WO2009061131A2 - Novel tricyclic derivatives or pharmaceutically acceptable salts thereof, process for the preparation thereof and pharmaceutical composition comprising the same - Google Patents

Abstract

The present invention relates to novel tricyclic derivatives having an excellent inhibitory activity on poly (ADP-ribose) polymerase, or pharmaceutically acceptable salts thereof, a process for the preparation thereof, and a pharmaceutical composition comprising the same. The tricyclic derivatives of the present invention inhibit the activity of poly (ADP-ribose) polymerase, thereby being used for the prevention or treatment of diseases that are caused by excessive activation of PARP, in particular, neuropathic pain, neurodegenerative diseases, cardiovascular diseases, diabetic neuropathic pain, inflammatory diseases, osteoporosis, and cancer.

Description

[DESCRIPTION] [Invention Title]

NOVEL TRICYCLIC DERIVATIVES OR PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF, PROCESS FOR THE PREPARATION THEREOF AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME

[Technical Field]

The present invention relates to novel tricyclic derivatives having an excellent inhibitory activity on poly (ADP-ribose) polymerase, or pharmaceutically acceptable salts thereof, a process for the preparation thereof, and a pharmaceutical composition comprising the same.

[Background Art] Poly (ADP-ribose) polymerases (PARPs), nuclear enzymes found in almost all eukaryotic cells, catalyze the transfer of ADP-ribose units from nicotinamide adenine dinucleotide (NAD⁺) to nuclear acceptor proteins, and are responsible for the formation of protein-bound linear and branched homo-ADP-ribose polymers. A PARP consists of 7 isozymes including PARP-I, PARP-2, PARP-3, PARP-4 (Vault-PARP) , tankyrases such as PARP-5 (TANK-I, TANK-2 and TANK-3), PARP-7, and PARP-10 [de Ia Lastra CA., et al., Curr Pharm Des., 13(9), 933-962, 2007]. Among them, the nuclear poly (ADP-ribose) polymerase-1 (PARP-I) is a major enzyme, and occupies 97% of poly (ADP-ribose) polymerase produced in the brain [Strosznajder R. P., et al. MoI Neurobiol . , 31, (1-3), 149-167, 2005] . Among the many functions attributed to PARP, especially PARP-I, is its major role in facilitating DNA repair by ADP-ribosylation and therefore coordinating a number of DNA repair proteins. As a result of PARP activation, NAD⁺ levels significantly decline . Extensive PARP activation leads to severe depletion of NAD⁺ in cells suffering from massive DNA damage. PARP-I is a 116 kDa nuclear enzyme composed of three functional domains: the N-terminal DNA binding domain containing two zinc fingers, the automodification domain and the C-terminal catalytic domain. Poly (ADP-ribose) polymerase synthesizes poly (ADP-ribose) , a branched polymer that can consist of over 200 ADP-ribose units. The protein acceptors of poly (ADP-ribose) are directly or indirectly involved in maintaining DNA integrity. They include histones, topoisomerases, DNA and RNA polymerases, DNA ligases, and Ca²⁺- and Mg²⁺-dependent endonucleases . PARP protein is expressed at a high level in many tissues, most notably in the immune system, heart, brain and germ-line cells. Under normal physiological conditions, there is minimal PARP activity. However, DNA damage causes an immediate activation of PARP by up to 500-fold.

Activation of PARP and the resultant formation of poly (ADP-ribose) can be induced by DNA strand breaks after exposure to chemotherapy, ionizing radiation, oxygen free radicals, or nitric oxide (NO) . Because this cellular ADP-ribose transfer process is associated with the repair of DNA strand breakage in response to DNA damage caused by radiotherapy or chemotherapy, it can contribute to the resistance that often develops to various types of cancer therapies. Consequently, inhibition of PARP may retard intracellular DNA repair and enhance the antitumor effects of cancer therapy. Moreover, it has recently been shown that tankyrases, which bind to the telomeric protein TRF-I, a negative regulator of telomere length maintenance, have a catalytic domain that is strikingly homologous to PARP and have been shown to have PARP activity in vitro. It has been proposed that telomere function in human cells is regulated by poly (ADP-ribosyl) ation. As a consequence of regulation of telomerase activity by tankyrase, PARP inhibitors should have utility as agents for regulation of cell life-span [BA. , et al. , Int JBiochem Cell Biol . , 37 , 1043-1053, 2005] . For example, for use in cancer therapy to shorten the life-span of immortal tumor cells, or as anti-aging therapeutics, since telomere length is believed to be associated with cell senescence .

In addition, it has been shown that inhibition of PARP promotes resistance to brain injury. Ischemic brain injury is caused by NAD⁺ depletion and energy failure, mediated by the activation of poly (ADP-ribose) polymerase [EndresM., et al., J. Cereb Blood Flow Metab. , 17(11), 1143-1151, 1997] . The activation of PARP by DNA damage is believed to play a role in the cell death consequent to stroke, head trauma, and neurodegenerative diseases. Cell death is believed to occur as a result of energy depletion as NAD⁺ is consumed by the enzyme-catalyzed PARP reaction. DNA is damaged by excessive amounts of NO produced when the NO synthase enzyme is activated as a result of a series of events initiated by the release of glutamic acid from depolarized nerve terminals . Oxygen deprived neurons release glutamate in great quantities during ischaemic brain insult such as during a stroke or heart attack. This excess release of glutamate in turn causes over-stimulation (excitotoxicity) of N-methyl-D-aspartate (NMDA) , AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) , Kainate and MGR (metabotropic glutamate receptor) receptors, which open ion channels and permit uncontrolled ion flow (e.g., Ca²⁺ and Na⁺ into the cells and K⁺ out of the cells) leading to overstimulation of the neurons. The over-stimulated neurons secrete more glutamate, creating a feedback loop or domino effect which ultimately results in cell damage or death via the production of proteases, lipases and free radicals. Excessive activation of glutamate receptors has been implicated in various neurological diseases and conditions including epilepsy, stroke, Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis (ALS), Huntington' s disease, schizophrenia, chronic pain, ischemia and neuronal loss following hypoxia, trauma, and nervous insult.

Another use for PARP inhibitors is the treatment of central nervous system diseases as well as peripheral nerve injuries such as neuropathic pain induced by chronic constriction injury (CCI) of the common sciatic nerve [Di Cesare Mannelli L., et al., Eur J Neurosci. , 26(4), 820-827, 2007] . The potential role of PARP inhibitors in the treatment of neuropathic pain has been recognized, even if the exact mechanism of action has not yet been elucidated. PARP inhibition is also an approach for treating inflammatory conditions such as arthritis [SzabC, et al., Proc. Natl. Acid. Sci. USA95{1), 3867-3872, 1998]. Synthesis of poly (ADP-ribose) is involved in the expression of a variety of genes involved in inflammatory responses. PARP inhibitors suppress production of inducible nitric oxide synthase (iNOS) in macrophages, P-type selectin and intercellular adhesion molecule-1 (ICAM-I) in endothelial cells. Such activity underlies the strong anti-inflammation effects exhibited by PARP inhibitors. PARP inhibition is able to reduce necrosis by preventing translocation and infiltration of neutrophils to the injured tissues. PARP inhibitors are therefore useful as therapeutics for inflammatory conditions .

Inhibition of PARP has usefulness for protection against myocardial ischemia [SzabC, Curr Vase Pharmacol ., 3 (3) , 301-303, 2005] and reperfusion injury [Zingarelli B., Cardiovascular Research, 36, 205-215, 1997] . Subsequent free radical production during reperfusion is assumed to be a major cause of tissue damage . Part of the ATP drop, which is typical in many organs during ischaemia and reperfusion, could be linked to NAD⁺ depletion due to poly (ADP-ribose) turnover. Thus, PARP inhibition is expected to preserve the cellular energy level thereby potentiating the survival of ischaemic tissues after insult. Therefore, PARP inhibitors are useful in therapy of cardiovascular diseases. Recently, PARP inhibitors could also provide a novel therapeutic approach for diabetic complications including neuropathy [Obrosova IG., Diabetes. 54(12), 3435-3441, 2005] . So far, several poly (ADP-ribose) polymerase (PARP) inhibitors have been developed: INO-1001 ( Inotek Pharmaceuticals) as a therapeutic agent for cardiovascular indications and malignant melanoma, AG014699 (Pfizer) as a therapeutic agent for malignant melanoma, BS-201 (BiPar Sciences) as a therapeutic agent for cancer, and BS-401 (BiPar Sciences) as a therapeutic agent for pancreatic cancer. In addition, the PARP inhibitor, AZD2281 (AstraZeneca) is being tested for efficacy in breast cancer, and MGI Pharma is focused on evaluating PARP inhibition as a chemotherapy and radiation therapy sensitizer [News, Nature biotechnology, 24(10), 1179-1180, 2006] .

To date, there have been no studies on the development of poly (ADP-ribose) polymerase (PARPs) inhibitors in the treatment of neurodegenerative diseases. As the elderly population increases, there is an urgent need for their development in terms of improvement in quality of life.

Accordingly, there continues to be a need for effective and potent poly (ADP-ribose) polymerase (PARPs) inhibitors which produce minimal side effects.

[Disclosure] [Technical Problem] The present inventors have made studies on low molecular weight PARP inhibitors which can be used for the treatment of various diseases caused by excessive activation of poly (ADP-ribose) polymerase (PARP) . They found that novel tricyclic derivatives show an excellent inhibitory activity on poly (ADP-ribose) polymerase (PARP), thereby completing the present invention.

[Technical Solution]

It is an object of the present invention to provide novel tricyclic derivatives having an excellent inhibitory activity on poly (ADP-ribose) polymerase, or pharmaceutically acceptable salts thereof, a process for the preparation thereof, and a pharmaceutical composition comprising the same.

[Description of Drawings]

FIG. 1 is a graph showing the result of quantifying the amount of NAD(P)H secreted into a culture medium at 4 hrs after treating Chinese hamster ovary cells (CHO-Kl) with various concentrations of the compounds of the present invention and then with MMS. [Best Mode]

The present invention provides a tricyclic derivative represented by the following Formula 1 or pharmaceutically acceptable salts thereof.

[Formula 1]

wherein Y is ORi, SRi, COORi, NR₂R₃ or -A-B; Ais-0-, -S-, -CH₂-, -C≡C-, -CO-, -CONH-, -NHCO-Or-NHSO₂-; B is - (CH₂) ni-NR₂R₃, - (CH₂) ni-halogen, - (CH₂) Xi₁-Z₁,

- (CH₂) m-C (CH₃) ₂- (CH₂) n₂-Zi, -C (CH₃) 2"CO-Zi, -C (CH₃) 2-CONH- (CH₂) ni-NR₂R3, -C (CH₃) ₂-CONH- (CH₂) ni-Zi, or COORi;

Zi is C₆-C_2O aryl unsubstituted or substituted with R₄, or C₅-C_2O heterocyclic compound unsubstituted or substituted with R₄;

Ri, R₂ and R₃ are each independently H; Ci~Cio straight or branched chain alkyl; or C₆-C₂₀ aryl;

R₄ is H, Ci~Cio straight or branched chain alkyl, - (CH₂) Ft₃-R₅,

- ( CH₂ ) n₃-NR₂R₃ or -0- ( CH₂ ) n₃-NR₂R₃ ; R₅ is ORi ; CORi ; COORi ; -CF₃ ; -CF₂CF₃ ; CN; halogen ; CONR₂R₃ ;

NRiCOCF₃ ; C₃-Ci₀ cycloalkyl ; C₃-Ci₀ cycloalkenyl ; C₆-C₂₀ aryl unsubstituted or substituted with CN; or C₆-C₂O aryl unsubstituted or substituted with C_x-C₄ alkyl or halogen, C₃~C₂₀ heteroaryl unsubstituted or substituted with Ci-C₄ alkyl or halogen, or C3-C20 heterocyclic compound unsubstituted or substituted with CORi; and ni to n₃ are each an integer of 0 to 15.

Preferably, in Formula 1,

Zi is one group selected from the group consisting of the following Formulae Cl to C12;

C1 C2 C3 C4

C5 C6 C7 C8

C9 C10 C11 C12

Ri, R₂ andR₃ are each independently H, methyl, ethyl, isopropyl, t-butyl or phenyl,

R₄ is H, methyl, ethyl, propyl, isopropyl, butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, heptyl, - (CH₂) n₃~Rs, -(CH₂)H₃-NR₂R₃ or -0-(CH₂Jn₃-NR₂R₃;

R₅ is OH; OCH₃; COC₆H₅; COOH; COOCH₃; -CF₃; -CF₂CF₃; CN; Cl; F; CONH₂; NHCOCF₃; cyclopropyl; cyclopentyl; cyclohexyl; cycloheptyl; cyclohexenyl; phenyl; or

ni to n₃ are each an integer of 0 to 10.

Among the tricyclic derivatives of Formula 1 of the present invention, preferred compounds are as follows: 1) 9-methoxy-4, 6-dihydro-lH-thiopyrano [3, 4-c] quinolin -5 (2H) -one,

2 ) 8-methoxy-4 , 6-dihydro-lH-thiopyrano [3, 4-c] quinolin -5 (2H) -one,

3) 9-hydroxy-4 , 6-dihydro-lH-thiopyrano [3,4-c]quinolin- 5 (2H) -one,

4) ethyl 5-oxo-2, 4, 5, 6-tetrahydro-lH-thiopyrano [3, 4-c] quinoline-9-carboxylate,

5) 5-oxo-2, 4,5, 6-tetrahydro-lH-thiopyrano [3, 4-c] quinoline-9-carboxylic acid, 6) 9- (2-chloroethyl) -4, 6-dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one,

7 ) 9- [2- (piperidin-1-yl) ethyl] -4, 6-dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

8) 9- [3- (dimethylamino) prop-1-ynyl] -4, 6-dihydro-lH- thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

9) 9-amino-4 , 6-dihydro-IH-thiopyrano [3, 4-c] quinolin- 5 (2H) -one,

10) N- (5-oxo-2, 4, 5, 6-tetrahydro-lH-thiopyrano [3, 4-c] quinolin-9-yl) -3- (piperidin-1-yl) propanamide hydrochloride, 11) 3- (dimethylamino) -N- (5-oxo-2, 4, 5, 6-tetrahydro-lH- thiopyrano [3, 4-c] quinolin-9-yl) propanamide hydrochloride, 12) N- (5-oxo-2, 4, 5, 6-tetrahydro-lH-thiopyrano [3, 4-c] quinolin-9-yl) -3- (4-phenyl-5, 6-dihydropyridin-l (2H) -yl) propanamide hydrochloride, 13) 3-chloro-N- (5-oxo-2, 4 , 5, 6-tetrahydro-lH-thiopyrano [3,4-c]quinolin-9-yl) propane-1-sulfonamide,

14 ) 9- [3- (dimethylamino) propanoyl] -4, 6-dihydro-lH- thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

15) 9- [2, 2-dimethyl-3- (piperidin-1-yl) propoxy] -4, 6- dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

16) N- [3- (dimethylamino) propyl] -2-methyl-2- (5-oxo- 2,4,5, 6-tetrahydro-lH-thiopyrano [3, 4-c] quinolin-9-yloxy) propanamide hydrochloride,

17 ) N- [3- (diethylamino) propyl] -2-methy1-2- (5-oxo- 2,4,5, 6-tetrahydro-lH-thiopyrano [3, 4-c] quinolin-9-yloxy) propanamide hydrochloride,

18 ) 9- [1- (4-ethylpiperazin-l-yl] -2-methyl-l-oxopropan- 2-yloxy) -4, 6-dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one,

19) 2-methy1-2- (5-oxo-2, 4,5, 6-tetrahydro-lH-thiopyrano [3, 4-c] quinolin-9-yloxy) -N- [3- (4 -phenyl-5, β-dihydropyridin-1

(2H) -yl) propyl] propanamide hydrochloride,

20) N- (3-chloropropyl) -5-oxo-2, 4 , 5, 6-tetrahydro-lH- thiopyrano [3, 4-c] quinoline-9-carboxamide,

21) 5-oxo-N- [2- (piperidin-1-yl) ethyl] -2, 4, 5, 6-tetrahydro -lH-thiopyrano [3, 4-c] quinoline-9-carboxamide hydrochloride,

22) 9- (piperazine-1-carbonyl) -4, 6-dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

23) 9- [4- (2-aminoethyl) piperazine-1-carbonyl] -4, 6- dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one dihydrochloride, 24) N- [2- (dimethylamino) ethyl] -5-oxo-2, 4, 5, β-tetrahydro -lH-thiopyrano [3, 4-c] quinoline-9-carboxamide hydrochloride,

25) N- [3- (dimethylamino) propyl] -5-oxo-2, 4,5, 6-tetrahydro -lH-thiopyrano [3, 4-c] quinoline-9-carboxamide hydrochloride, 26) N- [4- (dimethylamino) phenyl] -5-OXO-2, 4 , 5, 6-tetrahydro -lH-thiopyrano [3, 4-c] quinoline-9-carboxamide hydrochloride,

27) 5-oxo-N- [2- (4-phenyl-5, 6-dihydropyridin-l (2H) -yl) ethyl] -2,4,5, 6-tetrahydro-lH-thiopyrano [3, 4-c] quinoline-9- carboxamide hydrochloride, 28) N- (2-morpholinoethyl) -5-OXO-2, 4, 5, 6-tetrahydro-lH- thiopyrano [3, 4-c] quinoline-9-carboxamide hydrochloride,

29) N- (2-aminoethyl) -5-oxo-2, 4, 5, 6-tetrahydro-lH- thiopyrano [3, 4-c] quinoline-9-carboxamide hydrochloride,

30) 5-oxo-N- [2- (piperazin-1-yl) ethyl] -2,4,5, 6-tetrahydro -lH-thiopyrano [3, 4-c] quinoline-9-carboxamide dihydrochloride,

31) N- [2- (4-methylpiperazin-l-yl) ethyl] -5-oxo-2, 4,5,6- tetrahydro-lH-thiopyrano [3, 4-c] quinoline-9-carboxamide dihydrochloride,

32) 5-oxo-N- [2- (4-oxopiperidin-l-yl) ethyl] -2, 4, 5, 6- tetrahydro-lH-thiopyrano [3, 4-c] quinoline-9-carboxamide hydrochloride,

33) 9- (4-phenylpiperazine-l-carbonyl) -4, 6-dihydro-lH- thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

34) N- {4- [2- (diethylamino) ethoxy] phenyl } -5-oxo-2, 4,5,6 -tetrahydro-lH-thiopyrano [3, 4-c] quinoline-9-carboxamide hydrochloride .

