy-8-(1,2,3,4-tetrahydroquinolin-1-carbonyl)-2H- chromen-2-one (8) was obtained in 63 % yield (0.22 g) as a beige solid; mp 161-163 °C as a mixture of two rotamers in a ratio 2.9:1. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR.1H NMR (600 MHz, DMSO) ? 8.07 (1H, d, J = 8.1 Hz, CH, B), 7.85 (1H, d, J = 8.1 Hz, CH, B), 7.69 (1H, d, J = 9.0 Hz, CH, A), 7.20-7.14 (3H, m, CH, B), 7.11-7.02 (1H, m, CH, A, 1H, m, CH, B), 6.95 (1H, d, J = 9.0 Hz, CH, A), 6.87 (1H, t, J = 7.4 Hz, CH, A), 6.66 (1H, t, J =7.4 Hz, CH, A), 6.48 (1H, d, J = 7.4 Hz, CH, A), 6.19 (1H, s, CH, B), 6.04 (1H, s, CH, A), 4.03-3.94 (1H, m, CH2, A), 3.90 (3H, s, CH3, B), 3.74 (3H, s, CH3, A), 3.73-3.67 (1H, m, CH2, A), 3.42-3.36 (2H, m, CH2, B), 2.88-2.57 (4H, m, CH2, A, 4H, m, CH2, B), 2.12-2.03 (1H, m, CH2, A), 1.94-1.87 (1H, m, CH2, A), 1.87-1.80 (2H, m, CH2, B), 1.63- 1.53 (2H, m, CH2, B), 1.53-1.42 (2H, m, CH2, A), 1.41-1.35 (2H, m, CH2, B), 1.33-1.25 (2H, m, CH2, A), 0.90 (3H, t, J = 7.2 Hz, CH3, B), 0.85 (3H, t, J = 7.5 Hz, CH3, A). Isomer A:13C NMR (150 MHz, DMSO)δ 163.3, 159.4, 158.5, 157.0, 150.4, 138.3, 133.4, 128.0, 127.0, 125.4, 125.3, 122.8, 114.8, 112.4, 110.5, 108.2, 56.5, 42.5, 30.7, 30.1, 26.1, 23.5, 21.9, 13.8. Isomer B:13C NMR (150 MHz, DMSO)δ 163.0, 159.7, 157.7, 157.2, 150.1, 137.5, 129.8, 129.3, 126.9, 125.6, 124.7, 124.1, 114.6, 113.0, 110.9, 108.6, 56.7, 46.5, 30.9, 30.3, 26.5, 23.3, 22.1, 13.9. Elem. Anal. Calcd for C24H25NO4: C, 73.64; H, 6.44; N, 3.58. Found: C, 73.25; H, 6.61; N, 3.42. EXAMPLE 19: 4-Methyl-7-propoxy-8-(1,2,3,4-tetrahydroquinolin-1-carbonyl)- 2H-chromen-2-one (9) 4-Methyl-7-propoxy-8-(1,2,3,4-tetrahydroquinolin-1-carbonyl)-2H-chromen-2- one (9) was synthesized according to Scheme 1 by reaction of 7-hydroxy-4-methyl-8- (1,2,3,4-tetrahydroquinolin-1-carbonyl)-2H-chromen-2-one 1 (0.18 g, 0.54 mmol) with 1- brompropane (0.2 g, 0.15 mL, 1.63 mmol) and K2CO3 (0.23 g, 1.63 mmol) in DMF (7 mL). The reaction mixture was heated to 75 °C for 12 hours. After cooling, the reaction mixture was diluted with EtOAc (50 mL), washed with water (3 × 30 mL) and brine (1 × 30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Product was suspended with diethyl ether (10-15 mL), filtered off and obtained in high quality without additional purification.4-Methyl-7-propoxy-8-(1,2,3,4- tetrahydroquinolin-1-carbonyl)-2H-chromen-2-one (9) was obtained in 69 % yield (0.14 g) as a white solid; mp 158-159 °C as a mixture of two rotamers in ratio 2.2:1. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR.1H NMR (500 MHz, DMSO)δ 8.06 (1H, d, J = 8.9 Hz, CH, B), 7.80 (1H, d, J = 8.9 Hz, CH, B), 7.65 (1H, d, J = 8.8 Hz, CH, A), 7.25-7.16 (3H, m, CH, B), 7.14-7.06 (1H, m, CH, A, 1H, m, CH, B), 6.98 (1H, d, J = 8.8 Hz, CH, A), 6.91 (1H, t, J = 7.6 Hz CH, A), 6.70 (1H, t, J = 7.6 Hz, CH, A), 6.56 (1H, d, J = 7.6 Hz, CH, A), 6.27 (1H, s, CH, B), 6.14 (1H, s, CH, A), 4.16-4.10 (2H, m, CH2, B), 4.04-3.97 (1H, m, CH2, A), 3.97-3.82 (3H, m, CH2, A), 3.51-3.42 (1H, m, CH2, B), 3.41-3.34 (1H, m, CH2, B), 2.92-2.83 (1H, m, CH2, A), 2.83-2.69 (1H, m, CH2, A, 2H, m, CH2, B), 2.43 (3H, s CH3, B), 2.33 (3H, s CH3, A), 2.15-2.06 (1H, m CH2, A), 2.00-1.82 (1H, m CH2, A, 2H, m CH2, B), 1.75-1.59 (2H, m CH2, A, 2H, m CH2, B), 0.92 (3H, t, J = 7.3 Hz, CH3, A, 3H, t, J = 7.3 Hz, CH3, B). Isomer A:13C NMR (125 MHz, DMSO) ? 163.3, 159.4, 157.9, 153.5, 150.4, 138.2, 132.9, 128.2, 127.1, 125.4, 125.4, 122.6, 114.8, 113.0, 111.5, 108.8, 70.3, 42.6, 26.3, 23.4, 22.0, 18.3, 10.3. Isomer B:13C NMR (125 MHz, DMSO)δ 162.1, 159.6, 157.3, 153.6, 150.0, 137.5, 129.9, 129.3, 127.1, 125.6, 124.7, 124.0, 114.5, 113.7, 111.8, 109.3, 70.4, 46.4, 26.5, 23.5, 22.1, 18.4, 10.4. Elem. Anal. Calcd for C23H23NO4: C, C, 73.19; H, 6.14; N, 3.71; Found: C, 72.97; H 5.94; N 3.65. EXAMPLE 20: 4-Ethyl-7-propoxy-8-(1,2,3,4-tetrahydroquinolin-1-carbonyl)- 2H-chromen-2-one (10)

[0174] 4-Ethyl-7-propoxy-8-(1,2,3,4-tetrahydroquinolin-1-carbonyl)-2H-chromen-2-one (10) was synthesized according to Scheme 1 by reaction of 4-ethyl-7-hydroxy-8-(1,2,3,4- tetrahydroquinolin-1-carbonyl)-2H-chromen-2-one 2 (0.19 g, 0.54 mmol) with 1- brompropane (0.2 g, 0.15 mL, 1.63 mmol) and K2CO3(0.23 g, 1.63 mmol) in DMF (7 mL). The reaction mixture was heated to 75oC for 12 hours and then worked up according to above-mentioned procedure.4-Ethyl-7-propoxy-8-(1,2,3,4- tetrahydroquinolin-1-carbonyl)-2H-chromen-2-one (10) was obtained in 75 % yield (0.16 g) as a white solid; mp 139-140 °C as a mixture of two rotamers in ratio 2:1. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR.1H NMR (600 MHz, DMSO)δ 8.01 (1H, d, J = 8.5 Hz, CH, B), 7.80 (1H, d, J = 8.5 Hz, CH, B), 7.65 (1H, d, J = 9.0 Hz, CH, A), 7.20-7.12 (3H, m, CH, B), 7.09-7.02 (1H, m, CH, A, 1H, m, CH, B), 6.93 (1H, d, J = 9.0 Hz, CH, A), 6.85 (1H, t, J = 7.6 Hz, CH, A), 6.65 (1H, t, J = 7.6 Hz, CH, A), 6.51 (1H, d, J = 7.6 Hz, CH, A), 6.16 (1H, s, CH, B), 6.03 (1H, s, CH, A), 4.13-4.04 (2H, m, CH2, B), 4.00-3.77 (4H, m, CH2, A), 3.45-3.38 (1H, m, CH2, B), 3.36-3.30 (1H, m, CH2, B), 2.86-2.62 (4H, m, CH2, A, 4H, m, CH2, B), 2.10-2.00 (1H, m, CH2, A), 1.94-1.84 (1H, m, CH2, A), 1,84- 1.77 (2H, m, CH2, B), 1.70-1.55 (2H, m, CH2, A, 2H, m, CH2, B), 1.19 (3H, t, J = 7.5 Hz, CH3, B), 1.11 (3H, t, J = 7.7 Hz, CH3, A), 0.87 (3H, t, J = 7.4 Hz, CH3, A), 0.84 (3H, t, J = 7.2 Hz, CH3, B). Isomer A:13C NMR (150 MHz, DMSO)δ 163.6, 160.0, 158.5, 158.1, 150.9, 138.6, 133.2, 128.6, 127.0, 125.7, 125.7, 122.9, 115.3, 112.6, 109.9, 109.2, 70.7, 42.9, 26.7, 24.5, 23.7, 22.3, 12.6, 10.7. Isomer B:13C NMR (150 MHz, DMSO)δ 163.4, 160.2, 158.7, 157.5, 150.5, 137.9, 130.3, 129.7, 127.0, 126.0, 125.0, 124.3, 115.1, 113.2, 110.3, 109.7, 70.7, 46.8, 26.8, 24.6, 23.8, 22.5, 12.8, 10.7. Elem. Anal. Calcd for C24H25NO4: C, 73.64; H, 6.44; N, 3.58. Found: C, 73.00; H, 6.54; N 3.55.

[0175] EXAMPLE 21: 7-Propoxy-4-propyl-8-(1,2,3,4-tetrahydroquinolin-1-carbonyl)- 2H-chromen-2-one (11) 7-Propoxy-4-propyl-8-(1,2,3,4-tetrahydroquinolin-1-carbonyl)-2H-chromen-2- one (11) was synthesized according to Scheme 1 by reaction of 7-hydroxy-4-propyl-8- (1,2,3,4-tetrahydroquinolin-1-carbonyl)-2H-chromen-2-one 3 (0.2 g, 0.54 mmol) with 1- brompropane (0.2 g, 0.15 mL, 1.63 mmol) and K2CO3 (0.23 g, 1.63 mmol) in DMF (7 mL). The reaction mixture was heated to 75oC for 12 hours and then worked up according to above-mentioned procedure.7-Propoxy-4-propyl-8-(1,2,3,4- tetrahydroquinolin-1-carbonyl)-2H-chromen-2-one (11) was obtained in 73 % yield (0.16 g) as a white solid; mp 122-123 °C as a mixture of two rotamers in ratio 2:1. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR.1H NMR (500 MHz, DMSO)δ 8.06 (1H, d, J = 8.5 Hz, CH, B), 7.86 (1H, d, J = 8.5 Hz, CH, B), 7.71 (1H, d, J = 8.9 Hz, CH, A), 7.24-7.15 (3H, m, CH, B), 7.14-7.01 (1H, m, CH, A, 1H, m, CH, B), 6.97 (1H, d, J = 8.9 Hz, CH, A), 6.90 (1H, t, J = 7.5 Hz, CH, A), 6.69 (1H, t, J = 7.5 Hz, CH, A), 6.55 (1H, d, J = 7.5 Hz, CH, A), 6.21 (1H, s, CH, B), 6.08 (1H, s, CH, A), 4.13 (2H, t, J = 5.8 Hz, CH2, B), 4.04-3.81 (4H, m, CH2, A), 3.52-3.43 (1H, m, CH2, B), 3.42-3.35 (1H, m, CH2, B), 2.93-2.59 (4H, m, CH2, A, 4H, m, CH2, B), 2.15-2.06 (1H, m, CH2, A), 2.00-1.91 (1H, m, CH2, A), 1.91- 1.84 (2H, m, CH2, B), 1.75-1.47 (4H, m, CH2, A, 4H, m, CH2, B), 0.99 (3H, t, J = 7.5 Hz, CH3, B), 0.92 (3H, t, J = 7.5 Hz, CH3, A), 0.91 (3H, t, J = 7.2 Hz, CH3, A), 0.91 (3H, t, J = 7.2 Hz, CH3, B). Isomer A:13C NMR (125 MHz, DMSO)δ 163.3, 159.5, 157.8, 156.8, 150.6, 138.2, 132.9, 128.2, 126.9, 125.4, 125.3, 122.6, 115.0, 112.3, 110.5, 108.8, 70.3, 42.6, 32.8, 26.3, 23.3, 22.0, 21.3, 13.7, 10.3. Isomer B:13C NMR (125 MHz, DMSO) ? 163.1, 159.7, 157.2, 156.9, 150.2, 137.5, 129.9, 129.3, 126.9, 125.6, 124.7, 124.0, 114.8, 112.9, 110.9, 109.3, 70.4, 46.4, 33.0, 26.5, 23.5, 22.1, 21.5, 13.9, 10.3. Elem. Anal. Calcd for C25H27NO4: C, 74.05; H, 6.71; N, 3.45. Found: C, 74.24; H, 6.93; N 3.70. EXAMPLE 22: 4-Butyl-7-propoxy-8-(1,2,3,4-tetrahydroquinolin-1-carbonyl)- 2H-chromen-2-one (12) 4-Butyl-7-propoxy-8-(1,2,3,4-tetrahydroquinolin-1-carbonyl)-2H-chromen-2-one (12) was synthesized according to Scheme 1 by reaction of 4-butyl-7-hydroxy-8-(1,2,3,4- tetrahydroquinolin-1-carbonyl)-2H-chromen-2-one 4 (0.2 g, 0.54 mmol) with 1- brompropane (0.2 g, 0.15 mL, 1.63 mmol) and K2CO3(0.23 g, 1.63 mmol) in DMF (7 mL). The reaction mixture was heated to 75 °C for 12 hours and then worked up according to above-mentioned procedure.4-Butyl-7-propoxy-8-(1,2,3,4- tetrahydroquinolin-1-carbonyl)-2H-chromen-2-one (12) was obtained in 59 % yield (0.13 g) as a white solid; mp 116-117 °C as a mixture of two rotamers in ratio 2.5:1. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR.1H NMR (600 MHz, DMSO)δ 8.03 (1H, d, J = 9.0 Hz, CH, B), 7.82 (1H, d, J = 9.0 Hz, CH, B), 7.67 (1H, d, J = 8.7 Hz, CH, A), 7.21-7.12 (3H, m, CH, B), 7.11-7.03 (1H, m, CH, A, 1H, m, CH, B), 6.94 (1H, d, J = 8.7 Hz, CH, A), 6.87 (1H, t, J = 7.4 Hz, CH, A), 6.66 (1H, t, J = 7.4 Hz, CH, A), 6.51 (1H, d, J = 7.4 Hz, CH, A), 6.18 (1H, s, CH, B), 6.05 (1H, s, CH, A), 4.12-4.07 (2H, m, CH2, B), 4.00-3.94 (1H, m, CH2, A), 3.94-3.78 (3H, m, CH2, A), 3.46-3.40 (1H, m, CH2, B), 3.38-3.31 (1H, m, CH2, B), 2.88-2.60 (4H, m, CH2, A, 4H, m, CH2, B), 2.11-2,03 (1H, m, CH2, A,), 1.97- 1.87 (1H, m, CH2, A), 1,87-1.81 (2H, m, CH2, B), 1.70-1.43 (4H, m, CH2, A, 4H, m, CH2, B), 1.41-1,35 (2H, m, CH2, B), 1.35-1,26 (2H, m, CH2, A), 0.90 (3H, t, J = 7.5 Hz, CH3, B), 0.89 (3H, t, J = 7.5 Hz, CH3, A), 0.89 (3H, t, J = 7.5 Hz, CH3, B), 0.86 (3H, t, J = 7.5 Hz, CH3, A). Isomer A:13C NMR (150 MHz, DMSO) ? 163.3, 159.5, 157.7, 157.0, 150.6, 138.2, 132.9, 128.2, 126.9, 125.3, 125.3, 122.6, 115.0, 112.2, 110.4, 108.8, 70.3, 42.6, 30.7, 30.2, 26.3, 23.3, 22.0, 22.0, 13.8, 10.3. Isomer B:13C NMR (150 MHz, DMSO)δ 163.1, 159.7, 157.2, 157.2, 150.2, 137.5, 129.9, 129.3, 126.9, 125.6, 124.7, 124.0, 114.8, 112.9, 110.8, 109.3, 70.3, 46.4, 30.9, 30.4, 26.4, 23.4, 22.1, 22.1, 13.9, 10.3. Elem. Anal. Calcd for C26H29NO4: C, 74.44; H, 6.97; N, 3.34. Found: C, 74.69; H, 6.97; N 3.27. EXAMPLE 23: 7-(2-Hydroxyethoxy)-4-methyl-8-(1,2,3,4-tetrahydroquinolin-1- carbonyl)-2H-chromen-2-one (13) 7-(2-Hydroxyethoxy)-4-methyl-8-(1,2,3,4-tetrahydroquinolin-1-carbonyl)-2H- chromen-2-one (13) was synthesized according Scheme 1 by reaction of 7-hydroxy-4- methyl-8-(1,2,3,4-tetrahydroquinoline-1-carbonyl)-2H-chromen-2-one 1 (0.2 g, 0.6 mmol) with 2-bromoethan-1-ol (0.23 g, 0.13 mL, 1.8 mmol) and potassium carbonate (0.25 g, 1.8 mmol) in DMF (7 mL). The reaction mixture was heated to 75oC for 12 hours. After cooling, the reaction mixture was diluted with EtOAc (50 mL), washed with water (3 × 30 mL) and brine (1 × 30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The product 13 was purified by column chromatography (mobile phase: hexane / EtOAc, 1:1; then hexane / EtOAc / acetic acid, 5:5:1).7-(2-Hydroxyethoxy)-4-methyl-8-(1,2,3,4-tetrahydroquinolin-1-carbonyl)-2H- chromen-2-one (13) was obtained in 29 % yield (0.07 g) as a white solid; mp 171-172 °C as a mixture of two rotamers in ratio 2.5:1. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR.1H NMR (500 MHz, DMSO)δ 8.09 (1H, d, J = 8.6 Hz, CH, B), 7.80 (1H, d, J = 8.6 Hz, CH, B), 7.65 (1H, d, J = 8.8 Hz, CH, A), 7.25-7.18 (3H, m, CH, B), 7.13-7.06 (1H, m, CH, A, 1H, m, CH, B), 7.03 (1H, d, J = 8.8 Hz, CH, A), 6.90 (1H, t, J = 7.5 Hz, CH, A), 6.70 (1H, t, J = 7.5 Hz, CH, A), 6.63 (1H, d, J = 7.5 Hz, CH, A), 6.27 (1H, s, CH, B), 6.14 (1H, s, CH, Attorney Docket No. 07039.2229WO1 / 2023-174 A), 4.23-4.18 (2H, m, CH2, B), 4.13-4.06 (1H, m, CH2, A), 4.02-3.92 (1H, m, CH2, A, 1H, m, CH2, A), 3.83-3.76 (1H, m, CH2, A), 3.69 (2H, t, J = 4.9 Hz, CH2, B), 3.64 (2H, t, J = 4.9 Hz, CH2, A), 3.50-3.45 (2H, m, CH2, B), 2.92-2.71 (2H, m, CH2, A, 2H, m, CH2, B), 2.44 (3H, s, CH3, B), 2.33 (3H, s, CH3, A), 2.17-2.07 (1H, m, CH2, A,), 2.00-1.89 (1H, m, CH2, A), 1.89-1.72 (2H, m, CH2, B). Isomer A:13C NMR (125 MHz, DMSO)δ 163.3, 159.4, 158.1, 153.5, 150.3, 138.3, 133.0, 128.1, 127.1, 125.4, 125.4, 122.9, 114.9, 113.1, 111.5, 109.1, 70.8, 59.4, 42.6, 26.3, 23.4, 18.3. Isomer B:13C NMR (125 MHz, DMSO) ? 163.1, 159.6, 157.4, 153.6, 150.0, 137.6, 130.1, 129.3, 127.1, 125.6, 124.7, 124.2, 114.7, 113.8, 111.9, 109.6, 71.0, 59.6, 46.4, 26.5, 23.4, 18.4. Elem. Anal. Calcd for C22H27NO8 (trihydrate): C, 60.96; H, 6.28; N 3.23. Found: C, 60.82; H, 6.03; N 3.25. EXAMPLE 24: 4-Ethyl-7-(2-hydroxyethoxy)-8-(1,2,3,4-tetrahydroquinolin-1- carbonyl)-2H-chromen-2-one (14) 4-Ethyl-7-(2-hydroxyethoxy)-8-(1,2,3,4-tetrahydroquinolin-1-carbonyl)-2H- chromen-2-one (14) was synthesized according Scheme 1 by reaction of 4-ethyl-7- hydroxy-8-(1,2,3,4-tetrahydroquinoline-1-carbonyl)-2H-chromen-2-one 2 (0.21 g, 0.6 mmol) with 2-bromoethan-1-ol (0.23 g, 0.13 mL, 1.8 mmol) and potassium carbonate (0.25 g, 1.8 mmol) in DMF (7 mL). The reaction mixture was heated to 75oC for 12 hours and then worked up according to above-mentioned procedure.4-Ethyl-7-(2- hydroxyethoxy)-8-(1,2,3,4-tetrahydroquinolin-1-carbonyl)-2H-chromen-2-one (14) was obtained in 60 % yield (0.14 g) as a white solid; mp 130-131 °C as a mixture of two rotamers in ratio 2.5:1. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR.1H NMR (500 MHz, DMSO)δ 8.09 (1H, d, J = 8.6 Hz, CH, B), 7.85 (1H, d, J = 8.6 Hz, CH, B), 7.70 (1H, d, J = 9.0 Hz, CH, A), 7.25-7.18 (3H, m, CH, B), 7.14-7.06 (1H, m, CH, A, 1H, m, CH, B), 7.02 (1H, d, J = 9.0 Hz, CH, A), 6.90 (1H, dt, J = 7.3 Hz, J = 1.0 Hz, CH, A), 6.69 (1H, t, J = 7.3 Hz, CH, A), 6.63 (1H, d, J = 7.3 Hz, CH, A), 6.22 (1H, s, CH, B), 6.07 (1H, s, CH, A), 4.23-4.18 (2H, m, CH2, B), 4.13-4.06 (1H, m, CH2, A), 4.02-3.92 (1H, m, CH2, A, 1H, m, CH2, A), 3.83- 3.76 (1H, m, CH2, A), 3.70-3.67 (2H, m, CH2, B), 3.64 (2H, t, J = 5.1 Hz, CH2, A), 3.51- 3.34 (2H, m, CH2, B), 2.93-2.63 (4H, m, CH2, A, 4H, m, CH2, B), 2.18-2.05 (1H, m, CH2, A), 2.02-1.88 (1H, m, CH2, A), 1.88-1.79 (2H, m, CH2, B), 1.24 (3H, t, J = 7.3 Hz, CH3, B), 1.16 (3H, t, J = 7.3 Hz, CH3, A). Isomer A:13C NMR (125 MHz, DMSO)δ 163.4, 159.7, 158.2, 158.0, 150.4, 138.3, 133.0, 128.2, 126.7, 125.5, 125.4, 122.9, 115.1, 112.3, 109.6, 109.2, 70.8, 59.4, 42.7, 26.3, 24.1, 23.4, 12.2. Isomer B:13C NMR (125 MHz, DMSO) ? 163.1, 159.9, 158.4, 157.3, 150.2, 137.6, 130.1, 129.3, 126.7, 125.6, 124.7, 124.2, 114.9, 113.0, 110.0, 109.6, 71.0, 59.6, 46.5, 26.5, 24.3, 23.4, 12.5. Elem. Anal. Calcd for C24H27NO6: C, 70.21; H, 5.89; N, 3.56. Found: C, 70.0; H, 6.2; N 3.55. EXAMPLE 25: 7-(2-Hydroxyethoxy)-4-propyl-8-(1,2,3,4-tetrahydroquinolin-1- carbonyl)-2H-chromen-2-one (15) 7-(2-Hydroxyethoxy)-4-propyl-8-(1,2,3,4-tetrahydroquinolin-1-carbonyl)-2H- chromen-2-one (15) was synthesized according Scheme 1 by reaction of 7-hydroxy-4- propyl-8-(1,2,3,4-tetrahydroquinoline-1-carbonyl)-2H-chromen-2-one 3 (0.22 g, 0.6 mmol) with 2-bromoethan-1-ol (0.23 g, 0.13 mL, 1.8 mmol) and potassium carbonate (0.25 g, 1.8 mmol) in DMF (7 mL). The reaction mixture was heated to 75oC for 12 hours and then worked up according to above-mentioned procedure.7-(2- Hydroxyethoxy)-4-propyl-8-(1,2,3,4-tetrahydroquinolin-1-carbonyl)-2H-chromen-2-one (15) was obtained in 82 % (0.2 g) as a white solid; mp 148-149 °C as a mixture of two rotamers in ratio 2.2:1. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR.1H NMR (500 MHz, DMSO) ? 8.10 (1H, d, J = 8.8 Hz, CH, B), 7.86 (1H, d, J = 8.8 Hz, CH, B), 7.70 (1H, d, J = 9.0 Hz, CH, A), 7.24-7.18 (3H, m, CH, B), 7.13-7.06 (1H, m, CH, A, 1H, m, CH, B), 7.01 (1H, d, J = 9.0 Hz, CH, A), 6.90 (1H, dt, J = 7.6 Hz, J = 1.5 Hz, CH, A), 6.69 (1H, dt, J = 7.6 Hz, J = 1.5 Hz, CH, A), 6.62 (1H, d, J = 7.6 Hz, CH, A), 6.22 (1H, s, CH, B), 6.08 (1H, s, CH, A), 4.23-4.18 (2H, m, CH2, B), 4.13-4.06 (1H, m, CH2, A), 4.03-3.92 (1H, m, CH2, A, 1H, m, CH2, A), 3.82-3.75 (1H, m, CH2, A), 3.71-3.67 (2H, m, CH2, B), 3.65 (2H, t, J = 5.1 Hz, CH2, A), 3.51-3.34 (2H, m, CH2, B), 2.92-2.59 (4H, m, CH2, A, 4H, m, CH2, B), 2.18- 2.06 (1H, m, CH2, A), 2.02-1.89 (1H, m, CH2, A), 1.89-1.80 (2H, m, CH2, B), 1.71-1.49 (2H, m, CH2, A, 2H, m, CH2, B), 0.99 (3H, t, J = 7.3 Hz, CH3, B), 0.91 (3H, t, J = 7.3 Hz, CH3, A). Isomer A:13C NMR (125 MHz, DMSO)δ 163.4, 159.5, 158.0, 156.8, 150.5, 138.2, 133.0, 128.1, 126.9, 125.4, 125.3, 122.9, 115.1, 112.4, 110.5, 109.1, 70.8, 59.4, 42.7, 32.8, 26.3, 23.4, 21.3, 13.7. Isomer B:13C NMR (125 MHz, DMSO)δ 163.1, 159.8, 157.3, 156.9, 150.3, 137.6, 130.1, 129.3, 126.8, 125.6, 124.7, 124.2, 114.9, 113.0, 111.0, 109.6, 71.0, 59.6, 46.5, 33.0, 26.5, 23.4, 21.5, 13.9. Elem. Anal. Calcd for C24H25NO5 (hydrate): C, 67.75; H, 6.40; N, 3.29. Found: C, 68.13; H, 6.05; N 3.14. EXAMPLE 26: 4-Butyl-7-(2-hydroxyethoxy)-8-(1,2,3,4-tetrahydroquinolin-1- carbonyl)-2H-chromen-2-one (16) 4-Butyl-7-(2-hydroxyethoxy)-8-(1,2,3,4-tetrahydroquinolin-1-carbonyl)-2H- chromen-2-one (16) was synthesized according Scheme 1 by reaction of 4-butyl-7- hydroxy-8-(1,2,3,4-tetrahydroquinoline-1-carbonyl)-2H-chromen-2-one 4 (0.23 g, 0.6 mmol) with 2-bromoethan-1-ol (0.23 g, 0.13 mL, 1.8 mmol) and potassium carbonate (0.25 g, 1.8 mmol) in DMF (7 mL). The reaction mixture was heated to 75 °C for 12 hours and then worked up according to above-mentioned procedure.4-Butyl-7-(2- hydroxyethoxy)-8-(1,2,3,4-tetrahydroquinolin-1-carbonyl)-2H-chromen-2-one (16) was obtained in 78 % yield (0.2 g) as a white solid; mp 114-115 °C as a mixture of two rotamers in ratio 2.2: 1. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR.JH NMR (500 MHz, DMSO) δ 8.09 (1H, d, J= 8.3 Hz, CH, B), 7.85 (1H, d, J= 8.3 Hz, CH, B), 7.70 (1H, d, J= 8.8 Hz, CH, A), 7.24-7.18 (3H, m, CH, B), 7.13-7.05 (1H, m, CH, A, 1H, m, CH, B), 7.02 (1H, d, J= 8.8 Hz, CH, A), 6.90 (1H, dt, J = 7.6 Hz, J = 1.0 Hz, CH, A), 6.69 (1H, dt, J = 7.6 Hz, J = 1.0 Hz, CH, A), 6.61 (1H, d, J= 7.6 Hz, CH, A), 6.22 (1H, s, CH, B), 6.08 (1H, s, CH, A), 4.23-4.19 (2H, m, CH2, B), 4.13-4.06 (1H, m, CH2, A), 4.03-3.92 (1H, m, CH2, A, 1H, m, CH2, A), 3.83-3.76 (1H, m, CH2, A), 3.70-3.67 (2H, m, CH2, B), 3.64 (2H, t, J= 5.2 Hz, CH2, A), 3.51-3.36 (2H, m, CH2, B), 2.92-2.61 (4H, m, CH2, A, 4H, m, CH2, B), 2.18- 2.07 (1H, m, CH2, A), 2.02-1.80 (1H, m, CH2, A), 1.80-1.72 (2H, m, CH2, B), 1.67-1.45 (2H, m, CH2, A, 2H, m, CH2, B), 1.45-1.37 (2H, m, CH2, B), 1.37-1.28 (2H, m, CH2, A), 0.93 (3H, t, J= 7.2 Hz, CH3, B), 0.88 (3H, t, J= 7.2 Hz, CH3, A). Isomer A:13C NMR (125 MHz, DMSO) 5 163.4, 159.5, 158.0, 157.1, 150.5, 138.2, 133.0, 128.1, 126.9, 125.4, 125.3, 122.9, 115.1, 112.3, 110.4, 109.1, 70.8, 59.4, 42.6, 30.7, 30.2, 26.3, 23.4, 22.0, 13.9. Isomer B:13C NMR (125 MHz, DMSO) δ 163.1, 159.8, 157.3, 157.2, 150.3, 137.6, 130.1, 129.3, 126.8, 125.6, 124.7, 124.2, 114.9, 113.0, 110.9, 109.6, 71.0, 59.6, 46.5, 30.9, 30.4, 26.5, 23.4, 22.1, 13.9. Elem. Anal. Calcd for C25H3INO7(dihydrate): C, 65.63; H, 6.83; N 3.06. Found: C, 65.25; H, 6.46; N, 3.21.

[0176] EXAMPLE 27 : 2-((2-Oxo-4-propyl-8-( 1,2,3, 4-tetrahydroquinoline-l-carbonyl)- 2J / -chromen-7-yl)oxy)ethan-l-amin hydrochloride (17)

[0177] Cl H3N J

[0178] C>

[0179] O N

[0180] Tert-Butyl (2-((2-oxo-4-alkyl-8-( 1,2,3, 4-tetrahydroquinoline- 1 -carbonyl)-2Z7- chromen-7-yl)oxy)ethyl)carbamate 27 (0.4 g, 0.8 mmol) was dissolved in acetic acid (5 mb), bubbled with hydrogen chloride and stirred at rt for 2 hours. The reaction mixture was diluted with diethyl ether (20 mL) and concentrated under reduced pressure. The product was dried over P2O5 in a desiccator. Compound 17 was obtained in 70 % yield (0.25 g) as a white solid; mp 129-130 °C as a mixture of two rotamers in ratio 2.7: 1. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR.JH NMR (500 MHz, DMSO) 5 8.34 (3H, bs, NH3, A, 3H, bs, NH3, B), 8.12 (1H, d, J= 8.6 Hz, CH, B), 7.91 (1H, d, J= 8.6 Hz, CH, B), 7.77 (1H, d, J = 9.0 Hz, CH, A), 7.28 (1H, d, J= 9.1 Hz, CH, B), 7.24-7.18 (2H, m, CH, B), 7.12 (1H, d, J= 9.0 Hz, CH, A), 7.11-7.07 (1H, m, CH, A, 1H, m, CH, B), 6.91 (1H, t, J= 7.7 Hz, CH, A), 6.70 (1H, t, J= 7.7 Hz, CH, A), 6.56 (1H, d, J= 7.7 Hz, CH, A), 6.26 (1H, s, CH, B), 6.08 (1H, s, CH, A), 4.43 (2H, d, J= 5.7 Hz, CH, B), 4.40-4.32 (1H, m, CH2, A), 4.27-4.20 (1H, m, CH2, A), 4.20-4.11 (1H, m, CH2, A), 3.71-3.63 (1H, m, CH2, A), 3.51- 3.41 (2H, m, CH2, B), 3.20-3.08 (2H, m, CH2, A, 2H, m, CH2, B), 2.95-2.59 (4H, m, CH2, A, 4H, m, CH2, B), 2.23-2.12 (1H, m CH2, A), 1.96-1.83 (1H, m, CH2, A, 2H, m, CH2, B), 1.72-1.48 (2H, m CH2, A, 2H, m CH2, B), 0.99 (3H, t, J= 13 Hz, CH3, B), 0.90 (3H, t, J= 13 Hz, CH3, A). Isomer A:13C NMR (125 MHz, DMSO) 8 163.2, 159.2

[0181] 157.3, 156.6, 150.2, 138.1, 133.2, 128.1, 127.2, 125.5, 125.3, 123.1, 115.5, 113.1, 111.0, 109.9, 66.1, 42.8, 38.0, 32.8, 26.3, 23.4, 21.3, 13.7. Isomer B:13C NMR (125 MHz, DMSO) 8 162.8, 159.6 156.9, 156.4, 150.2, 137.6, 130.1, 129.3, 127.0, 125.6, 124.8,

[0182] 124.3, 115.3, 113.7, 111.4, 110.2, 66.2, 46.5, 38.1, 33.0, 26.6, 23.4, 21.5, 13.9. Elem. Anal. Calcd for C24H27CIN2O4: C, 65.08; H, 6.14; N, 6.32. Found: C, 64.88; H, 6.17; N, 6.24.

[0183] EXAMPLE 28: 7-(2-(Dimethylamino)ethoxy)-4-propyl-8-(l, 2,3,4- tetrahydroquinolin- 1 -carbonyl )-2 / / -chromen-2-one (18)

[0184] CT N 7-(2-(Dimethylamino)ethoxy)-4-propyl-8-(l,2,3,4-tetrahydroquinolin-l- carbonyl)-27 / -chromen-2-onc (18) was synthesized according to Scheme 1. 2-Chloro- A'A'-dimethylethan-l -amine hydrochloride (0.18 g, 1.25 mmol) was added to a suspension of 7-hydroxy-4-propyl-8-(l,2,3,4-tetrahydroquinolin-l-carbonyl)-277- chromen-2-one 3 (0.3 g, 0.82 mmol) and potassium carbonate (0.23 g, 1.64 mmol) in DMF (10 mL). The reaction mixture was heated to 130 °C for 24 hours. After cooling to rt, the reaction mixture was diluted with EtOAc (50 mL) and washed with water (3 x 50 mL) and brine (1x50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Product 18 was suspended with diethyl ether (15 mL), filtered off and obtained in high quality without additional purification. 7-(2- (Dimethylamino)ethoxy)-4-propyl-8-(l,2,3,4-tetrahydroquinolin-l-carbonyl)-277- chromen-2-one (18) was obtained in 74 % yield (0.26 g) as a white solid; mp 128-129 °C as a mixture of two rotamers in ratio 2: 1. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR.rH NMR (500 MHz, DMSO) 5 8.06-8.03 (1H, m, CH, B), 7.86 (1H, d, J= 8.4 Hz, CH, B), 7.71 (1H, d, J= 9.3 Hz, CH, A), 7.23-7.18 (3H, m, CH, B), 7.13-7.06 (1H, m, CH, A, 1H, m, CH, B), 7.01 (1H, d, J= 9.1 Hz, CH, A), 6.90 (1H, dt, J = 7.7 Hz, J = 1.0 Hz, CH, A), 6.69 (1H, dt, J = 7.7 Hz, J= 1.0 Hz, CH, A), 6.59 (1H, dd, J= 7.7 Hz, J= 0.9 Hz, CH, A), 6.22 (1H, s, CH, B), 6.09 (1H, s, CH, A), 4.30-4.21 (2H, m, CH2, B), 4.18-4.10 (1H, m, CH2, A), 4.01-3.89 (1H, m, CH2, A, 1H, m, CH2, A), 3.88-3.81 (1H, m, CH2, A), 3.50-3.30 (2H, m, CH2, B), 2.91-2.57 (4H, m, CH2, A, 6H, m, CH2, B), 2.53-2.48 (2H, m, CH2, A), 2.18 (6H, s, CH3, B), 2.15 (6H, s, CH3, A), 2.14-2.05 (1H, m, CH2, A), 2.00-1.83 (1H, m, CH2, A, 2H, m, CH2, B), 1.71-1.50 (2H, m, CH2, A, 2H, m, CH2, B), 0.99 (3H, t, J= 7.4 Hz, CH3, B), 0.92 (3H, t, J= 7.2 Hz, CH3, A). Isomer A:13C NMR (125 MHz, DMSO) 5

[0185] 163.3, 159.5, 157.6, 156.8, 150.6, 138.2, 132.9, 128.2, 126.9, 125.4, 125.3, 122.8, 115.0,

[0186] 112.4, 110.6, 108.9, 67.2, 57.4, 45.8, 45.7, 32.8, 26.4, 23.3, 21.3, 13.7. Isomer B:13C NMR (125 MHz, DMSO) 8 163.1, 159.7, 157.0, 156.9, 150.2, 137.5, 130.0, 129.3, 126.9, 125.6, 124.7, 124.1, 114.8, 113.0, 111.0, 109.2, 67.8, 57.6, 46.5, 42.6, 33.0, 26.5, 23.4, 21.5, 13.9. Elem. Anal. Calcd for C26H3oN204: C, 71.87; H, 6.96; N, 6.45. Found: C, 71.92; H, 6.57; N, 6.18. EXAMPLE 29: 7-(3-(Piperidin-l-yl)propoxy)-4-propyl-8-(l,2,3,4- tetrahydroquinolin- 1 -carbonyl )-27 / -chromcn-2-one (19)

[0187] 7-(3-(Piperi din- l-yl)propoxy)-4-propyl-8-( 1,2,3, 4-tetrahydroquinolin-l- carbonyl)-2 / 7-chromen-2-one (19) was synthesized according to Scheme 1. l-(3- Chloropropyl)piperidine hydrochloride (0.25 g, 1.26 mmol) was added to a suspension of 7-hydroxy-4-propyl-8-(l,2,3,4-tetrahydroquinolin-l-carbonyl)-2Zf-chromen-2-one 3 (0.3 g, 0.82 mmol) and potassium carbonate (0.23 g, 1.64 mmol) in DMF (10 mL). The reaction mixture was heated to 130 °C for 24 hours. After cooling to rt, the reaction mixture was diluted with EtOAc (50 mL) and washed with water (3 x 50 mL) and brine (1 x 50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Product 19 was suspended with diethyl ether (15 mL), fdtered off and obtained in high quality without additional purification. 7-(3- (Piperidin-l-yl)propoxy)-4-propyl-8-(l,2,3,4-tetrahydroquinolin-l-carbonyl)-2 / f- chromen-2-one (19) was obtained in 98 % yield (0.39 g) as a white solid; mp 154-155 °C as a mixture of two rotamers in ratio 2: 1. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR.rH NMR (500 MHz, DMSO) 5 8.09-8.05 (1H, m, CH, B), 7.86 (1H, d, J= 9.0 Hz, CH, B), 7.71 (1H, d, J= 9.0 Hz, CH, A), 7.23-7.17 (3H, m, CH, B), 7.13-7.06 (1H, m, CH, A, 1H, m, CH, B), 6.98 (1H, d, J= 9.0 Hz, CH, A), 6.90 (1H, dt, J= 7.8 Hz, J= 1.4 Hz, CH, A), 6.69 (1H, t, J = 7.8 Hz, CH, A), 6.54 (1H, d, J= 7.8 Hz, CH, A), 6.22 (1H, s, CH, B), 6.09 (1H, s, CH, A), 4.19 (2H, t, J = 6.2, CH2, B), 4.11-4.05 (1H, m, CH2, A), 3.99-3.90 (1H, m, CH2, A, 1H, m A), 3.88-3.81 (1H, m, CH2, A), 3.51-3.44 (1H, m, CH2, B), 3.40-3.31 (1H, m, CH2, B), 2.93-2.59 (4H, m, CH2, A, 4H, m, CH2, B), 2.37-2.15 (6H, m, CH2, A, 6H, m, CH2, B), 2.15-2.05 (1H, m, CH2, A), 2.01-1.91 (1H, m, CH2, A), 1.91-1.51 (4H, m, CH2, A, 6H, m, CH2, B), 1.51-1 .25 (6H, m, CH2, A, 6H, tn, CH2, B), 0.99 (3H, t, J= 7.4 Hz, CH3, B), 0.92 (3H, t, J= 7.2 Hz, CH3, A). Isomer A:13C NMR (125 MHz, DMSO) 8

[0188] 163.3, 159.5, 157.7, 156.8, 150.6, 138.2, 132.9, 128.2, 126.9, 125.4, 125.3, 122.7, 115.0,

[0189] 112.3, 110.5, 108.9, 67.2, 54.7, 54.2, 42.6, 32.8, 26.4, 26.1, 25.8, 24.3, 23.4, 21.3, 13.7. Isomer B:13C NMR (125 MHz, DMSO) 8 163.1, 159.7, 157.2, 156.9, 150.2, 137.5, 129.9, 129.3, 126.9, 125.6, 124.7, 124.0, 114.8, 113.0, 110.9, 109.3, 67.3, 54.9, 54.2, 46.5, 33.0, 26.5, 26.3, 25.7, 24.2, 23.5, 21.5, 13.9. Elem. Anal. Calcd for C3oH36N204: C, 73.74; H, 7.43; N, 5.73. Found: C, 73.90; H, 7.40; N, 5.71.

[0190] EXAMPLE 30: 7-(2-(4-Methylpiperazin-l-yl)ethoxy)-4-propyl-8-(l, 2,3,4- tetrahydroquinolin- 1 -carbonyl )-27 / -chromen-2-one (20)

[0191] N I

[0192] O N

[0193] 7-(2-(4-Methylpiperazin-l-yl)ethoxy)-4-propyl-8-(l,2,3,4-tetrahydroquinolin-l- karbonyl)-2 / f-chromen-2-one (20) was synthesized according to Scheme 2. 1- Methylpiperazine (0.18 g, 0.2 mL, 1.8 mmol) was added to a suspension of 7-(2- bromoethoxy)-4-propyl-8-(l,2,3,4-tetrahydroquinoline-l-carbonyl)-2 / 7-chromen-2-one 33 (0.28 g, 0.6 mmol) and potassium carbonate (0.25 g, 1.8 mmol) in DMF (5 mL). The reaction mixture was heated to 60 °C for 5 hours. After cooling, the reaction mixture was diluted with EtOAc (50 mL) and washed with water (3 x 70 mL) and brine (1 x 50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Product 20 was suspended with diethyl ether (10 mL), filtered off and obtained in high quality without additional purification. 7-(2-(4-Methylpiperazin-l- yl)ethoxy)-4-propyl-8-(l,2,3,4-tetrahydroquinolin-l-carbonyl)-2Z7-chromen-2-one (20) was obtained in 78 % yield (0.23 g) as a white solid; mp 45-46 °C as a mixture of two rotamers in ratio 1.7: 1. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR.1H NMR (500 MHz, DMSO) 8 8.09-8.00 (1H, m, CH, B), 7.86 (1H, d, J= 9.0 Hz, CH, B), 7.71 (1H, d, J= 9.0 Hz, CH, A), 7.23- 7.17 (3H, m, CH, B), 7.13-7.07 (1H, m, CH, A, 1H, m, CH, B), 7.01 (1H, d, J= 9.0 Hz, CH, A), 6.90 (1H, td, J= 7.8 Hz, J= 1.3 Hz, CH, A), 6.69 (1H, td, J= 7.8 Hz, J= 1.3 Hz, CH, A), 6.59 (1H, dd, J= 7.8 Hz, J= 1.3 Hz, CH, A), 6.22 (1H, s, CH, B), 6.08 (1H, s, CH, A), 4.31-4.20 (2H, m, CH2, B), 4.20-4.13 (1H, m, CH2, A), 4.05-3.93 (2H, m, CH2, A), 3.83-3.76 (1H, m, CH2, A), 3.51-3.43 (1H, m, CH2, B), 3.43-3.36 (1H, m, CH2, B), 2.91-2.54 (6H, m, CH2, A, 6H, m, CH2, B), 2.48-2.34 (4H, m, CH2, A, 4H, m, CH2, B), 2.34-2.21 (4H, m, CH2, A, 4H, m, CH2, B), 2.11 (3H, s, CH3, A), 2.06 (3H, s, CH3, B), 2.00-1.82 (2H, m CH2, A, 2H, m CH2, B), 1.71-1.62 (2H, m CH2, B), 1.62-1.50 (2H, m CH2, A), 0.99 (3H, t, J= 7.3 Hz, CH3, B), 0.91 (3H, t, J= 7.3 Hz, CH3, A). Isomer A:13C NMR (125 MHz, DMSO) 8 163.3, 159.5, 157.6, 156.8, 150.6, 138.2, 133.0, 128.2, 126.9, 125.4, 125.3, 122.8, 115.0, 112.4, 110.6, 109.0, 67.0, 56.3, 54.9, 53.2, 45.9, 42.6, 32.8, 26.4, 23.4, 21.3, 13.7. Isomer B:13C NMR (125 MHz, DMSO) 8 163.1, 159.7, 157.0, 156.9, 150.2, 137.5, 129.9, 129.3, 126.9, 125.6, 124.6, 124.0, 114.8, 113.0, 111.0, 109.2, 67.7, 56.5, 54.8, 53.2, 46.5, 45.9, 33.0, 26.6, 23.4, 21.5, 13.9. Elem. Anal. Calcd for C29H35N3O4: C, 71.14; H, 7.21; N 8.58. Found: C, 71.06; H, 7.32; N, 8.5.

[0194] EXAMPLE 31: 7-(2-(4-Methyl-l,4-diazepan-l-yl)ethoxy)-4-propyl-8-(l, 2,3,4- tetrahydroquinoline- 1 -carbony l)-27 / -chromen-2-one dihydrochloride (21)

[0195] J 0

[0196] 2 Cl

[0197] 7-(2-(4-Methyl-l,4-diazepan-l-yl)ethoxy)-4-propyl-8-(l,2,3,4- tetrahydroqui noli ne- l -carbonyl )-2F / -chromen-2-one was synthesized according to Scheme 2. 1 -Methylhomopiperazine (0.37 g, 0.4 mL, 3.15 mmol) was added to a solution of 7-(2-bromoethoxy)-4-propyl-8-( 1,2,3, 4-tetrahydroquinoline-l -carbonyl )-2 / / -chromen- 2-one 33 (0.5 g, 1.05 mmol) and potassium carbonate (0.44 g, 3.15 mmol) in DMF (20 mL). The reaction mixture was heated to 60 °C for 15 hours. After cooling, the reaction mixture was diluted with EtOAc (50 mL), washed with water (3 * 30 mL) and brine (1 x 30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Product was suspended with diethyl ether (20 mL), fdtered off and obtained in 76 % yield as a brownish solid as a mixture of two rotamers in ratio 2: 1. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR. 'H NMR (500 MHz, DMSO) 5 8.08 (1H, d, J= 8.7 Hz CH, B), 7.86 (1H, d, J= 8.7 Hz, CH, B), 7.71 (1H, d, J= 8.9 Hz, CH, A), 7.26-7.16 (3H, m, CH, B), 7.15-7.03 (1H, m, CH, A, 1H, m, CH, B), 7.01 (1H, d, J= 8.9 Hz, CH, A), 6.90 (1H, td, J= 7.6 Hz, J= 1.4 Hz, CH,

[0198] A), 6.69 (1H, td, J= 7.6 Hz, J= 1.4 Hz, CH, A), 6.58 (1H, d, J= 7.6 Hz, CH, A), 6.22 (1H, s, CH, B), 6.07 (1H, s, CH, A), 4.32-4,05 (1H, m, CH2, A, 2H, m, CH2, B), 4.02- 3.94 (2H, m, CH2, A), 3.81-3.74 (1H, m, CH2, A), 3.54-3.33 (2H, m, CH2, A, 4H, m, CH2, B), 2.93-2.57 (12H, m, CH2, A, 12H, m, CH2, B), 2.53-2.34 (2H, m, CH2, A), 2.38- 2.33 (2H, m, CH2, B), 2.22 (3H, s, CH3, A), 2.14 (3H, s, CH3, B), 2.14-2.07 (1H, m CH2,

[0199] B), 2.00-1.85 (2H, m, CH2, A, 1H, m, CH2, B), 1.72-1.63 (2H, m CH2, B), 1.63-1.49 (2H, m CH2, A), 0.99 (3H, t, J= 7.3 Hz, CH3, B), 0.91 (3H, t, J= 13 Hz, CH3, A). Isomer A:13C NMR (125 MHz, DMSO) 3 163.2, 159.4, 157.7, 156.8, 150.5, 138.2, 133.0, 128.1, 126.8, 125.4, 125.3, 122.8, 115.0, 112.3, 110.5, 108.9, 67.6, 57.6, 56.3, 55.9, 54.5, 54.2, 46.7, 42.5, 32.8, 27.1, 26.3, 23.4, 21.3, 13.7. Isomer B:13C NMR (125 MHz, DMSO) 8 163.1, 159.7, 157.1, 156.9, 150.2, 137.5, 129.8, 129.2, 126.8, 125.5, 124.6, 124.0, 114.8, 113.0, 110.9, 109.2, 68.1, 57.5, 56.3, 56.3, 54.5, 54.2, 46.6, 46.5, 33.0, 27.1, 26.6, 23.4, 21.5, 13.9.

[0200] 7-(2-(4-Methyl-l, 4-diazepan-l-yl)ethoxy)-4-propyl-8-(l, 2,3,4- tetrahydroquinoline- l -carbonyl)-27 / -chromen-2-one is highly hydroscopic and therefore without additional purification it was transferred into its dihydrochloride 21. 7-(2-(4- Methyl-l,4-diazepan-l-yl)ethoxy)-4-propyl-8-(l,2,3,4-tetrahydroquinoline-l-carbonyl)- 27 / -chromen-2-one (0.62 g, 1.23 mmol) was dissolved in EtOAc (25 mL), bubbled with hydrogen chloride and the reaction mixture was stirred for 1 hour. The formed solid was filtered off to give 7-(2-(4-methyl-l,4-diazepan-l-yl)ethoxy)-4-propyl-8-(l, 2,3,4- tetrahydroquinoline-l-carbonyl)-2 / / -chromen-2-one dihydrochloride 21 in 75 % yield (0.53 g) as a white solid; mp 153-155 °C as a mixture of two rotamers in a ratio 1.9:1. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR. 'H NMR (600 MHz, DMSO) 8 12.40 (bs, 1H, NH, A), 12.22 (bs, 1H, NH, B), 11.81 (bs, 1H, NH, A), 11.59 (bs, 1H, NH, B), 8.09 (1H, bs, CH, B), 7.89 (1H, d, J= 9.0 Hz, CH, B), 7.75 (1H, d, J= 8.7 Hz, CH, A), 7.24-7.17 (3H, m, CH, B), 7.16-7.03 (1H, m, CH, A, 1H, m, CH, B), 7.05 (1H, d, J= 7.5 Hz, CH, A), 6.87 (1H, t, J= 7.5 Hz, CH, A), 6.67 (1H, t, J= 7.5 Hz, CH, A), 6.59-6.53 (1H, m, CH, A), 6.23 (1H, s, CH, B), 6.00 (1H, s, CH, A), 4.77-4.57 (2H, m, CH2, A, 2H, m, CH2, B), 4.41- 4.20 (1H, m, CH2, A), 4.30-3,12 (13H, m, CH2, A, 3H s, CH3, A, 14H, m, CH2, B, 3H s, CH3, B), 2.92-2.51 (4H, m, CH2, A, 4H, m, CH2, B), 2.36-1.77 (2H, m, CH2, A, 2H, m, CH2, B), 1.69-1.58 (2H, m CH2, B), 1.58-1.44 (2H, m CH2, A), 0.96 (3H, t, J= 7.4 Hz, CH3, B), 0.84 (3H, t, J= 7.3 Hz, CH3, A). Elem. Anal. Calcd for C30H4IC12N3O5(hydrate): C, 60.60; H, 6.95; N, 7.07. Found: C, 60.96; H, 6.80; N, 6.76

[0201] EXAMPLE 32: 7-(2-(4-Benzylpiperazin-l -yl)ethoxy)-4-propyl-8-(l, 2,3,4- tetrahydroquinoline- 1 -carbonyl )-2 / / -chromen-2-one (22)

[0202] 7-(2-(4-Benzylpiperazin-l-yl)ethoxy)-4-propyl-8-(l,2,3,4-tetrahydroquinoline-l- carbonyl)-2Z / -chromen-2-one (22) was synthesized according to Scheme 2. N- benzylpiperazine (0.29 g, 1.65 mmol) was added to a solution of 7-(2-bromoethoxy)-4- propyl-8-(l,2,3,4-tetrahydroquinoline-l-carbonyl)-277-chromen-2-one 33 (0.5 g, 1.06 mmol) and potassium carbonate (0.3 g, 2.17 mmol) in DMF (10 mL). The reaction mixture was heated to 60 °C for 24 hours. After cooling, the reaction mixture was diluted with EtOAc (50 mL), washed with water (3 x 30 mL) and brine (1x30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Product 22 was purified by column chromatography (mobile phase: CHC13 / CH3OH, 25: 1) and was obtained in 42 % yield (0.25 g) as a white solid; mp 64-66 °C as a mixture of two rotamers in a ratiol.6:l. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR. 'H NMR (500 MHz, DMSO) 8 8.03 (1H, d, J= 8.6 Hz, CH, B), 7.86 (1H, d, J= 8.6 Hz, CH, B), 7.70 (1H, d, J= 9.0 Hz, CH, A), 7.34-7.03 (6H, m, CH, A, 9H, m, CH, B), 7.01 (1H, d, J= 9.0 Hz, CH, A), 6.90 (1H, td, J = 7.7 Hz, J= 1.3 Hz, CH, A), 6.68 (1H, td, J= 7.7 Hz, J= 1.3 Hz, CH, A), 6.59 (1H, dd, J= 7.7 Hz, J= 1.3 Hz, CH, A), 6.22 (1H, s, CH, B), 6.08 (1H, s, CH, A), 4.31-4.20 (2H, m, CH2, B), 4.20-4.13 (1H, m, CH2, A), 4.05-3.99 (1H, m, CH2, A), 3.99-3.91 (1H, m, CH2, A), 3.82-3.75 (1H, m, CH2, A), 3.49-3.34 (2H, m, CH2, B), 3.42 (2H, s, CH2, A), 3.35 (2H, s, CH2, B), 2.93-2.02 (15H, m, CH2, A, 14H, m, CH2, B), 2.01-1.79 (1H, m CH2, A, 2H, m CH2, B), 1.72-1.47 (2H, m CH2, A, 2H, m CH2, B), 0.99 (3H, t, J= 7.3 Hz, CH3, B), 0.91 (3H, t, J= 7.3 Hz, CH3, A). Isomer A:13C NMR (125 MHz, DMSO) 8

[0203] 163.3, 159.5, 157.6, 156.8, 150.6, 138.4, 138.2, 133.0, 129.0, 128.3, 128.2, 127.1, 126.9,

[0204] 125.4, 125.3, 122.8, 115.0, 112.4, 110.6, 109.0, 66.9, 62.3, 56.3, 53.3, 52.8, 42.6, 32.8,

[0205] 26.4, 23.4, 21.3, 13.7. Isomer B:13C NMR (125 MHz, DMSO) 8 163.0, 159.7, 157.0, 156.9, 150.2, 138.3, 137.5, 129.8, 129.3, 129.0, 128.3, 127.0, 126.9, 125.5, 124.6, 123.9, 114.8, 113.0, 111.0, 109.2, 67.7, 62.2, 56.5, 53.3, 52.7, 46.5, 33.0, 26.5, 23.4, 21.5, 13.9. Elem. Anal. Calcd for C3sH39N3O4: C, 74.31; H, 6.95; N, 7.43. Fond: C, 73.94; H, 7.04; N, 7.33.

[0206] EXAMPLE 33: 7-(2-Morpholinoethoxy)-4-propyl-8-(l,2,3,4- tetrahydroquinoline-l-carbonyl)-2H-chromen-2-one (23)

[0207] 7-(2-Morpholinoethoxy)-4-propyl-8-(l,2,3,4-tetrahydroquinoline-l-carbonyl)-277- chromen-2-one (23) was synthesized according to Scheme 2. Morpholine (0.17 g, 0.17 mL, 1.95 mmol) was added to a solution of 7-(2-bromoethoxy)-4-propyl-8-(l,2,3,4- tetrahydroquinoline-l-carbonyl)-2 / / -chromen-2-one 33 (0.3 g, 0.64 mmol) and potassium carbonate (0.27 g, 1.95 mmol) in DMF (10 mL). The reaction mixture was heated to 60 °C for 7 hours. After cooling, the reaction mixture was diluted with EtOAc (50 mL), washed with water (3 x 30 mL) and brine (1 x 30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Product 23 was suspended with diethyl ether (10 mL), filtered off and obtained in high quality without addition purification. 7- (2-Morpholinoethoxy)-4-propyl-8-(l,2,3,4-tetrahydroquinoline-l-carbonyl)-2H-chromen- 2-one (23) was obtained in 77 % (0.23 g) yield as a white solid; mp 107-109 °C as a mixture of two rotamers in a ratio 1.7: 1. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR.3H NMR (500 MHz, DMSO) 8 8.07 (1H, d, J= 8.5 Hz, CH, B), 7.87 (1H, d, J= 8.5 Hz, CH, B), 7.71 (1H, d, J = 9.0 Hz, CH, A), 7.24-7.17 (3H, m, CH, B), 7.13-7.06 (1H, m, CH, A, 1H, m, CH, B), 7.02 (1H, d, J= 9.0 Hz, CH, A), 6.91 (1H, td, J= 7.6 Hz, J= 1.4 Hz, CH, A), 6.69 (1H, td, J= 7.6 Hz, J= 1.4 Hz, CH, A), 6.59 (1H, dd, J= 7.6 Hz, J= 1.4 Hz, CH, A), 6.22 (1H, s, CH, B), 6.08 (1H, s, CH, A), 4.34-4.16 (1H, m, CH2, A, 2H, m, CH2, B), 4.08- 3.94 (2H, m, CH2, A), 3.82-3.74 (1H, m, CH2, A), 3.57-3.44 (4H, m, CH2, A, 1H, m, CH2, B), 3.44-3.34 (5H, m, CH2, B), 2.93-2.56 (6H, m, CH2, A, 6H, m, CH2, B), 2.47- 2.35 (4H, m, CH2, A, 4H, m, CH2, B), 2.17-2.08 (1H, m, CH2, A), 1.97-1.82 (1H, m, CH2, A, 2H, m, CH2, B), 1.71-1.50 (2H, m CH2, A, 2H, m CH2, B), 0.99 (3H, t, J= 7.4 Hz, CH3, B), 0.91 (3H, t, J= 7.4 Hz, CH3, A). Isomer A:13C NMR (125 MHz, DMSO) 8

[0208] 163.3, 159.4, 157.6, 156.8, 150.5, 138.2, 133.0, 128.2, 126.8, 125.4, 125.3, 122.8, 115.1,

[0209] 112.4, 110.6, 109.0, 66.3, 66.2, 56.7, 53.8, 42.5, 32.8, 26.3, 23.4, 21.3, 13.7. Isomer B:13C NMR (125 MHz, DMSO) 8 163.1, 159.7, 156.9, 156.9, 150.2, 137.5, 129.9, 129.3, 126.8, 125.6, 124.6, 123.9, 114.8, 113.1, 111.0, 109.2, 67.6, 66.8, 56.9, 53.8, 46.5, 33.0, 26.5, 23.4, 21.5, 13.9. Elem. Anal. Calcd for C28H32N2O5: C, 70.57; H, 6.77; N, 5.88. Found: C, 70.93; H, 6.91; N, 5.64.

[0210] EXAMPLE 34: 7-(3-Hydroxypropoxy)-4-propyl-8-(l,2,3,4-tetrahydroquinoline-

[0211] 1 -carbonyl)-2J7-chromen-2-one (24)

[0212] 7-(3-Hydroxypropoxy)-4-propyl-8-(l,2,3,4-tetrahydroquinoline-l-carbonyl)-2 / 7- chromen-2-one (24) was synthesized according to Scheme 1. 2-Bromopropan-l-ol (1.6 g, 1.04 mL, 11.51 mmol) was added to a solution of 7-hydroxy-4-propyl-8-(l,2,3,4- tetrahydroquinoline-l-carbonyl)-27 / -chromen-2-one 3 (0.85 g, 2.3 mmol) and potassium carbonate (1.59 g, 11.51 mmol) in DMF (20 mL). The reaction mixture was stirred at 75 °C for 3 hours. After cooling, the reaction mixture was diluted with EtOAc (50 mL), washed with water (3 x 30 mL) and brine (1 x 30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The product was purified by column chromatography (mobile phase: hexane / EtOAc / acetic acid, 5:5: 1). 7-(3- Hydroxypropoxy)-4-propyl-8-( l,2,3,4-tetrahydroquinoline- l -carbonyl )-27 / -chromen-2- one (24) was obtained in 58 % yield (0.56 g) as a white solid; mp 134-135 °C as a mixture of two rotamers in a ratio 2.1 :1. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR.JH NMR (500 MHz, DMSO) 8 8.07-8.03 (1H, m, CH, B), 7.87 (1H, d, J= 9.0 Hz, CH, B), 7.72 (1H, d, J= 9.0 Hz, CH, A), 7.26-7.17 (3H, m, CH, B), 7.13-7.07 (1H, m, A, 1H, m, CH, B), 6.99 (1H, d, J= 9.0 Hz, CH, A), 6.90 (1H, td, J= 7.7 Hz, J= 1.2 Hz, CH, A), 6.69 (1H, td, J= 7.7 Hz, J = 1.4 Hz, CH, A), 6.54 (1H, dd, J= 7.7 Hz, J = 1.4 Hz, CH, A), 6.21 (1H, s, CH, B), 6.08 (1H, s, CH, A), 4.24 (2H, t, J= 6.2 Hz, B) 4.13 (1H, dt, J= 9.8 Hz, J= 6.4 Hz, CH2, A), 4.01 (1H, dt, J= 9.8 Hz, J= 6.4 Hz, CH2, A), 3.98-3.92 (1H, m, CH2, A), 3.86-3.79 (1H, m, CH2, A), 3.53-3.33 (2H, m, CH2, A, 4H, m, CH2, B), 2.92-2.59 (4H, m, CH2, A, 4H, m, CH2, B), 2.17-2.06 (1H, m, CH2, A), 1.99-1.49 (5H, m, CH2, A, 6H, m, CH2, B), 0.99 (3H, t, J= 7.3 Hz, CH3, B), 0.91 (3H, t, J= 7.3 Hz, CH3, A). Isomer A:13C NMR (125 MHz, DMSO) 5 163.3, 159.5, 157.8, 156.8, 150.6, 138.2, 132.9, 128.2, 126.9,

[0213] 125.4, 125.3, 122.7, 115.0, 112.3, 110.5, 108.8, 66.2, 57.2, 42.6, 32.9, 32.0, 26.3, 23.4,

[0214] 21.4, 13.7. Isomer B:13C NMR (125 MHz, DMSO) 5 163.1, 159.8, 157.2, 157.0, 150.2, 137.5, 130.0, 129.3, 129.9, 125.7, 124.7, 124.1, 114.7, 112.9, 110.9, 109.3, 66.1, 57.1,

[0215] 46.4, 33.1, 32.1, 26.5, 23.5, 21.5, 13.9. Elem. Anal. Calcd for C25H27NO5: C, 71.24; H, 6.46; N, 3.32. Found: C, 71.11; H, 6.08; N, 2.97.

[0216] EXAMPLE 35: 7-(3-(4-Methylpiperazin- l-yl)propoxy)-4-propyl-8-(l, 2,3,4- tetrahydroquinolin-l-carbonyl)-2 / / -chromen-2-one (25)

[0217] 7-(3 -(4-Methy Ipiperazin- 1 -yl)propoxy)-4-propyl-8-( 1,2,3 ,4-tetrahy droquinolin- 1 - carbonyl)-2 / / -chromen-2-one (25) was synthesized according to Scheme 2 by reaction of 7-(3-bromopropoxy)-4-propyl-8-(l,2,3,4-tetrahydroquinoline-l-carbonyl)-2 / 7-chromen- 2-one 34 (0.29 g, 0.6 mmol) with 1 -methylpiperazine (0.18 g, 0.2 mL, 1.8 mmol) and potassium carbonate (0.25 g, 1.8 mmol) in DMF (10 mL). The reaction mixture was heated to 60 °C for 5 hours. After cooling, the reaction mixture was diluted with EtOAc (50 mL) and washed with water (3 x 70 mL) and brine (1 x 50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Product 25 was suspended with diethyl ether (10 mL), fdtered off and obtained in high quality without additional purification. 7-(3-(4-Methylpiperazin-l-yl)propoxy)-4-propyl-8-(l,2,3,4- tetrahydroquinolin-l-carbonyl)-27 / -chromen-2-one (25) was obtained in 91 % yield (0.27 g) as a white solid; mp 130-131 °C as a mixture of two rotamers in a ratio 2.1 : 1. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR. 'H NMR (500 MHz, DMSO) 8 8.08-8.05 (1H, m, CH, B), 7.86 (1H, d, J= 9.0 Hz, CH, B), 7.71 (1H, d, J= 9.0 Hz, CH, A), 7.23-7.15 (3H, m, CH, B), 7.14-7.05 (1H, m, CH, A, 1H, m, CH, B), 6.98 (1H, d, ,7= 9.0 Hz, CH, A), 6.90 (1H, td, J = 7.7 Hz, J= 1.3 Hz, CH, A), 6.68 (1H, td, J= 7.7 Hz, J= 1.3 Hz, CH, A), 6.54 (1H, dd, J= 7.7 Hz, J= 1.3 Hz, CH, A), 6.22 (1H, s, CH, B), 6.08 (1H, s, CH, A), 4.19 (2H, t, J = 6.1 Hz, CH2, B), 4.08 (1H, dt, J= 9.7 Hz, J= 6.3 Hz, CH2, A), 4.01-3.91 (2H, m, CH2, A), 3.87-3.80 (1H, m, CH2, A), 3.52-3.43 (1H, m, CH2, B), 3.41-3.31 (1H, m, CH2, B), 2.92-2.60 (4H, m, CH2, A, 6H, m, CH2, B), 2.17-2.06 (10H, m, CH2, A, 8H, m, CH2, B), 2.17-2.06 (1H, m, CH2, A), 2.13 (3H, s, CH3, A), 2.10 (3H, s, CH3, B), 2.00-1.72 (3H, m CH2, A, 4H, m CH2, B), 1.71-1.50 (2H, m CH2, A, 2H, m CH2, B), 0.99 (3H, t, J= 7.3 Hz, CH3, B), 0.92 (3H, t, J = 7.3 Hz, CH3, A). Isomer A:13C NMR (125 MHz, DMSO) 8 163.3, 159.4, 157.7, 156.7, 150.6, 138.2, 132.9, 128.2, 126.9, 125.3, 125.3, 122.7, 115.0, 112.3, 110.5, 108.9, 67.0, 54.9, 53.9, 52.8, 45.9, 42.6, 32.8, 26.3, 26.0, 23.4, 21.3, 13.7.