35) 9- [4- (3-aminopropyl) piperazine-1-carbonyl] -4,6- dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one dihydrochloride, 36) 9- [4- (pyridin-4-yl) piperazine-1-carbonyl] -4 , 6- dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

37) 9-{ 4- [2- (4-oxopiperidin-l-yl) ethyl] piperazine-1- carbonyl } -4 , 6-dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one dihydrochloride, 38) 5-oxo-N-{ 3- [4- (pyridin-4-yl) piperazin-1-yl] propyl }- 2,4,5, 6-tetrahydro-lH-thiopyrano [3, 4-c] quinoline-9- carboxamide dihydrochloride,

39) 9_ (4_ (2- (4- (4-fluorophenyl) -5, 6-dihydropyridin- 1 (2H) -yl) ethyl) piperazine-1-carbonyl) -4 , 6-dihydro-lH- thiopyrano [3, 4-c] quinolin-5 (2H) -one dihydrochloride,

40) 9- { 4- [2- ( 4-phenylpiperazin-l-yl) ethyl] piperazine-1 -carbonyl } -4 , 6-dihydro-IH-thiopyrano [3, 4-c] quinolin-5 (2H) - one trihydrochloride,

41) 9- (piperidine-1-carbonyl) -4, 6-dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one,

42) 9- (4-methylpiperazine-l-carbonyl) -4, 6-dihydro-lH- thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

43) 9- (4-benzylpiperazine-l-carbonyl) -4, 6-dihydro-lH- thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride, 44) 9- (4-ethylpiperazine-l-carbonyl) -4, 6-dihydro-lH- thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

45) 9-{4- [2- (4-phenyl-5, 6-dihydropyridin-l (2H) -yl) ethyl] piperazine-1-carbonyl } -4 , 6-dihydro-IH-thiopyrano [3, 4-c] quinolin-5 (2H) -one dihydrochloride, 46) 9- (4- (l-methylpiperidin-4-yl)piperazine-l-carbonyl) -4, 6-dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one,

47 ) N- [5- (ethylamino) pentyl] -5-oxo-2, 4,5, 6-tetrahydro- lH-thiopyrano [3, 4-c] quinoline-9-carboxamide hydrochloride,

48) 9- [4- ( 4-methylpentyl) piperazine-1-carbonyl] -4,6- dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

49) 9- (4-hexylpiperazine-l-carbonyl) -4, 6-dihydro-lH- thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

50) 9- [4- (pentan-2yl) piperazine-1-carbonyl] -4, 6-dihydro -lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride, 51) 9- (4-isopropylpiperazine-l-carbonyl) -4 , 6-dihydro -lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

52) 9- (4-phenethylpiperazine-l-carbonyl) -4, 6-dihydro -lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

53) 9- { 4- [2- (dimethylamino) ethyl] piperazine-1-carbonyl } -4, 6-dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one dihydrochloride,

54) 9-{4- [2- (piperidin-1-yl) ethyl] piperazine-1-carbonyl } -4, 6-dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one dihydrochloride, 55) N- (5-aminopentyl) -5-OXO-2, 4, 5, 6-tetrahydro-lH- thiopyrano [3, 4-c] quinoline-9-carboxamide hydrochloride,

56) 5-oxo-N-{2- [4- (pyridin-4-yl) piperazin-1-yl] ethyl}

-2,4,5, 6-tetrahydro-lH-thiopyrano [3, 4-c] quinoline-9- carboxaraide dihydrochloride, 57) N- [5- (dimethylamino) pentyl] -5-oxo-2, 4, 5, 6-tetrahydro

-lH-thiopyrano [3, 4-c] quinoline-9-carboxamide hydrochloride,

58 ) N- [4- (isopropylamino) butyl] -5-^'oxo-2, 4,5, 6-tetrahydro

-lH-thiopyrano [3, 4-c] quinoline-9-carboxamide hydrochloride,

59) N- (3-aminopropyl) -5-oxo-2, 4, 5, 6-tetrahydro-lH- thiopyrano [3, 4-c] quinoline-9-carboxamide hydrochloride,

60) N- (4-aminobutyl) -5-oxo-2, 4, 5, 6-tetrahydro-lH- thiopyrano [3, 4-c] quinoline-9-carboxamide hydrochloride,

61) 9- (4-isopentylpiperazine-l-carbonyl) -4, 6-dihydro- lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride, 62) 9- (4-propylpiperazine-l-carbonyl) -4 , 6-dihydro-lH- thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

63) 9- (4-butylpiperazine-l-carbonyl) -4, 6-dihydro-lH- thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

64 ) 9- [4- (cyclopropylmethyl) piperazine-1-carbonyl] -4,6- dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

65) 9- (4-pentylpiperazine-l-carbonyl) -4, 6-dihydro-lH- thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

66) 9- (4-heptylpiperazine-l-carbonyl) -4, 6-dihydro-lH- thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride, 67) 9- [4- (4 , 4, 4-trifluorobutyl) piperazine-1-carbonyl] - 4, 6-dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

68) 9- [4- (2, 2, 2-trifluoroethyl)piperazine-l-carbonyl] - 4 , 6-dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

69) 5-oxo-N- [2- (4-phenylpiperazin-l-yl) ethyl] -2,4,5,6- tetrahydro-lH-thiopyrano [3, 4-c] quinoline-9-carboxamide dihydrochloride,

70) 5-oxo-N- [3- (4-phenyl-5, 6-dihydropyridin-l (2H) -yl) propyl] -2,4,5, 6-tetrahydro-lH-thiopyrano [3, 4-c] quinoline-9- carboxamide hydrochloride,

71) N- [4- (ethyl (methyl) amino) butyl] -5-oxo-2,4, 5, 6- tetrahydro-lH-thiopyrano [3, 4-c] quinoline-9-carboxamide hydrochloride, 72) 9- (4-cyclopentylpiperazine-l-carbonyl) -4, 6-dihydro -lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

73) 9- (4-cyclohexylpiperazine-l-carbonyl) -4, 6-dihydro-lH -thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

74) 9- (4-cycloheptylpiperazine-l-carbonyl) -4, 6-dihydro -lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

75) 9-[4-(4,4,5,5, 5-pentafluoropentyl) piperazine-1- carbonyl] -4 , 6-dihydro-IH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

76) 9- (4-neopentylpiperazine-l-carbonyl) -4, 6-dihydro- lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride, 77 ) 9- (piperidin-4-ylthio) -4 , 6-dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

78) 9- [2- (piperidin-1-yl) ethoxy] -4, 6-dihydro-lH- thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride, 79) 9- (piperidin-4-yloxy) -4 , 6-dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

80) 9- (l-isopentylpiperidin-4-yloxy) -4, 6-dihydro-lH- thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

81) 9- ( l-propylpiperidin-4-yloxy) -4, 6-dihydro-lH- thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

82) 9- (l-ethylpiperidin-4-yloxy) -4, 6-dihydro-lH- thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

83 ) 9- ( 1-aminoethyl) piperidin-4-yloxy] -4 , 6-dihydro-lH- thiopyrano [3, 4-c] quinolin-5 (2H) -one dihydrochloride, 84) methyl 2- [4- (5-oxo-2, 4 , 5, 6-tetrahydro-lH-thiopyrano [3, 4-c] quinolin-9-yloxy] piperidin-1-yl) acetate hydrochloride,

85) 3- [4- (5-oxo-2, 4, 5, 6-tetrahydro-lH-thiopyrano [3, 4-c] quinolin-9-yloxy) piperidin-1-yl] propanenitrile hydrochloride,

86) 9- [1- (2-chloroethyl) piperidin-4-yloxy] -4 , β-dihydro -lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

87) 2- [4- (5-oxo-2, 4, 5, 6-tetrahydro-lH-thiopyrano [3, 4-c] quinolin-9-yloxy) piperidin-1-yl] acetic acid hydrochloride,

88) 2- [4- (5-oxo-2, 4, 5, 6-tetrahydro-lH-thiopyrano [3, 4-c] quinolin-9-yloxy) piperidin-1-yl] acetamide hydrochloride, 89) 9- [1- (2-hydroxyethyl) piperidin-4-yloxy] -4, 6-dihydro -lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

90) 9- [1- (2-methoxyethyl)piperidin-4-yloxy] -4, β-dihydro -lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

91) 9- [1- (2- (piperidin-1-yl) ethyl) piperidin-4-yloxy] -4, 6 -dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one dihydrochloride,

92 ) 9- ( l-neopentylpiperidin-4-yloxy) -4 , 6-dihydro-lH- thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

93) 9-[l-(4,4,5,5, 5-pentafluoropentyl) piperidin-4-yloxy] -4, 6-dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

94) 9- (l-methylpiperidin-4-yloxy) -4, 6-dihydro-lH- thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

95) 9- [1- (2-oxobutyl) piperidin-4-yloxy] -4, β-dihydro-IH- thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

96) 9- [1- (2, 2, 2-trifluoroethyl) piperidin-4-yloxy] -4,6- dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

97) 9- [1- (cyclohexenylmethyl) piperidin-4-yloxy] -4,6- dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride, 98) 9- (piperidin-3-yloxy) -4, 6-dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

99) 9- (l-methylpiperidin-3-yloxy) -4, 6-dihydro-lH- thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

100) 9- (l-methylpyrrolidin-3-yloxy) -4, 6-dihydro-lH- thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride, 101) 9- ( l-propylpiperidin-3-yloxy) -4, 6-dihydro-lH- thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

102) 9- (l-ethylpiperidin-3-yloxy) -4, 6-dihydro-lH- thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride, 103) 9- (l-ethylpyrrolidin-3-yloxy) -4, 6-dihydro-lH- thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

104 ) 9- (l-benzylpiperidin-4-yloxy) -4 , β-dihydro-IH- thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

105) 9- (1- (pyrimidin-2-yl) piperidin-4-yloxy) -4, β-dihydro -lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one,

106) 9- ( l-phenylpiperidin-4-yloxy) -4, 6-dihydro-lH- thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

107) 9-{l- [2- (4-phenyl-5, 6-dihydropyridin-l (2H) -yl) ethyl] piperidin-4-yloxy} -4, β-dihydro-IH-1hiopyrano [3, 4-c] quinolin-5 (2H) -one dihydrochloride,

108) 9- (l-phenethylpiperidin-4-yloxy) -4, 6-dihydro-lH- thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

109) 9- [1- (4,4, 4-trifluorobutyl) piperidin-4-yloxy] -4, 6- dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride, 110) 9- [1- (pyridin-4-ylmethyl)piperidin-4-yloxy] -4, 6- dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride, 111) 2,2,2-trifluoro-N-{2- [4- (5-oxo-2,4, 5, β-tetrahydro- lH-thiopyrano [3, 4-c] quinolin-9-yloxy) piperidin-1-yl] ethyl } acetamide hydrochloride, 112) 9- [1- (2-oxo-2-phenylethyl) piperidin-4-yloxy] -4, 6- dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

113) 4-{ [4- (5-oxo-2,4,5, 6-tetrahydro-lH-thiopyrano [3, 4-c] quinolin-9-yloxy) piperidin-1-yl] methyl }benzonitrile hydrochloride, 114) 9- [1- (3-chloropropyl) piperidin-4-yloxy] -4, β-dihydro -lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

115) 9-(l-{2-[4-(pyrimidin-2-yl)piperazin-l-yl]ethyl} piperidin-4-yloxy) -4, 6-dihydro-lH-thiopyrano [3, 4-c] quinolin- 5 (2H) -one dihydrochloride, 116) tert-butyl 5-oxo-2, 4 , 5, 6-tetrahydro-lH-thiopyrano [3, 4-c] quinolin-9-yl carbonate,

117) 9- (l-butylpiperidin-4-yloxy) -4, 6-dihydro-lH- thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

118 ) 9- [1- (3-fluoropropyl) piperidin-4-yloxy] -4 , 6-dihydro -lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

119) 9- [4- (dimethylamino) phenethoxy] -4 , 6-dihydro-IH- thiopyrano [3, 4-c] quinolin-5 (2H) -one,

120) 9- (l-pentylpiperidin-4-yloxy) -4, 6-dihydro-lH- thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride, and 121) 9-{l- [2- (4-acetylpiperazin-l-yl) ethyl] piperidin-4- yloxy } -4 , 6-dihydro-IH-thiopyrano [3, 4-c] quinolin-5 (2H) -one dihydrochloride .

The compounds of Formula 1 of the present invention may be prepared in the form of a pharmaceutically acceptable salt and solvate according to the conventional method in the related art.

As the pharmaceutically acceptable salt, acid addition salts produced with pharmaceutically acceptable free acids are preferred. The acid addition salts may be prepared through conventional methods. For example, acid addition salt may be prepared by dissolving the compound in an excessive amount of an acid aqueous solution, and precipitating the salt in a water-miscible organic solvent, such as methanol, ethanol, acetone or acetonitrile . Acid addition salt may be also prepared by heating a mixture including the same amount of the compound and an acid in water or alcohol (e.g., glycol monomethylether) , and then drying the mixture or performing suction filtration onto the educed salt.

As the free acids, organic acids and inorganic acids may be used. Examples of the inorganic acids may include hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, and tartaric acid, and examples of the organic acids may include methanesulphonic acid, p-toluenesulphonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycollic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, and hydroiodic acid, but are not limited thereto. Further, the pharmaceutically acceptable metal salt form may be prepared by using a base. The alkali metal or alkali-earth metal salt thereof may be prepared by the conventional method; for example, after dissolving the compound in the excess amount of alkali metal hydroxide or alkali-earthmetal hydroxide solution, the insoluble salts are filtered and remaining filtrate is subjectedto evaporation and drying to obtain the metal salt thereof. As a metal salt, sodium, potassium or calcium salt is pharmaceutically suitable, but is not limited thereto. In addition, the corresponding silver salt may be prepared by reacting alkali metal salt or alkali-earth metal salt with suitable silver salt (e.g., silver nitrate) .

The pharmaceutically acceptable salt of the compound of Formula 1 comprises all the acidic or basic salts which may be present in the compound of Formula 1, if it is not indicated specifically herein. For example, the pharmaceutically acceptable salt comprises the salts of hydroxyl groups such as the sodium, calcium and potassium salt thereof; the salts of amino groups such as hydrogen bromide salt, sulfuric acid salt, hydrogen sulfuric acid salt, phosphate salt, hydrogen phosphate salt, dihydrophosphate salt, acetate salt, succinate salt , citrate salt, tartarate salt, lactate salt, mandelate salt, methanesulfonate (mesylate) salt and p-toluenesulfonate (tosylate) salt etc, which may be prepared by the conventional method well known in the art. Further, the compound of Formula 1 has an asymmetric center, thereby existing in the form of a different enantiomer, and all of the optical isomers, R or S type stereoisomer, and a mixture thereof of the compound of Formula 1 are included in the scope of the present invention. The present invention comprises the uses of racemates, one or more enantiomers, one or more diastereomers, or mixtures thereof, and separation methods or preparation methods thereof known in the art.

Further, the present invention provides a preparation method of the compound of Formula 1.

In a preferred embodiment, the present invention provides a preparation method of the tricyclic derivative represented by the following Formula 1 or pharmaceutically acceptable salt thereof, comprising the following steps of 1) to 3) : 1) reacting the ketone compound of Formula 2 with the morpholine compound of Formula 3 in the presence of p-toluenesulfonic acid to prepare the enamine compound of Formula 4,

2) reacting the enamine compound of Formula 4 obtained in step 1) with the isocyanate compound of Formula 5 to prepare the β-ketoamide compound of Formula 6, and

3 ) adding an acid aqueous solution to the β-ketoamide compound of Formula 6 prepared in step 2) for cyclization reaction to prepare the tricyclic derivative of Formula 1 or pharmaceutically acceptable salts thereof:

[Formula 2\

[Formula 5]

^'Formula 6]

wherein Y is the same as defined in Formula 1.

In another preferred embodiment, the present invention provides a preparation method of the tricyclic derivative represented by the following Formula 9 or pharmaceutically acceptable salt thereof, comprising the following steps of 1) to 2) : 1) reacting the compound of Formula Ia with boron tribromide to prepare the demethylated hydroxy compound of Formula 7; and

2) reacting the hydroxy compound of Formula 7 obtained in step 1) and the alkyl halide compound of Formula 8 with a catalytic amount of sodium iodide in the presence of a base to prepare the tricyclic derivative of Formula 9 or pharmaceutically acceptable salts thereof:

[Formula Ia]

wherein Y is OCH₃, X is halogen, and Ri is the same as defined in Formula 1.

Specifically, the compound of Formula 1 may be chemically preparedby themethods indicated in the following Reaction Schemes, but is not limited thereto. In particular, it is understood by those skilled in the art that the compound of Formula 1 of the present invention may be prepared by various methods using the technology well known in the art.

The following Reaction Schemes describe the steps of preparing the representative compounds according to the present invention, and the compounds of the present invention may be preparedby various changes or modifications in a reagent, a solvent, and reaction sequence that are employed in <Reaction Scheme 1> to <Reaction Scheme 10>. Some compounds of the present invention were prepared according to procedures which are not included in the scope of <Reaction Scheme 1> to <Reaction Scheme 10>, and the preparation procedures thereof are described in detail in the Examples.

[Reaction Scheme 1]

4

70% H₂SO₄

wherein Y is the same as defined in Formula 1 . <Reaction Scheme 1> represents a three-step process for preparing a compound (1) using a ketone compound (2), which is commercially available or prepared by the known method, as a starting material.

In step 1, the ketone compound (2) and morpholine (3) are dissolved in an organic solvent such as benzene and toluene in the presence of p-toluenesulfonic acid using a Dean-stark condenser with molecular sieves to prepare an enamine compound (4) . At this time, the reaction is preferably performed under heating. In step 2, the enamine compound (4) prepared in step 1 is reacted with an isocyanate compound (5) to prepare a β-ketoamide compound (6) . At this time, benzene or toluene may be used as an organic solvent, and demorpholinization of the intermediate is induced by using an acid such as hydrochloric acid. Such reactions may be performed at room temperature or under heating, preferably under heating.

In step 3, an acid aqueous solution such as sulfuric acid is added to the β-ketoamide compound (6) prepared in step 2 to prepare the cyclized compound (1) . At this time, an organic solvent is not preferably used, and the reaction may be performed at room temperature or under heating, preferably at room temperature .

[Reaction Scheme 2]

wherein Y is OCH₃, X is halogen, and, Ri is the same as defined in Formula 1.

<Reaction Scheme 2> represents a two-step process for preparing a compound (9) using the compound (Ia), which is prepared by Reaction Scheme 1, as a starting material.

In step 1, the compound (Ia) prepared in step 3 of <Reaction Scheme 1> is reacted with boron tribromide to prepare the demethylated hydroxy compound (7) . At this time, dichloromethane or chloroform that causes no adverse effect on the reaction may^¬ be used as the organic solvent, and the reaction is, performed at room temperature, but is not specifically limited to it.

In step 2, the hydroxy compound (7) prepared in step 1 and alkyl halide compound (8) such as 4-bromopiperidine and 2-chloroethyl piperidine are reacted with a catalytic amount of sodium iodide in the presence of a base such as potassium carbonate to prepare an alkoxy compound (9) . The reaction leads to ether formation from the alcohol compound and alkyl halide, and is performed in the presence of a base which can be used for ether production. Preferred examples of the base may include sodium hydride, cesium carbonate, sodium or potassium hydroxide, and sodium alcoholate. In addition, the reaction is preferably performed in the presence of a solvent that causes no adverse effect on the reaction, and preferred examples thereof may include dichloromethane, chloroform, tetrahydrofuran, diethylether, toluene, dimethylformamide, and benzene. At this time, the reaction is preferably performed under cooling or at room temperature but is not specifically limited thereto. [Reaction Scheme 3]

wherein R₂ , R₃ and ni are the same as defined in Formula

1

<Reaction Scheme 3> represents a three-step process for preparing a compound (14) using the compound (7a) , which is prepared by <Reaction Scheme 2>, as a starting material.

In step 1, the compound (7a) prepared in step 1 of <Reaction Scheme 2> is reacted with ethyl 2-bromo-2-methylpropanoate (10) to prepare a compound (11) in the same manner as the conversion of compound (7) to compound (9) in step 2 of <Reaction Scheme 2>. At this time, the reaction is preferably, performed under heating but is not specifically limited thereto.