[0218] Isomer B:13C NMR (125 MHz, DMSO) 5 163.1, 159.7, 157.1, 156.9, 150.2, 137.5, 129.9, 129.3, 126.9, 125.6, 124.6, 124.0, 114.8, 113.0, 110.9, 109.3, 67.2, 54.8, 54.1, 52.8, 46.4, 45.8, 33.0, 26.5, 26.2, 23.4, 21.5, 13.9. Elem. Anal. Calcd for C30H37N3O4: C, 71.54; H, 7.41; N, 8.34. Found: C, 71.28; H, 7.36; N, 7.97.

[0219] EXAMPLE 36 : 4-Buty l-7-(2-(4-methylpiperazin- 1 -yl)ethoxy)-8-( 1 ,2, 3,4- tetrahydroquinolin-l-c arbonyl)-2 / 7-chromen-2-one (26)

[0220] N I

[0221] O' N

[0222] 4-Butyl-7-(2-(4-methylpiperazin-l-yl)ethoxy)-8-(l,2,3,4-tetrahydroquinolin-l- carbonyl)-2 / 7-chromen-2-one (26) was synthesized according to Scheme 2 by reaction of 4-butyl-7-(2-bromoethoxy)-8-(l,2,3,4-tetrahydroquinoline-l-carbonyl)-2 / / -chromen-2- one 35 (0.28 g, 0.6 mmol) with 1 -methylpiperazine (0.18 g, 0.2 mL, 1.8 mmol) and potassium carbonate (0.25 g, 1.8 mmol) in DMF (10 mL). The reaction mixture was heated to 60 °C for 5 hours and then worked up according to above-mentioned procedure. 4-Butyl-7-(2-(4-Methylpiperazin- l-yl)ethoxy)-8-( 1 ,2, 3,4-tetrahydroquinolin- 1 -carbonyl)- 2Z7-chromen-2-one (26) was obtained in 84 % yield (0.28 g) as a yellowish solid; mp 40- 42 °C as a mixture of two rotamers in ratio 1.7: 1. The rotamers in the mixture are cis- trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR. 'H NMR (500 MHz, DMSO) 5 8.07 (1H, d, J= 8.9 Hz, CH, B), 7.85 (1H, d, J= 8.9 Hz, CH, B), 7.70 (1H, d, J= 9.0 Hz, CH, A), 7.23-7.15 (3H, m, CH, B), 7.13-7.07 (1H, m, CH, A, 1H, m, CH, B), 7.02 (1H, d, J= 9.0 Hz, CH, A), 6.90 (1H, td, J= 7.7 Hz, J= 1.3 Hz, CH, A), 6.69 (1H, td, J= 7.7 Hz, J= 1.3 Hz, CH, A), 6.59 (1H, dd, J= 7.7 Hz, J= 1.3 Hz, CH, A), 6.22 (1H, s, CH, B), 6.08 (1H, s, CH, A), 4.31-4.20 (2H, m, CH2, B), 4.20-4.14 (1H, m, CH2, A), 4.06-3.92 (2H, m, CH2, A), 3.84-3.77 (1H, m, CH2, A), 3.51-3.43 (1H, m, CH2, B), 3.43-3.36 (1H, m, CH2, B), 2.92-2.54 (6H, m, CH2, A, 6H, m, CH2, B), 2.48- 2.35 (4H, m, CH2, A, 4H, m, CH2, B), 2.35-2.22 (4H, m, CH2, A, 4H, m, CH2, B), 2.19- 2.08 (1H, m CH2, A) 2.12 (3H, s, CH3, A), 2.06 (3H, s, CH3, B), 2.00-1.83 (1H, m CH2, A, 2H, m CH2, B), 1.66-1.56 (2H, m CH2, B), 1.56-1.46 (2H, m CH2, A), 1.46-1.37 (2H, m CH2, B), 1.37-1.28 (2H, m CH2, A), 0.93 (3H, t, J= 7.3 Hz, CH3, B), 0.89 (3H, t, J= 7.3 Hz, CH3, A). Isomer A:13C NMR (125 MHz, DMSO) 5 163.2, 159.4, 157.6, 157.0,

[0223] 150.6, 138.2, 133.0, 128.2, 126.8, 125.4, 125.3, 122.8, 115.1, 112.4, 110.5, 109.0, 67.0, 56.3, 54.8, 53.2, 45.9, 42.5, 30.7, 30.2, 26.3, 23.3, 22.0, 13.9. Isomer B:13C NMR (125 MHz, DMSO) 5 163.1, 159.7, 157.2, 157.0, 150.2, 137.5, 129.9, 129.2, 126.8, 125.5,

[0224] 124.6, 124.0, 114.8, 113.0, 110.9, 109.2, 67.6, 56.5, 54.8, 53.1, 46.5, 45.9, 30.9, 30.3, 26.5, 23.4, 20.1, 13.9. Elem. Anal. Calcd for C30H37N3O4: C, 71.54; H, 7.41; N, 8.34. Found: C, 71.43; H, 7.39; N, 8.10.

[0225] EXAMPLE 37: Ze / V-Butyl (2-((2-oxo-4-propyl-8-(l,2,3,4-tetrahydroquinolin-l- carbonyl)-2rt-chromen-7-yl)oxy)ethyl)carbamate (27)

[0226] Ze / V-Butyl (2-((2-oxo-4-propyl-8-( 1,2,3, 4-tetrahydroquinolin-l-carbonyl)-27 / - chromen-7-yl)oxy)ethyl)carbamate (27) was synthesized according to Scheme 1. Tert- Butyl (2-bromoethyl)carbamate (0.45 g, 2 mmol) was added to a suspension of 7- hydroxy-4-propyl-8-(l,2,3,4-tetrahydroquinolin-l-carbonyl)-2rt-chromen-2-one 3 (0.47 g, 1.3 mmol) and potassium carbonate (0.36 g, 2.6 mmol) in DMF (10 mb). The reaction mixture was heated to 130 °C for 24 hours. After cooling, the reaction mixture was diluted with EtOAc (50 mL) and washed with water (3 * 70 mL) and brine (1 x 50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Product 27 was purified by column chromatography (mobile phase: hexane / EtOAc, 1 : 1). tert-Butyl (2-((2-oxo-4-propyl-8-(l,2,3,4-tetrahydroquinolin-l- carbonyl)-2J7-chromen-7-yl)oxy)ethyl)carbamate (27) was obtained in 47 % yield (0.31 g) as a white solid; mp 73-74 °C as a mixture of two rotamers in ratio 2.4: 1 . The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR. 'H NMR (500 MHz, DMSO) 5 8.07 (1H, d, J= 8.7 Hz, CH, B), 7.88 (1H, d, J = 8.7 Hz, CH, B), 7.72 (1H, d, J= 9.0 Hz, CH, A), 7.24-7.16 (3H, m, CH, B), 7.14-7.08 (1H, m, CH, A, 1H, m, CH, B), 7.01 (1H, d, J= 9.0 Hz, CH, A), 6.94-6.86 (1H, NH, A, 1H, NH, B), 6.90 (1H, td overlapped, J= 7.7 Hz, J= 1.2 Hz, CH, A), 6.69 (1H, td, J = 1.TOL, J= 1.2 Hz, CH, A), 6.56 (1H, dd, J= 7.7 Hz, J= 1.2 Hz, CH, A), 6.23 (1H, s, CH, B), 6.09 (1H, s, CH, A), 4.27-4.13 (2H, m, CH2, B), 4.08-4.00 (1H, m, CH2, A), 4.00-3.89 (2H, m, CH2, A), 3.86-3.78 (1H, m, CH2, A), 3.42 (2H, t, J= 6.5 Hz, CH2, B), 3.30-3.25 (2H, m, CH2, B), 3.23-3.17 (2H, m CH2, A), 2.91-2.60 (4H, m CH2, A, 4H, m CH2, B), 2.16-2.25 (1H, m CH2, A), 1.99-1.83 (1H, m CH2, A, 2H, m CH2, B), 1.71-1.50 (2H, m CH2, A, 2H, m CH2, B), 1.36 (9H, s, CH3, A), 1.35 (9H, s, CH3, B), 0.99 (3H, t, J = 13 Hz, CH3, B), 0.91 (3H, t, J= 13 Hz, CH3, A). Isomer A:13C NMR (125 MHz, DMSO) 8 163.2, 159.4, 157.5, 156.8, 155.8, 150.6, 138.2, 133.0, 128.1, 127.0, 125.4,

[0227] 125.3, 122.8, 115.1, 112.5, 110.7, 108.9, 78.1, 67.5, 42.6, 39.2, 32.8, 28.3, 26.3, 23.4,

[0228] 21.3, 13.7. Isomer B:13C NMR (125 MHz, DMSO) 8 162.9, 159.7 156.9, 156.8, 155.7,

[0229] 150.3, 137.6, 130.0, 129.2, 126.9, 125.5, 124.7, 124.3, 114.9, 113.2, 111.1, 109.4, 78.0, 67.5, 46.4, 39.4, 33.0, 28.3, 26.5, 23.5, 21.5, 13.9. Elem. Anal. Calcd for C29H34N2O6: C, 68.76; H, 6.77; N, 5.53. Found: C, 68.55; H, 6.74; N, 5.44.

[0230] EXAMPLE 38: 4-Propyl-8-(l,2,3,4-tetrahydroquinoline-l-carbonyl)-7-(2- thiomorpholinoethoxy)-27 / -chromen-2-one (28) s

[0231] J

[0232] CT

[0233] 4-Propyl-8-(l, 2, 3, 4-tetrahydroquinoline-l-carbonyl)-7-(2 -thiomorpholinoethoxy)-

[0234] 2Z / -chromen-2-one (28) was synthesized according to Scheme 2. Thiomorpholine (0.19 g, 0.18 mb, 1.8 mmol) was added to a suspension of 7-(2-bromoethoxy)-4-propyl-8- (l ,2,3,4-tetrahydroquinoline-l-carbonyl)-2 / 7-chromen-2-one 33 (0.28 g, 0.6 mmol) and potassium carbonate (0.25 g, 1.8 mmol) in DMF (5 mL). The reaction mixture was heated to 60 °C for 5 hours. After cooling, the reaction mixture was diluted with EtOAc (50 mL) and washed with water (3 x 70 mL) and brine (1x50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Product was purified by column chromatography (mobile phase: CHCI3 / CH3OH, 40: 1). 4-Propyl-8- (l,2,3,4-tetrahydroquinoline-l-carbonyl)-7-(2-thiomorpholinoethoxy)-2Z7-chromen-2-one 28 was obtained in 46 % (0.13 g) as an orange solid; mp 59-61 °C as a mixture of two rotamers in a ratio 1.7: 1. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR.!H NMR (500 MHz, DMSO) 8 8.08 (1H, d, J= 8.9 Hz, CH, B), 7.87 (1H, d, J= 8.9 Hz, CH, B), 7.71 (1H, d, J= 9.0 Hz, CH, A), 7.24-7.16 (3H, m, CH, B), 7.14-7.06 (1H, m, CH, A, 1H, m, CH, B), 7.02 (1H, d, J = 9.0 Hz, CH, A), 6.91 (1H, td, J= 7.7 Hz, J= 1.3 Hz, CH, A), 6.69 (1H, td, J= 7.7 Hz, J = 1.3 Hz, CH, A), 6.59 (1H, dd, J= 7.7 Hz, J= 1.3 Hz, CH, A), 6.22 (1H, s, CH, B), 6.08 (1H, s, CH, A), 4.31-4.14 (1H, m, CH2, A, 2H, m, CH2, B), 4.07-3.95 (2H, m, CH2, A), 3.83-3.73 (1H, m, CH2, A), 3.52-3.46 (1H, m, CH2, B), 3.43-3.35 (1H, m, CH2, B), 2.92- 2.59 (10H, m, CH2, A, 10H, m, CH2, B), 2.58-2.53 (4H, m, CH2, A), 2.44-2.38 (4H, m, CH2, B), 2.21-2.06 (1H, m, CH2, A), 2.01-1.81 (1H, m, CH2, A, 2H, m, CH2, B), 1.72- 1.49 (2H, m CH2, A, 2H, m CH2, B), 0.99 (3H, t, J= 13 Hz, CH3, B), 0.91 (3H, t, J= 13 Hz, CH3, A). Isomer A:13C NMR (125 MHZ, DMSO) 8 163.3, 159.4, 157.7, 156.8, 150.5, 138.2, 133.0, 128.2, 126.9, 125.4, 125.3, 122.8, 115.0, 112.4, 110.6, 109.0, 67.0, 57.0, 55.1, 42.5, 32.8, 27.3, 26.3, 23.4, 21.3, 13.7. Isomer B:13C NMR (125 MHz, DMSO) 8 163.1, 159.7, 157.0, 157.0, 150.2, 137.5, 129.9, 129.3, 126.9, 125.6, 124.7, 123.9, 114.8, 113.1, 111.0, 109.2, 67.4, 57.3, 54.9, 46.5, 33.0, 27.3, 26.6, 23.4, 21.5, 13.9. Anal. Calcd for C28H32N2O4S: C, 68.27; H, 6.55; N, 5.69; S, 6.51. Found: C, 68.58; H, 6.61; N, 5.44; S, 6.72.

[0235] EXAMPLE 39: 7 -Hydroxy -4-isobutyl-8-(l, 2,3, 4-tetrahydroquinoline-l- carbonyl)-27 / -chromen-2-one (29)

[0236] 7-Hydroxy-4-isobutyl-8-(l,2,3,4-tetrahydroquinoline-l-carbonyl)-2 / 7-chromen-2- one (29) was synthesized according to Scheme 1 by reaction of 7-hydroxy-4-isobutyl-2- oxo-2H-chromene-8-carboxylic acid IVj (0.25 g, 0.95 mmol) with 1,2, 3, 4- tetrahydroquinoline (0.44 g, 0.41 mb, 3.3 mmol) and EDC.HC1 (0.37 g, 1.93 mmol) in CH2CI2 (50 mL) at the presence of DMAP (5 mg, 0.04 mmol). The reaction mixture was stirred at rt for 72 hours. Then, the reaction mixture was washed with water (1 x 50 mL), IN HC1 (2 x 50 mL), water (2 x 50 mL), and brine (1x50 mL). Organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Product was purified by column chromatography (mobile phase: hexane / EtOAc / acetic acid, 20:20:1). 7-Hydroxy-4-isobutyl-8-(l,2,3,4-tetrahydroquinoline-l-carbonyl)-277-chromen-2-one 29 was obtained in 61 % as a beige solid; mp 83-85 °C as a mixture of two rotamers in a ratio 2.2:1. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR. ’H NMR (500 MHz, DMSO) 8 11.2 (1H, bs, OH, A, 1H, bs, OH, B), 8.10 (1H, d, J= 8.7 Hz, CH, B), 7.72 (1H, d, J= 8.7 Hz, CH, B), 7.56 (1H, d, J= 8.9 Hz, CH, A), 7.23-7.17 (2H, m, CH, B), 7.13-7.08 (1H, m, CH, B), 7.07 (1H, d, J= 7.6 Hz, CH, A), 6.95 (1H, d, J= 8.8 Hz, CH, B), 6.89 (1H, td, J= 7.6 Hz, J= 1.1 Hz CH, A), 6.76 (1H, d, J= 8.9 Hz, CH, A), 6.71 (1H, t, J= 7.6 Hz, CH, A), 6.62 (1H, d, J = 7.6 Hz, CH, A), 6.13 (1H, s, CH, B), 5.95 (1H, s, CH, A), 4.16-4.05 (1H, m, CH2, A), 3.68- 3.58 (1H, m, CH2, A), 3.51-3.42 (2H, m, CH2, B), 2.91-2.78 (1H, m, CH2, A, 2H, m, CH2, B), 2.77-2.64 (1H, m, CH2, A), 2.62-2.52 (1H, m, CH2, A, 2H, m, CH2, B), 2.49-2.41 (1H, m, CH2, A), 2.20-2.09 (1H, m, CH2, A), 2.00-1.76 (1H, m, CH2, A, 1H, m CH, A, 1H, m , CH, B, 2H, m, CH2, B), 0.96 (3H, d, J= 6.5 Hz, CH3, B), 0.94 (3H, d, J= 6.5 Hz, CH3, B), 0.86 (3H, d, J = 6.7 Hz, CH3, A), 0.84 (3H, d, J = 6.7 Hz, CH3, A). Isomer A:13C NMR (125 MHz, DMSO) 5 163.9, 159.5, 158.0, 156.1, 151.1, 138.5, 133.4, 128.0, 126.8, 125.3, 125.2, 122.8, 113.6, 1 12.5, 110.9, 110.4, 42.5, 27.9, 26.2, 23.5, 22.5, 22.2. Isomer B:13C NMR (125 MHz, DMSO) 8 163.6, 159.8, 157.0, 156.3, 151.1, 137.7, 129.8, 129.3, 126.8, 125.6, 124.6, 124.1, 113.5, 112.9, 111.7, 110.9, 46.5, 27.9, 26.6, 23.4, 22.7, 22.4. Elem. Anal. Calcd for C23H23NO4: C, 73.19; H, 6.14; N, 3.71. Found: C, 72.84; H, 6.24; N, 3.41.

[0237] EXAMPLE 40: 7 -Methoxy-2-oxo-8-( 1,2, 3, 4-tetrahydroquinoline-l -carbonyl)- 2 / / -chromene-4-carboxylic acid (30)

[0238] HCX

[0239] N

[0240] Dioxan (100 mL) was added to a mixture of 7-methoxy-4-methyl-8-(l,2,3,4- tetrahydroquinolin-l-carbonyl)-2 / / -chromen-2-one 5 (3.9 g, 11.16 mmol) and selenium dioxide (6.2, 55.88 mmol) under inert atmosphere. The reaction mixture was heated to reflux for 72 hours. After cooling to rt, the reaction mixture was filtered and concentrated. The products were separated by column chromatography (mobile phase: hexane / EtOAc, 2:1 —> hexane / EtOAc / acetic acid, 20:20: 1-10:50:2).

[0241] 7-Methoxy-2-oxo-8-(l, 2, 3, 4-tetrahydroquinoline-l -carbonyl )-2 / / -chromene-4- carboxylic acid 30 was obtained in 51 % yield (2.17 g) as an yellow solid; mp 230-232 °C as a mixture of two rotamers in a ratio 2.5: 1. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR.3H NMR (500 MHz, DMSO) 8 8.23 (1H, d, J = 9.3 Hz, CH, B), 8.10 (1H, d, J= 7.8 Hz, CH, B), 8.08 (1H, d, J = 9.3 Hz, CH, A), 7.25 (1H, d, J = 9.3 Hz, CH, B), 7.23-7.19 (2H, m, CH, B), 7.14-7.09 (1H, m, CH, A, 1H, m, CH, B), 7.04 (1H, d, J= 9.3 Hz, CH, A), 6.95-6.90 (1H, m, CH, A), 6.74-6.69 (1H, m, CH, A), 6.72 (1H, s, CH, B), 6.59 (1H, s, CH, A), 6.57-6.53 (1H, m, CH, A), 4.02-3.92 (1H, m, CH2, A), 3.94 (3H, s, CH3, B), 3.83-3.76 (1H, m, CH2, A), 3.76 (3H, s, CH3, A), 3.51-3.37 (2H, m, CH2, B), 2.91-2.70 (2H, m, CH2, A, 2H, m, CH2, B), 2.14-2.05 (1H, m, CH2, A), 2.01-1.91 (1H, m, CH2, A), 1.90 (2H, m, CH2, B). Isomer A:13C NMR (150 MHz, DMSO) 8 165.4, 163.0, 159.1, 158.8, 151.0, 144.0, 138.2, 133.4, 128.8, 128.0, 125.6, 125.4, 122.9, 1 14.9, 1 14.7, 109.3, 108.7, 56.6, 42.6, 26.1 , 23.5. Isomer B:13C NMR (150 MHz, DMSO) 5 165.6, 162.7, 159.5, 158.1, 150.7, 144.1, 137.5, 130.0, 129.4, 128.7, 125.6, 124.8, 124.1, 115.2, 114.7, 110.0, 109.0, 56.9, 46.5, 26.5, 23.4. Elem. Anal. Calcd for C21H17NO6: C, 66.49; H, 4.52; N, 3.69. Found: C, 66.21; H, 4.47; N, 3.85.

[0242] EXAMPLE 41: 7-Methoxy-2-oxo-8-( 1,2,3, 4-tetrahydroquinoline-l -carbonyl)- 2 / / -chromene-4-carbaldehyde (31)

[0243] Dioxan (100 mL) was added to a mixture of 7-methoxy-4-methyl-8-(l, 2,3,4- tetrahydroquinolin-l-carbonyl)-2Z / -chromen-2-one 5 (3.9 g, 11.16 mmol) and selenium dioxide (6.2, 55.88 mmol) under inert atmosphere. The reaction mixture was heated to reflux for 72 hours. The products were separated by column chromatography (mobile phase: hexane / EtOAc, 2: 1 —> hexane / EtOAc / acetic acid, 20:20: 1-10:50:2). 7-Methoxy-2-oxo-8-(l,2,3,4-tetrahydroquinoline-l-carbonyl)-2 / / -chromene-4- carbaldehyde (31) was obtained in 35 % yield (1.43 g) as an yellow solid; mp 172-173 °C as a mixture of two rotamers in a ratio 1.9: 1. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR. ’H NMR (500 MHz, DMSO) 8 10.13 (1H, s, CHO, B), 10.02 (1H, s, CHO, A), 8.52 (1H, d, J= 8.7 Hz, CH, B), 8.37 (1H, d, J= 8.8 Hz, CH, A), 8.12 (1H, d, J= 8.7 Hz, CH, B), 7.28 (1H, d, J = 8.7 Hz, CH, B), 7.23-7.18 (2H, m, CH, B), 7.14-7.04 (2H, m, CH, A, 2H, m, CH, B), 6.94- 6.89 (2H, m, CH, A), 6.72-6.67 (1H, m, CH, A), 6.56 (1H, d, J = 8.2 Hz, CH, A), 4.03- 3.91 (1H, m, CH2, A), 3.95 (3H, s, CH3, B), 3.84-3.77 (1H, m, CH2, A), 3.76 (3H, s, CH3, A), 3.50-3.37 (2H, m, CH2, B), 2.90-2.70 (2H, m, CH2, A, 2H, m, CH2, B), 2.15-2.05 (1H, m, CH2, A), 2.01-1.92 (1H, m, CH2, A), 1.91 (2H, m, CH2, B). Isomer A:13C NMR (150 MHz, DMSO) 5 193.5, 162.9, 159.6, 158.8, 151.1, 143.5, 138.1, 133.4, 128.0, 127.9, 125.6, 125.4, 122.9, 121.6, 114.9, 108.9, 108.4, 56.6, 42.5, 26. 1, 23.5. Isomer B:13C NMR (150 MHz, DMSO) 5 193.7, 162.7, 159.9, 158.0, 150.8, 143.5, 137.4, 129.9, 129.3, 127.7, 125.6, 124.7, 124.0, 122.3, 114.7, 109.2, 109.1, 56.9, 46.5, 26.5, 23.4. Elem. Anal. Calcd for C21H17NO5: C, 69.41; H, 4.72; N, 3.85. Found: C, 69.05; H, 4.94; N, 3.71.

[0244] EXAMPLE 42: 4-(Hydroxymethyl)-7-methoxy-8-(l,2,3,4-tetrahydroquinoline-l- carbonyl)-2 / / -chromen-2-one (32)

[0245] JOH

[0246] N

[0247] Sodium borohydride (0.084 g, 2.2 mmol) was added to a solution of 7-methoxy-2- oxo-8-(l,2,3,4-tetrahydroquinoline-l-carbonyl)-2Z / -chromene-4-carbaldehyde 31 (0.4 g, 1.1 mmol) in dry THF (15 mb) at cooling and under inert atmosphere. The reaction mixture was heated to rt, stirred for 2 hours and then a mixture acetic acid-water (3 mL, 1 :2) was added. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 25 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated. The product was purified using column chromatography (mobile phase: hexane / EtOAc / acetic acid, 10:20:1). 4-(Hydroxymethyl)-7-methoxy-8-(l, 2,3,4- tetrahydroquinoline-l-carbonyl)-27 / -chromen-2-one 32 was obtained in 53 % yield (0.22 g) as a while solid; mp 227-229 °C as a mixture of two rotamers in a ratio 2.6: 1. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR. 'H NMR (500 MHz, DMSO) 8 8.10 (1H, d, J= 8.9 Hz, CH, B), 7.77 (1H, d, J = 8.9 Hz, CH, B), 7.60 (1H, d, J= 8.9 Hz, CH, A), 7.24-7.15 (3H, m, CH, B), 7.15-7.07 (1H, m, CH, A, 1H, m, CH, B), 6.97 (1H, d, J= 8.9 Hz, CH, A), 6.91 (1H, td, J= 7.7 Hz, J= 1.2 Hz CH, A), 6.70 (1H, td, J= 7.7 Hz, J= 1.2 Hz, CH, A), 6.53 (1H, d, .7= 7.7 Hz, CH, A), 6.35 (1H, s, CH, B), 6.21 (1H, s, CH, A), 5.68 (1H, bs, OH, B), 5.57 (1H, bs, OH, A), 4.77 (2H, s, CH2, B), 4.66 (2H, s, CH2, A), 4.06-3.97 (1H, m, CH2, A), 3.93 (3H, s, CH3, B), 3.77 (3H, s, CH3, A), 3.80-3.69 (1H, m, CH2, A), 3.48-3.37 (2H, m, CH2, B), 2.91-2.79 (1H, m, CH2, A, 2H, m, CH2, B), 2.79-2.69 (1H, m, CH2, A), 2.17-2.06 (1H, m CH2, A), 2.00-1.82 (1H, m CH2, A, 2H, m CH2, B). Isomer A:13C NMR (125 MHz, DMSO) 5 163.3, 159.6, 158.5, 156.7, 150.1, 138.3, 133.5, 128.0, 126.2, 125.5, 125.4, 122.8, 114.7, 110.7, 108.2, 107.8, 59.2, 56.5, 42.5, 26.1, 23.5. Isomer B:13C NMR (125 MHz, DMSO) 5 163.0, 159.9, 157.7, 156.9, 149.9, 137.5, 129.9, 129.4, 126.2, 125.6, 124.7, 124.1, 114.5, 111.4, 108.5, 108.2, 59.3, 56.8, 46.5, 26.5, 23.3. Elem. Anal. Calcd for C2IHI9NO5: C, 69.03; H, 5.24; N, 3.83. Found: C, 69.35; H, 5.74; N, 3.47.

[0248] EXAMPLE 43: 7-(2-Bromoethoxy)-4-propyl-8-(l,2,3,4-tetrahydroquinolin-l- carbonyl)-2 / / -chromen-2-one (33)

[0249] J

[0250] O"^

[0251] The compound was synthesized according to Scheme 2. Tetrabromomethane (0.53 g, 1.6 mmol) was added to a solution of 7-(2-hydroxyethoxy)-4-propyl-8-(l,2,3,4- tetrahydroquinoline-l-carbonyl)-2 / / -chromen-2-one 15 (0.5 g, 1.23 mmol) and triphenylphosphine (0.42 g, 1.6 mmol) in acetonitrile (50 mb). The reaction mixture was stirred at rt for 48 hours. The reaction mixture was concentrated under reduced pressure. The product was purified by column chromatography (mobile phase: hexane / EtOAc, 2: 1). 7-(2-Bromoethoxy)-4-propyl-8-(l,2,3,4-tetrahydroquinolin-l-carbonyl)-2 / 7- chromen-2-one (33) was obtained in 52 % yield (0.3 g) as a white solid; mp 128-129 °C. There are two rotamers in ratio 1.6: 1. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR ’H NMR (500 MHz, DMSO) 8 8.09 (1H, d, J= 8.5 Hz, CH, B), 7.87 (1H, d, J= 8.5 Hz, CH, B), 7.73 (1H, d, J = 9.0 Hz, CH, A), 7.24-7.18 (3H, m, CH, B), 7.13-7.07 (1H, m, CH, A, 1H, m, CH, B), 7.02 (1H, d, J= 9.0 Hz, CH, A), 6.90 (1H, td, J= 7.6 Hz, J= 1.3 Hz, CH, A), 6.72-6.67 (1H, m, CH, A), 6.65 (1H, dd, J= 7.6 Hz, J= 1.3 Hz CH, A), 6.24 (1H, s, CH, B), 6.10 (1H, s, CH, A), 4.59-4.27 (2H, m, CH2, A, 2H, m, CH2, B), 4.05-3.97 (1H, m, CH2, A), 3.84-3.66 (3H, m, CH2, A, 2H, m, CH2, B), 3.49-3.42 (2H, m, CH2, B), 2.93-2.59 (4H, m, CH2, A, 4H, m, CH2, B), 2.18-2.07 (1H, m CH2, A), 2.02-1.81 (1H, m CH2, A, 2H, m CH2, B), 1.72-1.49 (2H, m CH2, A, 2H, m CH2, B), 0.99 (3H, t, J= 1A Hz, CH3, B), 0.91 (3H, t, J= 13 Hz, CH3, A). Isomer A:13C NMR (125 MHz, DMSO) 8 163.0, 159.4 157.0, 156.7, 150.5, 138.2, 132.9, 128.2, 126.9, 125.4, 125.3, 122.9, 115.2, 112.8, 110.8, 109.0, 69.0, 42.7, 32.8, 30.8, 26.3, 23.4, 21.3, 13.7. Isomer B:13C NMR (125 MHz, DMSO) 8 162.8, 159.7 156.9, 156.3, 150.2, 137.5, 130.1, 129.2, 126.1, 125.6, 124.7, 124.2, 115.0, 113.4, 111.2, 109.5, 69.0, 46.5, 33.0, 31.3, 26.5, 23.5, 21.5, 13.9. Elem. Anal. Calcd for C24H24BrNO4: C, 61.29; H, 5.14; N, 2.98. Found: C, 61.47; H, 5.02; N, 2.92.

[0252] EXAMPLE 44: 7-(3-B romopropoxy)-4-propyl-8-( 1,2,3, 4-tetrahydroquinoline-l - carbonyl )-27 / -chromen-2-one (34)

[0253] O N

[0254] 7-(3-Bromopropoxy)-4-propyl-8-(l,2,3,4-tetrahydroquinoline-l-carbonyl)-2 / / - chromen-2-one (34) was synthesized according to Scheme 2 by reaction of 7-(3- hydroxypropoxy)-4-propyl-8-( 1,2,3, 4-tetrahydroquinoline-l-carbonyl)-27 / -chromen-2- one (24) (0.52 g, 1.23 mmol) with tetrabromomethane (0.53 g, 1.6 mmol) and triphenylphosphine (0.42 g, 1.6 mmol) in acetonitrile (50 mL). The reaction mixture was stirred at rt for 48 hours and then worked up according to above-mentioned procedure. Product 34 was obtained in 62 % yield (0.37 g) as a white solid; mp 129-130 °C as a mixture of two rotamers in a ratio 2.2: 1. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR.1H NMR (500 MHz, DMSO) 8 8.06-8.0 (1H, m, CH, B), 7.74 (1H, d, J= 8.9 Hz, CH, B), 7.74 (1H, d, J= 9.0 Hz, CH, A), 7.27-7.18 (3H, m, CH, B), 7.16-7.07 (1H, m, A, 1H, m, CH, B), 7.03 (1H, d, J = 9.0 Hz, CH, A), 6.91 (1H, td, J = 7.7 Hz, J = 1.3 Hz, CH, A), 6.70 (1H, td, J = 7.7 Hz, J= 1.3 Hz, CH, A), 6.55 (1H, dd, J= 7.7 Hz, J= 1.3 Hz, CH, A), 6.23 (1H, s, CH, B), 6.09 (1H, s, CH, A), 4.35-4.24 (2H, m, CH2, B) 4.24-4.16 (1H, m, CH2, A), 4.14-4.06 (1H, m, CH2, A), 4.05-3.95 (1H, m, CH2, A), 3.85-3.77 (1H, m, CH2, A), 3.61-3.55 (2H, m, CH2, A, 2H, m, CH2, B), 3.51-3.44 (1H, m, CH2, B), 3.42-3.34 (1H, m, CH2, B), 2.96- 2.58 (4H, m, CH2, A, 4H, m, CH2, B), 2.32-2.05 (2H, m, CH2, A, 4H, m, CH2, B), 2.02- 1.81 (2H, m, CH2, A), 1.73-1.48 (2H, m, CH2, A, 2H, m, CH2, B), 1.00 (3H, t, J= 13 Hz, CH3, B), 0.91 (3H, t, J= 13 Hz, CH3, A). Isomer A:13C NMR (125 MHz, DMSO) 6 163.2, 159.3, 157.4, 156.7, 150.5, 138.1, 132.8, 128.2, 127.0, 125.4, 125.3, 122.7, 115.1,

[0255] 112.6, 110.7, 108.9, 66.7, 42.6, 32.8, 31.7, 30.9, 26.3, 23.4, 21.3, 13.7. Isomer B:13C NMR (125 MHz, DMSO) 5 163.0, 159.6, 157.4, 156.9, 150.2, 137.4, 130.0, 129.3, 127.0,

[0256] 125.7, 124.7, 124.0, 114.9, 113.2, 111.1, 109.4, 66.6, 46.5, 33.0, 31.7, 30.9, 26.4, 23.5, 21.4, 13.9. Elem. Anal. Calcd for C25H26BrNO4: C, 61.99; H, 5.41; N, 2.89. Found: C, 61.91; H, 5.47; N, 2.70.