Step 2 is ester hydrolysis reaction, in which the compound (11) prepared in step 1 is converted to a carboxylic acid compound

(12) . This reaction is performed by slowly adding an aqueous solution of potassium hydroxide or sodium hydroxide dropwise in the presence of an alcohol solvent such as ethanol or methanol under cooling. At this time, the reaction may be performed at room temperature or under heating, preferably under heating. The reaction may be performed under the general conditions of ester hydrolysis .

In step 3, the carboxylic acid compound (12) prepared in step 2 is reacted with an amine compound (13a) to prepare an amide compound (14) . At this time, the reaction is performed in the presence of a coupling reagent such as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDCI) , 1-hydroxybenzotriazole hydrate (HOBT) or 1, 3-dicyclohexyl carboimide (DCC) . The reaction may be performed without using a base, and is performed in the presence of a base that is generally used for amidation reaction, such as 4-dimethylaminopyridine, pyridine, triethylamine, diethylisopropylamine, N-methylmorpholine, anddimethylphenylamine, using a solvent that causes no adverse effect on the reaction, such as acetonitrile, dimethyl formamide, or dichloromethane . The reaction may be, performed under cooling or heating, preferably under cooling or at room temperature, but is not specifically limited thereto.

[Reaction Scheme 4]

wherein Y is - (CH₂) _n~halogen, and R₂, R3 and ni are the same as defined in Formula 1.

<Reaction Scheme 4> represents a process for preparing a compound (15) using the compound (Ib) , which is prepared by

<Reaction Scheme 1>, as a starting material, in which a compound (15) having an alkylamine group is prepared using an amine compound

(13b) and the compound (Ib) prepared in step 3 of <Reaction Scheme

1>. At this time, an organic solvent that causes no adverse effect on the reaction, such tetrahydrofuran, acetonitrile, dichloromethane, or chloroform, is used, and the reaction is performed under cooling or at room temperature but is not specifically limited thereto.

[Reaction Scheme 5]

wherein Y is halogen, and R₂ and R₃ are the same as defined in Formula 1.

<Reaction Scheme 5> represents a process for preparing a compound (17) using the compound (Ic) , which is prepared by <Reaction Scheme 1>, as a starting material, in which Suzuki reaction of amino-1-propyne compound (16) and the compound (Ic) prepared in step 3 of <Reaction Scheme 1> is performed to prepare a compound (17) . The reaction may be performed using a palladium (Pd) catalyst, in which a palladium reagent such as tetrakistriphenylphosphine palladium(O) ((PPh₃)₄Pd), Pd(OAc)₂, Pd₂dba₃, and PdCl₂ (PPh₃) ₂ may be used. Examples of the base used for the reaction include potassium t-butoxide, potassium and sodium carbonate, and potassium hydroxide, and an organic solvent that causes no adverse effect on the reaction, such as alcohol, water, tetrahydrofuran, toluene, piperidine andmixtures thereof, may be used. The reaction is performed at room temperature or under heating, but is not specifically limited thereto. [Reaction Scheme 6]

wherein Y is CO₂- (Ci~Cio straight or branched chain alkyl) , and R2 and R₃ are the same as defined in Formula 1. <Reaction Scheme 6> represents a two-step process for preparing a compound (19) using the compound (Id) , which is prepared by <Reaction Scheme 1>, as a starting material.

In step 1, the compound (Id) prepared in step 3 of <Reaction

Scheme 1> is subjected to the reaction in the same manner as the conversion of ester compound (11) to carboxylic acid compound

(12) in step 2 of <Reaction Scheme 3>, so as to prepare a compound

(18) .

In step 2, the compound (18) prepared in step 1 is reacted with the amine compound (13b) to prepare an amide compound (19) in the same manner as the conversion of compound (12) to compound (14) in step 3 of <Reaction Scheme 3>. [Reaction Scheme 7]

wherein X is halogen, and R₂, R₃ and n₃ are the same as defined in Formula 1. <Reaction Scheme 7> represents a process for preparing a compound (21) using the compound (19a) , which is prepared in step 2 of <Reaction Scheme 6>, as a starting material.

Hydrochloride of amide compound (19a) prepared in step 2 of <Reaction Scheme 6> is subjected to the reaction in the same manner as the conversion of compound (7) to compound (9) in step 2 of <Reaction Scheme 2>, so as to prepare a compound (21) .

[Reaction Scheme 8]

wherein X is halogen, and R₂, R₃ and ni are the same as defined in Formula 1. <Reaction Scheme 8> represents a three-step process for preparing a compound (25) using the compound (18) , which is prepared in step 1 of <Reaction Scheme β>, as a starting material.

In step 1, the compound (18) is reacted with thionyl chloride or oxalyl chloride to prepare a carbonyl chloride compound (22) . At this time, an organic solvent such as dichloromethane and chloroform is used, and the reaction is performed under cooling or at room temperature, but is not specifically limited thereto.

In step 2, the compound (22) prepared in step 1 is reacted with chloroalkylamine (23) to prepare an amide compound (24) . At this time, an organic amine such as triethylamine or pyridine may be used as a base, and a solvent that causes no adverse effect on the reaction, such as dichloromethane, chloroform, or tetrahydrofuran, may be used. The reaction is preferably, performed under cooling or at room temperature, but is not specifically limited thereto.

In step 3, the compound (24) prepared in step 2 is subjected to the reaction to prepare a compound (25) in the same manner as the conversion of compound (Ib) to compound (15) in step 1 of <Reaction Scheme 4>.

[Reaction Scheme 9]

wherein Y is NH₂, and B is the same as defined in Formula

1.

<Reaction Scheme 9> represents a process for preparing a compound (27) using the compound (Ie) , which is prepared by <Reaction Scheme 1>, as a starting material.

The compound (Ie) and a carboxylic acid compound (26) with a substituent is subjected to the reaction in the same manner as the conversion of compound (12) to compound (14) in step 3 of <Reaction Scheme 3>, so as to prepare a compound (27) . ^'Reaction Scheme 10^'

wherein Y is NH₂, and ni is the same as defined in Formula

1. <Reaction Scheme 10> represents a process for preparing a compound (29) using the compound (Ie) , which is prepared by

<Reaction Scheme 1>, as a starting material, in which the compound

(Ie) is reacted with chloroalkyl-1-sulfonic acid (28) in the presence of a base such as triethylamine, pyridine, or 4-dimethylaminopyridine, so as to prepare a sulfonamide compound (29) . At this time, the reaction is performed in the presence of a solvent that causes no adverse effect on the reaction, and examples of the solvent include dichloromethane, chloroform, tetrahydrofuran, and dimethylformamide . The reaction is preferably performed under cooling or at room temperature, but is not specifically limited thereto.

Further, the present invention provides a pharmaceutical composition for the prevention or treatment of diseases that are caused by excessive activation of PARP, comprising the tricyclic derivative of Formula 1 or pharmaceutically acceptable salt thereof.

Excessive activation of PARP has been implicated in various diseases, including neuropathic pain; epilepsy, stroke, Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis (ALS), Huntington's disease, schizophrenia, chronic and acute pain, ischemia and neuronal loss following hypoxia, neurodegenerative diseases such as trauma and nervous insult; cardiovascular diseases such as atherosclerosis, hyperlipidemia, cardiovascular tissue damage, coronary heart disease, myocardial infarction, angina pectoris, and cardiogenic shock; diabetic neuropathic pain; inflammatory diseases such as osteoarthritis, osteoporosis, and cancer.

The tricyclic derivatives of the present invention inhibits the activity of poly (ADP-ribose) polymerase, thereby being used for the prevention or treatment of diseases that are caused by excessive activation of PARP, in particular, neuropathic pain, neurodegenerative diseases, cardiovascular diseases, diabetic neuropathic pain, inflammatory diseases, osteoporosis, and cancer.

The pharmaceutical composition including the compound of the present invention may further include suitable carriers, excipients or diluents according to the ordinarymethod. Examples of the carriers, excipients and diluents may include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starches, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxy benzoate, propylhydroxy benzoate, talc, magnesium stearate and mineral oil.

According to conventional methods, the composition including the compound of the present invention may be formulated into an oral preparation such as a powder, a granule, a tablet, a capsule, a suspension, an emulsion, a syrup, and an aerosol, an external preparation, suppository, or a sterilized injectable solution.

Specifically, such preparations may be prepared using diluents or excipients ordinarily employed, such as a filler, extender, binder, wetting agent, disintegrating agent, and surfactant. Examples of the solid preparation for oral administration include a tablet, a pill, a powder, a granule, and a capsule, and the solid preparation may be prepared by mixing the compound with at least one excipient such as starch, calcium carbonate, sucrose, lactose, and gelatin. Further, in addition to the excipients, lubricants such as magnesium stearate and talc may be used. Examples of a liquid preparation for oral administration include a suspension, a liquid for internal use, an emulsion, and a syrup, and various excipients such as wetting agent, sweetener, flavor, and preservative may be contained, in addition to general diluents such as water and liquid paraffin. Examples of the preparation for parenteral administration include an aseptic aqueous solution, a non-aqueous solvent, a suspension, an emulsion, a lyophilized agent, and suppository. As the non-aqueous solvent and suspension, propylene glycol, polyethylene glycol, plant oil such as olive oil, injectable ester such as ethyloleate or the like may be used. As a suppository base, witepsol, macrogol, tween 61, cacao butter, lauric butter, glycerogelatin or the like may be used.

An effective dosage of the compound according to the present invention may be determined depending on the patient's health state and body weight, severity of the diseases, drug formulation, administration routes, and administration time, and may be suitably selectedby those skilled in the art . However, forbetter efficacy, the compound of Formula 1 of the present invention may be administered at a daily dosage of 0.0001 to 1000 mg/kg, preferably 0.01 to 500 mg/kg once or several times. In the composition of the present invention, the compound of Formula 1 may be blended in an amount of 0.0001 ~ 50% by weight, based on the total weight of the composition.

Further, the compound according to the present invention can be used in the form of the pharmaceutically acceptable salt thereof, and singly or collectively, as well as in combination with other pharmaceutically active compounds.

The pharmaceutical composition of the present invention may be administered to mammals, such as rats, mice, domestic animals and humans, via various routes. All modes of administration are contemplated, for example, administration can be made orally, rectally or by intravenous, intramuscular, subcutaneous, epidural or intracerebroventricular injection.

[Mode for Invention]

Herein, the present invention will be described in more detail with reference to Examples. Examples are provided only for the purpose of illustrating the present invention and not intended to limit the scope of the invention.

Example 1 : 9-methoxy-4 , 6-dihydro-lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one

Step 1. Preparation of 4- (3, 6-dihydro-2H-thiopyran-4-yl) morpholine

Dihydro-2H-thiopyran-4 (3H) -one (3.Og, 25.79mmol), morpholine (2.69ml, 30.96mmol), p-toluenesulfonic acid hydrate

(245mg, 1.29mmol) were dissolved in anhydrous toluene, and the mixture was refluxed for 12 hours with a Dean-Stark apparatus. After reaction, the reactionmixture was cooled to roomtemperature under anhydrous condition, and used to next step without further purification. Step 2. Preparation of

N- (4-methoxyphenyl) -4-oxotetrahydro-2H-thiopyran-3-carboxami de

To the compound prepared in the step 1 was added slowly the solution of l-isocyanato-4-methoxybenzene (5g, 33.53mol) in anhydrous toluene. The reaction mixture was stirred for 24 hours. Thereafter, 2N HCl solution (12ml) was added, and the reaction mixture was stirred for 24 hours. After reaction, water and ethyl acetate were added to the reaction mixture. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure . The residue was purified by column chromatography (n-hexane : ethyl acetate = 5:1) to afford 3.2g (yield: 47%, yellow solid) of the target compound. 1H NMR (400MHz, CDCl₃) ; δ 8.98 (s, IH) , 7.45 (d, J=8.8Hz, 2H) , 6.86(d, J=8.8Hz, 2H), 3.79(s, 3H), 3.65(q, J=4.8Hz, IH), 3.4β-3.42(m, IH), 3.22(dd, L7=10.2HZ, IH), 3.06-3.01 (m, 2H), 2.87-2.83(m, 2H)

Step 3. Preparation of

9-methoxy-4, 6-dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one

To the compound (3.2g, 12.06mmol) prepared in the step 2 was added 200ml of a 70% sulfuric acid. The reaction mixture was stirred for 14 hours at room temperature. After reaction, the reaction mixture was poured into ice water and stirred for 30 minutes. The resulting solid was filtered, washed with methanol and dried under reduced pressure to afford 2. Ig (yield: 72%, brown solid) of the target compound.

¹H NMR (400MHz, DMSO-d₆) ; δ 11.71 (s, IH), 7.23 (d, J=8.4Hz, IH), 7.14(s, IH), 7.13(d, <J=8.4Hz, IH), 3.79(s, 3H), 3.57(s, 2H), 3.10(t, J=β.0Hz, 2H), 2.92(t, J=5.6Hz, 2H)

Compounds listedbelow were preparedby the similar procedure as described in Example 1. Example 2 :

8-methoxy-4 , 6-dihydro-lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one [Table l]

Example 3 : 9-hydroxy-4 , 6-dihydro-lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one

To a solution of the compound (2.1g, 8.68rnmol) prepared in the step 3 of example 1 in anhydrous dichloromethane was added slowly the 1. OM solution of borone tribromide in dichloromethane (40ml) at room temperature. The reaction mixture was stirred for 2 hours at room temperature. After reaction, the reaction mixture was pour into ice-cold water and stirred for 30 minutes. The resulting solid was filtered under reduced pressure, washed with ethyl acetate and dried to afford 1.4g (yield: 75%, yellow solid) of the target compound.

¹H NMR (400MHz, DMSO-d₆) ; δ 11.61(s, IH), 7.14(d, J=8.4Hz, IH), 7.00(s, IH), 6.96(d, J=8.4Hz, IH), 3.56(s, 2H), 2.98 (d, J=5.2Hz, 2H), 2.90(t, J=6.0Hz, 2H) Example 4 : ethyl

5-OXO-2 ,4,5, 6-tetrahydro-lH-thiopyrano [3, 4-c]quinoline-9- carboxylate

Step 1. Preparation of ethyl 4-isocyanatobenzoate

To the solution of ethyl 4-aminobenzoate (1Og, 60.53mmol) in anhydrous toluene (700ml) was added triethylamine (9.73ml, 69. βmmol) . Asolutionof triphosgene (18g, 60.53mmol) in anhydrous toluene was added slowly at 0^°C, and the reaction mixture was stirred for 2 hours at room temperature, and then stirred at 90 ^°C . After reaction, toluene and water were added to the mixture. The organic layer was dried over sodium sulfate, and the solvent was removed under reduced pressure to afford 8.9g (yield: 74%, yellow oil) of the target compound. 1H NMR(400MHz, CDCl₃); δ 8.01(d, J=6.0Hz, 2H), 7.14(d, J=6.0Hz, 2H), 4.37 (q, J=6.8Hz, 2H), 1.39(t, J=7.2Hz, 3H)

Step 2. Preparation of ethyl 4- (4-oxotetrahydro-2H-thiopyran-3-carboxamido) benzoate

According to the similar procedure in the step 2 of example 1 by using the compound (8.9g, 4β.55mmol) prepared in the step 1 and the compound prepared in the step 1 of example 1, 3.4g (yield: 43%, yellow solid) of the target compound was obtained. 1H NMR (400MHz, CDCl₃) ; δ 9.39(s, IH) , 8.01 (d,

2H) , 7.63(d, J=8.4Hz, 2H), 7.35(d, J=7.2Hz, 2H), 3.69(q, J=4.8Hz, IH), 3.47-3.40(m, IH), 3.22(dd, J=IO.4Hz, IH), 3.0β-2.98(m, 2H), 2.91-2.80(m, 2H), 1.38(t,

3H)

Step 3. Preparation of ethyl 5-oxo-2, 4,5, 6-tetrahydro-lH-thiopyrano [3, 4-c] quinoline-9-car boxylate

To the compound (3.4g, ll.lmmol) prepared in the step 2 was added 240ml of a 70% sulfuric acid, and the reaction mixture was stirred for 14 hours at room temperature. After reaction, the reaction mixture was poured into ice-cold water and stirred for 30 minutes . The resulting solid was filtered under reduced pressure, washed with methanol and dried to afford 2.3g (yield: 72%, brown solid) of the target compound. 1H NMR (400MHz, DMSOd₆) ; δ 12.15 (s, IH) , 8.29 (s, IH) , 8.02 (d, J=8.4Hz, IH), 7.36(d, 8.4Hz, IH), 4.32(q, J=7.2Hz, 2H), 3.59(s, 2H) , 3.15 (d, J=4.8Hz, 2H) , 2.93 (t, J=5. βHz, 2H) , 1.32 (t, J=7.2Hz, 3H)

Example 5 : 5-OXO-2 ,4,5, 6-tetrahydro-lH—thiopyrano [3 , 4-c] quinoline-9- carboxylic acid

The compound (2.3g, 7.99mmol) prepared in the step 3 of example 4 was dissolved in IN sodium hydroxide aqueous solution, and the reaction mixture was stirred for 12 hours at 90 ^°C . After reaction, the reaction mixture was acidified to pH 3-4 with 2N HCl aqueous solution. The resulting solid was filtered and dried to afford 1.8g (yield: 86%, white solid) of the target compound. 1H NMR(400MHz, DMSO-d₆) ; δ 12.94(br s, IH), 12.14(s, IH), 9.30(s, IH), 8.02(d, J=8.0Hz, IH), 7.37(d, J=8.0Hz, IH), 3.61(s, 2H), 3.18(t, J=5.6Hz, 2H), 2.95(t, J=6.0Hz, 2H)

Example 6 :

9- (2-chloroethyl) -4 , 6-dihydro-lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one Step 1. Preparation of tert-butyl 4- (2-hydroxyethyi; phenylcarbamate

To a solution of 2- (4-aminophenyl) ethanol (Ig, 7.28mmol) in ethyl acetate (10ml) was added di-tert-butyl dicarbonate (1.75g, δ.Olmmol) , and the reaction mixture was stirred for 24 hours at room temperature. After reaction, water and ethyl acetate were added to the reaction mixture. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (n-hexane : ethyl acetate = 1:2) to afford 1.72g (yield: 99%, white solid) of the target compound.

¹H NMR(400MHz, CDCl₃); δ 7.29(d, J=8.4Hz, 2H), 7.16(d, J=8.4Hz, 2H), 6.45(br s, IH), 3.82(br s, 2H), 2.81(t, J=6.6Hz, 2H), 1.52(s, 9H)

Step 2. Preparation of tert-butyl 4- (2-chloroethyl) phenylcarbamate

To the solution of the compound (1.72g, 7.24mmol) prepared in the step 1 in carbon tetrachloride (20ml) was added triphenylphosphine (2.47g, 9.42mmol) . The reaction mixture was refluxed for 24 hours. After reaction, the solvent was removed under reduced pressure. The residue was purified by column chromatography (n-hexane: ethyl acetate = 5:1) to afford 1.3Og (yield: 70%, white solid) of the target compound. 1H NMR(400MHz, CDCl₃); δ 7.30(d, J=8.0Hz, 2H), 7.16(d, J=8.4Hz, 2H) , β.45(brs, IH) , 3.67 (t, J=7.3Hz, 2H) , 3.02 (t, J=7.5Hz, 2H), 1.52(s, 9H)

Step 3. Preparation of 4- (2-chloroethyl) aniline hydrochloride

To a solution of the compound (1.3Og, 5.08mmol) prepared in the step 2 in tetrahydrofuran (10ml) was added the 2. OM solution of HCl in diethyl ether (13ml, 25.41mmol) . The reaction mixture was stirred at room temperature for 1 day. After reaction, the resulting solid was filtered to afford 520mg (yield: 53%, white solid) of the target compound.