[0257] EXAMPLE 45: 4-Butyl-7-(2-bromoethoxy)-8-(l,2,3,4-tetrahydroquinoline-l- carbonyl)-2 / 7-chromen-2-one (35)

[0258] CT N

[0259] The compound was synthesized according to Scheme 2 by reaction of 4-butyl-7- (2-hydroxyethoxy)-8-(l,2,3,4-tetrahydroquinoline-l-carbonyl)-2 / f-chromen-2-one 16 (0.52 g, 1.23 mmol) with tetrabromomethane (0.53 g, 1.6 mmol) and triphenylphosphine (0.42 g, 1.6 mmol) in acetonitrile (50 mL). The reaction mixture was stirred at rt for 48 hours and then worked up according to above-mentioned procedure. 7-(2-Bromoethoxy)- 4-butyl-8-(l,2,3,4-tetrahydroquinolin-l-carbonyl)-2 / 7-chromen-2-one (35) was obtained in 57 % yield (0.34 g) as a white solid; mp 121-122 °C as a mixture of two rotamers in ratio 1.9:1. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR. 'H NMR (500 MHz, DMSO) 5 8.09 (1H, d, J = 8.8 Hz, CH, B), 7.87 (1H, d, J= 8.8 Hz, CH, B), 7.72 (1H, d, J= 9.0 Hz, CH, A), 7.24- 7.18 (3H, m, CH, B), 7.14-7.06 (1H, m, CH, A, 1H, m, CH, B), 7.02 (1H, d, J= 9.0 Hz, CH, A), 6.90 (1H, td, J= 7.7 Hz, J= 1.4 Hz, CH, A), 6.69 (1H, td, J= 7.7 Hz, J= 1.4 Hz, CH, A), 6.65 (1H, dd, J= 7.7 Hz, J= 1.4 Hz CH, A), 6.24 (1H, s, CH, B), 6.10 (1H, s, CH, A), 4.59-4.39 (1H, m, CH2, A, 2H, m, CH2, B), 4.35-4.27 (1H, m, CH2, A) 4.05-3.97 (1H, m, CH2, A), 3.84-3.65 (3H, m, CH2, A, 2H, m, CH2, B), 3.50-3.38 (2H, m, CH2, B), 2.93-2.62 (4H, m, CH2, A, 4H, m, CH2, B), 2.18-2.08 (1H, m CH2, A), 2.01-1.81 (1H, m CH2, A, 2H, m CH2, B), 1.66-1.57 (2H, m CH2, B), 1.57-1.46 (2H, m CH2, A), 1.46-1.37 (2H, m CH2, B), 1.37-1.28 (2H, m CH2, A) 0.93 (3H, t, J= 7.4 Hz, CH3, B), 0.88 (3H, t, J= 7.4 Hz, CH3, A). Isomer A:13C NMR (125 MHz, DMSO) 8 163.0, 159.3, 157.0, 156.9, 150.5, 138.2, 132.9, 128.2, 126.9, 125.4, 125.3, 122.9, 115.2, 112.8, 110.7, 109.0, 69.0, 42.6, 30.8, 30.7, 30.1, 26.3, 23.3, 22.0, 13.9. Isomer B:13C NMR (125 MHz, DMSO) 8 162.8, 159.7, 157.1, 156.3, 150.2, 137.5, 130.1, 129.2, 126.9, 125.6, 124.6, 124.2, 115.0, 113.4, 111.1, 109.5, 69.0, 46.5, 31.3, 30.9, 30.3, 26.5, 23.5, 22.1, 13.9. Elem. Anal. Calcd for C25H26BrNO4: C, 61.99; H, 5.41; N, 2.89. Found: C, 61.77; H, 5.41; N, 2.77.

[0260] EXAMPLE 46: 8-(3,4-Dihydro-2 / / -benzoxazine-4-carbonyl)-7-hydroxy-4- propyl-2 / / -chromen-2-one (36)

[0261] 8-(3,4-Dihydro-27 / -benzoxazine-4-carbonyl)-7-hydroxy-4-propyl-2 / / -chromen-2- one (36) was synthesized according to Scheme 3 by reaction of 7 -hydroxy -2-oxo-4- propyl-2 / 7-chromene-8-carboxylic acid IVc (0.55 g, 2.22 mmol) with 3,4-dihydro-277- 1,4-benzoxazine (0.3 g, 2.22 mmol), Et3N (0.56 g, 0.77 mL, 5.54 mmol) and EDC.HCl (0.64 g, 3.34 mmol) in CH2C12(30 mL) at the presence of DMAP (13 mg, 0.11 mmol).

[0262] The reaction mixture was stirred for 72 hours at rt. The reaction mixture was washed with water (1 x 50 mL), IN HC1 (1 x 50 mL), water (2 x 50 mL) and brine (1 x 50 mL), dried over anhydrous potassium sulfate and concentrated. The product was purified using column chromatography (mobile phase: hexane / EtOAc / acetic acid, 20:20: 1). 8-(3,4- Dihydro-27 / -benzoxazine-4-carbonyl)-7-hydroxy-4-propyl-2 / f-chromen-2-one 36 was obtained in 25 % (0.2 g) as a white solid; mp 195-196 °C as a mixture of two rotamers in a ratio 1.1 : 1. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR. 'H NMR (500 MHz, DMSO) 5 11.05 (1H, bs, OH, A, 1H, bs, OH, B), 8.35-8.30 (1H, m, CH, A), 7.75 (1H, d, J= 8.9 Hz, CH, A), 7.64 (1H, d, J= 8.8 Hz, CH, B), 7.12-7.07 (1H, m, CH, A), 6.99-6.87 (3H, m, CH, A, 1H, m, CH, B), 6.81 (1H, dd, J= 8.1 Hz, J= 1.2 Hz, CH, B), 6.77 (1H, d, J= 8.8 Hz, CH, B), 6.81 (1H, dd, J= 8.1 Hz, J= 1.2 Hz, CH, B), 6.46-6.41 (1H, m, CH, B), 6.15 (1H, s, CH, A), 6.05 (1H, s, CH, B), 4.51-4.43 (1H, m, CH2, B), 4.42-4.34 (1H, m, CH2, B), 4.29-4.19 (2H, m, CH2, A), 4.13-4.06 (1H, m, CH2, B), 4.06-3.99 (1H, m, CH2, B), 3.69-3.56 (2H, m, CH2, A), 2.80-2.58 (2H, m, CH2, A, 2H, m, CH2, B), 1.71-1.50 (2H, m, CH2, A, 2H, m, CH2, B), 0.98 (3H, t, J= 7.4 Hz, CH3, A), 0.93 (3H, t, J= 7.2 Hz, CH3, B). Isomer A:13C NMR (150 MHz, DMSO) 8 163.1, 159.9, 157.2, 157.1, 151.2, 146.2, 126.9, 126.3, 125.7, 125.7, 123.5, 120.1, 117.1, 112.8, 112.6, 110.0, 65.9, 44.6, 33.1, 21.6, 13.9. Isomer B:13C NMR (150 MHz, DMSO) 8 163.3, 159.6, 157.6, 157.1, 151.4, 146.7, 127.1, 125.5, 122.5, 119.3, 116.7, 112.5, 112.1, 111.6, 111.1, 109.6, 66.2, 39.9, 32.9, 31.4, 13.8. Elem. Anal. Calcd for C2IHI9NO5: C, 69.03; H, 5.24; N, 3.83. Found: C, 68.63; H, 5.40; N, 3.60.

[0263] EXAMPLE 47 : 3-Bromo-7-hydroxy-4-propyl-8-(l,2,3,4-tetrahydroquinoline-l- carbonyl)-277-chromen-2-one (37)

[0264] 3-Bromo-7-hydroxy-4-propyl-8-(l,2,3,4-tetrahydroquinoline-l-carbonyl)-2 / f- chromen-2-one (37) was synthesized according to Scheme 3 by reaction of 3-bromo-7- hydroxy-2-oxo-4-propyl-2 / f-chromene-8-carboxylic acid IVe (0.65 g, 2 mmol) with 1,2,3,4-tetrahydroquinoline (1 g, 0.94 mL, 7.5 mmol) and EDC.HC1 (0.88 g, 4.6 mmol) in CH2CI2 (50 mL) at the presence of DMAP (12 mg, 0.1 mmol). The reaction mixture was stirred at rt 48 hours. Then, the reaction mixture was washed with water (1 x 50 mL), IN HC1 (2 x 50 mL), water (2 x 50 mL), and brine (1 x 50 mL). Organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Product was purified by column chromatography (mobile phase: hexane / EtOAc / acetic acid, 20:20:1). 3-Bromo- 7-hydroxy-4-propyl-8-( 1,2, 3, 4-tetrahydroquinoline-l -carbonyl )-27 / -chromen-2-one 37 was obtained in 88 % yield as a light beige solid; mp 215-217 °C as a mixture of two rotamers in a ratio 1.9: 1. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR.1H NMR (500 MHz, DMSO) 5 11.32 (1H, bs, OH, B), 11.20 (1H, bs, OH, A), 8.09 (1H, d, J= 8.4 Hz, CH, B), 7.82 (1H, d, J= 8.4 Hz, CH, B), 7.67 (1H, d, J= 8.8 Hz, CH, A), 7.23-7.17 (2H, m, CH, B), 7.13-7.06 (1H, m, CH, A, 2H, m, CH, B), 6.90 (1H, dt overlapped, J = 7.5 Hz, J= 1.2 Hz, CH, A), 6.87 (1H, d overlapped, J= 8.8 Hz, CH, A), 6.72 (1H, td, J= 7.5 Hz, J= 1.2 Hz, CH, A), 6.64 (1H, d, J = 7.5 Hz, CH, A), 4.11-3.98 (1H, m, CH2, A), 3.75-3.65 (1H, m, CH2, A), 3.51-3.40 (2H, m, CH2, B), 3.01-2.77 (3H, m, CH2, A, 4H, m, CH2, B), 2.77-2.69 (1H, m, CH2, A), 2.17-2.05 (1H, m, CH2, A), 1.98-1.82 (1H, m, CH2, A, 2H, m, CH2, B), 1.66-1.56 (2H, m, CH2, B), 1.56-1.45 (2H, m, CH2, A), 1.04 (3H, t, J= 7.1 Hz, CH3, B), 0.95 (3H, t, J= 7.3 Hz, CH3, A). Isomer A:13C NMR (125 MHz, DMSO- / L) 8 163.4, 158.4, 156.1, 155.6,

[0265] 149.5, 138.4, 133.3, 128.1, 127.4, 125.4, 125.4, 122.7, 113.5, 113.4, 110.6, 107.3, 42.5, 34.1, 26.2, 23.6, 21.5, 14.0. Isomer B:13C NMR (125 MHz, DMSO-LL) 8 163.3, 157.4,

[0266] 156.5, 155.6, 149.4, 137.6, 129.9, 129.4, 127.3, 125.6, 124.7, 124.1, 113.7, 113.3, 111.3, 107.9, 46.5, 34.3, 26.6, 23.5, 21.6, 14.3. Elem. Anal. Calcd for C22H20BrNO4: C, 59.74; H, 4.56: N, 3.17. Found: C, 59.69; H, 4.34; N, 3.09.

[0267] EXAMPLE 48: 3-Ethyl-7-hydroxy-4-methyl-8-(l,2,3,4-tetrahydroquinoline-l- carbonyl)-2 / / -chromen-2-one (38)

[0268] 3-Ethyl-7-hydroxy-4-methyl-8-(l,2,3,4-tetrahydroquinoline-l-carbonyl)-2 / 7- chromen-2-one (38) was synthesized according to Scheme 3 by reaction of 3-ethyl-7- hydroxy-4-methyl-2-oxo-2H-chromene-8-carboxylic acid IVf (0.2 g, 0.8 mmol) with 1,2,3,4-tetrahydroquinoline (0.38 g, 0.36 mL, 2.85 mmol) and EDC.HCl (0.31 g, 1.62 mmol) in CH2C12(25 mL) at the presence of DMAP (5 mg, 0.04 mmol). The reaction mixture was stirred at rt 48 hours and then was worked up according to the above- mentioned procedure. 3-Ethyl-7-hydroxy-4-methyl-8-(l,2,3,4-tetrahydroquinoline-l- carbonyl)-2 / / -chromen-2-one 38 was obtained in 48 % as a white solid; mp 249-251 °C as a mixture of two rotamers in a ratio 1.9: 1. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR. 'H NMR (500 MHz, DMSO) 8 1 1.46 (1H, bs, OH, A, 1H, bs, OH, B), 8.12 (1H, d, J = 8.0 Hz, CH, B), 7.61 (1H, d, J= 8.0 Hz, CH, B), 7.46 (1H, d, J=8.9 Hz, CH, A), 7.20-7.17 (2H, m, CH, B), 7.12-7.05 (1H, m, CH, A, 1H, m, CH, B), 6.91-6.84 (1H, m, CH, A, 1H, m, CH, B), 6.75-6.67 (3H, m, CH, A), 4.11-4.03 (1H, m, CH2, A), 3.70-3.63 (1H, m, CH2, A), 3.47 (2H, t, J= 5.7 Hz, CH2, B), 2.90-2.69 (2H, m, CH2, A, 2H, m, CH2, B), 2.57-2.50 (2H, m, CH2, B), 2.47-2.40 (2H, m, CH2, A), 2.37 (3H, s, CH3, B), 2.26 (3H, s, CH3, A), 2.19- 2.10 (1H, m, CH2, A), 2.00-1.81 (1H, m, CH2, A, 2H, m, CH2, B), 1.03 (3H, t, J= 7.5 Hz, CH3, B), 0.95 (3H, t, J= 7.2 Hz, CH3, A). Isomer A:13C NMR (150 MHz, DMSO) 8 164.3, 160.3, 158.4, 149.4, 146.8, 138.7, 133.2, 127.9, 126.4, 125.3, 125.1, 122.8, 122.2, 113.2, 112.8, 111.3, 42.4, 26.2, 23.6, 20.2, 14.4, 13.1. Isomer B:13C NMR (150 MHz, DMSO) 5 164.2, 160.7, 158.0, 149.4, 147.1, 137.8, 129.7, 129.3, 126.4, 125.5, 124.4, 124.1, 122.4, 113.3, 113.0, 111.7, 46.5, 26.6, 23.4, 20.3, 14.5, 13.2. Elem. Anal. Calcd for C22H21NO4: C, 72.71; H, 5.82; N, 3.85. Found: C, 72.32; H, 6.14; N, 3.47.

[0269] EXAMPLE 49: 7-Hydroxy-6-(l,2,3,4-tetrahydroquinoline-l-carbonyl)-2,3- dihydrocyclopenta[c]chromen-4(17 / )-one (39)

[0270] 7-Hydroxy-6-( 1 ,2,3 ,4-tetrahydroquinoline- 1 -carbonyl)-2,3-dihydrocyclopenta[c] chromen-4(177)-one (39) was synthesized according to Scheme 3 by reaction of 7- hydroxy-4-oxo-l,2,3,4-tetrahydrocyclopenta[c]chromene-6-carboxylic acid IVg (0.3 g, 1.22 mmol) with 1,2,3,4-tetrahydroquinoline (0.57 g, 0.54 mL, 4.23 mmol) and EDC.HC1 (0.47 g, 2.45 mmol) in CH2Q2 (30 mL) at the presence of DMAP (7 mg, 0.057 mmol). The reaction mixture was stirred at rt for 48 hours and then was worked up according to the above-mentioned procedure. 7-Hydroxy-6-(l,2,3,4-tetrahydroquinoline-l-carbonyl)- 2,3-dihydrocyclopenta[c]chromen-4(177)-one 39 was obtained in 50 % yield (0.22 g) as a white solid; mp 265-267 °C as a mixture of two rotamers in a ratio 2.3: 1. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR ' H NMR (500 MHz, DMSO-c / 6) 5 11.18 (1H, bs, A, 1H, bs, B), 8.11 (1H, d, J = 8.4 Hz, CH, B), 7.48 (1H, d, J= 8.4 Hz, CH, B), 7.32 (1H, d, J= 8.6 Hz, CH, A), 7.24- 7.16 (2H, m, CH, B), 7.13-7.04 (1H, m, CH, A, 1H, m, CH, B), 6.96-6.86 (1H, m, CH, A, 1H, m, CH, B), 6.77-6.64 (3H, m, CH, A), 4.14-4.03 (1H, m, CH2, A), 3.73-3.62 (1H, m, CH2, A), 3.51-3.37 (2H, m, CH2, B), 3.11-2.99 (2H, m, CH2, B), 2.99-2.90 (2H, m, CH2, A), 2.90-2.68 (2H, m, CH2, A, 4H, m, CH2, B), 2.68-2.59 (2H, m CH2, A), 2.20-1.81 (4H, m CH2, A, 4H, m CH2, B). Isomer A:13C NMR (125 MHz, DMSO-t / 6) 5 164.0, 158.7, 157.8, 156.9, 151.3, 138.6, 133.3, 128.1, 126.6, 125.4, 125.3, 122.8, 122.8, 113.6, 112.6, 110.1, 42.5, 31.8, 30.1, 26.2, 23.6, 22.1. Isomer B:13C NMR (125 MHz, DMSO) 5 163.8, 159.0, 157.1, 156.9, 151.2, 137.7, 129.8, 129.3, 126.6, 125.5, 124.6, 124.2, 122.4, 113.2, 113.0, 110.7, 46.5, 32.0, 30.2, 26.6, 23.4, 22.2. Elem. Anal. Calcd for C22H21NO5 (hydrate) C, 69.65; H, 5.58; N, 3.69. Found: C, 70.03; H, 5.45; N, 3.50.

[0271] EXAMPLE 50: 3-Hydroxy-4-(l,2,3,4-tetrahydroquinoline-l-carbonyl)-7,8,9,10- tetrahydro-67 / -benzo[c]chromen-6-one (40)

[0272] 3-Hy droxy-4-( 1,2,3, 4-tetrahydroquinoline-l-carbonyl)-7, 8,9,10-tetrahydro-677- benzo[c]chromen-6-one (40) was synthesized according to Scheme 3 by reaction of 3- hydroxy-6-oxo-7,8,9, l 0-tetrahydro-6 / / -benzo[c]chromene-4-carboxylic acid IVh (1 g, 3.84 mmol) with 1,2,3,4-tetrahydroquinoline (1.79 g, 1.7 mb, 13.44 mmol) and EDC.HC1 (1.47 g, 7.67 mmol) in CH2CI2 (70 mL) at the presence of DMAP (23 mg, 0.19 mmol). The reaction mixture was stirred at rt for 72 hours and then was worked up according to the above-mentioned procedure. 3-Hydroxy-4-(l,2,3,4-tetrahydroquinoline-l-carbonyl)- 7,8,9,10-tetrahydro-6 / / -benzo[c]chromen-6-one 40 was obtained in 38 % (0.56 g) yield as a white solid; mp 259-261 °C as a mixture of two rotamers in a ratio 2.1 : 1. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR.JH NMR (500 MHz, DMSO) 5 10.78 (1H, bs, OH, A, 1H, bs, OH, B), 8.11 (1H, d, J= 8.8 Hz, CH, B), 7.60 (1H, d, J= 8.8 Hz, CH, B), 7.44 (1H, d, J = 8.8 Hz, CH, A), 7.24-7.17 (2H, m, CH, B), 7.13-7.05 (1H, m, CH, A, 1H, m, CH, B), 6.95-6.87 (1H, m, CH, A, 1H, m, CH, B), 6.77-6.66 (3H, m, CH, A), 4.11-4.01 (1H, m, CH2, A), 3.73-3.62 (1H, m, CH2, A), 3.51-3.38 (2H, m, CH2, B), 2.90-2.68 (2H, m, CH2, A, 4H, m, CH2, B), 2.68-2.60 (2H, m, CH2, A), 2.43-2.35 (2H, m CH2, B), 2.35-2.22 (2H, m, CH2, A), 2.19-2.07 (1H, m, CH2, A), 2.01-1.81 (1H, m, CH2, A, 2H, m, CH2, B), 1.81- 1.58 (4H, m CH2, A, 4H, m CH2, B). Isomer A:13C NMR (125 MHz, DMSO) 8 163.9, 160.3, 156.8, 149.1, 147.9, 138.6, 133.2, 128.1, 125.4, 125.3, 125.2, 122.8, 118.6, 113.3, 112.3, 11 1.6, 42.5, 26.2, 24.8, 23.6, 23.5, 21.3, 20.9. Isomer B:13C NMR (125 MHz, DMSO) 8 163.7, 160.6, 155.9, 149.0, 148.0, 137.7, 129.8, 129.3, 125.5, 125.2, 124.6, 124.2, 119.1, 113.0, 112.7, 112.2, 46.5, 26.6, 24.9, 23.7, 23.4, 21.4, 21.0. Elem. Anal. Calcd for C23H21NO4: C, 73.58; H, 5.64; N, 3.73. Found: C, 73.21; H, 5.60; N, 3.57.

[0273] EXAMPLE 51: 3-Hydroxy-4-(l,2,3,4-tetrahydroquinoline-l-carbonyl)-

[0274] 8,9, 10,1 l-tetrahydrocyclohepta[c]chromen-6(777)-one (41)

[0275] 3-Hydroxy-4-(l,2,3,4-tetrahydroquinoline-l-carbonyl)-8,9, 10,11- tetrahydrocyclohepta[c]chromen-6(77 / )-one (41) was synthesized according to Scheme 3 by reaction of 3-hydroxy-6-oxo-6,7,8,9, 10,1 l-hexahydrocyclohepta[c]chromene-4- carboxylic acid IVi (45 mg, 0.16 mmol) with 1,2,3,4-tetrahydroquinoline (76 mg, 71.6 pL, 0.57 mmol) and EDC.HC1 (63 mg, 0.33 mmol) in CH2Q2 (20 mb) at the presence of DMAP (few crystals). The reaction mixture was stirred at rt for 72 hours and then was worked up according to the above-mentioned procedure. 3-Hydroxy-4-(l,2,3,4- tetrahydroquinoline-l-carbonyl)-8,9,10, l l-tetrahydrocyclohepta[c]chromen-6(777)-one 41 was obtained in 32 % yield (15 mg) as a yellowish oil-like compound as a mixture of two rotamers in a ratio 2:1. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR.1H NMR (500 MHz, DMSO) 8 10.81 (1H, bs, OH, A, 1H, bs, OH, B), 8.11 (1H, d, .7= 8.5 Hz, CH, B), 7.79 (1H, d, J = 8.5 Hz, CH, B), 7.62 (1H, d, J= 8.9 Hz, CH, A), 7.23-7.17 (2H, m, CH, B), 7.13-7.05 (1H, m, CH, A, 1H, m, CH, B), 6.92 (1H, d overlapped, J= 8.9 Hz, CH, A), 6.90 (1H, t overlapped, J= 7.4 Hz, CH, B), 6.75-6.70 (2H, m, CH, A), 6.65 (1H, d, J= 7.9 Hz, CH, A), 4.12-4.02 (1H, m, CH2, A), 3.72-3.62 (1H, m, CH2, A), 3.51-3.41 (2H, m, CH2, B), 3.04-2.67 (5H, m, CH2, A, 6H, m, CH2, B), 2.62-2.53 (1H, m, CH2, A), 2.20-2.09 (1H, m, CH2, A), 1.98-1.26 (7H, m, CH2, A, 8H, m, CH2, B). Isomer A:13C NMR (125 MHz, DMSO) 5 164.0, 160.7, 157.2, 154.4, 149.8, 138.6, 133.2, 128.0, 126.1 , 125.3, 125.3, 123.5, 122.8, 113.5, 112.4, 111.3, 42.5, 31.5, 27.5, 26.2, 26.0, 25.6, 24.9, 23.6. Isomer B:13C NMR (125 MHZ, DMSO) 8 163.7, 161.0, 156.3, 154.6, 149.6, 137.7, 129.8, 129.3, 126.1, 125.5, 124.6, 124.1, 124.0, 113.3, 112.8, 112.0, 46.5, 31.6, 27.7, 26.6, 26.2, 25.6, 24.9, 23.4.

[0276] EXAMPLE 52

[0277] 3-Ethyl-7-(2-hydroxyethoxy)-4-methyl-8-(l,2,3,4-tetrahydroquinoline-l- carbonyl)-2 / f-chromen-2-one (42):

[0278] II

[0279] CT

[0280] N

[0281] 3-Ethyl-7-(2-hydroxyethoxy)-4-methyl-8-(l,2,3,4-tetrahydroquinoline-l- carbonyl)-277-chromen-2-one (42) was synthesized according to Scheme 3 by reaction of 3-ethyl-7-hydroxy-4-methyl-8-(l,2,3,4-tetrahydroquinoline-l-carbonyl)-27f-chromen-2- one (38) (0.57 g, 1.57 mmol) with 2-bromoethan-l-ol (0.98 g, 0.56 mb, 7.84 mmol) and potassium carbonate (1.1 g, 7.84 mmol) in DMF (10 mL). The reaction was heated to 75 °C for 12 hours. After cooling to rt, the reaction mixture was diluted with EtOAc (100 mL), washed with water (3 * 75 mL) and brine (1 x 100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Product was purified by column chromatography (mobile phase: hexane / EtOAc / acetic acid, 20:20: 1). 3-Ethyl-7-(2- hydroxyethoxy)-4-methyl-8-( l ,2,3,4-tetrahydroquinoline- l -carbonyl )-2 / / -chromen-2-one 42 was obtained in 45 % yield (0.29 g) as a white solid; mp 155-157 °C as a mixture of two rotamers in a ratio 2.2: 1. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR. . 'H NMR (600 MHz, DMSO) 8 8.08- 8.05 (1H, m, CH, B), 7.77 (1H, d, J = 8.9 Hz, CH, B), 7.62 (1H, d, J= 9.0 Hz, CH, A), 7.21-7.14 (3H, m, CH, B), 7.10-7.02 (1H, m, CH, A, 1H, m, CH, B), 6.95 (1H, d, J= 9.0 Hz, CH, A), 6.86 (1H, td, J= 7.9 Hz, J= 1.4 Hz, CH, A), 6.65 (1H, td, J= 7.9 Hz, J= 1.4 Hz, CH, A), 6.59 (1H, dd, J= 7.9 Hz, J= 1.4 Hz, CH, A), 4.18-4.12 (2H, m, CH2, B), 4.06- 4.00 (1H, m, CH2, A), 3.95-3.89 (1H, m, CH2, A), 3.89-3.84 (1H, m, CH2, A), 3.83-3.76 (1H, m, CH2, A), 3.68-3.63 (2H, m, CH2, B), 3.62-3.56 (2H, m, CH2, A), 3.47-3.30 (2H, m, CH2, B), 2.88-2.80 (1H, m, CH2, A), 2.79-2.71 (1H, m, CH2, A, 2H, m, CH2, B), 2.56- 2.50 (2H, m, CH2, B), 2.49-2.42 (2H, m, CH2, A), 2.39 (3H, s, CH3, B), 2.29 (3H, s, CH3, A), 2.13-2.04 (1H, m, CH2, A), 1.97-1.85 (1H, m, CH2, A, 1H, m, CH2, B), 1.84-1.77 (1H, m, CH2, B), 1.01 (3H, t, J= 7.4 Hz, CH3, B), 0.94 (3H, t, J= 7.5 Hz, CH3, A). Isomer A:13C NMR (150 MHz, DMSO) 5 163.4, 160.1, 157.0, 148.8, 146.5, 138.3, 133.0, 128.1, 126.9, 125.4, 125.3, 124.1, 122.9, 114.6, 113.7, 109.0, 70.7, 59.4, 42.6, 26.3, 23.4, 20.3,

[0282] 14.5, 13.0. Isomer B:13C NMR (150 MHz, DMSO) 8 163.2, 160.3, 156.4, 148.5, 146.7, 137.7, 130.0, 129.3, 126.9, 125.6, 124.6, 124.5, 124.1, 114.4, 114.4, 109.5, 70.9, 59.6, 46.5,

[0283] 26.5, 23.3, 20.5, 14.6, 13.1. Elem. Anal. Calcd for C24H25NO5: C, 70.75; H, 6.18; N, 3.44. Found: C, 70.36; H, 6.13; N, 3.21.

[0284] EXAMPLE 53

[0285] 7-(2-Bromoethoxy)-3-ethyl-4-methyl-8-(l, 2, 3, 4-tetrahydroquinoline-l -carbonyl)- 2 / 7-chromen-2-one (43):

[0286] 7-(2 -Bromoethoxy)-3-ethyl-4-methyl-8-(l, 2, 3, 4-tetrahydroquinoline-l -carbonyl)- 2 / / -chromen-2-one (43) was synthesized according to Scheme 4. A-Bromosuccinimide (0.18 g, 1 mmol) was added to a solution of 3-ethyl-7-(2-hydroxyethoxy)-4-methyl-8- (l,2,3,4-tetrahydroquinoline-l-carbonyl)-2A-chromen-2-one (42) (0.2 g, 0.49 mmol) and triphenylphosphine (0.26 g, 1 mmol) in CH2C12(20 mL). The reaction mixture was stirred at rt for 30 minutes, washed with water (1 * 20 mL) and brine (1 * 20 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Product was purified by column chromatography (mobile phase: hexane / EtOAc, 2: 1). 7-(2- Bromoethoxy)-3-ethyl-4-methyl-8-(l,2,3,4-tetrahydroquinoline-l -carbonyl)-2 / / - chromen-2-one (43) was obtained in 87 % (0.2 g) as a white solid; mp 80-82 °C as a mixture of two rotamers in a ratio 2: 1. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR.!H NMR (600 MHz, DMSO) 5 8.07-8.04 (1H, m, CH, B), 7.79 (1H, d, J= 9.0 Hz, CH, B), 7.65 (1H, d, J= 9.0 Hz, CH, A), 7.20-7.14 (3H, m, CH, B), 7.10-7.03 (1H, m, CH, A, 1H, m, CH, B), 6.97 (1H, d, J = 9.0 Hz, CH, A), 6.87 (1H, td, J= 7.6 Hz, J= 1.2 Hz, CH, A), 6.66 (1H, td, J= 7.6 Hz, J = l.2 Hz, CH, A), 6.62 (1H, dd J= 7.6 Hz, J= 1.2 Hz, CH, A), 4.55-4.41 (2H, m, CH2, B), 4.42-4.33 (1H, m, CH2, A), 4.26-4.18 (1H, m, CH2, A), 3.98-3.90 (1H, m, CH2, A), 3.85- 3.58 (3H, m, CH2, A, 2H, m, CH2, B), 3.46-3.36 (2H, m, CH2, B), 2.92-2.81 (1H, m, CH2, A), 2.81-2.70 (1H, m, CH2, A, 2H, m, CH2, B), 2.57-2.50 (2H, m, CH2, B), 2.50-2.42 (2H, m, CH2, A), 2.39 (3H, s, CH3, B), 2.29 (3H, s, CH3, A), 2.14-2.05 (1H, m, CH2, A), 1.99- 1.78 (1H, m, CH2, A, 2H, m, CH2, B), 1.01 (3H, t, J= 7.5 Hz, CH3, B), 0.95 (3H, t, J= 7.4 Hz, CH3, A). Isomer A:13C NMR (150 MHz, DMSO) 5 163.1, 160.0, 156.1, 148.9, 146.5, 138.2, 132.9, 128.2, 127.0, 125.4, 125.4, 124.4, 122.9, 114.7, 114.2, 108.9, 68.9, 42.7, 30.9, 26.4, 23.4, 20.4, 14.6, 13.0. Isomer B:13C NMR (150 MHz, DMSO) 5 162.9, 160.3, 155.4, 148.5, 146.7, 137.6, 130.1, 129.2, 127.0, 125.6, 124.8, 124.7, 124.2, 114.8, 114.5, 109.4, 68.9, 46.5, 31.4, 26.5, 23.5, 20.5, 14.7, 13.1. Elem. Anal. Calcd for C24H24BrNO4: C, 61.29; H, 5.14; N, 2.98. Found: C, 60.93; H, 5.15; N, 2.78.