¹H NMR (400MHz, DMSO-dg) ; δ 7.31 (d, J=8.1Hz, 2H), 7.1β(br s, 2H), 3.84(t, J=6.8Hz, 2H), 3.01(t, J=6.6Hz, 2H)

Step 4 . Preparation of 1- ( 2-chloroethyl ) -4 -isocyanato benzene

To a solution of the compound (310mg, l.lδmmol) prepared in the step 3 in toluene (10ml) was added triphosgene (526mg, 1.77mmol) . The reaction mixture was refluxed for 24 hours. After reaction, water and chloroform were added to the reaction mixture . The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was used in next step without further purification.

Step 5. Preparation of

N- [4- (2-chloroethyl) phenyl] -4-oxotetrahydro-2H-thiopyran-3- carboxamide

To the compound prepared in the step 4 was added slowly the solution of the compound prepared in the step 1 of example 1 in toluene (2ml) . The reactionmixture was stirred at roomtemperature for 24 hours. 2N HCl aqueous solution was added, and the reaction mixture was stirred at room temperature for 24 hours . The reaction mixture was neutralized with 2N sodium hydroxide aqueous solution and extracted with chloroform. Combined organic layers were dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (n-hexane : ethyl acetate = 4:1) to afford ββ.βmg (yield: 17%, yellow oil) of the target compound. ¹H NMR (400MHz, CDCl₃) ; δ lθ.24 (br s, IH) , 7.63 (d, J=8.3Hz, IH) , 7.27 (d, J=8.5Hz, IH) , 3.72~3.70 (m, 2H) , 3.57 (t, J=5.2Hz, IH) , 3.20-3.17 (m, 2H) , 2.87~2.71 (m, 6H)

Step 6. Preparation of

9- (2-chloroethyl) -4, 6-dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one

The compound (ββ.βmg, 0.22mmol) prepared in the step 5 was dissolved in 70% sulfuric acid (1.0ml) , and the reaction mixture was stirred at room temperature for 48 hours . The reaction mixture was poured into ice-cold water and extracted with ethyl acetate. Combined organic layers were dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (n-hexane : ethyl acetate = 1:1) to afford 34mg (yield: 55%, white solid) of the target compound.

¹HNMR (400MHz, DMSO-d_e) ; δ 11.81 (s, IH) , 7.67 (s, IH) , 7.44 (d, J=8.4Hz, IH), 7.28~7.25(m, IH), 4.25(t, J=7.3Hz, 2H), 3.86(t, J=7.1Hz, 2H), 3.59(s, 2H), 3.11(t, J=5.5Hz, 2H), 2.94(t, J=5.7Hz, 2H) Example 7 :

9- [2- (piperidin-1-yl) ethyl] -4 , 6-dihydro-lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one hydrochloride

Step 1. Preparation of 9- [2- (piperidin-1-yl) ethyl] -4, 6-dihydro-lH-thiopyrano [3, 4-c]

To a solution of the compound (15mg, 0.53mmol) prepared in the step 6 of example 6 in tetrahydrofuran (ImI) was added piperidine (lβmg, O.lβmmol) . The reaction mixture was stirred at room temperature for 24 hours. After reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (n-hexane : ethyl acetate = 1:3) to afford 3.7mg (yield: 22%, yellow solid) of the target compound. 1H NMR (400MHz, CDCl₃) ; δ 11.78 (br s, IH), 8.0 (s, IH), 7.25 (d, J=8.4Hz, IH), 7.13(d, J=8.3Hz, IH), 3.11(s, 2H), 2.69~2.66(m, 4H), 2.48~2.45(m, 6H), 2.34~2.31(m, 2H), 1.59-1.53 (in, 6H)

Step 2. Preparation of 9- [2- (piperidin-1-yl) ethyl] -4, 6-dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride

To a solution of the compound (3.7mg, O.Ollmmol) prepared in the step 1 in methanol (0.5ml) was added the 2.0M solution of HCl in diethylether (0.5ml) . The reaction mixture was stirred at room temperature for 5 hours. The solvent was removed under reduced pressure to afford 3.9mg (yield: 99%, yellow solid) of the target compound.

¹H NMR(400MHz, DMSO-d₆) ; δ 12.13 (br s, IH), 8.32 (s, IH), 7.95(d, J=8.7Hz, IH), 7.56(d, J=8.4Hz, IH), 3.43~3.35(m, 6H), 2.91-2.83 (m, 2H) , 2.67-2.54 (m, 2H) , 1.58-1.52 (m, 6H) , 1.41-1.39 (m, 4H)

Example 8 :

9- [3- (dimethylamino) prop-1-ynyl] -4 , 6-dihydro-lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one hydrochloride

Step 1. Preparation of 9-bromo-4, 6-dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one

According to the similar procedure in the step 2 and setp 3 of example 1 by using the compound prepared in the step 1 of example 1 and 4-bromophenyl isocyanate (723mg, 3.65mmol), 34mg (yield: 24%, white solid) of the target compound was obtained.

¹H NMR (400MHz, DMSO-d₆) ; δ 11.96 (s, IH), 7.87 (s, IH), 7.63 (d, J=8.4Hz, IH), 7.2β(d, J=8.8Hz, IH), 3.59(s, 2H), 3.10(t, J=5.5Hz, 2H), 2.91(t, J=5.8Hz, 2H)

Step 2. Preparation of

9- [3- (dimethylamino) prop-1-ynyl] -4 , 6-dihydro-lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one

To a solution of the compound (34mg, 0.096mmol) prepared in the step 1 in triethylamine (2ml) were added tetrakis (triphenylphosphin) palladium (0) ((PPh₃J₄Pd : 2.3mg, O.OOlβmmol), copper iodide (O.δmg, 0.004mmol) and l-dimethylamino-2-propyne (8.βmg, 0.08mmol) . The reaction mixture was stirred at room temperature for 4 hours . After reaction, saturated ammonium chloride aqueous solution and ethyl acetate were added to the reaction mixture. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (ethyl acetate) to afford 2.4mg (yield: 25%, white solid) of the target compound. 1H NMR (400MHz, CDCl₃) ; δ 11.82 (br s, IH) , 8.0 (s, IH) , 7.23 (d, J=8.4Hz, IH), 7.14(d, J=8.4Hz, IH), 3.78~3.75(m, 2H), 3.13(s, 2H), 2.49-2.47 (m, 2H), 2.33~2.30(m, 2H), 2.26(s, 6H)

Step 3. Preparation of

9- [3- (dimethylamino) prop-1-ynyl] -4 , 6-dihydro-lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one hydrochloride

According to the similar procedure in the step 2 of example 7 by using the compound (2.4mg, 0.008mmol) prepared in the step 2, 2.3mg (yield: 86%, yellow solid) of the target compound was obtained.

¹H NMR(400MHz, CDCl₃ + DMSO-dg) ; δ 11.38 (br s, IH), 7.69(s, IH), 7.44(d, J=8.4Hz, IH), 7.17(d, J=8.8Hz, IH), 3.69(s, 2H), 3.07(t, J=5.8Hz, 2H), 2.94~2.87(m, 4H), 1.18(s, 6H) Example 9 : 9-amino-4 , 6-dihydro-lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one

Step 1. Preparation of N- (4-nitrophenyl) -4-oxotetrahydro-2H-thiopyran-3-carboxamide

According to the similar procedure in the step 2 of example 1 by using the compound prepared in the step 1 of example 1 and 4-nitrophenyl isocyanate (600mg, 3.65mmol), 531mg (yield: 88.1%, yellow solid) of the target compound was obtained.

¹H NMR(400MHz,DMSO-d₆) ; δ 10.54(s, IH), 8.22(d, J=9.2Hz, IH), 7.77(d, J=9.2Hz, IH), 3.15 (m, 2H), 2.96(m, 2H), 2.68 (m, 2H) .

Step 2. Preparation of N- (4-aminophenyl) -4-oxotetrahydro-2H-thiopyran-3-carboxamide

To a solution of the compound (476mg, 0.17mmol) prepared in the step 1 in ethyl acetate (10ml) was added 10wt% Palladium on activated carbon (47βmg, 100wt%) . The reaction mixture was stirred under a hydrogen atmosphere for 24 hours. After reaction, the reaction mixture was filtered through celite. The solvent was concentrated under reduced pressure to afford 280mg (yield: 65.8%, white solid) of the target compound. ¹HNMR(400MHz, DMSO-d₆) ; δ 9.47 ( s, IH) , 7.16 (d, J=8.4Hz, IH) , 6.47 (d, J=8.8Hz, IH) , 3.16 (m, 2H) , 2.9β (m, 2H) , 2.61 (m, 2H) .

Step 3. Preparation of

4-oxo-N- [4- (2,2, 2-trifluoroacetamido) phenyl] tetrahydro-2H- thiopyran-3-carboxamide

The compound (1.7g, 6.79mmol) prepared in the step 2 was dissolved in tetrahydrofuran (20ml) and cooled to 0^°C . Thereafter, pyridine (1.65ml, 20.37mmol) and trifluoroacetanhydride (2.08ml, 14.94mmol) were added, and the reaction mixture was stirred ar room temperature for 1 hour. After reaction, ethyl acetate was added and washed with brine and saturated ammonium chloride aqueous solution. Organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Chloroform was added to the residue, and the resulting solid was filtered to afford 1.34g (yield: 57.2%, white solid) of the target compound. 1HNMR (400MHz, DMSO-d₆) ; δ 11.22 (s, IH) , 10.01 (s, IH) , 7.59(m, 4H), 3.21(m, 2H), 3.12(m, 2H), 2.99(m, 2H) . Step 4. Preparation of 9-antino-4, 6-dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one

According to the similar procedure in the step 3 of example 1 by using the compound (114mg, 0.33mmol) prepared in the step 3, 40.0mg (yield: 52.3%, brown solid) of the target compound was obtained.

¹H NMR(400MHz,DMSO-d₆) ; δ 11.47(s, IH), 7.03(d, J=8.4Hz, IH), 6.82 (m, 2H), 5.03(br, 2H), 3.56(s, 2H), 3.346(s, 2H), 2.94 (m, 2H) .

Example 10 :

N- (5-oxo-2 ,4,5, 6-tetrahydro-lH-thiopyrano [3,4-c]quinolin-9- yl) -3- (piperidin-l-yl)propanamide hydrochloride

Step 1. Preparation of

N- (5-oxo-2, 4,5, 6-tetrahydro-lH-thiopyrano [3,4-c]quinolin-9- yl) -3- (piperidin-1-yl) propanamide

To a solution of compound (45.1mg, 0.23mmol) prepared in the step 4 of example 9 in N, N, -dimethylformamide (3.0ml) were added 1-ethyl- (3-dimetylaminopropyl) -3-ethylcarbodiimide hydrochloride (45.1mg, 0.23mmol) and 1-hydroxybenzotriazole hydrate (31.8mg, 0.23mmol) . 1-piperidine propionic acid (30.8mg, 0.20mmol) was added slowly, and then the reaction mixture was stirred for 5 hours. After reaction, water and ethyl acetate were added to the reaction mixture. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane rmethanol = 10 : 1) to afford 30.5mg (yield: 37.9%, white solid) of the target compound.

¹H NMR (400MHz, CDCl₃) : δ 12.03 (s, IH), 10.04 (s, IH), 8.35 (s, IH) , 7.96(dd, J=4.4Hz, J=8.0Hz, IH) , 7.30 (d, J=8.4Hz, IH) , 3.71 (br, 2H), 3.62(br, 4H), 3.19-2.99 (br, 8H), 1.71(br, 4H) .

Step 2. Preparation of

N- (5-OXO-2, 4,5, 6-tetrahydro-lH-thiopyrano [3,4-c]guinolin-9- yl) -3- (piperidin-1-yl) propanamide hydrochloride

To a solution of the compound (28.2mg, 0.07βmmol) prepared in the step 1 in 1,4-dioxane (1.0ml) was added a 3.6M HCl in 1, 4-dioxane (3.0ml ) . The reaction mixture was stirred for 24 hours . The resulting solid was filtered and washed with 1,4-dioxane and ethyl acetate to afford 11.4mg (yield: 37%, white solid) of the target compound.

¹HNMR (400MHz, DMSO-d₆) : δ 12.03 (s, IH), 10.12 (s, IH), 9.04 (s, IH), 8.35(s, IH), 7.98 (a, J=8.0Hz, IH), 7.33(d, J=8.4Hz, IH), 3.72(br, 2H), 3.65(br, 4H), 3.19(br, 4H), 2.99(br, 4H), 1.76(br, 4H) .

Compounds listed below were prepared by the similar procedure as described in Example 10. Example 11 : 3- (dimethylamino) -N- (5-oxo-2 , 4 , 5 , 6- tetrahydro-lH-thiopyrano [3 , 4-c] quinolin-9-yl) propanamide hydrochloride

Example 12 : N- (5-oxo-2 , 4 ,5, 6-tetrahydro-lH-thiopyrano [3 , 4-c] quinolin-9-yl) -3- (4-phenyl-5 , 6-dihydropyridin-l (2H) - yl) propanamide hydrochloride [Table 2]

Example 13 : 3-chloro-N- (5-oxo-2 , 4,5, 6-tetrahydro-lH- thiopyrano [3, 4-c] quinolin-9-yl)propane-l-sulfonamide 3

To a solution of the compound (206.9mg, 0.89mmol) prepared in the step 4 of example 9 in N, N, -dimethylformamide (5.0ml) were added 3-chloropropane-l-sulfonic acid (141.2mg, 0.89mmol) and

4- (dimethylamino) -pyridine (108.8mg, 0.89mmol) . The reaction mixture was stirred for 24 hours. After reaction, the reaction mixture was concentrated, and the residue was purified by column chromatography (dichloromethane rmethanol = 15 : 1) to afford 12. Omg

(yield: 3.6%, yellow solid) of the target compound.

¹H NMR(400MHz, DMSOd₆) ; δ 11.78 (s, IH), 10.04 (s, IH), 8.04~7.23(m, 3H), 3.59(s, 2H), 3.29-2.45 (m, 10H)

Example 14 : 9- [3- (dimethylamino) propanoyl] -4 , 6-dihydro- lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one hydrochloride Step 1. Preparation of 3- (dimethylamino) -1- (4-nitrophenyl) propan-1-one

To a solution of 4-nitroacetophenone (3g, lδ.lβmmol) in ethanol (15.0ml) was added dimethylamine hydrochloride (1.75g, 8.01nnmol) and 1, 3, 5-trioxane (1.92g, 23. βlmmol) . The reaction mixture was refluxed for 2 hours with catalytic amount of HCl. After reaction, the reaction mixture was cooled to roomtemperaure, concentrated and washed with sodium bicarbonate aqueous solution. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (n-hexane : ethyl acetate = 1:1) to afford 1.2g (yield: 30%, colorless oil) of the target compound. 1H NMR (400MHz, CDCl₃) δ 8.33 (d, J=8.8Hz, 2H) , 8.12 (d, J=8.8Hz, 2H), 3.20(t, J=6.8Hz, 2H), 2,78(t, J=7.6Hz, 2H), 2.30(s, 6H) . Step 2. Preparation of 1- (4-aminophenyl) -3- (dimethylamino) propan-1-one

According to the similar procedure in the step 2 of example 9 by using the compound (850mg, 4.12mmol) prepared in the step 1, 250mg (yield: 32%, colorless oil) of the target compound was obtained.

¹H NMR(400MHz, CDCl₃); δ 7.83(d, J= 8.4Hz, 2H), 6.65(d, J=8.8Hz, 2H) , 4.13 (br, 2H) , 3.07 (t, J=6.8Hz, 2H) , 2.74 (t, J=β.8Hz, 2H) , 2.29 (s, 6H) .

Step 3. Preparation of methyl 4-oxotetrahydro-2H-thiopyran -3-carboxylate

The solution of methyl acrylate in diethyl ether was cooled to 0^°C, and then 3-mercaptopropionate was added slowly therein.

Sodium hydride was added and the reaction mixture was stirred at room temperature for 8 hours. After reaction, the reaction mixture was washed with water, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (n-hexane : ethyl acetate = 10:1) to afford 3.14g (yield: 52%, colorless oil) of the target compound.

¹H NMR (400MHz, CDCl₃) ; δ 3.78 (s, 3H), 3.35 (s, 2H), 2.78 (t, J=4.4Hz, 2H), 2.60(t, J=4.4Hz, 2H), 1.25~1.23(m, IH) Step 4. Preparation of methyl 1, 5-dioxa-9-thiaspiro [5.5] undecane-7-carboxylate

To a solution of the compound (1.7g, 9.7βmmol) prepared in the step 3 in benzene (30ml) were added 1, 3-propandiol (1.48g,

19.52mmol) and toluenesulfonic acid hydrate (371mg, 1.92mmol) . The reaction mixture was refluxed for 10 hours. After reaction, the reaction mixture was cooled to room temperature, neutralizes with a sodium bicarbonate aqueous solution and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (n-hexane : ethyl acetate = 10:1) to afford 1.33g

(yield: 52%, white solid) of the target compound.

¹H NMR (400MHz, CDCl₃) δ 4.41-4.00 (m, IH) , 3.94-3.93 (m, 2H) , 3.88-3.83 (m, IH), 3.74(s, 3H), 3.10-3.03 (m, 2H), 2.93-2.88(m, IH), 2.78-2.70(m, IH), 2.70-2.63(m, 2H), 1.95-1.88(m, 2H), 1.5-1.45(m, IH) .

Step 5. Preparation of 1, 5-dioxa-9-thiaspiro [5.5] undecane-7-carboxylic acid

According to the similar procedure in the example 5 by using the compound (500mg, 2.15mmol) prepared in the step 4, 465mg (yield: 98%, white solid) of the target compound was obtained.

¹H NMR(400MHz, CDCl₃) δ 10.61(br, IH), 4.24-4.13 (m, IH), 3.99-3.96 (m, 2H) , 3.09-3.03 (m, 2H) , 2.91-2.86 (m, 2H) , 2.76-2.68 (m, IH), 2.57-2.53(m, IH), 2.17-2.05 (m, 2H), 1.80-1.72(m, IH), 1.55-1.50 (m, IH) .

Step 6. Preparation of N-{ 4- [3- (dimethylamino) propanoyl] phenyl } -1, 5-dioxa-9-thiaspiro [5.5] undecane-7-carboxamide

To a solution of compound (150mg, 0.687mmol) in the step 5 in dichloromethane was added slowly thionyl chloride (98mg, 0.824mmol) at 0^°C. After addition of one drop of N, N, -dimethylformamide , the reaction mixture was stirred at room temperature for 1 hour. The reaction was quenched with methanol and the solvent was removed under reduced pressure. The residue

(146mg, O.δlδmmol) was dissolved in dichloromethane and cooled to 0^°C. The compound (130mg, 0.678mmol) prepared in the step 2 was added therein, and triethylamine (81mg, 0.58mmol) was slowly added. The reaction mixture was stirred at room temperature for 10 hours . After reaction, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (dichloromethane :methanol = 10:1) to afford 75mg (yield: 33%, yellow solid) of the target compound.