[0287] EXAMPLE 54

[0288] 3-Ethyl-4-methyl-7-(2-(4-methylpiperazin-l-yl)ethoxy)-8-(l,2,3,4- tetrahydroqui noli ne- 1 -carbonyl )-2 / / -chromen-2-one (44):

[0289] N 1 3-Ethyl-4-methyl-7-(2-(4-methylpiperazin-l-yl)ethoxy)-8-(l,2,3,4- tetrahydroqui noli nc-1 -carbonyl )-27 / -chromcn-2-onc (44) was synthesized according to Scheme 4 by reaction of 7-(2-bromoethoxy)-3-ethyl-4-methyl-8-(l,2,3,4- tetrahydroquinoline-l-carbonyl)-2 / / -chromen-2-one (43) (0.13 g, 0.28 mmol) and N- methylpiperazine (0.085 g, 0.09 mL, 0.85 mmol) and potassium carbonate (0.12 g, 0.86 mmol) in DMF (5 mL). The reaction mixture was heated to 60 °C for 5 hours. The reaction mixture was diluted with EtOAc (50 mL), washed with water (3 x 50 mL) and brine (1z50 mL), dried over anhydrous sodium sulfate and concentrated. Product was suspended with diethyl ether (10 mL), filtered off and obtained in high quality without additional purification. 3-Ethyl-4-methyl-7-(2-(4-methylpiperazin-l-yl)ethoxy)-8-(l,2,3,4- tetrahydroquinoline-l-carbonyl)-277-chromen-2-one (44) was obtained in 89 % (0.12 g) as a white solid; mp 58-60 °C as a mixture of two rotamers in a ratio 1.6:1. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR.XH NMR (600 MHz, DMSO) 8 8.05-8.02 (1H, m, CH, B), 7.78 (1H, d, J= 8.9 Hz, CH, B), 7.63 (1H, d, J= 9.0 Hz, CH, A), 7.19-7.13 (3H, m, CH, B), 7.10-7.04 (1H, m, CH, A, 1H, m, CH, B), 6.96 (1H, d, J = 9.0 Hz, CH, A), 6.87 (1H, td, J= 7.7 Hz, J= 1.2 Hz, CH, A), 6.66 (1H, td, J= 7.7 Hz, J= 1.2 Hz, CH, A), 6.56 (1H, dd, J= 7.7 Hz, J= 1.2 Hz, CH, A), 4.24-4.16 (2H, m, CH2, B), 4.14-4.07 (1H, m, CH2, A), 3.96-3.85 (2H, m, CH2, A), 3.85-3.78 (1H, m, CH2, A), 3.46-3.40 (1H, m, CH2, B), 3.39-3.32 (1H, m, CH2, B), 2.89-2.81 (1H, m, CH2, A), 2.80-2.71 (1H, m, CH2, A, 2H, m, CH2, B), 2.68-2.57 (2H, m, CH2, B), 2.57-2.03 (13H, m, CH2, A, 10H, m, CH2, B), 2.39 (3H, s, CH3, B), 2.29 (3H, s, CH3, A), 2.09 (3H, s, CH3, A), 2.02 (3H, s, CH3, B), 1.97-1.78 (1H, m, CH2, A, 2H, m, CH2, B), 1.01 (3H, t, J= 7.5 Hz, CH3, B), 0.95 (3H, t, J= 7.4 Hz, CH3, A). Isomer A:13C NMR (150 MHz, DMSO) 8 163.3, 160.1, 156.7, 148.9, 146.5, 138.3, 132.9, 128.1, 126.9, 125.3, 125.3, 124.1, 122.7, 114.6, 113.9, 108.8, 66.9, 56.3, 54.8, 53.2, 45.9, 42.6, 26.4,

[0290] 23.4, 20.3, 14.5, 13.0. Isomer B:13C NMR (150 MHz, DMSO) 8 163.1, 160.3, 156.1,

[0291] 148.4, 146.7, 137.6, 129.8, 129.3, 126.9, 125.5, 124.6, 124.5, 124.0, 114.4, 114.3, 109.1, 67.6, 56.5, 54.8, 53.2, 46.5, 45.9, 26.5, 23.4, 20.5, 14.6, 13.1. Elem. Anal. Calcd for C29H37N3O5 (monohydrate): C, 68.62; H, 7.35; N, 8.28. Found: C, 69.01; H, 7.17; N, 8.10.

[0292] EXAMPLE 55 3-(2-Hydroxyethoxy)-4-(l,2,3,4-tetrahydroquinoline-l-carbonyl)-7,8,9, 10- tetrahydro-677-benzo[c]chromen-6-one (45):

[0293] J

[0294] C> O

[0295] 3-(2-Hydroxyethoxy)-4-(l,2,3,4-tetrahydroquinoline-l-carbonyl)-7,8,9, 10- tetrahydro-67f-benzo[c]chromen-6-one (45) was synthesized according to Scheme 3 by reaction of 3-hydroxy-4-(l,2,3,4-tetrahydroquinoline-l-carbonyl)-7,8,9, 10-tctrahydro-6 / 7- benzo[c]chromen-6-one (40) (0.5 g, 1.33 mmol) with 2-bromoethan-l-ol (0.83 g, 0.48 mL, 6.64 mmol) and potassium carbonate (0.92 g, 6.65 mmol) in DMF (15 mL). The reaction was heated to 75 °C for 24 hours. After cooling to rt, the reaction mixture was diluted with EtOAc (100 mL), washed with water (3 * 75 mL) and brine (1 x 100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Product was purified by column chromatography (mobile phase: CHCh / MeOH, 30: 1). 3-(2-Hydroxyethoxy)-4- (l,2,3,4-tetrahydroquinoline-l-carbonyl)-7,8,9,10-tetrahydro-67f-benzo[c]chromen-6-one (45) was obtained in 58 % yield (0.33 g) as a white solid; mp 85-87 °C as a mixture of two rotamers in a ratio 2.4: 1. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR.JH NMR (500 MHz, DMSO) 5 8.12-8.09 (1H, m, CH, B), 7.73 (1H, d, J = 8.9 Hz, CH, B), 7.59 (1H, d, J = 8.9 Hz, CH, A), 7.24- 7.17 (3H, m, CH, B), 7.13-7.06 (1H, m, CH, A, 1H, m, CH, B), 6.98 (1H, d, J= 8.9 Hz, CH, A), 6.90 (1H, td, J= 7.8 Hz, J= 1.4 Hz, CH, A), 6.70 (1H, td, J= 7.8 Hz, J= 1.4 Hz, CH, A), 6.65 (1H, dd, J = 7.8 Hz, J = 1.4 Hz, CH, A), 4.87 (1H, d, J= 5.1 Hz, OH, A), 4.83 (1H, d, J= 5.3 Hz, OH, B), 4.18 (2H, t, J= 5.3 Hz, CH2, B), 4.10-4.00 (1H, m, CH2, A), 3.99-3.79 (3H, m, CH2, A), 3.68 (2H, q, J= 5.3 Hz, CH2, B), 3.63 (2H, q, J= 5.1 Hz, CH2, A), 3.50-3.35 (2H, m, CH2, B), 2.93-2.66 (4H, m, CH2, A, 4H, m, CH2, B), 2.40 (2H, t, ,7=6.1 Hz, CH2, B), 2.34 (2H, t, .7 = 6.1 Hz, CH2, A), 2.17-2.07 (1H, m, CH2, A), 2.02- 1.62 (5H, m, CH2, A, 6H, m, CH2, B). Isomer A:13C NMR (125 MHz, DMSO) 5 163.4, 160.2, 156.9, 148.7, 147.6, 138.3, 132.9, 128.1 , 125.5, 125.4, 125.4, 122.9, 119.9, 114.7,

[0296] 113.2, 108.9, 70.7, 59.4, 42.6, 26.3, 24.7, 23.6, 23.4, 21.2, 20.9. Isomer B:13C NMR (125 MHz, DMSO) 5 163.2, 160.4, 156.2, 148.3, 147.7, 137.7, 130.0, 129.3, 125.6, 125.5, 124.6,

[0297] 124.2, 120.3, 114.5, 113.8, 109.4, 70.9, 59.6, 46.4, 26.5, 24.9, 23.8, 23.3, 21.3, 21.0. Elem. Anal. Calcd for C25H25NO5: C, 71.58; H, 6.01; N, 3.34. Found: C, 71.22; H, 6.34; N, 3.19.

[0298] Example 56

[0299] 3-(2-Bromoethoxy)-4-(l,2,3,4-tetrahydroquinoline-l-carbonyl)-7,8,9, 10- tetrahydro-6 / / -benzo[c]chromen-6-one (46):

[0300] N

[0301] Product was synthesized according to Scheme 4. To the solution of 3-(2- hydroxyethoxy)-4-(l, 2,3, 4-tetrahydroquinoline-l-carbonyl)-7, 8,9,10-tetrahydro-677- benzo[c]chromen-6-one (45) (0.41 g, 0.98 mmol) and triphenylphosphine (0.52 g, 1.98 mmol) in CH2CI2 (75 mL), NBS (0.35 g, 1.97 mmol) was added. The reaction mixture was stirred at rt for 30 min, washed with water (2 x 50 mL) and brine (1 x 50 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Product was purified by column chromatography (mobile phase: hexane / EtOAc, 2: 1). 3-(2- Bromoethoxy)-4-(l,2,3,4-tetrahydroquinoline-l-carbonyl)-7,8,9,10-tetrahydro-6 / 7- benzo[c]chromen-6-one (46) was obtained in 90 % yield (0.42 g) as a while solid; mp 195- 197 °C as a mixture of two rotamers in a ratio 1.9:1. The rotamers in the mixture are cis- trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR. 'H NMR (600 MHz, DMSO) 5 8.07-8.04 (1H, m, CH, B), 7.72 (1H, d, J= 8.9 Hz, CH, B), 7.57 (1H, d, J = 9.0 Hz, CH, A), 7.20-7.13 (3H, m, CH, B), 7.09-7.05 (1H, m, CH, A, 1H, m, CH, B), 6.96 (1H, d, J = 9.0 Hz, CH, A), 6.88 (1H, dt, J = 7.3 Hz, J = 1.5 Hz, CH, A), 6.71- 6.61 (2H, m, CH, A), 4.53-4.41 (2H, m, CH2, B), 4.39-4.32 (1H, m, CH2, A), 4.25-4.18 (1H, m, CH2, A), 3.97-3.91 (1H, m, CH2, A), 3.84-3.59 (3H, m, CH2, A, 2H, m, CH2, B), 3.46-3.35 (2H, m, CH2, B), 2.90-2.81 (1H, m, CH2, A), 2.80-2.71 (1H, m, CH2, A, 4H, m, CH2, B), 2.71-2.64 (2H, m, CH2, A), 2.41-2.34 (2H, m, CH2, B), 2.34-2.27 (2H, m, CH2, A), 2.14-2.04 (1H, m, CH2, A), 1.99-1.78 (1H, m, CH2, A, 2H, m, CH2, B), 1.78-1.59 (4H, m, CH2, A, 4H, m, CH2, B). Isomer A:13CNMR (150 MHz, DMSO) 8 163.4, 160.5, 156.3, 149.1, 147.9, 138.6, 133.2, 128.6, 126.0, 125.8, 125.8, 123.2, 122.6, 115.2, 114.0, 109.2, 69.2, 43.0, 31.2, 26.7, 25.1, 24.0, 23.8, 21.5, 21.2. Isomer B:13C NMR (150 MHz, DMSO) 8 163.3, 160.7, 155.6, 148.7, 148.0, 138.0, 130.4, 129.5, 125.9, 125.9, 125.0, 124.6, 121.0, 114.9, 114.6, 109.7, 69.2, 46.9, 31.7, 26.9, 25.3, 24.1, 23.9, 21.7, 21.3. Elem. Anal. Calcd for C25H24BrNO4: C, 62.25; H, 5.02; N, 2.90. Found: C, 62.47; H, 5.15; N, 2.72.

[0302] EXAMPLE 57

[0303] 3-(2-(4-Methylpiperazin-l-yl)ethoxy)-4-(l,2,3,4-tetrahydroquinoline-l-carbonyl)-

[0304] 7,8,9,10-tetrahydro-6J7-benzo[c]chromen-6-one (47):

[0305] N I

[0306] 3-(2-(4-Methylpiperazin-l-yl)ethoxy)-4-(l,2,3,4-tetrahydroquinoline-l-carbonyl)-

[0307] 7.8.9.10-tetrahydro-67 / -benzo[c]chromen-6-one (47) was synthesized according to Scheme 4 by reaction of 3-(2-bromoethoxy)-4-(l,2,3,4-tetrahydroquinoline-l-carbonyl)-

[0308] 7.8.9.10-tetrahydro-6 / 7-benzo[c]chromen-6-one (46) (0.15 g, 0.31 mmol) with N- methylpiperazine (0.06 g, 0.07 mL, 0.6 mmol) and potassium carbonate (0.086 g, 0.6 mmol) in DMF (5 mL). The reaction mixture was heated to 60 °C for 6 hours. The reaction mixture was diluted with EtOAc (50 mL), washed with water (3 x 50 mL) and brine (1 x 50 mL), dried over anhydrous sodium sulfate and concentrated. Product was suspended with diethyl ether (10 mL), filtered off and obtained in high quality without additional purification. 3-(2-(4-Methylpiperazin-l-yl)ethoxy)-4-(l,2,3,4-tetrahydroquinoline-l- carbonyl)-7,8,9, 10-tetrahydro-6 / / -benzo[c]chromen-6-one (47) was obtained in 77 % yield (0.12 g) as a white solid; mp 73-75 °C as a mixture of two rotamers in a ratio 1.7: 1. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR. 'H NMR (600 MHz, DMSO) 8 8.04 (1H, dd, J= 8.7 Hz, J= 1.3 Hz, CH, B), 7.70 (1H, d, J= 8.9 Hz, CH, B), 7.55 (1H, d, J = 9.0 Hz, CH, A), 7.20-7.12 (3H, m, CH, B), 7.10-7.04 (1H, m, CH, A, 1H, m, CH, B), 6.95 (1H, d, J = 9.0 Hz, CH, A), 6.88 (1H, td, J= 7.7 Hz, J= 1.3 Hz, CH, A), 6.67 (1H, td, J= 7.7 Hz, J= 1.3 Hz, CH, A), 6.59 (1H, dd, J= 7.7 Hz, J= 1.3 Hz CH, A), 4.25-4.16 (2H, m, CH2, B), 4.13-4.07 (1H, m, CH2, A), 3.96-3.85 (2H, m, CH2, A), 3.85-3.78 (1H, m, CH2, A), 3.46-3.40 (1H, m, CH2, B), 3.37-3.31 (1H, m, CH2, B), 2.89-2.56 (4H, m, CH2, A, 6H, m, CH2, B), 2.56-2.00 (12H, m CH2, A, 11H, m CH2, B), 2.08 (3H, s, CH3, A), 2.02 (3H, s, CH3, B), 1.98-1.59 (6H, m CH2, A, 5H, m CH2, B). Isomer A:13C NMR (150 MHz, DMSO) 8 163.3, 160.2, 156.5, 148.7, 147.6, 138.3, 132.9, 129.8, 125.5, 125.4, 125.4, 122.8, 119.9, 114.7, 113.2, 108.8, 66.9, 56.3, 54.9, 53.3, 45.9, 42.5, 26.4, 24.7, 23.6, 23.4, 21.2, 20.9. Isomer B:13C NMR (150 MHz, DMSO) 6 163.1, 160.4, 156.0, 148.3, 147.7, 137.6, 129.3, 128.2, 125.4, 125.4, 124.6, 124.0, 120.3, 114.3, 113.8, 109.1, 67.6, 56.5, 54.8, 53.2, 46.5, 45.9, 26.5, 24.9, 23.7, 23.4, 21.3, 21.0. Elem. Anal. Calcd for C30H35N3O4: C, 71.83; H, 7.03; N, 8.38. Found: C, 71.45; H, 6.93; N, 8.01.

[0309] EXAMPLE 58

[0310] 4-(4-Ethoxy-4-oxobutyl )-7-hy droxy -2-oxo-2H-chromene-8 -carboxyl i c aci d (IVk) (intermediate compound):

[0311] The product was prepared according to Scheme 1. Diethyl 3-oxopimelate (2.24 g, 2.1 mL, 9.73 mmol) was added dropwise to a suspension of 2,6-dihydroxybenzoic acid (1 g, 6.49 mmol) and cone. H2SO4(3.31 g, 1.8 mL, 32.4 mmol). The reaction mixture was stirred at rt overnight and then poured into ice water (75 mL). The precipitation was fdtered off, suspended with EtOAc (15 mL) and fdtered off. The solid was dissolved in acetone and product was purified by column chromatography (mobile phase: hexane / EtOAc / acetic acid, 10:20: 1). 4-(4-Ethoxy-4-oxobutyl)-7-hydroxy-2-oxo-2 / 7-chromene-8-carboxylic acid (IVk) was obtained in 30 % yield (0.62 g) as a beige solid; mp 171-172 °C. 'H NMR (600 MHz, DMSO-A) 8 7.71 (dd, .7= 8.9, 1.1 Hz, 1H), 6.88 (dd, J= 8.9, 1.2 Hz, 1H), 6.10 (d, J= 1.2 Hz, 1H), 4.02 (qd, J = 7.1, 1.1 Hz, 2H), 2.73 (t, J = 7.7 Hz, 2H), 2.38 (td, J = 7.2, 1.1 Hz, 2H), 1.84 - 1.77 (m, 2H), 1.14 (td, J= 7.1, 1.1 Hz, 3H).13C NMR (151 MHz, DMSO-ZA) 6 173.03, 166.44, 160.12, 158.77, 156.84, 152.04, 127.50, 113.31, 111.39, 111.36, 110.52, 60.41, 33.33, 30.90, 24.01, 14.62. Elem. Anal. Calcd for Ci6Hi6O7: C, 60.0; H, 5.04. Found: C, 59.66; H, 5.34.

[0312] EXAMPLE 59

[0313] Ethyl 4-(7-hydroxy-2-oxo-8-(l,2,3,4-tetrahydroquinoline-l-carbonyl)-2H- chromen-4-yl) butanoate (48):

[0314] Ethyl 4-(7-hydroxy-2-oxo-8-(l,2,3,4-tetrahydroquinoline-l-carbonyl)-2H- chromen-4-yl) butanoate (48) was synthesized according to Scheme 1 by reaction of 4-(4- ethoxy-4-oxobutyl)-7-hydroxy-2-oxo-2H-chromene-8-carboxylic acid (IVk) (0.3 g, 0.94 mmol) with 1,2,3,4-tetrahydroquinoline (0.44 g, 0.41 mL, 3.3 mmol) and EDCxHCl (0.36 g, 1.88 mmol) in CH2CI2 (30 mL) in the presence of DMAP (6 mg, 0.049 mmol). The reaction mixture was stirred at rt for 72 hours. Then, the reaction mixture was washed with water (1 x 30 mL), IN HC1 (2 * 30 mL), and brine (2 x 30 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The product was purified by column chromatography (mobile phase: hexane / EtOAc / acetic acid, 20: 10: 1). Ethyl 4-(7-hydroxy-2-oxo-8-(l,2,3,4-tetrahydroquinoline-l-carbonyl)-2H- chromen-4-yl)butanoate (48) was obtained in 30 % yield (0.12 g) as a white solid; mp 157- 159 °C as a mixture of two rotamers in a ratio 2.1 :1. The rotamers in the mixture are cis- trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR. 'H NMR (600 MHz, DMSO) 8 11.14 (1H, bs, OH, A, 1H, bs, OH, B), 8.08 (1H, d, J= 6.8 Hz, CH, B), 7.70 (1H, d, J = 7.3 Hz, CH, B), 7.53 (1H, d, J = 8.8 Hz, CH, A), 7.20-7.14 (2H, m, CH, B), 7.10-7.01 (1H, m, CH, A, 1H, m, CH, B), 6.89 (1H, d, J = 7.3 Hz, CH, B), 6.86 (1H, dt, J = 7.0 Hz, J = 0.9 Hz, CH, A), 6.71 (1H, d, J = 7.0 Hz, CH, A), 6.70-6.67 (1H, m, CH, A), 6.62 (1H, d, J = 7.0 Hz, CH, A), 6.09 (1H, s, CH, B), 5.93 (1H, s, CH, A), 4.08-3.97 (3H, m, CH2, A, 2H, m, CH2, B), 3.66-3.59 (1H, m, CH2, A), 3.46-3.41 (2H, m, CH2, B), 2.86-2.55 (4H, m, CH2, A, 4H, m, CH2, B), 2.40 (2H, t, J=1.2 Hz, CH2, B), 2.31 (2H, t, J= 7.2 Hz, CH2, A), 2.16-2.06 (1H, m, CH2, A), 1.96-1.80 (3H, m, CH2, A, 2H, m, CH2, B), 1.80-1.67 (2H, m, CH2, B), 1.14 (3H, t, J= 5.9 Hz, CH3, B), 1.12 (3H, t, J= 5.9 Hz, CH3, A). Isomer A:13C NMR (150 MHz, DMSO) 6 172.6, 163.9, 159.6, 158.4, 156.4, 151.2, 138.5, 133.3, 128.0, 126.4, 125.3, 125.3, 122.8, 113.7, 112.6, 110.5, 109.5, 60.0, 42.5, 32.9, 30.4, 26.2, 23.6, 23.5, 14.3. Isomer B13C NMR (150 MHz, DMSO) 8 172.7, 163.7, 159.9, 157.5, 156.6, 151.1, 137.7, 129.8, 129.3, 126.4, 125.5, 124.6, 124.1, 113.5, 113.0, 111.1, 110.0, 60.1, 46.5, 33.0, 30.6, 26.6, 23.7, 23.4, 14.3. Elem. Anal. Calcd for C25H25NO6: C, 68.95; H, 5.79; N, 3.22. Found: C, 68.58; H, 5.82; N, 2.98.

[0315] EXAMPLE 60

[0316] 7-Hydroxy-8-(4-methyl-l,2,3,4-tetrahydroquinoxaline-l-carbonyl)-4-propyl-2H- chromen-2-one (49)

[0317] O N

[0318] CH

[0319] 7-Hy droxy-8-(4-methyl-l, 2,3, 4-tetrahydroquinoxaline-l -carbonyl )-4-propyl-2H- chromen-2-one (49) was synthesized according to Scheme 3 by reaction of 3 -hydroxy -4- propyl-2-oxo-277-chromene-8-carboxylic acid (IVc) (0.19 g, 0.765 mmol) with 1-methyl- 1,2,3,4-tetrahydroquinoxaline (95 %, 0.21 g, 0.90 mmol) and EDCXHC1 (0.29 g, 1.51 mmol) in CH2C12(30 mL) in the presence of DMAP (5 mg, 0.04 mmol). The reaction mixture was stirred at rt for 72 hours. Then, the reaction mixture was washed with water (1 x 30 mL), IN HC1 (2 x 30 mL), and brine (2 x 30 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Product was purified by column chromatography (mobile phase: CHCh / MeOH, 100: 1). 7-Hydroxy-8- (4-methyl-l,2,3,4-tetrahydroquinoxaline-l-carbonyl)-4-propyl-2H-chromen-2-one (49) was obtained in 35 % (0.1 g) yield as a white solid; mp 157-158 °C as a mixture of two rotamers in a ratio 1.8: 1. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR. 'H NMR (600 MHz, DMSO) 5 10.85 (1H, bs, OH, A, 1H, bs, OH, B), 7.91(1H, dd, J= 8.1 Hz, J= 1.7 Hz, CH, B), 7.73 (1H, d, J= 8.9 Hz, CH, B), 7.56 (1H, d, J= 8.8 Hz, CH, A), 7.06-7.00 (1H, m, CH, B), 6.94 (1H, d, J = 8.9 Hz, CH, B), 6.82-6.73 (2H, m, CH, A, 1H, m, CH, B), 6.67-6.62 (1H, m, CH, B), 6.60 (1H, dd, J= 8.0 Hz, J= 1.4 Hz, CH, A), 6.43 (1H, dd, J= 8.0 Hz, J= 1.4 Hz, CH, A), 6.11 (1H, s, CH, B), 6.07 (1H, td, J= 8.0 Hz, J= 1.4 Hz, CH, A), 5.97 (1H, s, CH, A), 4.28-4.20 (1H, m, CH2, A), 3.74-3.65 (1H, m, CH2, A), 3.61-3.48 (2H, m, CH2, A, 2H, m, CH2, B), 3.45-3.38 (2H, m, CH2, B), 2.92 (3H, s, CH3, A), 2.89 (3H, s, CH3, B), 2.81-2.53 (2H, m, CH2, A, 2H, m, CH2, B), 1.71-1.47 (2H, m, CH2, A, 2H, m, CH2, B), 0.95 (3H, t, J = 7.3 Hz, CH3, B), 0.86 (3H, t, J = 7.3 Hz, CH3, A). Isomer A:13C NMR (150 MHz, DMSO) 8 163.5, 169.6, 157.7, 156.9, 151.0, 140.0, 126.5, 126.5, 124.3, 122.3, 114.3,

[0320] 113.2, 112.4, 111.1, 110.8, 109.4, 49.8, 39.4, 38.0, 32.9, 21.4, 13.7. Isomer B:13C NMR (150 MHz, DMSO) 5 162.8, 159.9, 157.2, 157.1, 151.2, 139.5, 126.2, 125.9, 123.9, 123.9,

[0321] 115.3, 112.8, 112.7, 111.8, 111.5, 109.9, 50.5, 44.5, 38.4, 32.1, 21.5, 13.9. Elem. Anal. Calcd for C22H22N2O4: C, 69.83; H, 5.86; N, 7.40. Found: C, 69.44; H, 5.71; N, 7.16.

[0322] EXAMPLE 61 tert-Butyl 4-(7-hydroxy-2-oxo-4-propyl-2H-chromene-8-carbonyl)-3,4- dihy droquinoxaline- 1 -carboxyl ate (50) :

[0323] terZ-Butyl 4-(7-hydroxy-2-oxo-4-propyl-2H-chromene-8-carbonyl)-3,4- dihydroquinoxaline-l-carboxylate (50) was synthesized according to Scheme 3 by reaction of 3-hydroxy-4-propy]-2-oxo-2 / / -chromene-8-carboxylic acid (IVc) (0.88 g, 3.56 mmol) with / c / 7-butyl 3,4-dihydroquinoxaline-l -carboxylate (1 g, 4.27 mmol), triethylamine (0.72 g, 1 mL, 7.1 mmol) and EDCxHCl (1.37 g, 7.13 mmol) in CH2CI2 (50 mL) in the presence of DMAP (22 mg, 0.18 mmol). The reaction mixture was stirred at rt for 72 hours. Then, the reaction mixture was diluted with CH2CI2 (50 mL) and washed with water (2 x 50 mL), IN HC1 (2 x 50 mL), and brine (2 x 50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Product was purified by column chromatography (mobile phase: hexane / EtOAc, 2: 1). Ze / 7-Butyl 4-(7-hydroxy-2-oxo-4- propyl-2H-chromene-8-carbonyl)-3,4-dihydroquinoxaline-l -carboxylate (50) was obtained in 19 % yield (0.32 g) as a beige solid; mp 126-128 °C as a mixture of two rotamers in a ratio 1.8: 1. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR. 'H NMR (600 MHz, DMSO) 5 11.03 (1H, bs, OH, B), 10.84 (1H, bs, OH, A), 7.96 (1H, dd, J= 8.3 Hz, J= 1.4 Hz, CH, B), 7.83 (1H, d, J= 8.1 Hz, CH, A), 7.79 (1H, d, J = 8.3 Hz, CH, B), 7.72 (1H, d, J= 8.8 Hz, CH, B), 7.56 (1H, d, J = 8.9 Hz, CH, A), 7.16-7.12 (1H, m, CH, B), 7.10-7.06 (1H, m, CH, B), 6.98-6.89 (1H, m, CH, A, 1H, m, CH, B), 6.73 (1H, d, J= 8.9 Hz, CH, A), 6.65 (1H, dd, J= 8.1 Hz, J= 1.7 Hz, CH, A), 6.62-6.58 (1H, m, CH, A), 6.13 (1H, s, CH, B), 6.10 (1H, s, CH, A), 4.07-3.99 (1H, m, CH, A), 3.92-3.82 (3H, m, CH2, A), 3.77-3.71 (1H, m, CH2, B) 3.71-3.65 (1H, m, CH2, B), 3.59-3.49 (2H, m, CH2, B), 2.78-2.61 (1H, m, CH2, A, 2H, m, CH2, B), 2.61-2.53 (1H, m, CH2, A), 1.68-1.40 (2H, m, CH2, A, 2H, m, CH2, B), 1.47 (9H, s, CH3, A), 1.44 (9H, s, CH3, B), 0.95 (3H, t, ,7= 7.4 Hz, CH3, B), 0.89 (3H, t, J= 7.3 Hz, CH3, A). Isomer A:13C NMR (150 MHz, DMSO) 5 162.8, 159.4, 157.5, 156.8, 152.6, 151.4, 132.8, 130.5, 126.8, 125.8, 122.8, 122.6, 122.1, 112.6, 112.4, 111.0, 109.7, 80.9, 46.7, 41.7, 32.9, 28.1, 21.4, 13.8. Isomer B:13C NMR (150 MHz, DMSO) 8 163.1, 159.9, 157.1, 157.1, 152.5, 151.2, 131.8, 130.1, 126.9, 124.9, 123.9, 123.5, 122.9, 112.9, 112.2, 111.6, 110.0, 81.2, 46.5, 46.1, 33.1, 28.0, 21.6, 13.9. Elem. Anal. Calcd for C26H28N2O6: C, 67.23; H, 6.08; N, 6.03. Found: C, 66.87; H, 6.0; N, 5.62.

[0324] EXAMPLE 62

[0325] 7-Hy droxy-4-propyl-8-( 1 ,2,3 ,4-tetrahydroquinoxaline- 1 -carbonyl)-2H-chromen- 2-one (51)

[0326] Trifluoroacetic acid (0.4 mL) was added dropwise to the solution of tert-butyl 4- (7-hydroxy-2-oxo-4-propyl-2H-chromene-8-carbonyl)-3,4-dihydroquinoxaline-l- carboxylate (50) (0.25 g, 0.54 mmol) in CH2CI2 (20 mL) at 0 °C under inert atmosphere. The reaction mixture was warmed to rt and stirred for 24 hours. Then saturated solution of NaHCCh (25 mL) was carefully added and the reaction mixture was intensively stirred. The organic layer was separated, washed with saturated solution of NaHCCh (1 x 25 mL), water (1 x 25 mL) and brine (1 x 25 mL). 7-Hydroxy-4-propyl-8-(l, 2,3,4- tetrahydroquinoxaline-l-carbonyl)-2H-chromen-2-one (51) was purified by column chromatography (mobile phase: hexane / EtOAc, 1 :1) and obtained in 77 % yield (0.15 g) as a yellowish solid; mp 144-146 °C as a mixture of two rotamers in a ratio 1.3: 1. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR. 'H NMR (600 MHz, DMSO) 6 10.91 (1H, bs, OH, B), 10.80 (1H, bs, OH, A), 7.86 (1H, dd, J= 8.1 Hz, J= 1.5 Hz, CH, B), 7.69 (1H, d, J= 9.0 Hz, CH, B), 7.55 (1H, d, J= 8.8 Hz, CH, A), 6.91 (1H, d, J = 9.0 Hz, CH, B), 6.88-6.84 (1H, m, CH, B), 6.70 (1H, d, . / = 8.8 Hz, CH, A), 6.67-6.63 (1H, m, CH, A), 6.59 (1H, dd, . / = 8.1 Hz, J= 1.5 Hz, CH, B), 6.52-6.48 (1H, m, CH, B), 6.44 (1H, dd, 8.2 Hz, J= 1.5 Hz, CH, A), 6.38 (1H, dd, J= 8.2 Hz, J= 1.5 Hz, CH, A), 6.18 (1H, t, J= 2.7 Hz, NH, A), 6.11 (1H, s, CH, B), 6.10 (1H, t, J = 2.6 Hz, NH, B), 6.01 (1H, s, CH, A), 5.98-5.95 (1H, m, CH, A), 3.88-3.74 (2H, m, CH2, A), 3.54-3.18 (2H, m, CH2, A, 4H, m, CH2, B), 2.77-2.53 (2H, m, CH2, A, 2H, m, CH2, B), 1.68-1.47 (2H, m, CH2, A, 2H, m, CH2, B), 0.95 (3H, t, J = 13 Hz, CH3, B), 0.90 (3H, t, J = 7.4 Hz, CH3, A). Isomer A:13C NMR (150 MHz, DMSO) 6 163.1, 159.7, 157.4, 157.0, 151.4, 138.7, 126.4, 126.0, 124.1, 122.4, 113.7, 113.7, 113.6, 112.4, 110.9, 109.5, 41.1, 38.7, 32.9, 21.4, 13.8. Isomer B:13C NMR (150 MHz, DMSO) 5 162.8, 160.0, 157.2, 157.1, 151.1, 138.4, 126.5, 125.6, 122.8, 122.7, 114.6, 114.4, 112.8, 112.8, 111.5, 109.9, 44.3, 41.7, 33.1, 21.5, 13.9. Elem. Anal. Calcd for C2IH20N2O4: C, 69.22; H, 5.53; N, 7.69. Found: C, 68.87; H, 5.73; N, 7.52.

[0327] EXAMPLE 63

[0328] 3-(Ethoxycarbonyl)-8-hydroxy-5-oxo-l,3,4,5-tetrahydro-2H-chromeno[3,4- c]pyridine-7-carboxylic acid (IVm) (intermediate compound)

[0329] Ethyl chloroformate (6.7 g, 5.9 mL, 0.067 mol) was added dropwise to the solution of methyl 4-oxopiperidine-3-carboxylate hydrochloride (10 g, 0.052 mol) and triethylamine (13 g, 18 mL, 0.129 mol) in CH2C12(200 mL) at 0 °C. The reaction mixture was warmed to rt and stirred overnight. The reaction mixture was washed with water (2 x 150 mL), 2M HC1 (2 x 100 mL), water (1 x 150 mL) and brine (1 x 150 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. 1-Ethyl 3-methyl 4-oxopiperidine-l,3-dicarboxylate was obtained as an oil and was used in the next step without additional purification.