¹H NMR (400MHz, CDCl₃)O 9.29(s, IH), 7.96(d, J=8.4Hz, 2H), 7.64(d, J=8.8Hz, 2H), 4.21-4.17 (m, IH), 4.05(d, J=2.0Hz, 2H), 3.95-3.92 (m, IH) , 3.21-3.17 (m, 2H) , 3.11-3.07 (m, IH) , 2.96-2.92 (m, IH) , 2.87-2.81 (m, 3H) , 2.78-2.74 (m, IH) , 2.59-2.56 (m, IH) , 2.36 (s, 6H), 2.04-1.94 (m, 2H), 1.77-1.69 (m, IH), 1.55-1.52 (m, IH) .

Step 7. Preparation of 9- [3- (dimethylamino) propanoyl] -4 , 6-dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one

According to the similar procedure in the step 3 of example 1 by using the compound (85mg, 0.254mmol) prepared in the step 6, 9mg (yield: 13%, yellow solid) of the target compound was obtained. 1H NMR (400MHz, CDCl₃) δ 12.00 (br, IH) , 8.3β(s, IH) , 8.08 (d, J=8.4Hz, IH), 7.42(d, J=8.4Hz, IH), 3.82(s, 2H), 3.29-3.21 (m, 4H), 3.01(t, J=5.6Hz, 2H), 2.82(t, J=7.2Hz, 2H), 2.33(s, 6H) .

Step 8. Preparation of 9- [3- (dimethylamino) propanoyl] -4 , 6-dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride

According to the similar procedure in the step 2 of example 10 by using the compound (9mg, 0.0128mmol) prepared in the step 7, 5mg (yield: 50%, yellow solid) of the target compound was obtained.

¹HNMR(400MHz, DMSO-d₆) δl2.22(s, IH), 10.35(br, IH), 8.36(s, IH), 8.10(d, J=8.8Hz, IH), 7.42(d, J=8.8Hz, IH), 3.62(s, 2H), 3.42-3.41(m, 2H), 3.23-3.21(m, 2H), 3.00-2.87(m, 2H), 2.82(d, J=5.2Hz, 6H), 2.79-2.78(m, 2H) .

Example 15 : 9- [2 , 2-dimethyl-3- (piperidin-1-yl) propoxy] -4 , 6-dihydro-lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one hydrochloride

Step 1. Preparation of 2, 2-dimethyl-3- (piperidin-1-yl) propanal

Isobutylaldehyde (Ig, 13.87mmol), piperidine (1.1ml, 10.67mmol) andparaformaldehyde (420mg, 13.87mmol) were dissolved in ethanol (15ml) . The reaction mixture was stirred for 18 hours at 80^°C . After reaction, ice-cold water was added, and the reaction mixture was adjusted to pH 10 with 4M sodium hydroxide aqueous solution. The reaction mixture was extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography

(dichloromethaneimethanol = 10: 1) to afford 470mg (yield: 26.1%, colorless oil) of the target compound.

¹H NMR (400MHz, CDCl₃); δ 9.52(s, IH), 2.39(s, 2H), 2.32 (m, 4H), 1.52(m, 4H ), 1.46(m, 2H), 1.07(S, 6H) .

Step 2. Preparation of 2, 2-dimethyl-3- (piperidin-1-yl) propan-1-ol

To a solution of the compound (lOOmg, 0.59mmol) prepared in the step 1 in methanol (4ml) was added water (ImI) and cooled to 0^°C. Sodium borohydride (22.3mg, 0.59mmol) was added and the reaction mixture was stirred for 18 hours at room temperature. After reaction, ice water was added, and the reaction mixture was acidified to pH 2 with 2M HCl aqueous solution and extracted with diethyl ether. Aqueous layer was basified to pH 10 with 4% sodium hydroxide aqueous solution and extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to afford 101.2mg (yield: 99%, colorless oil) of the target compound. ¹H NMR (400MHz, CDCl₃) ; δ 3.48(s, 2H) , 2.50(br, 4H), 2.34 (s, 2H), 1.55 (m, 4H), 1.37(br, 2H), 0.88(s, 6Hz) .

Step 3. Preparation of 9- [2, 2-dimethyl-3- (piperidin-1-yl) propoxy] -4 , 6-dihydro-lH-thiopyrano [3,4-c]quinolin-5 (2H) -one

The compound (lOOmg, 0.58mmol) prepared in the step 2, the compound (136.2mg, 0.58mmol) prepared in the example 3 and triphenylphosphine (229.6mg, 0.87mmol) were dissolved in tetrahydrofurane (153 ml) , and the mixture was cooled to 0^°C . After addition of diisopropyl azodicarboxylate (170 fd, 0.87mmol) slowly, the reaction mixture was stirred at room temperature for 18 hours . The solvent was removed under reduced pressure, and the residue was purified by column chromatography (dichloromethane imethanol = 10:1) to afford 9. lmg (yield: 4.0%, colorless oil) of the target compound.

¹HNMR (400MHz, DMSOd₆) ; δ 12.04 (s, IH) , 7.20 (m, 3H) , 3.65 (m, 2H), 3.54-3.49(m, 4H), 3.12(br, 4H), 2.95(m, 4H), 1.72-1.70 (m, 6H), 0.94(s, 6H)

Step 4. Preparation of 9- [2, 2-dimethyl-3- (piperidin-1-yl) propoxy] -4, 6-dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride

According to the similar procedure in the step 2 of example 10 by using the compound (9mg, 0.02mmol) prepared in the step 3, β.4mg (yield: 65.9%, yellow solid) of the target compound was obtained.

¹H NMR (400MHz, DMSO-d₆) ; δ 11.78 (s, IH) , 8.35 (s, IH) , 7.19 (m, 3H), 3.68 (m, 2H), 3.57(s, 2H), 3.51(s, 2H), 3.21(br, 4H), 2.95(m, 4H), 1.77(br, 4H), 1.70(m, 2H), 0.95(s, 6H)

Example 16 : N- [3- (dimethylamino) propyl] -2-methyl

-2- (5-oxo-2 ,4,5, 6-tetrahydro-lH-thiopyrano [3, 4-c] quinolin-9- yloxy)propanamide hydrochloride

Step 1. Preparation of ethyl 2-methyl-2- (5-oxo-2, 4 , 5, 6- tetrahydro-lH-thiopyrano [3, 4-c] quinolin-9-yloxy) propanoate

To a solution of the compound (500mg, 2.14mmol) prepared in the step 3 in N,N-dimethylformamide (15ml) were added potassium carbonate (1.33g, 9.64mmol) and ethyl α-bromoisobutyrate (1.04ml, 7.07mmol) . The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was extracted with chloroform and washed with brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reducedpressure . The residue was purified by column chromatography (chloroform:methanol = 30: 1) to afford 400mg (yield: 54%, yellow solid) of the target compound.

¹H NMR (400MHz, CDCl₃); δ 11.66(br, IH), 7.27-7.25(m, IH), 7.20(d J=2.4Hz, IH), 7.09(dd, J=8.4Hz, 2.4Hz, IH), 4.25(qt, J=7.2Hz, 2H), 3.83(s, 2H), 3.11(t, J=5.6Hz, 2H), 2.98(t, J=6.0Hz, 2H), 1.60(s, 6H), 1.27(t, J=7.2Hz, 3H)

Step 2. Preparation of 2-methyl-2- (5-oxo-2, 4, 5, 6- tetrahydro-lH-thiopyrano [3, 4-c] quinolin-9-yloxy) propanoic acid

According to the similar procedure in the example 5 by using the compound (400mg, 1.15mmol) prepared in the step 1, 320mg (yield: 87%, yellow solid) of the target compound was obtained. ¹H NMR (400MHz, CDCl₃) ; δ 11.57 (br, IH) , 7.26 (d J=2.4Hz, IH) , 7.21 (d J=8.8Hz, IH), 7.13(dd, ,7=8.8Hz, 2.4Hz, IH), 3.76(s, 2H), 3.11(t, J=β.0Hz, 2H), 2.94(t, J=5.8Hz, 2H), 1.60(s, 6H)

Step 3. Preparation of N- [3- (dimethylamino) propyl] -2- methy1-2- (5-oxo-2, 4,5, 6-tetrahydro-lH-thiopyrano [3, 4-c] quinolin-9-yloxy) propanamide

According to the similar procedure in the step 1 of example 10 by using the compound (30mg, 0.09mmol) prepared in the step

2, 35mg (yield: 92%, yellow solid) of the target compound was obtained.

¹H NMR (400MHz, CDCl₃) ; δ 11.74 (br, IH) , 8.06 ( t J=5.0Hz, IH) ,

7.30 (d, J=8.8Hz, IH), 7.17 (d, J=2.0Hz, IH), 7.10 (dd, J=8.8Hz,

1.6Hz, IH), 3.82(s, 2H), 3.42(qt, J=6.0Hz, 2H), 3.12(t, J=5.4Hz, 2H), 2.98(t, J=5.6Hz, 2H), 2.41(t, J=6.2Hz, 2H), 2.18(s, 6H),

1.75-1.70(m, 2H), 1.51(s, 6H)

Step 4. Preparation of N- [3- (dimethylamino) propyl] -2- methyl-2- (5-oxo-2, 4, 5, 6-tetrahydro-lH-thiopyrano [3, 4-c] quinolin-9-yloxy) propanamide hydrochloride

According to the similar procedure in the step 2 of example 10 by using the compound (35mg, 0.09mmol) prepared in the step 3, 26mg (yield: 68%, pale yellow solid) of the target compound was obtained.

¹H NMR(400MHz, DMSO-d₆) ; δ 11.81 (s, IH), 10.24 (br, IH), 8.37 (t J=5.8Hz, IH), 7.26(d, J=8.8Hz, IH), 7.20(d, J=2.0Hz, IH), 7.13(dd, J=8.8Hz, 2.0Hz, IH), 3.58(s, 2H), 3.18(qt, J=6.4Hz, 2H), 3.01-3.00 (m, 2H), 2.95-2.94(m, 4H), 2.68(s, 6H), 1.84-1.77(m, 2H), 1.42(s, 6H)

Compounds listed below were prepared by the similar procedure as described in Example 16.

Example 17 : N- [3- (diethylamino) propyl] -2-methyl-2- (5-OXO-2 ,4,5, 6-tetrahydro-lH-thiopyrano [3 , 4-c] quinolin-9- yloxy) propanamide hydrichloride

Example 18 : 9- [1- (4-ethylpiperazin-l-yl] -2-methyl-l- oxopropan-2-yloxy) -4 , 6-dihydro-lH-thiopyrano [3 , 4-c] quinolin- 5 (2H) -one Example 19 : 2-methyl-2- (5-oxo-2 , 4 ,5, 6-tetrahydro-lH- thiopyrano [3, 4-c]quinolin-9-yloxy) -N- [3- (4-phenyl-5, 6- dihydropyridin-1 (2H) -yl) propyl] propanamide hydrochloride

[Table 3]

Example 20 : N- (3-chloropropyl) -5-oxo-2 ,4,5, 6- tetrahydro-lH-thiopyrano [3 , 4-c] quinoline-9-carboxamide

According to the similar procedure in the step 1 of example 10 by using the compound (60mg, 0.23mmol) prepared in the example 5, 16.4mg (yield: 21.2%, yellow solid) of the target compound was obtained.

¹H NMR (400MHz, CDCl₃) : δ 12.02 (s, IH) , 9.68 (s, IH) , 8.80 (m, IH) , 8.15 (t, J=8.8Hz, 2H) , 7.95 (t, J=8.0Hz, IH) , 7.56 (t, J=8.40Hz, IH), 3.64(br, 2H), 3.50(br, 2H), 3.41(br, 2H), 2.79(br, 2H), 1.60-1.85(m, 6H), 1.38(br, 2H).

Example 21 : 5-oxo-N- [2- (piperidin-1-yl) ethyl] -2 , 4 ,5, 6 -tetrahydro-lH-thiopyrano [3 , 4-c] quinoline-9-carboxamide hydrochloride Step 1. Preparation of N- (2-chloroethyl) -5-oxo-2, 4 , 5, 6- tetrahydro-lH-thiopyrano [3, 4-c] quinoline-9-carboxamide

To a solution of the compound (lOOmg , 0.38mmol) prepared in the example 5 in dichloromethane (5.0ml) were added oxalyl chloride (65 μi, 0.77mmol) and N, N, -dimethylformamide (ldrop, catalytic amount) at 0^°C. The reaction mixture was stirred at room temperature for 3 hours . The reactionmixture was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (5.0ml) . After addition of chloroethylamine hydrochloride (49mg, 0.42mmol) and triethylamine (108 βl, 0.84mmol) , the reaction mixture was stirred at room temperature for 12 hours. Cold water and dichloromethane were added to the mixture, and the organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (chloroform:methanol = 20:1) to afford 60mg (yield: 49%, white solid) of the target compound.

¹H NMR (400MHz, DMSOd₆) ; δ 12.06 (s, IH) , 8.86(m, IH) , 8.26 (s, IH), 7.96(d, J=8.8Hz, IH), 7.34(d, J=8.4Hz, IH), 3.75(t, J=5.8Hz, 2H), 3.61(m, 4H), 3.19(m, 2H), 2.97(t, J=5.4Hz, 2H) Step 2. Preparation of 5-oxo-N- [2- (piperidin-1-yl) ethyl] -

2,4,5, 6-tetrahydro-lH-thiopyrano [3, 4-c ] quinoline-9-carboxami de

According to the similar procedure in the step 1 of example 7 by using the compound (35mg, O.llmmol) prepared in the step 1, 14mg (yield: 34%, white solid) of the target compound was obtained.

¹H NMR(400MHz, CD₃OD + DMSO-d₆) ; δ 8.22(s, IH), 7.92(d, J=8.8Hz, IH), 7.33(d, J=8.4Hz, IH), 3.60(s, 2H), 3.4β(m, 2H), 3.18-3.16 (m, 2H) , 2.95 (t, J=5.8Hz, 2H) , 2.54-2.45 (m, 6H) , 1.55 (m, 4H), 1.42 (m, 2H)

Step 3. Preparation of 5-oxo-N- [2- (piperidin-1-yl) ethyl] - 2,4,5, 6-tetrahydro-lH-thiopyrano [3, 4-c] quinoline-9-carboxami de hydrochloride

According to the similar procedure in the step 2 of example 10 by using the compound (12mg, 0.03mmol) prepared in the step 2, llmg (yield: 83%, white solid) of the target compound was obtained. 1H NMR(400MHz, DMSO-d₆) ; δ 12.05 (s, IH), 10.20 (br, IH), 9.09(t, J=5.4Hz, IH), 8.34(s, IH), 8.00(d, J=8.8Hz, IH), 7.33(d, J=8.0Hz, IH), 3.68(qt, J=5.6Hz, 2H), 3.58(s, 2H), 3.54-3.50(m, 2H), 3.21-3.20(m, 4H), 2.94(t, J=6.0Hz, 2H), 2.91-2.84(m, 2H), 1.77 (m, 4H), 1.69-1.66(m, IH), 1.39-1.34 (in, IH)

Example 22 : 9- (piperazine-1-carbonyl) -4, 6-dihydro-lH- thiopyrano [3 , 4-c] quinolin-5 (2H) -one hydrochloride

Step 1. Preparation of tert-butyl 4- (5-oxo-2, 4, 5, 6- tetrahydro-lH-thiopyrano [3, 4-c] quinoline-9-carbonyl) piperazine-1-carboxylate

According to the similar procedure in the step 1 of example

10 by using the compound (50mg, 0.19mmol) prepared in the example

5 and tert-butyl piperazin-1-carboxylate (71mg, 0.38mmol), 49mg (yield: 60%, white solid) of the target compound was obtained. ¹H NMR (400MHz, CDCl₃) ; δ 11.99 (s, IH) , 7.83 (s, IH) , 7.42 (d, J=8.4Hz, IH) , 7.27 (d, J=8.4Hz, IH) , 3.83 (s, 2H) , 3.58-3.37 (m, 8H) , 3.23~3.20 (m, 2H) , 3.01-2.97 (m, 2H) , 1.48 (s, 9H)

Step 2. Preparation of 9- (piperazine-1-carbonyl) -4 , 6- dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride

According to the similar procedure in the step 2 of example 10 by using the compound (49mg, O.llmmol) prepared in the step 1, 26.5mg (yield: 66%, yellow solid) of the target compound was obtained.

¹H NMR(400MHz, DMSO-d_e) ; δ 12.04 (s, IH), 9.24 (br s, IH), 7.82(s, IH), 7.56(d, J=8.0Hz, IH), 7.37(d, J=8.4H, IH), 3.70~3.60(m, 6H), 3.16-3.15 (m, 6H), 2.96~2.93(m, 2H)

Example 23 : 9- [4- (2-aminoethyl) piperazine-1-carbonyl] -4 , 6-dihydro-lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one dihydrochloride

Step 1. Preparation of tert-butyl 2-chloroethylcarbamate

To a solution of 2-chloroethylamine hydrochloride (Ig,

8.62mmol) in dichoromethane (20ml) were added di-tert-butyl dicarbonate (2.07g, 9.48mmol) and triethylamine (1.56 va.1,

11.20ramol) . The reaction mixture was stirred at room temperature for 24 hours. Water and chloroform were added to the mixture and the organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (n-hexane: ethyl acetate

= 5:1) to afford 1.5Og (yield: 97%, yellow oil) of the target compound.

¹H NMR(400MHz, CDCl₃); δ 4.9β(br s, IH), 3.62~3.59(m, 2H), 3.49~3.45(m, 2H), 1.46(s, 9H)

Step 2. Preparation of tert-butyl 2- [4- (5-oxo-2, 4, 5, 6- tetrahydro-lH-thiopyrano [3, 4-c] quinoline-9-carbonyl) piperazin-1-yl] ethylcarbamate

To a solution of the compound (40mg, O.lOmmol) prepared in the step 2 of example 22 in N, N, -dimethylformamide (5ml) were added the compound (22mg, 0.12mmol) prepared in the step 1, potassium carbonate (33mg, 0.24mmol) and sodium iodide (lβmg,

O.lOmmol) . The reaction mixture was stirred at room temperature for 48 hours. Water and chloroform were added to the mixture and the organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (chloroform:methanol = 7:1) to afford 8mg (yield: 17%, yellow solid) of the target compound.

¹HNMR (400MHz, CDCl₃) ; δ 11.54 (brs, IH) , 7.82 (s, IH) , 7.49(d, J=8.2Hz, IH), 7.37(d, J=8.5Hz, IH), 4.49~4.4β(m, 2H), 3.68~3.59(m, 2H), 3.24~3.20(m, 4H), 3.00~2.97(m, 2H), 2.57~2.40(m, 4H), 1.69~1.50(m, 4H), 1.46(s, 9H)

Step 3. Preparation of 9- [4- (2-aminoethyl) piperazine -1-carbonyl] -4 , 6-dihydro-lH-thiopyrano [3,4-c]quinolin-5(2H)- one dihydrochloride

According to the similar procedure in the step 2 of example 10 by using the compound (8mg, O.Olβmmol) prepared in the step 2, 3. lmg (yield: 44%, yellow solid) of the target compound was obtained.