[0330] Methanesulfonic acid (50 mL) was added dropwise to the mixture of 1-ethyl 3- methyl 4-oxopiperidine-l,3-dicarboxylate (11.8 g, 0.052 mol) and 2,6-dihydroxybenzoic acid (6.1 g, 0.04 mol) at 0 °C. The reaction mixture was warmed to rt and stirred for 72 hours. Then, the reaction mixture was poured into ice water (800 mL) and stirred 30 minutes. The precipitation was fdtered off, washed with water, and then dissolved in a mixture of EtOAc and acetone. 3-(Ethoxycarbonyl)-8-hydroxy-5-oxo-l,3,4,5-tetrahydro- 2H-chromeno[3,4-c]pyridine-7-carboxylic acid (IVm) was purified by column chromatography (mobile phase: hexane / EtOAc / acetic acid, 10:40:1) and obtained in 28 % yield (3.71 g) as a white solid; mp 205-207 °C. ‘HNMR (600 MHz, DMSO- / A) 87.59 (d, J= 8.9 Hz, 1H), 6.88 (d, J= 8.8 Hz, 1H), 4.19 (s, 2H), 4.06 (q, J= 7.1 Hz, 2H), 3.62 (t, J = 5.8 Hz, 2H), 2.82 (td, J= 5.8, 2.8 Hz, 2H), 1.18 (t, J= 1A Hz, 3H).13C NMR (151 MHz, DMSO- / L) 8 166.60, 159.25, 158.66, 155.23, 150.38, 147.24, 126.83, 115.99, 113.53, 111.49, 110.64, 61.64, 41.79, 24.83, 24.70, 15.10. Elem. Anal. Calcd for CI6HI7NO8 (monohydrate): C, 54.70; H, 4.88; N, 3.99. Found: C, 54.45; H, 4.59; N, 3.88.

[0331] EXAMPLE 64

[0332] Ethyl 8-hydroxy-5-oxo-7-(l, 2, 3, 4-tetrahydroquinoline-l -carbonyl)-!, 5-dihydro- 2H-chromeno [3,4-c]pyridine-3(4H)-carboxylate (52)

[0333] Ethyl 8-hydroxy-5-oxo-7-(l, 2, 3, 4-tetrahydroquinoline-l -carbonyl)- 1,5-dihydro- 2H-chromeno [3,4-c]pyridine-3(4H)-carboxylate (52) was synthesized according to Scheme 3 by the reaction of 3-(ethoxycarbonyl)-8-hydroxy-5-oxo-l,3,4,5-tetrahydro-2H- chromeno[3,4-c]pyridine-7-carboxylic acid (IVm) (2.5 g, 7.5 mmol) with 1, 2,3,4- tetrahydroquinoline (3 g, 2.82 mL, 22.52 mmol) and EDOHC1 (2.88 g, 15 mmol) in CH2CI2 (100 mL) in the presence ofDMAP (45 mg, 0.37 mmol). The reaction mixture was stirred at rt for 72 hours. Then, the reaction mixture was washed with water (2 x 100 mL), IN HC1 (2 x 100 mL), and brine (2 x 100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Ethyl 8-hydroxy-5-oxo-7- (l,2,3,4-tetrahydroquinoline-l-carbonyl)-l,5-dihydro-2H-chromeno [3,4-c]pyridine- 3(4H)-carboxylate (52) was purified by column chromatography (mobile phase: hexane / EtOAc, 1 :2) and obtained in 43 % yield (1.44 g) as a white solid; mp 239-240 °C as a mixture of two rotamers in a ratio 2: 1. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR.JH NMR (600 MHz, DMSO) 8 10.88 (1H, bs, OH, B), 10.80 (1H, bs, OH, A), 8.08 (1H, d, J= 8.3 Hz, CH, B), 7.60 (1H, d, J = 8.7 Hz, CH, B), 7.44 (1H, d, J = 8.9 Hz, CH, A), 7.20-7.15 (2H, m, CH, B), 7.10-7.03 (1H, m, CH, A, 1H, m, CH, B), 6.94 (1H, d, J = 8.7 Hz, CH, B), 6.87 (1H, td, J= 7.5 Hz, J= 1.3 Hz, CH, A), 6.74 (1H, d, J= 8.9 Hz, CH, A), 6.72-6.69 (1H, m, CH, A), 6.65 (1H, d, J= 7.5 Hz, A), 4.28-3.96 (5H, m, CH2, A, 4H, m, CH2, B), 3.74-3.50 (3H, m, CH2, A, 2H, m, CH2, B), 3.49-3.37 (2H, m, CH2, B), 2.92-2.64 (4H, m, CH2, A, 4H, m, CH2, B), 2.16-2.02 (1H, m, CH2, A), 1.97-1.77 (1H, m, CH2, A, 2H, m, CH2, B), 1.19 (3H, t, 7 = 7.0 Hz, CH3, B), 1.17 (3H, t, J = 7.3 Hz, CH3, A). Isomer A:13C NMR (150 MHz, DMSO) 8 163.6, 158.7, 157.3, 154.8, 149.4, 146.9, 138.5, 133.3, 128.1, 125.6 125.5, 125.4, 122.8, 115.4, 113.5, 112.6, 110.8, 61.2, 42.5, 41.3, 38.8, 26.2, 24.2, 23.6, 14.7. Isomer B:13C NMR (150 MHz, DMSO) 8 163.4, 159.0, 156.4, 154.9, 149.2, 147.0, 137.7, 129.8,

[0334] 129.3, 125.6, 125.6, 124.6, 124.1, 115.8, 113.2, 113.0, 111.5, 61.2, 46.5, 41.5, 38.8, 26.5,

[0335] 24.3, 23.4, 14.7. Elem. Anal. Calcd for C25H24N2O6: C, 66.95; H, 5.39; N, 6.25. Found: C, 66.57; H, 5.31; N, 6.05.

[0336] EXAMPLE 65

[0337] Ethyl 8-(2-hydroxyethoxy)-5-oxo-7-(l,2,3,4-tetrahydroquinoline-l-carbonyl)-l,5- dihydro-2H-chromeno[3,4-c]pyridine-3(4H)-carboxylate (53) o

[0338] The compound 53 was synthesized according to Scheme 3 by reaction of ethyl 8- hydroxy-5-oxo-7-( 1,2, 3, 4-tetrahydroquinoline-l -carbonyl)-l,5-dihydro-2H- chromeno[3,4-c]pyridine-3(4H)-carboxylate (52) (1 g, 2.23 mmol) with 2-bromoethan-l- ol (1.4 g, 0.8 mb, 11.2 mmol) and potassium carbonate (1.54 g, 11.2 mmol) in DMF (10 mb). The reaction was heated to 100 °C for 4 hours. After cooling to rt, the reaction mixture was diluted with EtOAc (100 mL), washed with water (3 x 75 mb) and brine (1 * 100 mb), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Product was purified by column chromatography (mobile phase: CHCI3 / CH3OH, 30: 1). Ethyl 8-(2- hydroxyethoxy)-5-oxo-7-(l, 2, 3, 4-tetrahydroquinoline-l -carbonyl)-l,5-dihydro-2H- chromeno[3,4-c]pyridine-3(4H)-carboxylate (53) was obtained in 76 % yield (0.84 g) as a yellowish solid; mp 100-102 °C as a mixture of two rotamers in a ratio 2.2:1. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR.XH NMR (600 MHz, DMSO) 5 8.08-8.05 (1H, m, CH, B), 7.73 (1H, d, J= 9.1 Hz, CH, B), 7.58 (1H, d, J= 8.9 Hz, CH, A), 7.24-7.13 (3H, m, CH, B), 7.11-7.02 (1H, m, CH, A, 1H, m, CH, B), 7.00 (1H, d, J= 8.9 Hz, CH, A), 6.88 (1H, td, J= 7.7 Hz, J= 1.3 Hz, CH, A), 6.66 (1H, td, J= 7.7 Hz, J= 1.3 Hz, CH, A), 6.62 (1H, dd, J= 7.7 Hz, J= 1.3 Hz, CH, A), 4.84 (1H, t, J = 5.5 Hz, OH, A), 4.81 (1H, t, J = 5.4 Hz, OH, B), 4.28-4.11 (2H, m, CH2, A, 4H, m, CH2, B), 4.10-4.00 (3H, m, CH2, A, 2H, m, CH2, B), 3.94-3.79 (3H, m, CH2, A), 3.69-3.55 (4H, m, CH2, A, 4H, m, CH2, B), 3.46-3.33 (2H, m, CH2, B), 2.94-2.71 (4H, m, CH2, A, 4H, m, CH2, B), 2.12-2.02 (1H, m, CH2, A), 2.00-1.84 (1H, m, CH2, A, 1H, m, CH2, B), 1.84-1.75 (1H, m, CH2, B), 1.18 (3H, t, J= 7.6 Hz, CH3, B), 1.17 (3H, t, J = 7.0 Hz, CH3, A). Isomer A:13C NMR (150 MHz, DMSO) 5 163.1, 158.6, 157.4, 154.8, 148.9, 146.6, 138.2, 132.9, 128.2, 125.9 125.4, 125.4, 122.9, 116.7, 114.9, 112.4, 109.3, 70.8, 61.3, 59.4, 42.7, 41.4, 39.1, 26.3, 24.2, 23.4, 14.7. Isomer B:13C NMR (150 MHz, DMSO) 8 163.0, 158.8, 156.8, 154.9, 148.6, 146.7, 137.6, 130.1 , 129.3, 125.8, 125.6,

[0339] 124.7, 124.1, 116.5, 114.7, 113.0, 109.8, 71.0, 61.3, 59.6, 46.4, 41.5, 39.2, 26.5, 24.4, 23.4,

[0340] 14.7. Elem. Anal. Calcd for C27H30N2O8 (monohydrate): C, 63.52; H, 5.92; N, 5.49. Found: C, 63.66; H, 5.62; N, 5.41.

[0341] EXAMPLE 66

[0342] Ethyl 8-(2-chloroethoxy)-5-oxo-7-( 1 ,2, 3 ,4-tetrahy droquinoline- 1 -carbonyl)- 1,5- dihydro-2H-chromeno[3,4-c]pyridine-3(4H)-carboxylate (54):

[0343] N OEt

[0344] 1 X

[0345] Product 54 was synthesized according to Scheme 4 with some modifications by the reaction of ethyl 8-(2-hydroxyethoxy)-5-oxo-7-(l,2,3,4-tetrahydroquinoline-l-carbonyl)- l,5-dihydro-2H-chromeno[3,4-c]pyridine-3(4H)-carboxylate (53) (0.6 g, 1.22 mmol) with thionyl chloride (1 g , 0.62 mL, 8.53 mmol) and triethylamine (0.86 g, 1.2 mL, 8.53 mmol) in CH2CI2 (50 mL). The reaction mixture was refluxed for 4 hours and after cooling to rt it was washed with water (1 * 70 mL), 10 % NaHCCL (1x50 mL), brine (1 x 70 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Ethyl 8-(2- chl oroethoxy)-5-oxo-7-(l, 2,3, 4-tetrahy droquinoline- 1 -carbonyl)-!, 5-dihydro-2H- chromeno[3,4-c]pyridine-3(4H)-carboxylate (54) was purified by column chromatography (mobile phase: CHCI3 / CH3OH, 20: 1) and obtained in 65 % yield (0.41 g) as a beige solid as a mixture of two rotamers in a ratio 2:1. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR. 'H NMR (600 MHz, DMSO) 8 8.07-8.02 (1H, m, CH, B), 7.75 (1H, d, J= 8.9 Hz, CH, B), 7.60 (1H, d, J= 9.0 Hz, CH, A), 7.24-7.15 (3H, m, CH, B), 7.11-7.05 (1H, m, CH, A, 1H, m, CH, B), 7.01 (1H, d, ,7= 9.0 Hz, CH, A), 6.88 (1H, td, J= 7.3 Hz, J= 1.4 Hz, CH, A), 6.69-6.62 (2H, m, CH, A), 4.48-4.38 (2H, m, CH2, B), 4.34-4.27 (1H, m, CH2, A), 4.26-4.20 (2H, m, CH2, B), 4.20-4.12 (3H, m, CH2, A), 4.10-4.02 (2H, m, CH2, A, 2H, m, CH2, B), 3.94-3.75 (4H, m, CH2, A, 2H, m, CH2, B), 3.69-3.62 (2H, m, CH2, B), 3.62-3.55 (2H, m, CH2, A), 3.45-3.34 (2H, m, CH2, B), 2.95-2.72 (4H, m, CH2, A, 4H, m, CH2, B), 2.13-2.03 (1H, m, CH2, A), 2.00-1.91 (1H, m, CH2, A), 1.91-1.77 (2H, m, CH2, B), 1.17 (3H, t, J = 7.1 Hz, CH3, A), 1.13 (3H, t, J= 7.1 Hz, CH3, B). Isomer A:13C NMR (150 MHz, DMSO) 5 162.8, 158.5,

[0346] 156.5, 154.8, 148.9, 146.5, 138.2, 132.8, 128.3, 126.0 125.5, 125.5, 122.8, 117.1, 115.0, 112.8, 109.2, 69.2, 61.3, 42.8, 42.7, 41.4, 38.7, 26.4, 24.2, 23.4, 14.7. Isomer B:13C NMR (150 MHz, DMSO) 5 162.7, 158.7, 155.9, 154.8, 148.5, 146.6, 137.5, 130.1, 129.2, 125.9,

[0347] 125.6, 124.7, 124.1, 116.8, 114.7, 113.5, 109.7, 69.2, 61.3, 46.4, 43.1, 41.5, 38.8, 26.5, 24.4, 23.5, 14.2. Elem. Anal. Calcd for C27H27C1N2O6: C, 63.47; H, 5.33; N, 5.48. Found: C, 63.21; H, 5.59; N, 5.37

[0348] EXAMPLE 67

[0349] Ethyl 8-(2-(4-methylpiperazin-l-yl)ethoxy)-5-oxo-7-(l,2,3,4-tetrahydroquinoline- 1 -carbonyl)-!, 5-dihydro-2H-chromeno[3,4-c]pyridine-3(4H)-carboxylate (55)

[0350] N OEt

[0351] N I 1 X

[0352] Ethyl 8-(2-(4-methylpiperazin-l-yl)ethoxy)-5-oxo-7-(l,2,3,4-tetrahydroquinoline- l-carbonyl)-l,5-dihydro-2H-chromeno[3,4-c]pyridine-3(4H)-carboxylate (55) was synthesized according to Scheme 4. 1 -Methylpiperazine (0.1 g, 0.11 mb, 1 mmol) was added to a suspension of ethyl 8-(2-chloroethoxy)-5-oxo-7-(l,2,3,4-tetrahydroquinoline-l- carbonyl)-l,5-dihydro-2H-chromeno[3,4-c]pyridine-3(4H)-carboxylate (54) (0.1 g, 0.2 mmol), potassium carbonate (0.13 g, 0.1 mmol) and potassium iodide (0.03 g, 0.2 mmol) in DMF (2 mL). The reaction mixture was heated to 85 °C for 12 hours. After cooling, the reaction mixture was diluted with EtOAc (50 mL) and washed with water (2 x 30 mL) and brine (1 * 50 mb). The organic layer was dried over anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (mobile phase: CHCI3 / CH3OH, 15: 1). Ethyl 8-(2-(4-methylpiperazin-l-yl)ethoxy)-5-oxo-7-(l,2,3,4- tetrahydroquinoline-1 -carbonyl)- 1 ,5-dihy dro-2H-chromeno[3, 4-c]pyri dine-3(4H)- carboxylate (55) was obtained in 59 % yield (0.065 g) as a yellowish solid; mp 130-132 °C as a mixture of two rotamers in a ratio 1.8: 1. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR.JH NMR (500 MHz, DMSO) 5 8.08-8.05 (1H, m, CH, B), 7.77 (1H, d, J= 8.9 Hz, CH, B), 7.62 (1H, d, J = 9.0 Hz, CH, A), 7.27-7.16 (3H, m, CH, B), 7.14-7.07 (1H, m, CH, A, 1H, m, CH, B), 7.04 (1H, d, J= 9.0 Hz, CH, A), 6.92 (1H, td, J= 7.7 Hz, >1.3 Hz, CH, A), 6.70 (1H, td, J = 1.1 Hz, J = 1.3 Hz, CH, A), 6.63 (1H, dd, J = 1.1 Hz, J = 1.3 Hz, CH, A), 4.32-4.05 (5H, m, CH2, A, 6H, m, CH2, B), 4.01-3.92 (1H, m, CH2, A), 3.92-3.85 (2H, m, CH2, A), 3.73-3.59 (2H, m, CH2, A, 2H, m, CH2, B), 3.52-3.42 (1H, m, CH2, B), 3.41-3.36 (1H, m, CH2, B), 3.00-2.73 (4H, m, CH2, A, 4H, m, CH2, B), 2.71-2.59 (2H, m, CH2, B), 2.59-2.51 (2H, m, CH2, A), 2.50-2.03 (9H, m, CH2, A, 8H, m, CH2, B), 2.12 (3H, s, CH3, A), 2.06 (3H, s, CH3, B), 2.02-1.92 (1H, m, CH2, A), 1.92-1.80 (2H, m, CH2, B), 1.20 (3H, t, J = 7.0 Hz, CH3, A), 1.20 (3H, t, J= 7.0 Hz, CH3, B). Isomer A:13C NMR (125 MHz, DMSO) 8 163.1, 158.6, 157.0, 154.8, 149.0, 146.6, 138.2, 132.9, 128.2, 126.0 125.5, 125.5, 122.8,

[0353] 116.7, 114.9, 112.4, 109.2, 67.0, 61.3, 56.3, 54.8, 53.2, 45.9, 42.6, 41.4, 38.7, 26.4, 24.3, 23.4, 14.7. Isomer B:13C NMR (125 MHz, DMSO) 5 162.9, 158.8, 156.5, 154.9, 148.5,

[0354] 146.7, 137.5, 129.9, 129.3, 126.0, 125.6, 124.7, 124.0, 116.6, 114.5, 113.1, 109.4, 67.7, 61.3, 56.5, 54.8, 53.2, 46.5, 45.9, 41.5, 38.8, 26.5, 24.3, 23.5, 14.8. Elem. Anal. Calcd for C32H38N4O6: C, 66.88; H, 6.67; N, 9.75. Found: C, 66.71; H, 6.79; N, 9.48.

[0355] EXAMPLE 68

[0356] 3-Bromo-7-hydroxy-4-methyl-2-oxo-27 / -chromene-8-carboxylic acid (IVn) (intermediate compound)

[0357] 1 X

[0358] OH The solution of bromine (0.64 g, 0.21 mL, 4 mmol) in chloroform (20 mb) was added dropwise to a suspension of 7-hydroxy-4-mcthyl-2-oxo-2 / / -chromcnc-8-carboxylic acid (IVa) (0.88 g, 4 mmol) in chloroform (30 mL). The reaction mixture was heated to reflux overnight. After cooling to rt, a precipitation was fdtered and dried over P2O5. 3-Bromo-7- hydroxy-4-methyl-2-oxo-2 / Z-chromene-8-carboxylic acid (IVn) was obtained in 74 % yield (0.88 g) as a light beige solid; mp 245-247 °C (decomp.) 'H NAIR (600 MHz, DMSO- t76) 8 7.67 (d, .7= 9.0 Hz, 1H), 6.79 (d, J= 8.9 Hz, 1H), 2.51 (s, 3H).13C NMR (151 MHz, DMSO-tL) 8 166.48, 161.38, 156.66, 152.67, 150.82, 128.67, 114.43, 111.67, 110.00, 107.78, 20.03. Elem. Anal. Calcd. for CiiH7BrO5: C, 44.18; H, 2.36. Found: C, 44.06; H, 2.28.

[0359] EXAMPLE 69

[0360] 3-Bromo-7-hydroxy-4-methyl-8-(l,2,3,4-tetrahydroquinoline-l-carbonyl)-2 / f- chromen-2-one (56)

[0361] 3-Bromo-7-hydroxy -4-methyl-8-( 1,2,3, 4-tetrahydroquinoline-l-carbonyl)-2 / 7- chromen-2-one (56) was synthesized according to Scheme 3 by reaction of 3-bromo-7- hydroxy-4-methyl-2-oxo-2 / Z-chromene-8-carboxylic acid (IVn) (0.65 g, 2.2 mmol) with 1,2,3,4-tetrahydroquinoline (1.10 g, 1.04 mL, 8.2 mmol) and EDOHC1 (0.96 g, 5 mmol) in CH2CI2 (25 mL) at the presence of DMAP (0.013 g, 0.1 mmol). The reaction mixture was stirred at rt for 48 hours. Then, the reaction mixture was washed with water (1x40 mL), IN HC1 (2x40 mL), water (2x40 mL), and brine (1x40 mL). Organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Product was purified by column chromatography (mobile phase: hexane / EtOAc / acetic acid, 10: 10:0. 1). 3 -Bromo-7-hydroxy-4-methyl -8-( l ,2, 3, 4-tetrahydroqiiinoline-l -carbonyl )-2 / / -chromen- 2-one (56) was obtained in 52 % yield (0.47 g) as a white solid; mp 263-265 °C (decomp.) as a mixture of two rotamers in a ratio 1.8: 1. The retainers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR.1H NMR (600 MHz, DMSO-tZ) 8 11.08 (1H, bs, OH, B), 10.99 (1H, bs, OH, A), 8.07 (1H, d, J= 8.4 Hz, CH, B), 7.76 (1H, d, J= 8.9 Hz, CH, B), 7.60 (1H, d, J= 8.9 Hz, CH, A), 7.21-7.15 (2H, m, CH, B), 7.10-7.04 (1H, m, CH, A, 1H, m, CH, B), 6.96 (1H, d, J= 8.9 Hz, CH, B), 6.88 (1H, t, J= 13 Hz, CH, A), 6.76 (1H, d, J= 13 Hz, CH, A), 6.70 (1H, t, J= 7.3 Hz, CH, A), 6.62 (1H, d, J= 13 Hz, CH, A), 4.07-3.94 (1H, m, CH2, A), 3.75-3.62 (1H, m, CH2, A), 3.50-3.35 (2H, m, CH2, B), 2.89-2.64 (2H, m, CH2, A, 2H, m, CH2, B), 2.55 (3H, s, CH3, B), 2.44 (3H, s, CH3, A), 2.17-2.03 (1H, m CH2, A), 2.00-1.76 (1H, m CH2, A, 2H, m CH2, B). Isomer A:13C NMR ( 151 MHz, DMSO-tZ) 8 163.3, 158.2, 155.9, 152.3, 149.2, 138.4, 133.3, 128.1, 127.5, 125.4, 125.4, 122.8, 113.3, 113.1, 111.4, 107.7, 42.5, 26.2, 23.5,

[0362] 19.6. Isomer B:13C NMR (151 MHz, DMSO-rZ) 8 163.2, 157.2, 156.2, 152.3, 149.0,

[0363] 137.6. 129.9, 129.3, 127.5, 125.5, 124.6, 124.1, 113.4, 113.1, 112.2, 108.2, 46.5, 26.5, 23.4,

[0364] 19.6. Elem. Anal. Calcd. for C20Hi6BrNO4: C, 57.99; H, 3.89; N, 3.38. Found: C, 57.68; H, 3.72; N, 3.42.

[0365] EXAMPLE 70

[0366] Tert-Butyl 3-(2-((2-oxo-4-propyl-8-(l,2,3,4-tetrahydroquinoline-l-carbonyl)-277- chromen-7-yl)oxy)ethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (57)

[0367] Tert-Butyl 3-(2-((2-oxo-4-propyl-8-(l,2,3,4-tetrahydroquinoline-l-carbonyl)-27T- chromen-7-yl)oxy)ethyl)-3,8-diazabicyclo[3.2.1] octane- 8 -carb oxy late (57) was synthesized according to Scheme 2. Tert-Butyl 3,8-diazabicyclo[3.2.1]octane-8- carboxylate (0.42 g, 2.0 mmol) was added to a solution of 7-(2-bromoethoxy)-4-propyl-8- (l,2,3,4-tetrahydroquinoline-l-carbonyl)-2 / f-chromen-2-one 33 (0.47 g, 1.0 mmol) and potassium carbonate (0.27 g, 2.0 mmol) in DMF (10 mL). The reaction mixture was heated to 60 °C for 6 hours. After cooling to rt, the reaction mixture was diluted with EtOAc (50 mL), washed with water (3><30 mL) and brine (1x30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The product was purified by column chromatography (mobile phase: hexane / EtOAc / acetic acid, 30:20:1). Zc' / 'Z-Butyl 3-(2-((2- oxo-4-propyl-8-( 1,2,3, 4-tetrahydroquinoline-l-carbonyl)-2 / / -chromen-7-yl)oxy)ethyl)- 3,8-diazabicyclo[3.2. l]octane-8-carboxylate (57) was obtained in 82 % yield (0.49 g) as a beige solid; mp 66-67 °C as a mixture of two rotamers in a ratio 1.8:1. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR. 'H NMR (500 MHz, DMSO-tL) 8 8.08 (1H, dd, J = 8.7 Hz, J= 1.3 Hz, CH, B), 7.86 (1H, d, J = 9.0 Hz, CH, B), 7.71 (1H, d, J= 9.0 Hz, CH, A), 7.25-7.17 (3H, m, CH, B), 7.14-7.04 (1H, m, CH, A, 1H, m, CH, B), 7.02 (1H, d, J= 9.0 Hz, CH, A), 6.90 (1H, td, J= 7.7 Hz, J= 1.3 Hz, CH, A), 6.69 (1H, td, J= 7.7 Hz, J= 1.3 Hz, CH, A), 6.55 (1H, dd, J = 7.7 Hz, J = 1.3 Hz, CH, A), 6.22 (1H, s, CH, B), 6.08 (1H, s, CH, A), 4.35-4.07 (1H, m, CH2, A, 2H, m, CH2, B), 4.07-3.70 (5H, m, CH, CH2, A, 2H, m, CH, B), 3.56-3.44 (1H, m, CH2, B), 3.41-3.26 (1H, m, CH2, B), 2.94-2.49 (8H, m, CH2, A, 8H, m, CH2, B), 2.26-2.03 (3H, m, CH2, A, 2H, m, CH2, B), 2.03-1.80 (1H, m, CH2, A, 2H, m, CH2, B), 1.78-1.44 (6H, m, CH2, A, 6H, m, CH2, B), 1.39 (9H, s CH3, A), 1.34 (9H, s, CH3, B), 0.99 (3H, t, J = 13 Hz, CH3, B), 0.91 (3H, t, J = 1A Hz, CH3, A). Isomer A:13C NMR (125 MHz, DMSO-tL) 8 163.2, 159.4, 157.7, 156.8, 153.0, 150.5, 138.2, 133.0, 128.1, 126.8, 125.4, 125.3, 122.8, 115.1, 112.4, 110.6, 109.0, 78.6, 66.8, 58.0, 55.7, 54.3, 42.5, 32.8, 28.3, 27.2, 26.3, 23.4, 21.3, 13.7. Isomer B:13C NMR (125 MHz, DMSO-rL) 8 163.0, 159.7, 157.0, 156.9, 152.9, 150.2, 137.5, 129.8, 129.2, 126.8, 125.5, 124.7, 124.0, 114.8, 113.0, 111.0, 109.2, 78.6, 67.6, 57.6, 55.9, 53.4, 46.5, 33.0, 28.2, 27.9, 26.5, 23.4, 21.5, 13.9. Elem. Anal. Calcd. for C35H43N3O6: C, 69.86; H, 7.20; N 6.98. Found: C, 69.78; H, 7.12; N, 6.84.

[0368] EXAMPLE 71

[0369] 7-(2-(3,8-Diazabicyclo[3.2.1]octan-3-yl)ethoxy)-4-propyl-8-(l,2,3,4- tetrahydroquinoline- 1 -carbonyl )-2 / / -chromen-2-one (58)

[0370] A / 7-Butyl 3-(2-((2-oxo-4-propyl-8-(l,2,3,4-tetrahydroquinoline-l-carbonyl)-277- chromen-7-yl)oxy)ethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (57) (0.45 g, 0.7 mmol) was dissolved in acetic acid (20 mL), bubbled with hydrogen chloride and the reaction mixture was stirred for 1 hour. Then, diethyl ether (50 mL) was added and formed solid was filtered off, dissolved in water (25 mL) and alkalized with IM NaOH (0.33 mL). The aqueous phase was extracted with EtOAc (3x30 mL). Organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Product was purified by column chromatography (mobile phase: CHCl3 / MeOH / Et3N, 25:10:0.1). 7-(2-(3,8- Diazabicyclo[3.2.1 ]octan-3 -yl)ethoxy)-4-propyl-8-( 1 ,2, 3,4-tetrahydroquinoline- 1 - carbonyl)-27 / -chromen-2-one (58) was obtained in 54 % yield (0.20 g) as a white solid; mp 69-70 °C as a mixture of two rotamers in a ratio 1.9: 1. The rotamers in the mixture are cis- trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR.JH NMR (600 MHz, DMSO-tZ) 5 8.05-8.02 (1H, m, CH, B), 7.82 (1H, d, J= 9.0 Hz, CH, B), 7.67 (1H, d, J= 9.0 Hz, CH, A), 7.19-7.14 (3H, m, CH, B), 7.09-7.03 (1H, m, CH, A, 1H, m, CH, B), 6.97 (1H, d, ,7= 9.0 Hz, CH, A), 6.87 (1H, td, J= 7.7 Hz, J= 1.3 Hz, CH, A), 6.65 (1H, td, J= 7.7 Hz, J- 1.3 Hz, CH, A), 6.52 (1H, dd, J= 7.7 Hz, J - 1.3 Hz, CH, A), 6.18 (1H, s, CH, B), 6.04 (1H, s, CH, A), 4.24-4.14 (2H, m, CH2, B), 4.13-4.07 (1H, m, CH2, A), 3.97-3.90 (2H, m, CH2, A), 3.80-3.73 (1H, m, CH2, A), 3.49-3.42 (1H, m, CH2, B), 3.38-3.30 (1H, m, CH2, B), 3.21-3.15 (2H, m, CH, A), 3.11-3.00 (2H, m, CH, B), 2.89- 2.40 (8H, m, CH2, A, 10H, m, CH2, B), 2.17-2.01 (3H, m, CH2, A), 1.99-1.88 (1H, m, CH2, A), 1.88-1.80 (2H, m, CH2, B), 1.70-1.33 (6H, m, CH2, A, 6H, m, CH2, B), 0.96 (3H, t, J = 7.3 Hz, CH3, B), 0.88 (3H, t, J = 7.3 Hz, CH3, A). Isomer A:13C NMR (125 MHz, DMSO-tZ) 8 163.2, 159.4, 157.7, 156.8, 150.6, 138.2, 133.0, 128.1, 126.8, 125.3, 125.2, 122.8, 115.0, 112.3, 110.5, 109.0, 66.8, 60.3, 60.0, 56.3, 54.2, 54.1, 42.5, 32.8, 29.0, 26.3, 23.4, 21.3, 13.7. Isomer B:13C NMR (125 MHz, DMSO-rZ) 6 163.0, 159.7, 157.1, 156.9, 150.2, 137.5, 129.8, 129.2, 126.8, 125.5, 124.6, 124.0, 114.8, 113.0, 110.9, 109.2, 67.6,

[0371] 60.2, 60.2, 56.6, 54.1, 54.1, 46.5, 33.0, 29.1, 26.5, 23.3, 21.5, 13.8. Elem. Anal. Calcd. for C30H35N3O4: C, 71.83; H, 7.03; N, 8.38. Found: C, 71.78; H, 7.06; N, 8.26.

[0372] EXAMPLE 72

[0373] 7-(2-(8-Methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)ethoxy)-4-propyl-8-(l,2,3,4- tetrahydroquinoline- 1 -carbonyl )-2 / / -chromen-2-one (59)

[0374] 1 X

[0375] O D' X)

[0376] N

[0377] To the solution of 7-(2-(3,8-diazabicyclo[3.2.1]octan-3-yl)ethoxy)-4-propyl-8- (l,2,3,4-tetrahydroquinoline-l-carbonyl)-2 / 7-chromen-2-one (58) (0.17 g, 0.3 mmol) and paraformaldehyde (0.09 g, 1.0 mmol) in methanol (10 mL) was added acetic acid (catalytic amount) and the reaction mixture was stirred at 45 °C for 2 hours. Then, sodium cyanoborohydride (0. 10 g, 1.7 mmol) was added and reaction mixture was stirred at 45 °C for additional 12 hours. After completion, reaction mixture was concentrated under reduced pressure, diluted with saturated solution of sodium bicarbonate (15 mL), extracted with dichloromethane (3x15 mL), organic layers were washed with brine (1x30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure. Product was purified by column chromatography (mobile phase: CHCWMeOH / EbN, 25: 10:0.1). 7-(2-(8-Methyl- 3,8-diazabicyclo[3.2. l]octan-3-yl)ethoxy)-4-propyl-8-(l,2,3,4-tetrahydroquinoline-l- carbonyl)-2 / / -chromen-2-one (59) was obtained in 61 % yield (0.11 g) as a white solid; mp 60-61 °C as a mixture of two rotamers in a ratio 1.8: 1. The rotamers in the mixture are cis- trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR.JH NMR (600 MHz, DMSO-tL) 8 8.06-8.03 (1H, m, CH, B), 7.82 (1H, d, J= 9.0 Hz, CH, B), 7.67 (1H, d, J= 9.0 Hz, CH, A), 7.21-7.13 (3H, m, CH, B), 7.10-7.02 (1H, m, CH, A, 1H, m, CH, B), 6.97 (1H, d, J= 9.0 Hz, CH, A), 6.87 (1H, td, J= 7.7 Hz, J= 1.3 Hz, CH, A), 6.65 (1H, td, J= 7.7 Hz, J= 1.3 Hz, CH, A), 6.52 (1H, dd, J= 7.7 Hz, J= 1.3 Hz, CH, A), 6.18 (1H, s, CH, B), 6.04 (1H, s, CH, A), 4.25-4.14 (2H, m, CH2, B), 4.13-4.06 (1H, m, CH2, A), 3.97-3.89 (2H, m, CH2, A), 3.80-3.73 (1H, m, CH2, A), 3.50-3.42 (1H, m, CH2, B), 3.41-3.28 (1H, m, CH2, B), 2.96-2.90 (2H, m, CH, A), 2.87-2.43 (9H, m, CH2, A, 2H, m, CH, B, 9H, m, CH2, B), 2.27-2.18 (lH, m, CH2, A, 1H, m, CH2, B), 2.11-2.02 (1H, m, CH2, A), 2.09 (3H, s, CH3, A), 2.01 (3H, s, CH3, B), 1.98-1.88 (1H, m, CH2, A), 1.87-1.81 (2H, m, CH2, B), 1.76-1.68 (1H, m, CH2, A, 1H, m, CH2, B), 1.68-1.45 (5H, m, CH2, A, 5H, m, CH2, B), 0.96 (3H, t, J= 7.3 Hz, CH3, B), 0.88 (3H, t, J= 7.3 Hz, CH3, A). Isomer A:13C NMR (125 MHz, DMSO-tfc) 8 163.2, 159.4, 157.7, 156.8, 150.6, 138.2, 133.0, 128.1,

[0378] 126.8, 125.3, 125.2, 122.8, 115.0, 112.3, 110.5, 109.0, 66.9, 60.9, 60.9, 58.9, 58.5, 55.7, 42.5, 32.8, 26.3, 25.4, 23.4, 21.3, 13.7. Isomer B:13C NMR (125 MHz, DMSO-rL) 6 163.0, 159.7, 157.1, 156.9, 150.2, 137.5, 129.8, 129.2, 126.8, 125.5, 124.6, 124.0, 114.8, 113.0,

[0379] 110.9, 109.2, 67.6, 60.9, 60.8, 58.7, 58.5, 55.9, 46.5, 33.0, 26.5, 25.5, 23.4, 21.5, 13.8. Elem. Anal. Calcd. for C3IH37N3O4: C, 72.21; H, 7.23; N, 8.15. Found: C, 72.14; H, 7.12; N, 8.04.