¹H NMR (400MHz, DMSOd₆) ; δ 12.03 (br s, IH), 7.79(s, IH), 7.56(d, J=8.4Hz, IH), 7.38(d, J=8.3Hz, IH), 4.59~4.56(m, 2H), 4.37-4.34 (m, 2H) , 3.86-3.80 (m, 2H) , 3.42-3.51 (m, 2H) , 3.18-3.13 (m, 6H) , 2.95-2.90 (m, 4H)

Example 24 : N- [2- (dimethylamino) ethyl] -5-oxo-2 ,4,5, 6- tetrahydro-lH-thiopyrano [3 , 4-c] quinoline-9-carboxamide hydrochloride

Step 1. Preparation of N- [2- (dimethylamino) ethyl] -5-oxo- 2,4,5, 6-tetrahydro-lH-thiopyrano [3, 4-c] quinoline-9-carboxami de

According to the similar procedure in the step 1 of example

10 by using the compound (50mg, 0.19mmol) prepared in the example 5 and N, N, -dimethyIethylenediamine (22 μJt, 0.20mmol) , 56mg (yield: 88%, yellow solid) of the target compound was obtained. 1H NMR (400MHz, DMSO-d₆) ; δ l2.03(br, IH), 8.52 (t, J=5.4Hz, IH), 8.22(s, IH), 7.94(d, J=8.6Hz, IH), 7.32(d, J=8.4Hz, IH), 3.60(s, 2H), 3.40-3.38(m, 2H), 3.19(t, J=5.6Hz, 2H), 2.96(t, J=5.6Hz, 2H), 2.41(t, J=7.0Hz, 2H), 2.18(s, 6H)

Step 2. Preparation of N- [2- (dimethylamino) ethyl] -5-oxo- 2,4,5, 6-tetrahydro-lH-thiopyrano [3, 4-c] quinoline-9- carboxamide hydrochloride

According to the similar procedure in the step 2 of example 10 by using the compound (39mg, 0.12mmol) prepared in the step 1, 33mg (yield: 76%, yellow solid) of the target compound was obtained.

¹H NMR(400MHz, DMSO-d₆) ; δ 12.08 (s, IH), 10.19(br, IH), 9.02(t, J=5.4Hz, IH), 8.34(s, IH), 8.01 (d, J=8.8Hz, IH), 7.35(d, J=8.0Hz, IH), 3.65(qt, J=5.6Hz, 2H), 3.60(s, 2H), 3.29-3.25(m, 2H), 3.22(t, J=5.2Hz, 2H), 2.96(t, J-=5.6Hz, 2H), 2.83(s, 3H), 2.82(s, 3H)

Compounds listed below were prepared by the similar procedure as described in Example 24.

Example 25 : N- [3- (dimethylamino) propyl] -5-oxo-2 , 4 ,5, 6- tetrahydro-lH-thiopyrano [3 , 4-c] quinoline-9-carboxamide hydrochloride

Example 26 : N- [4- (dimethylamino) phenyl] -5-oxo-2 ,4,5, 6- tetrahydro-lH-thiopyrano [3 , 4-c] quinoline-9-carboxamide hydrochloride Example 27 : 5-oxo-N- [2- (4-phenyl-5 , 6-dihydropyridin- 1 (2H) -yl) ethyl] -2,4,5, 6-tetrahydro-lH-thiopyrano [3 , 4-c] quinoline-9-carboxamide hydrochloride

Example 28 : N- (2-morpholinoethyl) -5-oxo-2 , 4 ,5, 6- tetrahydro-lH-thiopyrano [3 , 4-c] quinoline-9-carboxamide hydrochloride

Example 29 : N- (2-aminoethyl) -5-oxo-2 , 4 ,5, 6-tetrahydro -lH-thiopyrano [3 , 4-c] quinoline-9-carboxamide hydrochloride

Example 30 : 5-oxo-N- [2- (piperazin-1-yl) ethyl] -2 , 4 ,5, 6- tetrahydro-lH-thiopyrano [3 , 4-c] quinoline-9-carboxamide dihydrochloride

Example 31 : N- [2- (4-methylpiperazin-l-yl) ethyl] -5-OXO-2 ,4,5, 6-tetrahydro-lH-thiopyrano [3 , 4-c] quinoline-9- carboxamide dihydrochloride Example 32 : 5-oxo-N- [2- (4-oxopiperidin-l-yl) ethyl] - 2,4,5, 6-tetrahydro-lH-thiopyrano [3 , 4-c] quinoline-9- carboxamide hydrochloride

Example 33 : 9- (4-phenylpiperazine-l-carbonyl) -4 , 6- dihydro-lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one hydrochloride Example 34 : N-{4- [2- (diethylamino) ethoxy] phenyl} -5-oxo- 2,4,5, 6-tetrahydro-IH-thiopyrano [3 , 4-c] quinoline-9- carboxamide hydrochloride

Example 35 : 9- [4- (3-aminopropyl)piperazine-l-carbonyl] -4 , 6-dihydro-lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one dihydrochloride Example 36 : 9- [4- (pyridin-4-yl)piperazine-l-carbonyl] -4 , 6-dihydro-lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one hydrochloride

Example 37 : 9- {4- [2- (4-oxopiperidin-l-yl) ethyl] piperazine-l-carbonyl}-4, 6-dihydro-lH-thiopyrano[3, 4-c] quinolin-5 (2H) -one dihydrochloride

Example 38 : 5-oxo-N-{3- [4- (pyridin-4-yl)piperazin-l- yl] propyl} -2 ,4,5, 6-tetrahydro-lH-thiopyrano [3 , 4-c] quinoline- 9-carboxamide dihydrochloride Example 39 : 9-{4- [2- (4-fluorophenyl) -5, 6-dihydropyridin- 1 (2H) -yl]ehtyl}piperazine-l-carbonyl) -4 , 6-dihydro-lH- thiopyrano [4 , 3-c] quinolin-5 (2H) -one dihyrochloride

Example 40 : 9-{4-] 2- (4-phenylpiperazin-l-yl) ethyl] piperazine-1-carbonyl } -4 , 6-dihydro-lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one trihydrochloride

Example 41 : 9- (piperidine-1-carbonyl) -4 , 6-dihydro-lH- thiopyrano [3 , 4-c] quinolin-5 (2H) -one

Example 42 : 9- (4-methylpiperazine-l-carbonyl) -4 , 6- dihydro-lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one hydrochloride Example 43 : 9- (4-benzylpiperazine-l-carbonyl) -4, 6- dihydro-lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one hydrochloride

Example 44 : 9- (4-ethylpiperazine-l-carbonyl) -4 , 6- dihydro-lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one hydrochloride Example 45 : 9- {4- [2- (4-phenyl-5, 6-dihydropyridin-l (2H) -yl) ethyl] piperazine-1-carbonyl} -4 , 6-dihydro-lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one dihydrochloride

Example 46 : 9-{4- [2- (l-methylpiperidin-4-yl) ethyl] piperazine-1-carbonyl} -4 , 6-dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one dihydrochloride

Example 47 : N- [5- (methylamino)pentyl] -5-oxo-2 , 4 ,5, 6- tetrahydro-lH-thiopyrano [3 , 4-c] quinoline-9-carboxamide hydrochloride Example 48 : 9- [4- (4-methylpentyl) piperazine-1-carbonyl] - 4 , 6-dihydro-lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one hydrochloride

Example 49 : 9- (4-hexylpiperazine-l-carbonyl) -4 , 6-dihydro -lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one hydrochloride Example 50 : 9- [4- (pentan-2yl) piperazine-1-carbonyl] -4, 6- dihydro-lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one hydrochloride

Example 51 : 9- (4-isopropylpiperazine-l-carbonyl) -4, 6- dihydro-lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one hydrochloride

Example 52 : 9- (4-phenethylpiperazine-l-carbonyl) -4 , 6- dihydro-lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one hydrochloride

Example 53 : 9-{4- [2- (dimethylamino) ethyl] piperazine-1- carbonyl} -4 , 6-dihydro-lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one dihydrochloride Example 54 : 9- {4- [2- (piperidin-1-yl) ethyl] piperazine -l-carbonyl}-4, 6-dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) - one dihyrdochloride

Example 55 : N- (5-aminopentyl) -5-oxo-2 , 4 ,5, 6-tetrahydro -lH-thiopyrano [3 , 4-c] quinoline-9-carboxamide hydrochloride

Example 56 : 5-oxo-N-{2- [4- (pyridin-4-yl)piperazin-l- yl] ethyl} -2 ,4,5, 6-tetrahydro-IH-thiopyrano [3,4-c]quinoline-9 -carboxamide dihydrochloride

Example 57 : N- [5- (dimethylamino) pentyl] -5-oxo-2 , 4 ,5, 6- tetrahydro-lH-thiopyrano [3 , 4-c] quinoline-9-carboxamide hydrochloride

Example 58 : N- [4- (isopropylamino) butyl] -5-oxo-2 , 4 ,5, 6- tetrahydro-lH-thiopyrano [3 , 4-c] quinoline-9-carboxamide hydrochloride Example 59 : N- (3-aminopropyl) -5-oxo-2 , 4,5, 6-tetrahydro -lH-thiopyrano [3 , 4-c] quinoline-9-carboxamide hydrochloride

Example 60 : N- (4-aminobutyl) -5-oxo-2 ,4,5, 6-tetrahydro -lH-thiopyrano [3 , 4-c] quinoline-9-carboxamide hydrochloride

Example 61 : 9- (4-isopentylpiperazine-l-carbonyl) -4 , 6- dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride

Example 62 : 9- (4-propylpiperazine-l-carbonyl) -4 , 6- dihydro-lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one hydrochloride

Example 63 : 9- (4-butylpiperazine-l-carbonyl) -4 , 6- dihydro-lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one hydrochloride Example 64 : 9- [4- (cyclopropylmethyl)piperazine-l- carbonyl] -4 , 6-dihydro-lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one hydrochloride

Example 65 : 9- (4-pentylpiperazine-l-carbonyl) -4, 6- dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride

Example 66 : 9- (4-heptylpiperazine-l-carbonyl) -4 , 6- dihydro-lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one hydrochloride

Example 67 : 9- [4- (4 , 4 , 4-trifluorobutyl)piperazine-l- carbonyl] -4 , 6-dihydro-lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one hydrochloride

Example 68 : 9- [4- (2 ,2 ,2-tri£luoroethyl)piperazine-l- carbonyl] -4 , 6-dihydro-lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one hydrochloride 9

Example 69 : 5-oxo-N- [2- (4-phenylpiperazin-l-yl) ethyl] - 2,4,5, 6-tetrahydro-lH-thiopyrano [3 , 4-c] quinoline-9- carboxamide dihydrochloride

Example 70 : 5-oxo-N- [3- (4-phenyl-5 , 6-dihydropyridin- 1 (2H) -yl)propyl] -2 , 4 ,5, 6-tetrahydro-lH-thiopyrano [3, 4-c] quinoline-9-carboxamide hydrochloride Example 71 : N- [4- (ethyl (methyl) amino) butyl] -5-oxo- 2,4,5, 6-tetrahydro-lH-thiopyrano [3 , 4-c] quinoline-9- carboxamide hydrochloride

Example 72 : 9- (4-cyclopentylpiperazine-l-carbonyl) -4,6- dihydro-lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one hydrochloride Example 73 : 9- (4-cyclohexylpiperazine-l-carbonyl) -4 , 6 -dihydro-lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one hydrochloride

Example 74 : 9- (4-cycloheptylpiperazine-l-carbonyl) -4 , 6 -dihydro-lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one hydrochloride

Example 75 : 9- [4- (4 , 4 ,5 ,5 ,5-pentafluoropentyl) piperazine-1-carbonyl] -4 , 6-dihydro-lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one hydrochloride

Example 76 : 9- (4-neopentylpiperazine-l-carbonyl) -4, 6- dihydro-lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one hydrochloride [Table 4]

Example 77 : 9- (piperidin-4-ylthio) -4 , 6-dihydro- lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one hydrochloride

Step 1. Preparation of tert-butyl 4- (4-nitrophenylthio) piperidine-1-carboxylate

To a solution of 4-nitrobenzenethiol (560mg, 3.6mmol) in N, N, -dimethylformamide (20ml) were added potassium carbonate (550mg, 3.96mmol), tert-butyl 4-bromopiperidine-l-carboxylate (550mg, 3.96mmol) and potassium iodide (30mg, O.lδmmol) . The reaction mixture was refluxed for 12 hours at 60^°C . After reaction, the reaction mixture was cooled to room temperature, and then water and chloroform were added to the mixture. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure . The residue was purified by column chromatography (n-hexane : ethyl acetate = 5:1) to afford l.lg

(yield: 90%, yellow oil) of the target compound.

¹H NMR (400MHz, CDCl₃) δ 8.13 (d, J=8.4Hz, 2H) , 7.39 (d, J=8.4Hz, 2H), 3.97(br s, 2H), 3.52-3.47(m, IH), 3.04(t, J=Il.2Hz, 2H), 2.04-1.99(m, 2H), 1.68-1.57(m, 2H), 1.45(s, 9H) .

Step 2. Preparation of tert-butyl 4- (4-aminophenylthio) piperidine-1-carboxylatet

To a solution of the compound (500mg, 1.48mmol) prepared in the step 1 in methanol (10ml) was added 10wt% palladium on activated carbon (50mg) . The reaction mixture was stirred under a hydrogen atmosphere for 18 hours. After reaction, the reaction mixture was filtered through celite pad. The solvent was concentrated, and the residue was purified by column chromatography (n-hexane: ethyl acetate = 1:1) to afford 340mg

(yield: 75%, colorless oil) of the target compound.

¹H NMR(400MHz, CDCl₃); δ 7.25 (d, J=8.4Hz, 2H), 6.60(d, J=8.4Hz, 2H), 3.95(br s, 2H), 3.80(br s, IH), 2.95-2.88(m, 2H), 2.81(s, 2H), 1.84(d, J=IO.4Hz, 2H), 1.42(s, 9H) . Step 3. Preparation of tert-butyl 4- [4- (1, 5-dioxa-9- thiaspiro [5.5] undecane-7-carboxamido) phenylthio] piperidine-1 -carboxylate

To a solution of compound (220mg, l.Olmmol) in the step 5 of example 14 in dichloromethane was added thionyl chloride (143mg, 1.21mmol) at 0^°C. After addition of 1 drop of N, N, -dimethylformamide , the reaction mixture was stirred at room temperature for 1 hour. The reaction was quenched with methanol, and the solvent was removed under reduced pressure . To a solution of the residue (210mg, 0.88mmol) in dichloromethane were added the compound (340mg, 1.02mmol) prepared in the step 2 of example 1 and triethylamine at 0^°C. The reaction mixture was stirred at room temperature for 10 hours. After reaction, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure . The residue was purified by column chromatography (dichloromethane :methanol = 10 : 1) to afford 400mg (yield: 78%, yellow solid) of the target compound.

¹H NMR(400MHz, CDCl₃) δ 9.07(s, IH), 7.49(d, J=8.4Hz, 2H), 7.40(d, J=8.4Hz, 2H), 4.18-4.09(m, IH), 4.04-3.89(m, 5H), 3.18-3.04 (m, 3H), 2.94-2.74(m, 5H), 2.57(d, J=13.6Hz, IH), 2.04-1.96(m, IH), 1.86(s, 2H), 1.74-1.59 (m, 2H), 1.54-1.44 (m, HH) Step 4. Preparation of 9- (piperidin-4-ylthio) -4, 6-dihydro -lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one

To the compound (400mg, 0.779mmol) prepared in the step 3 was added 100ml of a 70% sulfuric acid. The reaction mixture was stirred at room temperature for 8 hours. After reaction, the reaction mixture was poured into ice-cold water and stirred for

30 minutes. The resulting solid was filtered and washed with methanol. The solid was dried under reduced pressure to afford 31mg (yield: 12%, brown solid) of the target compound.

¹HNMR^OOMHZ, DMSO-d₆) 11.89(brs, IH), 10.07(s, IH), 7.73(s, IH), 7.54(d, J=7.6Hz, IH), 7.28(d, J=8.0hz, IH), 3.73(s, IH), 3.59(s, 2H), 3.16(s, 2H), 3.11(S, 2H), 2.92(s, 2H), 2.67(s, 2H), 1.86(S, 2H), 1.47(s, 2H) Step 5. Preparation of 9- (piperidin-4-ylthio) -4 , 6-dihydro

-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride

To a solution of the compound (15mg, 0.047mmol) prepared in the step 4 in 1,4-dioxane (1.0ml) was added the 3.7M HCl in 1,4-dioxane (1.0ml) . The reaction mixture was stirred at room temperature for 24 hours. To the reaction mixture was added ethyl acetate, and the resulting solid was filtered to afford 6.7mg (yield: 39%, yellow solid) of the target compound.

¹H NMR (400MHz, DMSO-d₆) δ 11.96 ( s, IH) , 8.96(br s, 2H) , 7.76(s, IH), 7.55(d, J=8.4Hz, 2H), 7.30(d, J=8.4Hz, 2H), 3.60(s, 2H), 3.55(s, IH), 3.20(d, J=IO.4Hz, 2H), 3.12(t, J=β.8Hz, 2H), 2.92(t, J=6.0Hz, 2H) , 2.86 (s, 2H) , 1.97 (d, J=Il.6Hz, 2H) , 1.62 (d, J=IO.8Hz, 2H)

Example 78 : 9- [2- (piperidin-1-yl) ethoxy] -4, 6-dihydro -lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one hydrochloride Step 1. Preparation of 9- [2- (piperidin-1-yl) ethoxy] - 4 , 6-dihydro-IH-thiopyrano [3, 4-c] quinolin-5 (2H) -one

According to the similar procedure in the step 2 of example 23 by using the compound (180mg, 0.77mmol) prepared in the example 3 and 1- (2-chloroethyl) piperidine (149mg, 0. δlmmol) , 97mg (yield: 36%, white solid) of the target compound was obtained. ¹H NMR(400MHz, CDCl₃); δ 11.22(s, IH), 7.26-7.24(m, IH), 7.14-7.11 (m, 2H), 4.17(t, J=β.0Hz, 2H), 3.83(s, 2H), 3.13(t, J=β.0Hz, 2H), 2.98(t, J=6.0Hz, 2H), 2.83(t, J=β.0Hz, 2H), 2.56(m, 4H), 1.65(m, 4H), 1.47 (m, 2H)

Step 2. Preparation of 9- [2- (piperidin-1-yl) ethoxy] -4, 6- dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride

According to the similar procedure in the step 2 of example 10 by using the compound (97mg, 0.28mmol) prepared in the step 1, 95mg (yield: 89%, yellow solid) of the target compound was obtained.

¹H NMR(400MHz, DMSO-d₆) ; δ 11.79 (s, IH), 10.25 (br, IH), 7.29-7.20(m, 3H), 4.44(m, 2H), 3.59-3.5β(m, 6H), 3.11(m, 2H), 2.94 (m, 4H), 1.79(m, 4H), 1.71 (m, IH), 1.39(m, IH)

Example 79 : 9- (piperidin-4-yloxy) -4 , 6-dihydro-lH- thiopyrano [3 , 4-c] quinolin-5 (2H) -one hydrochloride

Step 1. Preparation of tert-butyl 4-bromopiperidine-l- carboxylate

According to the similar procedure in the step 1 of example 23 by using the 4-bromopiperidine hydrobromide (200mg, O.δlβmmol), 220mg (yield: 99%, colorless oil) of the target compound was obtained.

¹H NMR(400MHz, CDCl₃) δ 4.3β(m, IH) , 3.70-3.65 (m, 2H), 3.35-3.28 (m, 2H), 2.12-2.05 (m, 2H), 1.95-1.92(m, 2H), 1.47(s, 9H) .

Step 2. Preparation of tert-butyl 4- (5-oxo-2, 4 , 5, 6- tetrahydro-lH-thiopyrano [3, 4-c] quinolin-9-yloxy) piperidine-1 -carboxylate

To a solution of the compound (50mg, 0.214mmol) prepared in the Example 3 in isopropanol were added potassium hydroxide (54mg, 0.963mmol) . The reaction mixture was refluxed for 1 hour. The compound (198mg, 0.75mmol) prepared in the step 1 was slowly added therein and reflxued for 24 hours. After reaction, the solvent was removed under reduced pressure, and the residue was purified by column chromatography (n-hexane : ethyl acetate = 1:1) to afford 23mg (yield: 26%, yellow solid) of the target compound.

¹H NMR(400MHz, CDCl₃) δ 10.90(s, IH), 7.31-7.15 (m, 3H) 4.51-4.46 (m, IH) ,3.83 (s, 2H) , 3.77-3.69 (m, 2H) , 3.39-3.30 (m, 2H) , 3.1β(t, J=5.2Hz, 2H), 2.99(t, J=5.2Hz, 2H), 1.98-1.90(m, 2H), 1.80-1.72(m, 2H), 1.48(s, 9H) .

Step 3. Preparation of 9- (piperidin-4-yloxy) -4 , 6-dihydro -lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride

According to the similar procedure in the step 2 of example 10 by using the compound (23mg, 0.055mmol) prepared in the step 2, 21.1mg (yield: 84%, yellow solid) of the target compound was obtained.

¹H NMR(400MHz, DMSO-d₆) δ 11.75 (s, IH), 8.77 (br, IH) 7.28-7.23(m, 3H), 4.69(s, IH), 3.83(s, 2H), 3.24(br, 2H), 3.15-3.01(m, 4H), 2.95(t, J=5.βHz, 2H), 2.13-2.06 (m, 2H), 1.89-1.79(m, 2H)

Example 80 : 9- (l-isopentylpiperidin-4-yloxy) -4, 6- dihydro-lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one hydrochloride Step 1. Preparation of 9- (l-isopentylpiperidin-4- yloxy) -4, 6-dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one

To a solution of the compound (lOmg, 0.028mmol) prepared in the step 3 of Example 79 in acetonitrile were added potassium carbonate (12mg, 0.085mmol) and isobutyl bromide (8.5mg, 0.057mmol) . The reaction mixture was stirred at 70^°C for 10 hours . After reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (n-hexane : ethyl acetate = 1:2) to afford 8mg (yield: 72%, yellow solid) of the target compound.

¹H NMR(400MHz, CDCl₃ ) δ 11.92(s, IH), 7.28-7.12 (m, 3H) 4.39(br, IH), 3.83(s, 2H), 3.16(t, J=5.6Hz, 2H), 2.99(t, ,7=5.2Hz, 2H) , 2.82 (br, 2H) , 2.47 (br, 3H) , 2.12(br, 2H) , 1.91(br, 3H) , 1.60 (m, 2H), 1.50-1.4β(m, 2H), 0.92(d, J=5.2Hz, 6H) .

Step 2. Preparation of 9- (l-isopentylpiperidin-4-yloxy) -4, 6-dihydro-lH-thiopyra no [3, 4-c] quinolin-5 (2H) -one hydrochloride

According to the similar procedure in the step 2 of example 10 by using the compound (8mg, 0.021mmol) prepared in the step 2, 6mg (yield: 70%, yellow solid) of the target compound was obtained.

¹H NMR(400MHz, DMSO-d₆) δ ll.75(s, IH), 9.92-9.77 (br, IH), 7.31-7.23(m, 3H), 4.62-4.53(m, IH), 3.60(s, 2H), 3.16-2.99(m, 4H), 2.94(t, J=5.2Hz, 2H), 2.32-2.05(m, 2H), 2.09-2.03(m, 3H), 1.91-1.83(m, 2H), 1.62-1.53 (m, 4H), 0.91(d, J=6.0Hz, 6H) .

Compounds listed below were prepared by the similar procedure as described in Example 80.

Example 81 : 9- (l-propylpiperidin-4-yloxy) -4, 6-dihydro -lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one hydrochloride

Example 82 : 9- (l-ethylpiperidin-4-yloxy) -4 , 6-dihydro -lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one hydrochloride

Example 83 : 9- [1- (2-aminoethyl)piperidin-4-yloxy] -4, 6- dihydro-lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one dihydrochloride Example 84 : methyl 2- [4- (5-oxo-2 ,4,5, 6-tetrahydro- lH-thiopyrano [3 , 4-c] quinolin-9-yloxy] piperidin-1-yl) acetate hydrochloride

Example 85 : 3- [4- (5-oxo-2 ,4,5, 6-tetrahydro-lH-thiopyrano [3, 4-c] quinolin-9-yloxy) piperidin-1-yl] propanenitrile hydrochloride

Example 86 : 9- [1- (2-chloroethyl)piperidin-4-yloxy] -4 , 6-dihydro-lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one hydrochloride Example 87 : 2- [4- (5-oxo-2 ,4,5, 6-tetrahydro-lH- thiopyrano [3, 4-c] quinolin-9-yloxy) piperidin-1-yl] acetic acid hydrochloride

Example 88 : 2- [4- (5-oxo-2 , 4 ,5, 6-tetrahydro-lH-thiopyrano [3 , 4-c] quinolin-9-yloxy) piperidin-1-yl] acetamide hydrochloride

Example 89 : 9- [1- (2-hydroxyethyl)piperidin-4-yloxy] -4 , 6-dihydro-lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one hydrochloride

Example 90 : 9- [1- (2-methoxyethyl)piperidin-4-yloxy] -4 , 6-dihydro-lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one hydrochloride

Example 91 : 9- [1- (2- (piperidin-1-yl) ethyl) piperidin -4-yloxy] -4 , 6-dihydro-lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one dihydrochloride Example 92 : 9- (l-neopentylpiperidin-4-yloxy) -4 , 6- dihydro-lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one hydrochloride

Example 93 : 9- [1- (4 , 4 , 5 , 5 , 5-pentafluoropentyl) piperidin-4-yloxy] -4 , 6-dihydro-lH-thiopyrano [3 , 4-c] quinolin- 5 (2H) -one hydrochloride

Example 94 : 9- (l-methylpiperidin-4-yloxy) -4 , 6-dihydro -lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one hydrochloride

Example 95 : 9- [1- (2-oxobutyl) piperidin-4-yloxy] -4, 6- dihydro-lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one hydrochloride

Example 96 : 9- [1- (2 ,2 ,2-tri£luoroethyl)piperidin-4- yloxy] -4 , 6-dihydro-lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one hydrochloride [Table 5]

Compounds listed below were prepared according to the above procedure .

Example 97 : 9- [1- (cyclohexenylmethyl)piperidin-4-yloxy] -4 , 6-dihydro-lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one hydrochloride

Example 98 : 9- (piperidin-3-yloxy) -4 , 6-dihydro-lH- thiopyrano [3 , 4-c] quinolin-5 (2H) -one hydrochloride

Example 99 : 9- (l-methylpiperidin-3-yloxy) -4 , 6-dihydro -lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one hydrochloride

Example 100: 9- (l-methylpyrrolidin-3-yloxy) -4,6- dihydro-lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one hydrochloride Example 101: 9- (l-propylpiperidin-3-yloxy) -4, 6-dihydro -lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one hydrochloride

Example 102 : 9- (l-ethylpiperidin-3-yloxy) -4 , 6-dihydro -IH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one hydrochloride Example 103: 9- (l-ethylpyrrolidin-3-yloxy) -4 , 6-dihydro -lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one hydrochloride

Example 104: 9- (l-benzylpiperidin-4-yloxy) -4 , 6-dihydro -lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one hydrochloride Example 105: 9- (1- (pyrimidin-2-yl)piperidin-4-yloxy) -4 , 6-dihydro-lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one

Example 106: 9- (l-phenylpiperidin-4-yloxy) -4 , 6-dihydro -lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one hydrochloride

Example 107: 9-{l-[2- (4-phenyl-5, 6-dihydropyridin- 1 (2H) -yl) ethyl] piperidin-4-yloxy} -4 , 6-dihydro-lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one dihydrochloride

Example 108 : 9- (l-phenethylpiperidin-4-yloxy) -4 , 6- dihydro-lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one hydrochloride

Example 109: 9- [1- (4 , 4,4-trifluorobutyl)piperidin-4- yloxy] -4 , 6-dihydro-lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one hydrochloride

Example 110 : 9- [1- (pyridin-4-ylmethyl)piperidin-4-yloxy] -4 , 6-dihydro-lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one hydrochloride Example 111; 2 ,2 ,2-trifluoro-N-{2- [4- (5-oxo-2 , 4 ,5, 6- tetrahydro-lH-thiopyrano [3 , 4-c] quinolin-9-yloxy)piperidin-l- yl] ethyl }acetamide hydrochloride

Example 112 : 9- [1- (2-oxo-2-phenylethyl)piperidin-4- yloxy] -4 , 6-dihydro-lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one hydrochloride Example 113: 4-{ [4- (5-oxo-2 , 4 ,5, 6-tetrahydro-lH- thiopyrano [3, 4-c]quinolin-9-yloxy)piperidin-l-yl] methyl} benzonitrile hydrochloride

Example 114 : 9- [1- (3-chloropropyl)piperidin-4-yloxy] - 4 , 6-dihydro-lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one hydrochloride

Example 115: 9- (l-{2- [4- (pyrimidin-2-yl)piperazin-l-yl] ethyl}piperidin-4-yloxy) -4 , 6-dihydro-lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one dihydrochloride Example 116: tert-butyl 5-oxo-2,4,5,6-tetrahydro- lH-thiopyrano [3 , 4-c] quinolin-9-yl carbonate

Example 117: 9- (l-butylpiperidin-4-yloxy) -4 , 6-dihydro -lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one hydrochloride

Example 118: 9- [1- (3-fluoropropyl)piperidin-4-yloxy] -4 , 6-dihydro-lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one hydrochloride

Example 119: 9- [4- (dimethylamino)phenethoxy] -4, 6- dihydro-lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one

Example 120: 9- (l-pentylpiperidin-4-yloxy) -4 , 6-dihydro -lH-thiopyrano [3 , 4-c] quinolin-5 (2H) -one hydrochloride

Example 121: 9-{l- [2- (4-acetylpiperazin-l-yl) ethyl] piperidin-4-yloxy} -4 , 6-dihydro-lH-thiopyrano [3 , 4-c] quinolin- 5 (2H) -one dihydrochloride [Table β] example chemical structure NMR spectrum data (¹H or 1¹3^J,C)

Experimental Example 1 : Poly (ADP-ribose)polymerase-l [PARP-I] Enzyme Inhibition Assay

The PARP-I enzyme-inhibitory activities of the compounds of the present invention were assayed using a PARP Assay kit

(4671-096-K) purchased from Trevigen, as described by Lee et al.

(Methods Find, Exp. Clin. Pharmacol., 27, 617-622, 2005) as follows .

A small volume PS plate (Greiner bio-one, 784101) , 384-well plate was coated with histone, and left at 25 ^°C for 2 hrs. Then the plate is washed with PBS (7.5 mM Na₂HPO₄, 2.5 mM NaH₂PO₄, 145 mM NaCl, pH 7.4) four times. To block the nonspecific signal, a Strep-diluent (providedin the kit of Trevigen) was added thereto, and left at 25 ^°C for 1 hr. Then, the plate was washed with PBS four times, and various concentrations of the compounds of the Examples were added to a reaction liquid containing PARP-I enzyme (0.12 unit/well) and PARP cocktail (NAD⁺, biotinylated NAD⁺, and activated DNA) , and incubated at 25 ^°C for 30min. Then, each well was washed with PBS four times. To measure the ribosylation activity of PARP enzyme, strepavidin-linkedperoxidase (Strep-HRP, 1:1000 dilution) was added, and incubated at 37 ^°C for 30 min. The plate was washed with PBS four times, and then TACS-Sapphire substrate was added thereto, followed by incubation at 25 ^°C for 10 min for the colorimetric reaction. Finally, 0.2 N HCl was added to terminate the reaction. Histone ribosylation by PARP-I enzyme was quantified using a Wallac Envision™ (PerkinElmer Oy, Turku, Finland) at 450 nm. The results obtained according to various concentrations of the compounds of the present invention are average values obtained from three wells, and the result analysis was performed using SigmaPlot 10 (Systat Software Inc., USA) to calculate the IC_5O values of the compounds. In addition, commercially available DPQ (Sigma) was used as a control to perform the comparative studies.

The results are shown in Table 7.

[Table 7]

*NT: not tested

As shown in Table 7, the compounds of the present invention showed excellent inhibitory activity on PARP-I.

Experimental Example 2 : PARP Enzyme Inhibition Assay using cells

To confirm the PARP-I enzyme-inhibitory activities of the compounds of the present invention, the amount of NAD(P)H accumulated in the cell culture media was measured. Chinese hamster ovary cells (Chinese hamster ovary; CHO-Kl) were cultured in RPMI media supplemented with 10% fetal bovine serum (FBS) . The cultured CHO-Kl cells were seeded at a density of 2.9 x 10³ cells/well in 96-well plate, and cultured at 37 °C and 5% CO₂ for 16 hrs. Then, the cells were treated with various concentrations of the compounds of Examples, and incubated at 37 ^°C for 2 hrs. DNA damage was induced using 1.5 itiM MMS (Methyl methanesulfonate) , and the cells were simultaneously treated with a CCK-8 (Cell count kit-8) solution (DOJINDO, (CKOl-13)) for colorimetric assay. At 3, 4, and 5 hrs after the treatment with MMS, the amount of NAD(P)H secreted into the culture media was quantified using a Wallac Envision™ (PerkinElmer Oy, Turku, Finland) at 450 nm. The results obtained according to various concentrations of the compounds of the present invention are the average values obtained from four wells, and the results were calculated by regression analysis. In addition, commercially available DPQ (Sigma) was used as a control to perform the comparative studies.

Table 8 represents the result of quantifying the amount of NAD(P)H secreted into culture medium after treating the Chinese hamster ovary cells (CHO-Kl) with various concentrations of the compounds of the present invention and then with MMS for 4 hrs, and FIG. 1 is a graph showing the values of Table 8.

[Table 8]

As shown in Table 8 and FIG. 1, the compounds of the present invention showed excellent inhibitory activity on PARP-I.

[Industrial Applicability]

The tricyclic derivatives of the present invention inhibit the activity of poly (ADP-ribose) polymerase, thereby being used for the prevention or treatment of diseases that are caused by excessive activation of PARP, in particular, neuropathic pain, neurodegenerative diseases, cardiovascular diseases, diabetic neuropathic pain, inflammatory diseases, osteoporosis, and cancer.

Claims

[CLAIMS] [Claim 1]

A tricyclic derivative represented by the following Formula 1 or pharmaceutically acceptable salt thereof:

<Formula 1>

wherein Y is ORi, SRi, COORi, NR₂R₃ or -A-B;

Ais-0-, -S-, -CH₂-, -C≡C-, -CO-, -CONH-, -NHCO-Or-NHSO₂-;

B is - (CH₂) ni-NR₂ R₃, - (CH₂) ni-halogen, - (CH₂) Ti₁-Z₁, - (CH₂) ni-C (CH₃) ₂- (CH₂) U₂-Z₁, -C (CH₃) ₂-CO-Z₁,

-C (CHs)₂-CONH- (CH₂) ni-NR₂R₃, -C (CH₃) ₂-C0NH- (CH₂) Ti₁-Z₁, or COORi;

Zi is C₆~C₂₀ aryl unsubstituted or substituted with R₄, or C₅-C_2O heterocyclic compound unsubstituted or substituted with R₄; Ri, R₂ and R₃ are each independently H; Ci~Cio straight or branched chain alkyl; or C₆-C₂₀ aryl;

R₄ is H, Ci~Cio straight or branched chain alkyl, - (CH₂) n₃-R₅, - (CH₂Jn₃-NR₂R₃ or -0- (CH₂) n₃-NR₂R₃;

R₅ is ORi; CORi,- COORi; -CF₃; -CF₂CF₃; CN; halogen; CONR₂R₃; NRiCOCF₃; C₃-Ci₀ cycloalkyl; C₃-Ci₀ cycloalkenyl; C₆-C₂₀ aryl unsubstituted or substituted with CN; or C₆-C₂₀ aryl unsubstituted or substituted with Ci-C₄ alkyl or halogen, C₃-C_2O heteroaryl unsubstituted or substituted with Ci~C₄ alkyl or halogen, or C₃~C₂o heterocyclic compound unsubstituted or substituted with CORi; and ni to n₃ are each an integer of 0 to 15.