[0380] EXAMPLE 73: 3-Methyl-3,8-diazabicyclo[3.2. l]octane dihydrochloride (intermediate compound)

[0381] 2HCI

[0382] To the solution of / e / V-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.50 g, 2.3 mmol) and paraformaldehyde (0.64 g, 7.1 mmol) in methanol (10 mL) was added acetic acid (catalytic amount) and reaction mixture was stirred at 45°C for 2 hours. Sodium cyanoborohydride (0.74 mg, 11.7 mmol) was added, and reaction mixture was stirred at 45°C for 12 hours. After completion, reaction mixture was concentrated under reduced pressure, diluted with saturated solution of sodium bicarbonate (15 mL), extracted with di chloromethane (3x 15 mL), organic layers were washed with brine (1x30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure. The product was obtained in sufficient purity without further purification. Tert-Butyl 3-methyl-3,8- diazabicyclo[3.2. l]octane-8-carboxylate was obtained in 95 % yield (0.51 g) as a light beige oil. ’H NMR (500 MHz, DMSO-tL) 8 3.99 (s, 2H), 2.57-2.53 (m, 2H), 2.11 (s, 3H), 2.01 (d, J= 10.6 Hz, 2H), 1.75-1.72 (m, 4H), 1.39 (s, 9H).13C NMR (126 MHz, DMSO- d6) 5 153.24, 78.90, 60.23, 59.61, 54.59, 53.66, 45.46, 28.57, 27.73.

[0383] A solution of / crz-butyl 3-methyl-3,8-diazabicyclo[3.2. l]octane-8-carboxylate (0.50 g, 2.2 mmol) in acetic acid (4 mL) was bubbled with dry hydrogen chloride and stirred at rt for 3 hours. The reaction mixture was concentrated under reduced pressure. The crude product was suspended with diethyl ether (15 mL) and filtered off. The product was obtained in high purity and wan not additionally purified. 3-Methyl-3,8- diazabicyclo[3.2.1]octane dihydrochloride was obtained in 82 % yield (0.32 g) as a white solid; mp 251-253 °C.XH NMR (600 MHz, DMSO-cL) 8 11.36 (s, 1H), 10.23 (s, 1H), 9.92 (s, 1H), 4.19-4.17 (m, 2H), 3.61-3.58 (m, 2H), 3.49-3.46 (m, 2H), 3.67 (s, 3H), 2.36-2.31 (m, 2H), 2.08-2.01 (m, 2H).13C NMR (126 MHz, DMSO-tL) 8 54.93, 52.96, 43.99, 24.53.

[0384] EXAMPLE 74

[0385] 7-(2-(3-Methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)ethoxy)-4-propyl-8-(l,2,3,4- tetrahydroquinoline-1 -carbonyl )-2 / / -chromen-2-one (60)

[0386] 1 X

[0387] 7-(2-(3-Methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)ethoxy)-4-propyl-8-(l,2,3,4- tetrahydroqui noline- 1 -carbonyl )-27 / -chromen-2-one (60) was synthesized according to Scheme 2. 3-Methyl-3,8-diazabicyclo[3.2.1]octane di hydrochloride (0.35 g, 1.7 mmol) was added to a solution of 7-(2-bromoethoxy)-4-propyl-8-(l,2,3,4-tetrahydroquinoline-l- carbonyl)-2 / / -chromen-2-one 33 (0.42 g, 0.9 mmol) and potassium carbonate (0.75 mg, 5.4 mmol) in DMF (10 mL). The reaction mixture was heated to 130 °C overnight. After cooling to rt, the reaction mixture was diluted with EtOAc (50 mL), washed with water (3x30 mL) and brine (1 x30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The product was purified by column chromatography (mobile phase: CTLCh / MeOH, 95:5). 7-(2-(3-Methyl-3,8-diazabicyclo[3.2. l]octan-8-yl)ethoxy)- 4-propyl-8-(l ,2,3,4-tetrahydroquinoline-l -carbonyl)-2 / / -chromen-2-one (60) was obtained in 46 % yield (0.21 g) as a white solid; mp 144-145 °C as a mixture of two rotamers in a ratio 1.7: 1. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR.3H NMR (600 MHz, DMSO-t / e) 8 8.08- 8.04 (1H, m, CH, B), 7.83 (1H, d, J = 9.0 Hz, CH, B), 7.67 (1H, d, J= 9.0 Hz, CH, A), 7.20-7.12 (3H, m, CH, B), 7.11-7.03 (1H, m, CH, A, 1H, m, CH, B), 7.00 (1H, d, J= 9.0 Hz, CH, A), 6.87 (1H, td, J = 7.8 Hz, J = 1.3 Hz, CH, A), 6.66 (1H, td, J = 7.8 Hz, J = 1.3 Hz, CH, A), 6.57 (1H, dd, J= 7.8 Hz, J= 1.3 Hz, CH, A), 6.18 (1H, s, CH, B), 6.03 (1H, s, CH, A), 4.24-4.14 (2H, m, CH2, B), 4.14-4.08 (1H, m, CH2, A), 4.02-3.94 (2H, m, CH2,

[0388] A), 3.72-3.66 (1H, m, CH2, A), 3.48-3.42 (1H, m, CH2, B), 3.39-3.32 (1H, m, CH2, B), 3.16-3.06 (2H, m, CH, A, 2H, m, CH, B), 2.88-2.56 (4H, m, CH2, A, 6H, m, CH2, B), 2.53- 2.48 (2H, m, CH2, A), 2.43-2.34 (2H, m, CH2, A), 2.32-2.27 (1H, m, CH2, B), 2.18-2.13 (1H, m, CH2, B), 2.13-1.78 (4H, m, CH2, A, 4H, m, CH2, B), 2.02 (3H, s, CH3, A), 1.96 (3H, s, CH3, B), 1.74-1.45 (6H, m, CH2, A, 6H, m, CH2, B), 0.96 (3H, t, J= 7.4 Hz, CH3,

[0389] B), 0.88 (3H, t, J= 7.3 Hz, CH3, A). Isomer A:13C NMR (125 MHz, DMSO-tC) 5 163.3,

[0390] 159.4, 157.8, 156.8, 150.5, 138.2, 133.1, 128.1, 126.8, 125.4, 125.3, 122.8, 115.0, 112.3,

[0391] 110.5, 108.9, 68.9, 60.6, 60.5, 60.0, 51.0, 45.2, 42.5, 32.8, 26.3, 26.2, 26.1, 23.4, 21.3, 13.7. Isomer B:13C NMR (125 MHz, DMSO-rC) 8 163.1, 159.7, 157.1, 156.9, 150.2, 137.5, 129.8, 129.2, 126.8, 125.5, 124.6, 124.0, 114.7, 113.0, 110.9, 109.2, 69.9, 60.4, 60.2, 60.1, 51.1, 46.5, 45.2, 33.0, 26.6, 26.1, 26.0, 23.4, 21.5, 13.9. Elem. Anal. Calcd. for C3IH37N3O4: C, 72.21; H, 7.23; N, 8.15. Found: C, 72.16; H, 7.28; N, 8.18.

[0392] EXAMPLE 75

[0393] 7-(Prop-2-yn-l-yloxy)-4-propyl-8-(l,2,3,4-tetrahydroquinoline-l-carbonyl)-277- chromen-2-one (61)

[0394] O 1 X

[0395] N 7-(Prop-2-yn-l -yloxy)-4-propyl-8-(l ,2,3,4-tetrahydroquinoline-l -carbonyl)-2 / 7- chromen-2-one (61) was synthesized according to Scheme 1. A solution of 7-hydroxy-4- propyl-8-(l,2,3,4-tetrahydroquinoline-l-carbonyl)-2J7-chromen-2-one (3) (0.25 g, 0.7 mmol) and potassium carbonate (0.28 g, 2.1 mmol) in DMF (10 mL) was stirred at 50 °C for 30 min. Propargyl bromide (solution 80 % in toluene; 0.13 g, 0.8 mmol 0.1 mL) was added and the reaction mixture was stirred at rt overnight. After cooling to rt, the reaction mixture was diluted with EtOAc (50 mL), washed with water (3><30 mL) and brine (1 x30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The product was washed with diethyl ether and dried over P2O5. 7-(Prop-2-yn-l-yloxy)-4- propyl-8-(l,2,3,4-tetrahydroquinoline-l-carbonyl)-2 / 7-chromen-2-one (61) was obtained in 48 % yield (0.13 g) as a white solid; mp 144-145 °C as a mixture of two rotamers. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR. ’H NMR (600 MHz, DMSO-t / e) 5 8.08-8.05 (1H, m, CH, B), 7.89 (1H, d, J= 7.5 Hz, CH, B), 7.72 (1H, d, J= 9.0 Hz, CH, A), 7.23 (1H, d, J= 7.5 Hz, CH, B), 7.20-7.16 (2H, m, CH, B), 7.08 (1H, td, J= 6.1 Hz, J= 0.9 Hz, CH, B), 7.06-7.01 (2H, m, CH, A), 6.87 (1H, td, J= 7.4 Hz, J= 1.2 Hz, CH, A), 6.64 (1H, td, J= 7.4 Hz, J = 1.2 Hz, CH, A), 6.57 (1H, dd, J = 7.4 Hz, J = 1.2 Hz CH, A), 6.22 (1H, s, CH, B), 6.05 (1H, s, CH, A), 5.03 (1H, dd, J= 13.5 Hz, J= 2.0 Hz, CH2, B), 4.99 (1H, dd, J= 13.5 Hz, .7= 2.0 Hz, CH2, B), 4.91 (1H, dd, J= 16.1 Hz, J= 2.4 Hz, CH2, A), 4.83 (1H, dd, J= 16.1 Hz, J = 2.4 Hz, CH2, A), 4.08-4.00 (1H, m, CH2, A), 3.70-3.62 (1H, m, CH2, A, 1H, m, CH, A), 3.62 (1H, t, J = 1.9 Hz, CH, B), 3.43-3.35 (2H, m, CH2, B), 2.87-2.72 (2H, m, CH2, A, 4H, m, CH2, B), 2.72-2.64 (1H, m, CH2, A), 2.64-2.55 (1H, m CH2, A), 2.17-2.06 (1H, m CH2, A), 1.96-1.80 (1H, m CH2, A, 2H, m CH2, B), 1.69-1.46 (2H, m CH2, A, 2H, m CH2, B), 0.96 (3H, t, J= 7.3 Hz, CH3, B), 0.87 (3H, t, J= 7.4 Hz, CH3, A). Isomer A:13C NMR (150 MHz, DMSO-rL) 6 163.1, 159.2, 156.7, 156.3, 150.3, 138.1, 133.3, 128.1, 126.7, 125.5, 125.2, 123.0, 115.3, 112.8, 110.9, 109.2, 79.2, 78.4, 56.5, 42.5, 32.8, 26.1, 23.4, 21.3, 13.7. Isomer B:13C NMR (150 MHz, DMSO-rfc) 8 162.7, 159.6, 156.8, 155.5, 150.2, 137.5, 129.9, 129.3, 126.7, 125.6, 124.8, 124.1, 115.2, 113.6, 111.4, 109.7, 79.3, 78.6, 56.7, 46.5, 33.0, 26.5, 23.4, 21.4, 13.9. Elem. Anal. Calcd. for C25H23NO4: C, 74.80; H, 5.77; N, 3.49. Found: C, 74.64; H, 5.64; N, 3.41. EXAMPLE 76

[0396] 2-((2-Oxo-4-propyl-8-(l,2,3,4-tetrahydroquinoline-l-carbonyl)-27 / -chromen-7- yl)oxy)ethyl ( / c / 7-butoxy carbonyl (glycinate (62)

[0397] N Y

[0398] Ho

[0399] EDOHC1 (1.41 g, 7.4 mmol) was added to the solution of 7-(2 -hydroxyethoxy )-4- propyl-8-(l,2,3,4-tetrahydroquinoline-l-carbonyl)-2 / / -chromen-2-one (15) (1.00 g, 2.4 mmol), (tert-butoxycarbonyl)glycine (1.29 g, 7.4 mmol) and DMAP (0.015 g, 0.1 mmol) in CH2CI2 (15 mb). The reaction mass was stirred under inert atmosphere at rt for 24 hours. After completion, the reaction mass was filtered off, filtrate was washed with acidified water (H2O / HCI, 50 mL: 1 mL), water (50 mL), brine (50 mL) and water (50 mL). Organic layer was dried over anhydrous sodium sulfate and concentrated. The product was purified using column chromatography (mobile phase: hexane / EtOAc, 2:3). 2-((2-Oxo-4-propyl-8- (l,2,3,4-tetrahydroquinoline-l-carbonyl)-21f-chromen-7-yl)oxy)ethyl (tert- butoxycarbonyl)glycinate (62) was obtained in 87 % yield (1.20 g) as a white solid; mp 94- 95 °C as a mixture of two rotamers in a ratio 2.3: 1. The rotamers in the mixture are cis- trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR.JH NMR (600 MHz, DMSO-t / e) 5 8.02 (1H, d, J= 6.8 Hz, CH, B), 7.84 (1H, d, J= 7.5 Hz, CH, B), 7.69 (1H, d, J= 9.0 Hz, CH, A), 7.22-7.13 (3H, m, CH, B), 7.10-7.04 (1H, m, CH, A, 1H, m, CH, B), 6.99 (1H, d, J= 9.0 Hz, CH, A), 6.87 (1H, td, J= 13 Hz, J= 1.2 Hz, CH, A), 6.68 (1H, td, J= 13 Hz, J= 1.2 Hz, CH, A), 6.55 (1H, d, J= 13 Hz, CH, A), 6.20 (1H, s, CH, B), 6.07 (1H, s, CH, A), 4.44-4.32 (4H, m, CH2, B), 4.32-4.21 (3H, m, CH2, A), 4.19- 4.12 (1H, m, CH2, A), 3.97-3.89 (1H, m, CH2, A), 3.84-3.75 (1H, m, CH2, A), 3.64 (2H, d, J= 5.1 Hz, CH2, A), 3.62-3.50 (2H, m, CH2, B), 3.42-3.37 (2H, m, CH2, B), 2.90-2.54 (4H, m, CH2, A, 4H, m, CH2, B), 2.13-2.03 (1H, m, CH2, A), 1.97-1.79 (1H, m, CH2, A, 2H, m, CH2, B), 1.69-1.46 (2H, m, CH2, A, 2H, m, CH2, B), 1.34 (9H, s, CH3, A), 1.32 (9H, s, CH3, B), 0.96 (3H, t, J= 13 Hz, CH3, B), 0.89 (3H, t, J= 13 Hz, CH3, A). Isomer A:13C NMR (150 MHz, DMSO-cL) 8 170.5, 163.1, 159.4, 157.2, 156.7, 155.9, 150.5, 138.2, 133.0, 128.2, 126.9, 125.4, 125.4, 122.7, 115.5, 112.7, 110.8, 109.1, 78.4, 67.1, 62.8, 42.6, 41.9, 32.8, 28.3, 26.2, 23.4, 21.3, 13.7. IsomerB:13C NMR(150 MHz, DMSO-c / <) 8 170.4, 162.8, 159.6, 156.8, 156.6, 155.9, 150.2, 137.5, 130.0, 129.3, 126.9, 125.6, 124.7, 124.1, 115.0, 113.4, 111.2, 109.5, 78.4, 67.2, 62.9, 46.4, 41.8, 33.0, 28.3, 26.4, 23.4, 21.5, 13.9. Elem. Anal. Calcd. for C3IH36N2O8: C, 65.94; H, 6.43; N, 4.96. Found: C, 65.76; H, 6.29; N, 4.62.

[0400] EXAMPLE 77

[0401] 2-((2-oxo-4-propyl-8-(l,2,3,4-tetrahydroquinoline-l-carbonyl)-2H-chromen-7- yl)oxy)ethyl glycinate hydrochloride (63)

[0402] 2-((2-Oxo-4-propyl-8-(l,2,3,4-tetrahydroquinoline-l-carbonyl)-277-chromen-7- yl)oxy)ethyl ( / erLbutoxycarbonyl)glycinate (62) (0.50 g, 0.9 mmol) was dissolved in acetic acid (5 mL), bubbled with hydrogen chloride and the reaction mixture was stirred at rt for 2 hours. Diethyl ether (25 mL) was added and the formed solid was filtered off to give 2-((2-oxo-4-propyl-8-(l,2,3,4-tetrahydroquinoline-l-carbonyl)-2H-chromen-7- yl)oxy)ethyl glycinate hydrochloride (63) in 81 % yield (0.36 g) as a white solid; mp 119- 120 °C as a mixture of two rotamers in a ratio 2.4:1. The rotamers in the mixture are cis- trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR. ’H NMR (500 MHz, DMSO-tL) 8 8.51 (3H, bs, -(NH3)+, A, 3H, bs, -(NH3)+, B), 8.06 (1H, d, J= 8.8 Hz, CH, B), 7.89 (1H, d, J = 8.8 Hz, CH, B), 7.74 (1H, d, J = 9.0 Hz, CH, A), 7.28-7.19 (3H, m, CH, B), 7.14-7.04 (1H, m, CH, A, 1H, m, CH, B), 7.06 (1H, d, J= 9.0 Hz, CH, A), 6.92 (1H, t, J = 7.4 Hz, CH, A), 6.72 (1H, t, J= 7.4 Hz, CH, A), 6.59 (1H, d, J= 7.4 Hz, CH, A), 6.24 (1H, s, CH, B), 6.10 (1H, s, CH, A), 4.51-4.32 (3H, m, CH2, A, 4H, m, CH2, B), 4.28-4.21 (1H, m, CH2, A), 4.07-3.98 (1H, m, CH2, A), 3.81-3.71 (1H, m, CH2, A), 3.77 (2H, s, CH2, A), 3.66 (2H, s, CH2, B), 3.47-3.39 (2H, m, CH2, B), 2.93-2.58 (4H, m, CH2, A, 4H, m, CH2, B), 2.20-2,07 (1H, m, CH2, A), 1.98-1.85 (1H, m, CH2, A, 2H, m, CH2, B), 1.71-1.49 (2H, m, CH2, A, 2H, m, CH2, B), 0.99 (3H, t, J = 7.2 Hz, CH3, B), 0.91 (3H, t, J = 7.5 Hz, CH3, A). Isomer A:13C NMR (125 MHz, DMSO-d6) ? 167.8, 163.2, 159.4, 157.3, 156.8, 150.4, 138.2, 133.1, 128.2, 127.0, 125.6, 125.4, 122.8, 115.3, 112.8, 110.8, 109.3, 67.0, 63.7, 42.7, 39.8, 32.8, 26.3, 23.4, 21.3, 13.7. Isomer B:13C NMR (125 MHz, DMSO-d6) ? 167.8, 162.9, 159.7, 156.9, 156.5, 150.2, 137.5, 130.1, 129.4, 127.0, 125.7, 124.8, 124.1, 115.1, 113.5, 111.3, 109.7, 67.2, 63.9, 46.5, 39.7, 33.1, 26.5, 23.4, 21.5, 13.9. Elem. Anal. Calcd. for C26H29ClN2O6: C, 62.34; H, 5.84; N, 5.59. Found: C, 62.02; H, 5.62; N, 5.29. EXAMPLE 78 8-(3,4-Dihydro-2H-benzo[b][1,4]thiazine-4-carbonyl)-7-hydroxy-4-propyl-2H- chromen-2-one (64) 8-(3,4-Dihydro-2H-benzo[b][1,4]thiazine-4-carbonyl)-7-hydroxy-4-propyl-2H- chromen-2-one (64) was synthesized according to Scheme 3. EDC×HCl (0.53 g, 2.7 mmol) and DMAP (catalytic amount) were added to a solution of 7-hydroxy-2-oxo-4-propyl-2H- chromene-8-carboxylic acid (IVc) (0.3 g, 1.2 mmol) and 3,4-dihydro-2H- benzo[b][1,4]thiazine (0.69 g, 4.6 mmol) in dry CH2Cl2 (20 mL). The reaction mixture was stirred under inert atmosphere at rt for 24 hours. Then, the reaction mixture was washed with 0.5N HCl (3×20 mL), water (1×20 mL), and brine (1 × 20 mL). Organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Product was purified by column chromatography (mobile phase: hexane / EtOAc, 2:1).8-(3,4-Dihydro- 2H-benzo[b][1,4]thiazine-4-carbonyl)-7-hydroxy-4-propyl-2H-chromen-2-one (64) was obtained in 38 % yield (0.17 g) as a light beige solid; mp 97-99°C as a mixture of two rotamers in a ratio 2.8: 1. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR.JH NMR (500 MHz, DMSO-tL) 8 10.96 (1H, bs, OH, A, 1H, bs, OH, B), 7.77-7.73 (2H, m, CH, B), 7.57 (1H, d, J= 8.7 Hz, CH, A), 7.24-7.20 (1H, m, CH, B), 7.16-7.11 (2H, m, CH, B), 7.09 (1H, dd, J= 7.9 Hz, >1.2 Hz, CH, A), 6.96 (1H, d, J= 8.7 Hz, CH, B), 6.93-6.89 (1H, m, CH, A), 6.70-6.62 (3H, m, CH, A), 6.15 (1H, s, CH, B), 6.06 (1H, s, CH, A), 4.31-4.17 (1H, m, CH2, A), 4.03-3.91 (1H, m, CH2, A), 3.74-3.63 (2H, m, CH2, B), 3.40-3.09 (2H, m, CH2, A, 2H, m, CH2, B), 2.81-2.56 (2H, m, CH2, A, 2H, m, CH2, B), 1.70-1.49 (2H, m, CH2, A, 2H, m, CH2, B), 0.98 (3H, t, J= 7.2 Hz, CH3, B), 0.92 (3H, t, >7.3 Hz, CH3, A). Isomer A:13C NMR (125 MHz, DM SO) 5 163.9, 159.6, 157.3, 157.0, 151.5, 136.1, 128.0, 126.8, 126.3, 126.3, 124.8, 123.4, 112.8, 112.3, 110.9, 109.7, 40.4, 33.0, 27.5, 21.4, 13.8. Isomer B:13C NMR (125 MHz, DMSO-L) 8 163.9, 159.9, 157.2, 157.1, 151.2, 135.4, 126.9, 126.8, 126.7, 126.6, 125.9, 123.8, 112.9, 112.2, 111.6, 110.0, 40.9, 33.2, 28.3, 21.6, 13.9. Elem. Anal. Calcd. for C2IHI9NO4S: C, 66.12; H, 5.02; N, 3.67; S, 8.40. Found: C, 66.16; H, 4.98; N, 3.61; S, 8.28.

[0403] EXAMPLE 79

[0404] 2-Oxo-4-propyl-8-(l,2,3,4-tetrahydroquinoline-l-carbonyl)-2Z / -chromen-7-yl 2- butenoate (65)

[0405] 2-Oxo-4-propyl-8-(l,2,3,4-tetrahydroquinoline-l-carbonyl)-2 / / -chromen-7-yl 2- butenoate (65) was synthesized according to Scheme 1. 2-Butenoyl chloride (150 mg, 1.4 mmol, 0.12 mL) was added dropwise to a solution of 7-hydroxy-4-propyl-8-(l,2,3,4- tetrahydroqui noline- 1 -carbonyl )-27 / -chromen-2-one (3) (270 mg, 0.7 mmol), DMAP (9 mg, 0.07 mmol) and triethylamine (140 mg, 1.4 mmol, 0.2 mL) in dry toluene (10 mL) at 0 °C under inert atmosphere and the reaction mixture was stirred at 70 °C for 5 hours. After completion, the reaction mass was concentrated, diluted with diethyl ether, the formed precipitation was fdtered off, and diethyl ether was concentrated. The crude product was purified by column chromatography (mobile phase: hexane / EtOAc, 3:2). 2-Oxo-4-propyl- 8-(l,2,3,4-tetrahydroquinoline-l-carbonyl)-2 / / -chromen-7-yl 2-butenoate (65) was obtained in 94 % yield (300 mg) as a white solid; mp 51-52 °C as a mixture of two rotamers in a ratio 1.6: 1. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR.XH NMR (600 MHz, DMSO-t / g) 8 7.94 (1H, d, J = 8.7 Hz, CH, B), 7.90 (1H, dd, J = 7.8 Hz, J = 1.5 Hz, CH, B), 7.80 (1H, d, J= 8.9 Hz, CH, A), 7.33 (1H, d, J= 8.7 Hz, CH, B), 7.20-7.14 (1H, m, CH, A, 2H, m, CH, B), 7.13- 7.02 (2H, m, CH, A, 2H, m, CH, B), 6.88 (1H, td, J = 7.8 Hz, J = 1.3 Hz, CH, A), 6.65 (1H, td, J= 7.8 Hz, J= 1.3 Hz, CH, A), 6.53 (1H, dd, J= 7.8 Hz, J= 1.3 Hz, CH, A), 6.37 (1H, s, CH, B), 6.18 (1H, s, CH, A), 6.11-6.04 (1H, m, CH, A, 1H, m, CH, B), 4.09-4.01 (1H, m, CH2, A), 3.68-3.61 (1H, m, CH2, A), 3.50-3.43 (1H, m, CH2, B), 3.35-3.27 (1H, m, CH2, B), 2.91-2.60 (4H, m, CH2, A, 4H, m, CH2, B), 2.16-2.05 (2H, m, CH2, B), 1.93 (3H, dd, J= 7.0 Hz, J= 1.7 Hz, CH3, A), 1.90-1.77 (2H, m, CH2, A), 1.86 (3H, dd, J= 7.0 Hz, J= 1.6 Hz, CH3, B), 1.70-1.61 (2H, m, CH2, B), 1.61-1.48 (2H, m, CH2, A), 0.98 (3H, t, J = 7.4 Hz, CH3, B), 0.88 (3H, t, J = 7.3 Hz, CH3, A). Isomer A:13C NMR (150 MHz, DMSO-rC) 8 163.1, 161.9, 158.6, 156.2, 150.0, 149.7, 149.4, 137.8, 133.1, 128.3, 126.4,

[0406] 125.6, 125.3, 122.9, 120.8, 119.4, 119.3, 116.4, 112.9, 42.8, 32.8, 26.2, 23.3, 21.2, 18.2,

[0407] 13.6, Isomer B:13C NMR (150 MHz, DMSO-tC) 8 163.5, 161.8, 159.1, 156.4, 149.8,

[0408] 149.6, 148.7, 137.2, 130.0, 129.5, 126.3, 125.6, 125.0, 123.9, 120.6, 119.7, 119.7, 117.3, 113.5, 46.6, 33.1, 26.3, 23.3, 21.3, 18.2, 13.8. Elem. Anal. Calcd. for C26H2sNO5: C, 72.37; H, 5.84; N, 3.25. Found: C, 72.07; H, 5.97; N, 3.02.

[0409] EXAMPLE 80: 2-((2-Oxo-4-propyl-8-(l,2,3,4-tetrahydroquinoline-l-carbonyl)-2 / 7- chromen-7-yl)oxy)ethyl but-3 -enoate (66)

[0410] 2-Butenoyl chloride (250 mg, 2.4 mmol, 0.19 mL) was added dropwise to a solution of 7-(2 -hydroxyethoxy )-4-propyl-8-(l, 2,3, 4-tetrahydroquinoline- l -carbonyl)-277- chromen-2-one (15) (480 mg, 1.2 mmol), DMAP (14 mg, 0.12 mmol) and triethylamine (240 mg, 2.4 mmol, 0.33 mL) in dry toluene (15 mL) at 0 °C under inert atmosphere and the reaction mixture was stirred at 70 °C for 5 hours. After completion, the reaction mass was concentrated, diluted with diethyl ether, the formed precipitation was filtered off, and diethyl ether was concentrated. The crude product was purified by column chromatography (mobile phase: hexane / EtOAc, 3:2). 2-((2-Oxo-4-propyl-8-(l,2,3,4-tetrahydroquinoline-l- carbonyl)-27 / -chromen-7-yl)oxy)ethyl but-3-enoate (66) was obtained in 68 % yield (380 mg) as a white solid; mp 110-111 °C as a mixture of two rotamers in a ratio 1.6: 1. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR. 'H NMR (500 MHz, DMSO-cL) 8 8.06-8.02 (1H, m, CH, B), 7.88 (1H, d, J = 9.0 Hz, CH, B), 7.73 (1H, d, J= 9.0 Hz, CH, A), 7.25-7.14 (3H, m, CH, B), 7.05-7.00 (2H, m, CH, A, 1H, m, CH, B), 6.91 (1H, td, J = 7.2 Hz, J = 1.8 Hz, CH, A), 6.72-6.67 (1H, m, Hz, CH, A), 6.60-6.56 (1H, m, CH, A), 6.24 (1H, s, CH, B), 6.10 (1H, s, CH, A), 6.90-5.78 (1H, m, CH, A), 5.76-5.65 (1H, m, CH, B), 5.17-5.07 (2H, m, CH2, A), 5.06-4.98 (2H, m, CH2, B), 4.47-4.26 (3H, m, CH2, A, 4H, m, CH2, B), 4.25-4.19 (1H, m, CH2, A), 4.05-3.94 (1H, m, CH2, A), 3.82-3.73 (1H, m, CH2, A), 3.50-3.35 (2H, m, CH2, B), 3.12 (2H, dt, J= 6.8 Hz, J= 1.5 Hz, CH3, A), 3.05-2.92 (2H, m, CH2, B), 2.91- 2.60 (4H, m, CH2, A, 4H, m, CH2, B), 2.18-2.05 (1H, m, CH2, A), 1.97-1.83 (1H, m, CH2, A, 2H, m, CH2, B), 1.71-1.50 (2H, m, CH2, A, 2H, m, CH2, B), 0.99 (3H, t, J = 7.2 Hz, CH3, B), 0.91 (3H, t, J =7.3 Hz, CH3, A). Isomer A:13C NMR (125 MHz, DMSO-tfe) 8 171.0, 163.1, 159.4, 157.3, 156.8, 150.5, 138.2, 133.0, 130.8, 128.2, 126.9, 125.5, 125.3, 122.7, 118.7, 115.2, 112.7, 110.8, 109.1, 67.1, 62.6, 42.6, 38.4, 32.8, 26.2, 23.4, 21.3, 13.7. Isomer B:13C NMR (125 MHz, DMSO-tL) 8 170.9, 162.8, 159.7, 156.9, 156.6, 150.2, 137.5, 130.7, 130.0, 129.3, 126.9, 125.6, 124.7, 124.1, 118.5, 1 15.0, 1 13.4, 111.2, 109.5, 67.2, 62.6, 46.4, 38.2, 33.0, 26.5, 23.4, 21.5, 13.9. Elem. Anal. Calcd. for C28H29NO6: C, 70.72; H, 6.15; N 2.95. Found: C, 70.56; H, 6.00; N, 3.22.

[0411] EXAMPLE 81: A-(2-((2-Oxo-4-propyl-8-(l,2,3,4-tetrahydroquinoline-l-carbonyl)- 27 / -chromen-7-yl)oxy)ethyl)but-2-enamide (67)

[0412] 2-Butenoyl chloride (30 mg, 0.30 mmol, 0.03 mL) was added dropwise to a solution of 2-((2-oxo-4-propyl-8-(l,2,3,4-tetrahydroquinoline-l-carbonyl)-2 / 7-chromen-7- yl)oxy)ethan-l-amin hydrochloride (17) (66 mg, 0.15 mmol), DMAP (2 mg, 0.015 mmol) and triethylamine (45 mg, 0.45 mmol, 0.06 mL) in dry toluene (5 mL) at 0 °C under inert atmosphere and the reaction mixture was stirred at 70 °C overnight. After completion, the reaction mass was concentrated and the crude product was purified by column chromatography (mobile phase: CHCh / MeOH, 9: 1). A-(2-((2-Oxo-4-propyl-8-(l,2,3,4- tetrahydroquinoline-1 -carbonyl)-2 / / -chromen-7-yl)oxy)ethyl)but-2-enamide (67) was obtained in 50 % yield (50 mg) as a white solid; mp 155-156 °C as a mixture of two rotamers in a ratio 2.1: 1. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR. 'H NMR (600 MHz, DMSO-cC) 8 8.02 (1H, t overlapped, J= 5.6 Hz, NH, A), 8.07-8.00 (1H, m, CH, B), 7.95 (1H, t, J= 7.4 Hz, NH, B), 7.84 (1H, d, J= 8.9 Hz, CH, B), 7.69 (1H, d, J= 9.0 Hz, CH, A), 7.23-7.14 (3H, m, CH, B), 7.10-7.00 (2H, m, CH, A, 1H, m, CH, B), 6.87 (1H, t, J= 7.5 Hz, CH, A), 6.67- 6.55 (2H, m, CH, A), 6.54-6.46 (1H, m, CH, A, 1H, m, CH, B), 6.19 (1H, s, CH, B), 6.05 (1H, s, CH, A), 5.88-5.83 (1H, m, CH, A), 5.79-5.75 (1H, m, CH, B), 4.27-4.12 (2H, m, CH2, B), 4.12-4.03 (1H, m, CH2, A), 4.03-3.91 (2H, m, CH2, A), 3.79-3.68 (1H, m, CH2, A), 3.50-3.31 (2H, m, CH2, A, 4H, m, CH2, B), 2.88-2.56 (4H, m, CH2, A, 4H, m, CH2, B), 2.15-2.05 (1H, m, CH2, A), 1.96-1.76 (1H, m, CH2, A, 2H, m, CH, B), 1.73 (3H, dd, J = 6.8 Hz, J= 1 .3 Hz, CH3, A), 1 .69 (3H, dd, J= 7.0 Hz, J= 1.3 Hz, CH3, B), 1 .66-1 .59 (2H, m, CH2, B), 1.59-1.47 (2H, m, CH2, A), 0.96 (3H, t, J= 7.2 Hz, CH3, B), 0.88 (3H, t, J = 7.3 Hz, CH3, A). Isomer A:13C NMR (150 MHz, DMSO-rL) 8 165.5, 163.2, 159.4, 157.5,

[0413] 156.7, 150.5, 138.3, 138.2, 133.0, 128.1, 127.0, 125.7, 125.4, 125.3, 122.8, 115.1, 112.5,

[0414] 110.7, 109.1, 67.4, 42.6, 38.0, 32.8, 26.2, 23.4, 21.3, 17.5, 13.7. Isomer B:13C NMR (150 MHz, DMSO-rL) 8 165.4, 162.9, 159.7, 156.9, 156.8, 150.2, 138.1, 137.5, 130.0, 129.2, 126.9, 125.7, 125.5, 124.6, 124.3, 115.0, 113.2, 111.1, 109.5, 67.4, 46.4, 38.1, 33.0, 26.5, 23.4, 21.5, 17.5, 13.9. Elem. Anal. Calcd. for C28H30N2O6: C, 70.87; H, 6.37; N, 5.90. Found: C, 70.52; H, 6.15; N, 6.01.

[0415] EXAMPLE 82: 2-Oxo-4-propyl-8-(l,2,3,4-tetrahydroquinoline-l-carbonyl)-277- chromen-7-yl acrylate (68)

[0416] 2-Oxo-4-propyl-8-(l,2,3,4-tetrahydroquinoline-l-carbonyl)-27 / -chromen-7-yl acrylate (68) was synthesized according to Scheme 1. Acryloyl chloride (90 mg, 1 mmol, 0.1 mL) was added dropwise to a solution of 7-hydroxy-4-propyl-8-(l,2,3,4- tetrahydroquinoline-l-carbonyl)-2 / 7-chromen-2-one (3) (300 mg, 0.8 mmol) and triethylamine (170 mg, 1.6 mmol, 0.23 mL) in dry THF (10 mL) at 0 °C under inert atmosphere and the reaction mixture was stirred under inert atmosphere at rt for 2 hours. After completion, the reaction mass was diluted with water (15 mL), extracted with EtOAc (3x 15 mL), combined organic layers were washed with water (1 x20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (mobile phase: hexane / EtOAc, 3:2). 2-Oxo-4-propyl- 8-(l,2,3,4-tetrahydroquinoline-l-carbonyl)-2J7-chromen-7-yl acrylate (68) was obtained in 68 % yield (230 mg) as a white solid; mp 46-47 °C as a mixture of two rotamers in a ratio 1.8:1. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR 'H NMR (600 MHz, DMSO-ak) 7.97 (1H, d, J = 8.8 Hz, CH, B), 7.89 (1H, dd, J= 7.8 Hz, J= 1.3 Hz, CH, B), 7.82 (1H, d, J= 8.7 Hz, CH,

[0417] A), 7.38 (1H, d, J = 8.8 Hz, CH, B), 7.21 (1H, d, J = 8.7 Hz, CH, A), 7.19-7.14 (2H, m, CH, B), 7.09 (1H, td, J= 7.8 Hz, J= 1.3 Hz, CH, B), 7.05 (1H, dd, J= 7.5 Hz, J= 1.2 Hz, CH, A), 6.88 (1H, td, J= 7.5 Hz, J= 1.2 Hz, CH, A), 6.66 (1H, td, J= 7.5 Hz, J= 1.2 Hz, CH, A), 6.55-6.52 (1H, m, CH, A), 6.50-6.45 (1H, m, CH2, A, 1H, m, CH, B), 6.40-6.31 (1H, m, CH, A, 1H, m, CH2, B, 1H, m, CH, B), 6.19 (1H, s, CH, A), 6.17 (1H, dd, J= 10.3 Hz, J= 1.2 Hz, CH, A), 6.13 (1H, dd, J= 10.3 Hz, J= 1.2 Hz, CH, B), 4.07-3.98 (1H, m, CH2, A), 3.72-3.64 (1H, m, CH2, A), 3.53-3.45 (1H, m, CH2, B), 3.36-3.28 (1H, m, CH2,

[0418] B), 2.928-2.61 (4H, m, CH2, A, 4H, m, CH2, B), 2.16-2.06 (2H, m, CH2, B), 1.92-1.77 (2H, m, CH2, A), 1.70-1.61 (2H, m, CH2, B), 1.61-1.47 (2H, m, CH2, A), 0.98 (3H, t, J = 7.3 Hz, CH3, B), 0.88 (3H, t, J= 7.3 Hz, CH3, A). Isomer A:13C NMR (150 MHz, DMSO-tfe) 8 163.1, 161.8, 158.6, 156.2, 150.1, 149.4, 137.7, 134.9, 133.1, 128.4, 127.0, 126.5, 125.6,

[0419] 125.3, 122.9, 119.3, 119.3, 116.6, 113.0, 42.8, 32.8, 26.2, 23.3, 21.2, 13.6. Isomer B:13C NMR (150 MHz, DMSO-^) 8 163.5, 161.7, 159.1, 156.4, 149.8, 148.4, 137.1, 135.0, 130.1, 129.5, 126.9, 126.5, 125.6, 125.1, 123.9, 119.6, 119.6, 117.5, 113.6, 46.6, 33.1, 26.2,

[0420] 23.3, 21.3, 13.8. Elem. Anal. Calcd. for C25H23NO5: C, 71.93; H, 5.55; N, 3.36. Found: C, 71.62; H, 5.14; N, 3.24.

[0421] EXAMPLE 83: 2-((2-Oxo-4-propyl-8-(l ,2,3,4-tetrahydroquinoline-l -carbonyl)-2 / 7- chromen-7-yl)oxy)ethyl acrylate (69)

[0422] Acryloyl chloride (76 mg, 0.8 mmol, 0.08 mL) was added dropwise to a solution of 7- (2-hydroxyethoxy)-4-propyl-8-( l,2,3,4-tetrahydroquinoline-l -carbonyl)-2 / / -chromen-2- one (15) (300 mg, 0.7 mmol) and triethylamine (140 mg, 1.4 mmol, 0.2 mL) in dry THE (10 mL) under inert atmosphere and the reaction mixture was stirred under inert atmosphere at rt for 2 hours. After completion, the reaction mass was diluted with water (15 mL), extracted with EtOAc (3>< 15 mL), combined organic layers were washed with water (1 x20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (mobile phase: hexane / EtOAc, 1 : 1). 2-((2-Oxo-4-propyl-8-(l,2,3,4-tetrahydroquinoline-l-carbonyl)-277- chromen-7-yl)oxy)ethyl acrylate (69) was obtained in 53 % yield (180 mg) as a white solid; mp 127-128 °C as a mixture of two rotamers in a ratio 2: 1. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR.3H NMR (600 MHz, DMSO-rC) 8 7.99 (1H, d, J = 7.9 Hz, CH, B), 7.85 (1H, d, J = 9.0 Hz, CH, B), 7.70 (1H, d, J= 9.0 Hz, CH, A), 7.20 (1H, d, J= 9.0 Hz, CH, B), 7.18-7.12 (2H, m, CH, B), 7.10-6.98 (2H, m, CH, A, 1H, m, CH, B), 6.86 (1H, td, J= 7.5 Hz, J= 1.4 Hz, CH, A), 6.64 (1H, td, J= 7.5 Hz, J= 1.4 Hz, CH, A), 6.54 (1H, d, J= 7.5 Hz, CH, A), 6.29 (1H, dd, J= 17.4 Hz, J= 1.7 Hz, CH2, A), 6.20 (1H, s, CH, B), 6.16 (1H, dd, J= 17.3 Hz, J= 1.7 Hz, CH2, B), 6.13 (1H, dd, J= 17.4 Hz, J= 10.8 Hz, CH, A), 6.06 (1H, s, CH, A), 6.02 (1H, dd, J= 17.3 Hz, J= 10.5 Hz, CH, B), 5.92 (1H, dd, J= 10.6 Hz, J= 1.7 Hz, CH2,

[0423] A), 5.82 (1H, dd, J= 10.5 Hz, J= 1.7 Hz, CH2, B), 4.46-4.36 (4H, m, CH2, B), 4.35-4.28 (3H, m, CH2, A), 4.28-4.19 (1H, m, CH2, A), 3.96-3.88 (1H, m, CH2, A), 3.79-3.71 (1H, m, CH2, A), 3.51-3.22 (2H, m, CH2, B), 2.88-2.57 (4H, m, CH2, A, 4H, m, CH2, B), 2.12- 2.02 (1H, m, CH2, A), 1.92-1.78 (1H, m, CH2, A, 2H, m, CH2, B), 1.67-1.59 (2H, m, CH2,

[0424] B), 1.59-1.46 (2H, m, CH2, A), 0.96 (3H, t, J= 7.4 Hz, CH3, B), 0.88 (3H, t, J= 7.4 Hz, CH3, A). Isomer A:13C NMR (150 MHz, DMSO-t / <) 5 165.5, 163.1, 159.4, 157.2, 156.7,

[0425] 150.5, 138.2, 132.2, 128.2, 128.1, 127.9, 126.9, 125.5, 125.3, 122.7, 115.2, 112.7, 110.8, 109.0, 67.0, 62.7, 42.6, 32.8, 26.2, 23.3, 21.3, 13.7. Isomer B:13C NMR (150 MHz, DMSO-t / e) 8 165.4, 162.8, 159.7, 156.9, 156.6, 150.2, 137.5, 132.9, 132.0, 129.9, 129.2, 126.9, 125.5, 124.7, 124.1, 115.0, 113.4, 111.2, 109.4, 67.2, 62.6, 46.4, 33.0, 26.4, 23.4,

[0426] 21.5, 13.9. Elem. Anal. Calcd. for C27H27NO6: C, 70.27; H, 5.90; N 3.04. Found: C, 70.06; H, 6.02; N, 3.12.

[0427] EXAMPLE 84

[0428] 8-Hydroxy-7-(l, 2,3, 4-tetrahydroquinoline-l -carbonyl)- 1,2,3, 4-tetrahydro-5H- chromeno[3,4-c]pyridin-5-one (70) NH

[0429] 8-Hydroxy-7-(l, 2,3, 4-tetrahydroquinoline-l -carbonyl)- 1,2,3, 4-tetrahydro-5H- chromeno[3,4-c]pyridin-5-one (70) was synthesized by the reaction of ethyl 8-hydroxy-5- oxo-7-(l, 2, 3, 4-tetrahydroquinoline-l -carbonyl)-l,5-dihydro-2H-chromeno[3,4-c] pyridine-3(4H)-carboxylate (52) (0.2 g, 0.446 mmol) with potassium hydroxide (0.09 g, 2.25 mmol) in water (3 mL). The reaction mixture was heated to 100 °C for 3 hours. After cooling, the reaction mixture was acidified to slightly basic pH and then extracted with EtOAc (3 x 30 mL). The organic layer was washed with brine (2 x 20 mL) and dried over anhydrous potassium sulfate. The product 70 was purified by column chromatography (mobile phase: CHCI3 / CH3OH, 4:1) and was obtained in 15 % yield (0.025 g) as a yellowish solid; mp 240-242 °C (with decomposition) as a mixture of two rotamers in a ratio 1.7: 1. The rotamers in the mixture are cis-trans amide bond rotamers in dynamic equilibrium, distinguishable by NMR ’H NMR (600 MHz, DMSO) 5 8.07 (1H, d, J= 8.1 Hz, CH, B), 7.53 (1H, d, J= 8.8 Hz, CH, B), 7.37 (1H, d, J= 8.8 Hz, CH, A), 7.20-7.12 (2H, m, CH, B), 7.07 (1H, d, J= 8.1 Hz, CH, B), 7.04 (1H, d, J= 7.5 Hz, CH, A), 6.97 (1H, d, J - 8.8 Hz, CH, B), 6.87 (1H, td, J= 7.5 Hz, J= 1.7 Hz, CH, A), 6.77 (1H, d, J= 8.8 Hz, CH, A), 6.73-6.65 (2H, m, CH, A), 4.11-3.98 (1H, m, CH2, A), 3.67-3.55 (1H, m, CH2, A), 3.54-3.47 (2H, m, CH2, B), 3.46-3.34 (2H, m, CH2, A, 2H, m, CH2, B), 3.00-2.92 (2H, m, CH2, B), 2.92-2.84 (2H, m, CH2, A), 2.84-2.63 (2H, m, CH2, A, 4H, m, CH2, B), 2.62-2.51 (2H, m, CH2, A), 2.16-2.04 (1H, m, CH2, A), 1.99-1.76 (1H, m, CH2, A, 2H, m, CH2, B). Isomer A:13C NMR (150 MHz, DMSO) 8 164.1, 159.2, 158.0, 149.4, 147.3, 138.6, 132.2, 128.0, 125.4, 125.3, 125.9, 122.8, 117.5, 113.4,

[0430] 112.8, 110.8, 42.7, 42.4, 41.2, 26.2, 24.5, 23.6. Isomer B:13C NMR (150 MHz, DMSO) 8 163.9, 159.5, 158.0, 149.3, 147.5, 137.8, 129.8, 129.3, 125.5, 124.9, 124.5, 124.1,

[0431] 117.9, 113.3, 113.1, 111.3, 46.5, 42.8, 41.3, 26.6, 24.6, 23.4. Elem. Anal. Calcd for C22H20N2O4: C, 70.20; H, 5.36; N, 7.44. Found: C, 70.01 H, 5.15; N, 7.21. EXAMPLE 85

[0432] (2,3-Diamino-6-methoxyphenyl)(3,4-dihydroquinolin-l(2H)-yl)methanone (Va)

[0433] (intermediate compound)

[0434] (2,3-Diamino-6-methoxyphenyl)(3,4-dihydroquinolin-l(2H)-yl)methanone (Va) was synthesized according to Scheme 5.

[0435] To a solution of 2-amino-6-methoxy-3-nitrobenzoic acid (5.40 g, 25.45 mmol) in THF (80 ml), 1,2,3,4-tetrahydroquinoline (11.86 g, 11.2 ml, 89.08 mmol) was added, followed by addition of EDCXHC1 (9.76 g, 50.90 mmol) and DMAP (0. 16 g, 1.27 mmol). The reaction mixture was stirred at rt for 24 h. The solvent was evaporated, and the residue was dissolved in EtOAc (200 ml) and washed with IM HC1 (3 * 150 ml), saturated solution of NaHCCh (3 x 150 ml), and brine (2 x 150 ml). The organic phase was dried over anhydrous sodium sulfate and purified by column chromatography (mobile phase: hexane / EtOAc, 3 : 1). 2 -Amino-6-m ethoxy-3 -nitrophenyl)(3,4-dihydroquinolin-l(2H)- yl)methanone was obtained in 66 % yield (5.5 g) as a yellow solid; mp 149-151 °C, and used in the following reaction.

[0436] (2-amino-6-methoxy-3-nitrophenyl)(3,4-dihydroquinolin-l(2H)-yl)methanone (5.50 g, 16.80 mmol) was stirred with hydrogen in MeOH (120 ml) in the presence of 10% Pd / C (0.89 g, 0.84 mmol) at rt for 12 h. After completion, Pd / C was filtered off and the solution was concentrated under reduced pressure to give a product as a brown oil. (2,3- diamino-6-methoxyphenyl)(3,4-dihydroquinolin-l(2H)-yl)methanone (Va) was used in the following reactions without further purification.

[0437] EXAMPLE 86

[0438] 7-Methoxy-8-(l,2,3,4-tetrahydroquinoline-l-carbonyl)quinoxalin-2(lH)-one (71)

[0439] 7-Methoxy-8-(l,2,3,4-tetrahydroquinoline-l-carbonyl)quinoxalin-2(lH)-one (71) was synthesized according to Scheme 5. To a solution of (2,3-diamino-6- methoxyphenyl)(3,4-dihydroquinolin-l(2H)-yl)methanone (Va) (4.99 g, 16.78 mmol) in MeOH (100 ml) cooled at 0 °C, ethyl glyoxylate (50% solution in toluene (4.33 ml, 21.81 mmol) was added. The reaction mixture was stirred at rt for 18 h. The solvent was evaporated, and the residue was purified by column chromatography (mobile phase: CHCh / MeOH, 20: 1). 7-Methoxy-8-(l,2,3,4-tetrahydroquinoline-l-carbonyl)quinoxalin- 2(lH)-one (71) was obtained in 44 % (4.31 g) yield as a white solid; mp 233-234 °C.

[0440] 1H NMR (600 MHz, CDC13) 8 10.90 (1H, bs, OH), 8.15 (1H, s, CH), 7.76 (1H, d, .7=9.0 Hz, CH), 7.17 (1H, d, .7=7.7 Hz, CH), 6.99 (1H, t, .7=7.7 Hz, CH), 6.70 (1H, t, .7=7.7 Hz, CH), 6.54 (1H, d, .7=9.0 Hz, CH), 6.28 (1H, d, .7=7.7 Hz, CH), 4.71-4.50 (1H, m, CH2), 3.95-3.65 (2H, m, CH2), 3.49-3.33 (1H, m, CH2), 3.24 (3H, s, CH3), 2.41-2.19 (1H, m, CH2), 1.93-1.81 (1H, m, CH2).13C NMR (125 MHz, CDCI3) 8 164.5, 157.0, 154.8, 148.6, 138.6, 133.6, 132.6, 132.0, 127.8, 127.6, 125.5, 125.4, 122.2, 109.3, 107.1, 55.5, 43.3, 26.8, 23.8. Elem. Anal. Calcd for C19H17N3O3: C, 68.05; H, 5.11; N, 12.53; O, 14.31

[0441] EXAMPLE 87

[0442] 7-Methoxy-3-methyl-8-(l,2,3,4-tetrahydroquinoline-l-carbonyl)quinoxalin-

[0443] 2(lH)-one (72)

[0444] 7-Methoxy-3-methyl-8-(l,2,3,4-tetrahydroquinoline-l-carbonyl)quinoxalin-

[0445] 2(lH)-one (72) was synthesized according to Scheme 5. To a solution of (2,3-diamino-6- methoxyphenyl)(3,4-dihydroquinolin-l(2H)-yl)methanone (Va) (0.72 g; 2.42 mmol) in MeOH (50 ml) cooled at 0 °C, ethyl 2-oxopropanoate (0.37 g, 0.35 ml, 3.14 mmol) was added. The reaction mixture was stirred at rt for 18 h. The solvent was evaporated, and the residue was purified by column chromatography (mobile phase: CHCh / MeOH, 20: 1). 7- Methoxy-3-methyl-8-(l,2,3,4-tetrahydroquinoline-l-carbonyl)quinoxalin-2(lH)-one (72) was obtained in 27 % yield (0.23 g) as a white solid; mp 243-244 °C.

[0446] ‘HNMR (600 MHz, CDC13) 5 9.99 (1H, bs, OH), 7.67 (1H, d, J=8.8 Hz, CH), 7.13 (1H, d, .7=7,5 Hz, CH), 6.95 (1H, t, J=7.5 Hz, CH), 6.70-6.60 (1H, m, CH), 6.49 (1H, d, .7=8,8 Hz, CH), 6.24 (1H, d, J=7.5 Hz, CH), 4.67-4.48 (1H, m, CH2), 3.45-3.32 (1H, m, CH2), 3.20 (3H, s, CH3), 2.89-2.67 (2H, m, CH2), 2.53 (3H, s, CH3), 2.38-2.19 (1H, m CH2), 1.92-1.77 (1H, m CH2).13C NMR (125 MHz, CDC13) 8 164.7, 156.8, 156.0, 155.0, 138.7, 133.5, 132.0, 131.4, 127.6, 127.3, 125.4, 125.3, 122.3, 109.1, 106.9, 55.4, 42.2, 26.8, 23.8, 20.4. Elem. Anal. Calcd for C20HI9N3O3: C, 68.75; H, 5.48; N, 12.03. Found: C, 69.01; H, 5.54; N, 11.84.

[0447] EXAMPLE 88

[0448] 3-Ethyl-7-methoxy-8-(l,2,3,4-tetrahydroquinoline-l-carbonyl)quinoxalin-2(lH)- one (73)

[0449] N

[0450] N H N'"

[0451] 3-Ethyl-7-methoxy-8-(l,2,3,4-tetrahydroquinoline-l-carbonyl)quinoxalin-2(lH)- one (73) was synthesized according to Scheme 5. To a solution of (2,3-diamino-6- methoxyphenyl)(3,4-dihydroquinolin-l(2H)-yl)methanone (Va) (0.68 g, 2.29 mmol) in MeOH (50 ml) cooled at 0 °C ethyl 2-oxobutano...

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula (II): or a pharmaceutically acceptable salt thereof, whereinR1is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, CH2OH, CORel, ORal, and SRal;Relis selected from H, OH, C1.3 alkoxy, NH2, C1-3 alkylamino, and di(C1-3 alkyl)amino;R3and R4are each independently selected from H, C1-6 alkyl, halogen, CN, OH, NO2, OCN, SCN, SeCN, N3, C1-3 alkoxy, C1-3 haloalkoxy, NH2, C1-3 alkylamino, di( C1-3 alkyl)amino, and Cy1; or R1and R3taken together with the atoms connecting them form a five, six, or seven-membered carbocyclic ring, a six-membered aromatic ring, a five, six, or seven- membered heterocyclic ring containing one or more heteroatoms independently selected from O and NR5, or a five or six-membered heteroaromatic ring containing one or more heteroatoms independently selected from O, N and NR3, wherein each R3is independently selected from H, C 1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C(O)-C1-6 alkyl, C(O)-C2-6 alkenyl, C(O)-C2.6alkynyl, C(O)- C3-6 cycloalkyl, and C(O)- C1-6 alkoxy;Y = O, S, CH2, or NRb3;R2is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C(O)-C1-6 alkyl, C(O)-C1-6 haloalkyl, C(O)-C2-6 alkenyl, C(O)-C2-6 alkynyl, and C(O)-C3-6 cycloalkyl, wherein each of said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C(O)-C1-6 alkyl, C(O)-C1-6 haloalkyl, C(O)-C2-6 alkenyl, C(O)-C2-6 alkynyl,and C(O)-C3-6 cycloalkyl is optionally substituted with a substituent elected from ORa2and NRc2Rd2; Ralis selected from C1-6 alkyl and C1-6 haloalkyl;Ra2, Rc2, and Rd2are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C(=O)ORal, C(O)-C1-6 alkyl, C(O)-C2-6 alkenyl, and C(O)-C1-6 haloalkyl, wherein said C1-6 alkyl, C(O)-C1-6 alkyl, and C(O)-C1-6 haloalkyl is optionally independently substituted with 1, 2, or 3 substituents independently selected from Rb2; or Re2and Rd2together with the N atom to which they are attached form 4 to 7- membered heterocyclic ring, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rb3; each Rb2is independently selected from CN, OH, NO2, OCN, SCN, SeCN, N3, C1.3 alkoxy, C1-3 haloalkoxy, NH2, C1-3 alkylamino, di(C1-3 alkyl)amino, C1-6 alkoxycarbonyl, (C1-6 alkoxycarbonyl)amino, and Cy1; each Rb3is independently selected from C1-6 alkyl and Rb2, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from Rb2; each Cy1is independently selected from Ce-io aryl and 5-10 membered heteroaryl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCyl; and each RCylis independently selected from C1-3 alkyl, C1.3 haloalkyl, halo, CN, NO2, OCN, SCN, SeCN, N3, OH, C1.3 alkoxy, C1-3 haloalkoxy, NH2, C1-3 alkylamino, di (C 1-3alkyl)amino, tri(C1-3 alkyl)amino, C(=O)OH, C(=0)(C1-6 alkoxy), C(=O)H, and C(=O)(Ci-6alkyl).

2. The compound of claim 1, wherein the compound is a compound of Formula (I):

3. A compound of Formula (III):(III), or a pharmaceutically acceptable salt thereof, whereinR3and R4are each independently selected from H, C1-6 alkyl, halogen, CN, OH, NO2, OCN, SCN, SeCN, N3, C1-3 alkoxy, C1-3 haloalkoxy, NH2, C1-3 alkylamino, di(C1-3 alkyl)amino, and Cy1;Y = O, S, CH2, or NRb3 ;Z = N or CR1;A = NH or O; q = 0 or 1;R1is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, CH2OH, CORel, ORal, and SRal;Re1is selected from H, OH, C1.3 alkoxy, NH2, C1-3 alkylamino, and di(C1-3 alkyl)amino;R2is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C(O)-C1-6 alkyl, C(O)-C1-6 haloalkyl, C(O)-C2-6 alkenyl, C(O)-C2-6 alkynyl, and C(O)-C3-6 cycloalkyl, wherein each of said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C(O)-C1-6 alkyl, C(O)-C1-6 haloalkyl, C(O)-C2-6 alkenyl, C(O)-C2-6 alkynyl, and C(O)-C3-6 cycloalkyl is optionally substituted with a substituent elected from ORa2and NRc2Rd2;Ralis selected from C1-6 alkyl and C1-6 haloalkyl;Ra2, Re2, and Rd2are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C(=O)ORal, C(O)-C1-6 alkyl, C(O)-C2-6 alkenyl, and C(O)-C1-6 haloalkyl, wherein said C1-6 alkyl, C(O)-C1-6 alkyl, and C(O)-C1-6 haloalkyl is optionally independently substituted with 1, 2, or 3 substituents independently selected from Rb2; or Rc2and Rd2together with the N atom to which they are attached form 4 to 7- membered heterocyclic ring, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rb3; each Rb2is independently selected from CN, OH, NO2, OCN, SCN, SeCN, N3, C1.3 alkoxy, C1-3 haloalkoxy, NH2, C1-3 alkylamino, di(C1-3 alkyl)amino, C1-6 alkoxycarbonyl, (C1-6 alkoxycarbonyl)amino, and Cy1; each Rb3is independently selected from C1-6 alkyl and Rb2, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from Rb2; each Cy1is independently selected from Ce-io aryl and 5-10 membered heteroaryl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCyl; and each RCylis independently selected from C1-3 alkyl, C1-3 haloalkyl, halo, CN, NO2, OCN, SCN, SeCN, N3, OH, C1.3 alkoxy, C1-3 haloalkoxy, NH2, C1-3 alkylamino, di(C1-3 alkyl)amino, tri(C1-3 alkyl)amino, C(=O)OH, C(=O)(C1-6 alkoxy), C(=O)H, and C(=O)(C1-6 alkyl); or R1and R3taken together with the atoms connecting them form a five, six, or seven-membered carbocyclic ring, a six-membered aromatic ring, a five, six, or seven- membered heterocyclic ring containing one or more heteroatoms independently selected from O and NR5, or a five or six-membered heteroaromatic ring containing one or more heteroatoms independently selected from O, N and NR5, wherein each R5isindependently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C(O)-C1-6 alkyl, C(O)-C2-6 alkenyl, C(O)-C2-6 alkynyl, C(O)-C3-6 cycloalkyl, and C(O)- Ci -6 alkoxy.

4. The compound of claim 1, 2 or 3, wherein R1is C1-6 alkyl.

5. The compound of claim 1, 2 or 3, wherein R1is C1-6 haloalkyl.

6. The compound of claim 1, 2 or 3, wherein R1is C3-6 cycloalkyl.

7. The compound of claim 1, 2 or 3, wherein R1is selected from C1-3 alkoxy and C1-3 haloalkoxy.

8. The compound of any one of claims 1-7, wherein R2is H.

9. The compound of any one of claims 1-7, wherein R2is C1-6 alkyl.

10. The compound of any one of claims 1-7, wherein R2is C1-6 haloalkyl.

11. The compound of any one of claims 1-7, wherein R2is C1-6 alkyl-ORa2.

12. The compound of claim 11, wherein R2is C1-6 alkyl-OH.

13. The compound of claim 11, wherein R2is C1-6 alkyl substituted with C1-3 alkoxy or C1.3 haloalkoxy.

14. The compound of any one of claims 1-7, wherein R2is C(O)-C1-6 alkyl.

15. The compound of any one of claims 1-7, wherein R2is C1-6 alkyl-NRc2Rd2.

16. The compound of claim 15, wherein R2is C1-6 alkyl-NH?.

17. The compound of claim 15, wherein R2is C1-6 alkyl-NHC(=O)ORal.

18. The compound of claim 15, wherein R2is C1-6 alkyl-NH(C1-6 alkyl).

19. The compound of claim 15, wherein R2is C1-6 alkyl-N(C1-6 alkyl)?.

20. The compound of claim 15, wherein Rc2and Rd2together with the N atom to which they are attached form 4 to 7-membered heterocyclic ring, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rb3.21 . The compound of claim 20, wherein the heterocyclic ring has formula: wherein: m is 1 or 2; andX is selected from CH2, CHRb3, O, S, NH, and NRb3.

22. The compound of claim 21, wherein m is 1.

23. The compound of claim 21, wherein m is 2.

24. The compound of claim 21, wherein the heterocyclic ring has formula:

25. The compound of claim 21, wherein the heterocyclic ring has formula:

26. The compound of claim 21, wherein the heterocyclic ring has formula:

27. The compound of claim 26, wherein the heterocyclic ring has formula:

28. The compound of claim 26, wherein Rb3is C1-6 alkyl.

29. The compound of claim 26, wherein Rb3is C1-6 alkyl substituted with Cy1.

30. The compound of any one of claims 1- 29, wherein R3is H.

31. The compound of any one of claims 1- 29, wherein R5is C1-6 alkyl.

32. The compound of any one of claims 1 - 29, wherein R3is C(O)-C1-6 alkyl.

33. The compound of any one of claims 3-32, wherein Z = N.

34. The compound of any one of claims 3-32, wherein Z = CR1.

35. The compound of any one of claims 3-32, wherein A = NH, 36. The compound of any one of claims 3-32, wherein A = O.

37. The compound of any one of claims 3-32, wherein q = 0.

38. The compound of any one of claims 3-32, wherein q = 139. A compound selected from any one of the following compounds:BrHO3738394041, or a pharmaceutically acceptable salt thereof.

40. A compound selected from any one of the following compounds:66, or a pharmaceutically acceptable salt thereof.

41. A compound selected from any one of the following compounds:O52, or a pharmaceutically acceptable salt thereof.

42. A compound selected from any one of the following compounds:, or a pharmaceutically acceptable salt thereof.

43. A pharmaceutical composition comprising a compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

44. A method of treating or preventing a disease or condition associated with topoisomerase lip, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1- 42, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 43.

45. The method of claim 44, wherein the disease or condition is heart dysfunction or heart failure.

46. The method of claim 44, wherein the disease or condition is cardiotoxicity.

47. The method of claim 46, wherein the cardiotoxicity is induced by administering to the subject an anthracy cline chemotherapeutic agent, or a pharmaceutically acceptable salt thereof.

48. The method of claim 47, wherein the anthracycline chemotherapeutic agent is selected from doxorubicin, daunorubicin, epirubicin, and idarubicin, or a pharmaceutically acceptable salt thereof.

49. A method of treating cancer in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of an anthracycline chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 43.

50. The method of claim 49, wherein the cancer is selected from breast cancer, leukemia, lymphoma, and sarcoma.

51. The method of claim 49, wherein the anthracycline chemotherapeutic agent is selected from doxorubicin, daunorubicin, epirubicin, and idarubicin, or a pharmaceutically acceptable salt thereof.

52. The method of claim 49, wherein the anthracycline chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, and the compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, are administered simultaneously.

53. The method of claim 49, wherein the anthracycline chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, and the compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, are administered consecutively.

54. The method of any one of claims 49-53, wherein the subject does not develop a cardiotoxicity or a cardiomyopathy associated with the administration of the anthracycline chemotherapeutic agent.

55. A method of treating cancer in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of etoposide, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a compound any one of claims 1-42, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 43.

56. A method of treating cancer in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of mAMSA, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a compound any one of claims 1-42, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 43.

57. A method of treating extravasation in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 43.

58. A method of treating extravasation in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of an anthracycline chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a compound of any one ofclaims 1-42, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 43.

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