[Claim 2]

The tricyclic derivative or pharmaceutically acceptable salt thereof according to claim 1, wherein Zi is one group selected from the group consisting of the following Formulae Cl to C12;

C1 C2 C3 C4

C5 C6 C7 C8

C9 C10 C11 C12

Ri, R₂ andR₃ are each independently H, methyl, ethyl, isopropyl, t-butyl or phenyl,

R₄ is H, methyl, ethyl, propyl, isopropyl, butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, heptyl, -(CI^n₃-R₅, - (CH₂Jn₃-NR₂R₃ or -0- (CH₂) n₃-NR₂R₃; R₅ is OH; OCH₃; COC₆H₅; COOH; COOCH₃; -CF₃; -CF₂CF₃; CN; Cl; F; CONH₂; NHCOCF₃; cyclopropyl; cyclopentyl; cyclohexyl; cycloheptyl; cyclohexenyl; phenyl; or

rii to ri₃ are each an integer of 0 to 10. [Claim 3]

The tricyclic derivative or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of Formula 1 is any one selected from the group consisting of

1) 9-methoxy-4, 6-dihydro-lH-thiopyrano [3, 4-c] quinolin -5 ( 2H ) -one ,

2 ) 8-methoxy-4, 6-dihydro-lH-thiopyrano [3, 4-c] quinolin -5 (2H) -one,

3) 9-hydroxy-4 , 6-dihydro-lH-thiopyrano [3,4-c]quinolin- 5 (2H) -one,

4) ethyl 5-oxo-2, 4 , 5, 6-tetrahydro-lH-thiopyrano [3, 4-c] quinoline-9-carboxylate,

5) 5-oxo-2, 4,5, 6-tetrahydro-lH-thiopyrano [3, 4-c] quinoline-9-carboxylic acid, 6) 9- (2-chloroethyl) -4, 6-dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one,

7 ) 9- [2- (piperidin-1-yl) ethyl] -4, 6-dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

8 ) 9- [3- (dimethylamino) prop-1-ynyl] -4 , 6-dihydro-lH- thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

9) 9-amino-4 , β-dihydro-IH-thiopyrano [3, 4-c] quinolin- 5 (2H) -one,

10) N- (5-oxo-2, 4,5, 6-tetrahydro-lH-thiopyrano [3, 4-c] quinolin-9-yl) -3- (piperidin-1-yl) propanamide hydrochloride, 11) 3- (dimethylamino) -N- (5-oxo-2,4,5, 6-tetrahydro-lH- thiopyrano [3, 4-c] quinolin-9-yl) propanamide hydrochloride, 12) N- (5-oxo-2,4,5, 6-tetrahydro-lH-thiopyrano [3, 4-c] quinolin-9-yl) -3- (4-phenyl-5, 6-dihydropyridin-l (2H) -yl) propanamide hydrochloride, 13) 3-chloro-N- (5-oxo-2, 4 , 5, 6-tetrahydro-lH-thiopyrano [3, 4-c] quinolin-9-yl) propane-1-sulfonamide,

14 ) 9- [3- (dimethylamino) propanoyl] -4, 6-dihydro-lH- thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

15) 9- [2, 2-dimethyl-3- (piperidin-1-yl) propoxy] -4,6- dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

16) N- [3- (dimethylamino) propyl] -2-methyl-2- (5-oxo- 2,4,5, 6-tetrahydro-lH-thiopyrano [3, 4-c] quinolin-9-yloxy) propanamide hydrochloride,

17) N- [3- (diethylamino) propyl] -2-methyl-2- (5-oxo- 2,4,5, 6-tetrahydro-lH-thiopyrano [3, 4-c] quinolin-9-yloxy) propanamide hydrochloride,

18 ) 9- [1- (4-ethylpiperazin-l-yl] -2-methyl-1-oxopropan- 2-yloxy) -4 , 6-dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one,

19) 2-methyl-2- (5-oxo-2, 4 , 5, 6-tetrahydro-lH-thiopyrano [3, 4-c] quinolin-9-yloxy) -N- [3- (4-phenyl-5, 6-dihydropyridin-l

(2H) -yl) propyl] propanamide hydrochloride,

20) N- (3-chloropropyl) -5-oxo-2, 4 , 5, 6-tetrahydro-lH- thiopyrano [3, 4-c] quinoline-9-carboxamide,

21) 5-oxo-N- [2- (piperidin-1-yl) ethyl] -2, 4,5, 6-tetrahydro -lH-thiopyrano [3, 4-c] quinoline-9-carboxamide hydrochloride,

22) 9- (piperazine-1-carbonyl) -4, 6-dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

23) 9- [4- (2-aminoethyl) piperazine-1-carbonyl] -4,6- dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one dihydrochloride, 24) N- [2- (dimethylamino) ethyl] -5-oxo-2, 4,5, 6-tetrahydro -lH-thiopyrano [3, 4-c] quinoline-9-carboxamide hydrochloride,

25) N- [3- (dimethylamino) propyl] -5-oxo-2, 4,5, β-tetrahydro -lH-thiopyrano [3, 4-c] quinoline-9-carboxamide hydrochloride, 26) N- [4- (dimethylamino) phenyl] -5-OXO-2, 4, 5, 6-tetrahydro -lH-thiopyrano [3, 4-c] quinoline-9-carboxamide hydrochloride,

27) 5-oxo-N- [2- (4-phenyl-5, 6-dihydropyridin-l (2H) -yl) ethyl] -2,4,5, 6-tetrahydro-IH-thiopyrano [3, 4-c] quinoline-9- carboxamide hydrochloride, 28) N- (2-morpholinoethyl) -5-OXO-2, 4, 5, 6-tetrahydro-lH- thiopyrano [3, 4-c] quinoline-9-carboxamide hydrochloride,

29) N- (2-aminoethyl) -5-oxo-2, 4, 5, 6-tetrahydro-lH- thiopyrano [3, 4-c] quinoline-9-carboxamide hydrochloride,

30) 5-oxo-N- [2- (piperazin-1-yl) ethyl] -2,4,5, 6-tetrahydro -lH-thiopyrano [3, 4-c] quinoline-9-carboxamide dihydrochloride,

31) N- [2- (4-methylpiperazin-l-yl) ethyl] -5-oxo-2, 4,5,6- tetrahydro-lH-thiopyrano [3, 4-c] quinoline-9-carboxamide dihydrochloride,

32) 5-oxo-N- [2- (4-oxopiperidin-l-yl) ethyl] -2,4,5,6- tetrahydro-lH-thiopyrano [3, 4-c] quinoline-9-carboxamide hydrochloride,

33) 9- (4-phenylpiperazine-l-carbonyl) -4, 6-dihydro-lH- thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

34) N-{4- [2- (diethylamino) ethoxy] phenyl } -5-oxo-2, 4, 5, 6 -tetrahydro-lH-thiopyrano [3, 4-c] quinoline-9-carboxamide hydrochloride .

35) 9- [4- (3-aminopropyl) piperazine-1-carbonyl] -4, 6- dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one dihydrochloride, 36) 9- [4- (pyridin-4-yl) piperazine-1-carbonyl] -4, 6- dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

37) 9-{4- [2- (4-oxopiperidin-l-yl) ethyl] piperazine-1- carbonyl } -4 , 6-dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one dihydrochloride, 38) 5-oxo-N- { 3- [4- (pyridin-4-yl) piperazin-1-yl] propyl }- 2,4,5, 6-tetrahydro-lH-thiopyrano [3, 4-c] quinoline-9- carboxamide dihydrochloride,

39) 9- (4- (2- (4- (4-fluorophenyl) -5, β-dihydropyridin- 1 (2H) -yl) ethyl) piperazine-1-carbonyl) -4, 6-dihydro-lH- thiopyrano [3, 4-c] quinolin-5 (2H) -one dihydrochloride,

40) 9-{ 4- [2- (4-phenylpiperazin-l-yl) ethyl] piperazine-1 -carbonyl}-4, β-dihydro-IH-thiopyrano [3, 4-c] quinolin-5 (2H) - one trihydrochloride,

41) 9- (piperidine-1-carbonyl) -4, 6-dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one,

42) 9- (4-methylpiperazine-l-carbonyl) -4, 6-dihydro-lH- thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

43) 9- (4-benzylpiperazine-l-carbonyl) -4, 6-dihydro-lH- thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride, 44) 9- (4-ethylpiperazine-l-carbonyl) -4, 6-dihydro-lH- thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

45) 9-{4- [2- (4-phenyl-5, 6-dihydropyridin-l (2H) -yl) ethyl] piperazine-1-carbonyl } -4 , β-dihydro-IH-thiopyrano [3, 4-c] quinolin-5 (2H) -one dihydrochloride, 46) 9- (4- (l-methylpiperidin-4-yl) piperazine-1-carbonyl) -4 , 6-dihydro-IH-thiopyrano [3, 4-c] quinolin-5 (2H) -one,

47 ) N- [5- (ethylamino) pentyl] -5-oxo-2, 4,5, 6-tetrahydro- lH-thiopyrano [3, 4-c] quinoline-9-carboxamide hydrochloride,

48 ) 9- [4- (4-methylpentyl) piperazine-1-carbonyl] -4,6- dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

49) 9- (4-hexylpiperazine-l-carbonyl) -4, 6-dihydro-lH- thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

50) 9- [4- (pentan-2yl) piperazine-1-carbonyl] -4, 6-dihydro -lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride, 51) 9- (4-isopropylpiperazine-l-carbonyl) -4, β-dihydro -lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

52) 9- (4-phenethylpiperazine-l-carbonyl) -4, 6-dihydro -lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

53) 9- { 4- [2- (dimethylamino) ethyl] piperazine-1-carbonyl } -4, 6-dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one dihydrochloride,

54) 9-{ 4- [2- (piperidin-1-yl) ethyl] piperazine-1-carbonyl } -4, 6-dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one dihydrochloride, 55) N- (5-aminopentyl) -5-OXO-2, 4, 5, 6-tetrahydro-lH- thiopyrano [3, 4-c] quinoline-9-carboxamide hydrochloride,

56) 5-oxo-N- { 2- [4- (pyridin-4-yl) piperazin-1-yl] ethyl }

-2,4,5, 6-tetrahydro-lH-thiopyrano [3, 4-c]quinoline-9- carboxamide dihydrochloride, 57) N- [5- (dimethylamino) pentyl] -5-0X0-2, 4, 5, β-tetrahydro

-lH-thiopyrano [3, 4-c] quinoline-9-carboxamide hydrochloride,

58 ) N- [4- (isopropylamino) butyl] -5-oxo-2, 4,5, β-tetrahydro

-lH-thiopyrano [3, 4-c] quinoline-9-carboxamide hydrochloride,

59) N- (3-aminopropyl) -5-oxo-2, 4, 5, 6-tetrahydro-lH- thiopyrano [3, 4-c] quinoline-9-carboxamide hydrochloride,

60) N- (4-aminobutyl) -5-oxo-2, 4, 5, 6-tetrahydro-lH- thiopyrano [3, 4-c] quinoline-9-carboxamide hydrochloride,

61) 9- (4-isopentylpiperazine-l-carbonyl) -4, 6-dihydro- lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride, 62) 9- (4-propylpiperazine-l-carbonyl) -4 , 6-dihydro-lH- thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

63) 9- (4-butylpiperazine-l-carbonyl) -4, 6-dihydro-lH- thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

64 ) 9- [4- (cyclopropylmethyl) piperazine-1-carbonyl] -4,6- dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

65) 9- (4-pentylpiperazine-l-carbonyl) -4, 6-dihydro-lH- thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

66) 9- (4-heptylpiperazine-l-carbonyl) -4, 6-dihydro-lH- thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride, 67) 9- [4- (4, 4, 4-trifluorobutyl)piperazine-l-carbonyl] - 4 , 6-dihydro-lH-thiopyrano [3,4-c]quinolin-5(2H) -one hydrochloride,

68) 9- [4- (2,2,2-trifluoroethyl)piperazine-l-carbonyl] - 4 , 6-dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

69) 5-oxo-N- [2- (4-phenylpiperazin-l-yl) ethyl] -2, 4, 5, 6- tetrahydro-lH-thiopyrano [3, 4-c] quinoline-9-carboxamide dihydrochloride,

70) 5-oxo-N- [3- (4-phenyl-5, β-dihydropyridin-1 (2H) -yl) propyl] -2,4,5, 6-tetrahydro-lH-thiopyrano [3, 4-c] quinoline-9- carboxamide hydrochloride,

71) N- [4- (ethyl (methyl) amino) butyl] -5-oxo-2, 4, 5, 6- tetrahydro-lH-thiopyrano [3, 4-c] quinoline-9-carboxamide hydrochloride, 72) 9- (4-cyclopentylpiperazine-l-carbonyl) -4 , 6-dihydro -lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

73) 9- (4-cyclohexylpiperazine-l-carbonyl) -4, 6-dihydro-lH -thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

74) 9- ( 4-cycloheptylpiperazine-l-carbonyl) -4, 6-dihydro -lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

75) 9-[4-(4,4,5,5, 5-pentafluoropentyl) piperazine-1- carbonyl] -4 , 6-dihydro-IH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

76) 9- (4-neopentylpiperazine-l-carbonyl) -4, 6-dihydro- lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride, 77) 9- (piperidin-4-ylthio) -4, 6-dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

78) 9- [2- (piperidin-l-yl)ethoxy]-4, 6-dihydro-lH- thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride, 79) 9- (piperidin-4-yloxy) -4, 6-dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

80) 9- (l-isopentylpiperidin-4-yloxy) -4, 6-dihydro-lH- thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

81) 9- ( l-propylpiperidin-4-yloxy) -4, 6-dihydro-lH- thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

82) 9- (l-ethylpiperidin-4-yloxy) -4, 6-dihydro-lH- thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

83) 9- (1-aminoethyl) piperidin-4-yloxy] -4 , 6-dihydro-lH- thiopyrano [3, 4-c] quinolin-5 (2H) -one dihydrochloride, 84) methyl 2- [4- (5-oxo-2, 4 , 5, 6-tetrahydro-lH-thiopyrano [3, 4-c] quinolin-9-yloxy] piperidin-1-yl) acetate hydrochloride,

85) 3- [4- (5-oxo-2,4,5, 6-tetrahydro-lH-thiopyrano [3, 4-c] quinolin-9-yloxy) piperidin-1-yl] propanenitrile hydrochloride,

86) 9- [1- (2-chloroethyl) piperidin-4-yloxy] -4, 6-dihydro -lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

87) 2- [4- (5-oxo-2,4,5, 6-tetrahydro-lH-thiopyrano [3, 4-c] quinolin-9-yloxy) piperidin-1-yl] acetic acid hydrochloride,

88) 2- [4- (5-oxo-2, 4, 5, 6-tetrahydro-lH-thiopyrano [3, 4-c] quinolin-9-yloxy) piperidin-1-yl] acetamide hydrochloride, 89) 9- [1- (2-hydroxyethyl) piperidin-4-yloxy] -4 , β-dihydro -lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

90) 9- [1- (2-methoxyethyl) piperidin-4-yloxy] -4 , β-dihydro -lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

91) 9- [1- (2- (piperidin-1-yl) ethyl) piperidin-4-yloxy] -4,6 -dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one dihydrochloride,

92) 9- (l-neopentylpiperidin-4-yloxy) -4, 6-dihydro-lH- thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

93) 9-[l-(4,4,5,5, 5-pentafluoropentyl) piperidin-4-yloxy] -4, 6-dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

94) 9- (l-methylpiperidin-4-yloxy) -4, 6-dihydro-lH- thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

95) 9- [1- (2-oxobutyl) piperidin-4-yloxy] -4, 6-dihydro-lH- thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

96) 9- [1- ( 2, 2, 2-trifluoroethyl) piperidin-4-yloxy] -4,6- dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

97 ) 9- [1- (cyclohexenylmethyl) piperidin-4-yloxy] -4,6- dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride, 98) 9- (piperidin-3-yloxy) -4, 6-dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

99) 9- (l-methylpiperidin-3-yloxy) -4, 6-dihydro-lH- thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

100) 9- (l-methylpyrrolidin-3-yloxy) -4, 6-dihydro-lH- thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride, 101) 9- ( l-propylpiperidin-3-yloxy) -4, 6-dihydro-lH- thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

102) 9- (l-ethylpiperidin-3-yloxy) -4, 6-dihydro-lH- thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride, 103) 9- (l-ethylpyrrolidin-3-yloxy) -4, 6-dihydro-lH- thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

104) 9- (l-benzylpiperidin-4-yloxy) -4, 6-dihydro-lH- thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

105) 9- (1- (pyrimidin-2-yl) piperidin-4-yloxy) -4, 6-dihydro -lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one,

106) 9- ( l-phenylpiperidin-4-yloxy) -4, 6-dihydro-lH- thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

107) 9-{ 1- [2- (4-phenyl-5, 6-dihydropyridin-l (2H) -yl) ethyl] piperidin-4-yloxy} -4 , 6-dihydro-1H-thiopyrano [3, 4-c] quinolin-5 (2H) -one dihydrochloride,

108) 9- (l-phenethylpiperidin-4-yloxy) -4, 6-dihydro-lH- thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

109) 9- [1- (4,4, 4 -trifluorobutyl) piperidin-4-yloxy] -4,6- dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride, 110) 9- [1- (pyridin-4-ylmethyl) piperidin-4-yloxy] -4, 6- dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride, .111) 2,2,2-trifluoro-N-{2-[4- (5-oxo-2,4, 5, 6-tetrahydro- IH-thiopyrano [3, 4-c] quinolin-9-yloxy) piperidin-1-yl] ethyl } acetamide hydrochloride, 112) 9- [1- (2-oxo-2-phenylethyl) piperidin-4-yloxy] -4, 6- dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

113) 4-{ [4- (5-oxo-2, 4, 5, 6-tetrahydro-lH-thiopyrano [3, 4-c] quinolin-9-yloxy) piperidin-1-yl] methyl }benzonitrile hydrochloride, 114) 9- [1- (3-chloropropyl) piperidin-4-yloxy] -4, 6-dihydro -lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

115) 9- (l-{2-[4- (pyrimidin-2-yl)piperazin-l-yl] ethyl} piperidin-4-yloxy) -4 , 6-dihydro-lH-thiopyrano [3, 4-c] quinolin- 5 (2H) -one dihydrochloride, 116) tert-butyl 5-oxo-2, 4 , 5, 6-tetrahydro-lH-thiopyrano [3, 4-c] quinolin-9-yl carbonate,

117) 9- (l-butylpiperidin-4-yloxy) -4, 6-dihydro-lH- thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

118 ) 9- [1- (3-fluoropropyl) piperidin-4-yloxy] -4, 6-dihydro -lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride,

119) 9- [4- (dimethylamino) phenethoxy] -4, 6-dihydro-lH- thiopyrano [3, 4-c] quinolin-5 (2H) -one,

120) 9- (l-pentylpiperidin-4-yloxy) -4, 6-dihydro-lH- thiopyrano [3, 4-c] quinolin-5 (2H) -one hydrochloride, and 121) 9-{l-[2- (4-acetylpiperazin-l-yl)ethyl]piperidin-4- yloxy}-4, 6-dihydro-lH-thiopyrano [3, 4-c] quinolin-5 (2H) -one dihydrochloride .

[Claim 4]

A preparation method of a tricyclic derivative represented by the followinq Formula 1 or pharmaceutically acceptable salt thereof, comprising the following steps of 1) to 3) :

1) reacting a ketone compound of Formula 2 with a morpholine compound of Formula 3 in the presence of p-toluenesulfonic acid to prepare an enamine compound of Formula 4,

2) reacting the enamine compound of Formula 4 obtained in step 1) with an isocyanate compound of Formula 5 to prepare a β-ketoamide compound of Formula 6, and

3 ) adding an acid aqueous solution to the β-ketoamide compound of Formula 6 prepared in step 2 ) for cyclization reaction to prepare the tricyclic derivative of Formula 1 or pharmaceutically acceptable salt thereof:

[Formula 1]

[Formula 2

Formula 3]

[Formula 4]

[Formula 6]

wherein Y is the same as defined in claim 1.

[Claim 5] A preparation method of a tricyclic derivative represented by the following Formula 9 or pharmaceutically acceptable salt thereof, comprising the following steps of 1) to 2) :

1) reacting a compound of Formula Ia with boron tribromide to prepare a demethylated hydroxy compound of Formula 7; and 2) reacting the hydroxy compound of Formula 7 obtained in step 1) and an alkyl halide compound of Formula 8 with catalytic amount of sodium iodide in the presence of a base to prepare the tricyclic derivative of Formula 9 or pharmaceutically acceptable salt thereof:

[Formula Ia]

[Formula 8^ R₁-X

[Formula 9^

wherein Y is OCH₃, X is halogen, and Ri is the same as defined in claim 1.

[Claim 6] A pharmaceutical composition for the prevention or treatment of any one disease selected from the group consisting of diseases caused by excessive activation of PARP, including neuropathic pain, epilepsy, stroke, Alzheimer' s disease, Parkinson' s disease, Amyotrophic Lateral Sclerosis (ALS), Huntington's disease, schizophrenia, chronic pain, ischemia, neuronal loss following hypoxia, trauma, and nervous insult, comprising the tricyclic derivative or pharmaceutically acceptable salt thereof of any one of claims 1 to 3. [Claim 7] A pharmaceutical composition for the prevention or treatment of any one disease selected from the group consisting of diseases caused by excessive activation of PARP, including atherosclerosis, hyperlipidemia, cardiovascular tissue damage, coronary heart disease, myocardial infarction, angina pectoris, and cardiogenic shock, comprising the tricyclic derivative or pharmaceutically acceptable salt thereof of any one of claims 1 to 3. [Claim 8]

A pharmaceutical composition for the prevention or treatment of any one disease selected from the group consisting of diseases caused by excessive activation of PARP, including diabetic neuropathic pain, osteoarthritis, and osteoporosis, comprising the tricyclic derivative or pharmaceutically acceptable salt thereof of any one of claims 1 to 3. [Claim 9]

A pharmaceutical composition for the prevention or treatment of cancer caused by excessive activation of PARP, comprising the tricyclic derivative or pharmaceutically acceptable salt thereof of any one of claims 1 to 3.