WO2006112666A1

WO2006112666A1 - Pyridine derivatives, methods of their preparations, and pharmaceutical compositions containing the same

Info

Publication number: WO2006112666A1
Application number: PCT/KR2006/001461
Authority: WO
Inventors: Hyung Ook Kim; Je Ho Ryu; Jae Yoon Jung; Nam Kyu Lee; Joo Hyon Kim; Eun Jeong Kim; Sun-Duck Joen; Ji-Hong Kim; Hae In Rhee; Yong-Baik Cho; Wie-Jong Kwak; Sun-Ho Kim; Seon-Mi Kim; Eun Jung Noh
Original assignee: Sk Chemicals Co., Ltd.
Priority date: 2005-04-20
Filing date: 2006-04-19
Publication date: 2006-10-26
Also published as: KR100781704B1; AR053232A1; KR20060110764A

Abstract

The present invention relates to pyridine derivatives having inhibitory effects on synthesis of cytokines, which are involved in inflammatory reactions, thus being useful as a therapeutic agent for treatment of inflammation-related diseases, immune-related diseases and chronic inflammatory diseases methods as well as an anti-inflammatory and analgesic agent, methods for their preparations, and pharmaceutical compositions containing the same.

Description

PYRIDINE DERIVATIVES, METHODS OF THEIR PREPARATIONS, AND PHARMACEUTICAL COMPOSITIONS

CONTAINING THE SAME

[i]

Technical Field

[2]

[3] The present invention relates to pyridine derivatives having inhibitory effects on synthesis of cytokines, which are involved in inflammatory reactions, thus being useful as a therapeutic agent for treatment of inflammation-related diseases, immune-related diseases, and chronic inflammatory diseases methods as well as an anti-inflammatory and analgesic agent, methods for their preparations, and pharmaceutical compositions containing the same.

[4]

Background Art

[5]

[6] Inflammatory reactions, being a type of defensive mechanism in a body, consist of a very complicated biological signal transduction pathway occurring as a result of an immunological recognition of inflammation or injury on a body, and mediated by various kinds of inflammatory cytokines. When one of such inflammatory reactions becomes abnormal and leads to destruction of normal tissues it is often called as 'inflammatory disease' and numerous studies have been done to elucidate the exact mechanisms of inflammatory diseases. Further, it has been known that the increase in inflammatory cytokines is related with autoimmune diseases.

[7] The inflammation-related signal transduction pathways are a series of phos- phorylation-dephosphorylation and can be largely divided into three stages: that is, (a) the initial stage wherein an inflammation signal in a biomembrane binds with a biomembrane receptor thereby triggering a series of signal transduction cascade; (b) a terminal stage wherein gene expression of an inflammation-related proteins are regulated within a nucleus via a transcription factor; and (c) an intermediate stage which is a series of signal transduction cascade in cytoplasm to interconnect between the initial stage and the terminal stage. Examples of the inflammation signal factors at the initial stage are tumor necrosis factor (TNF, also mentioned as secretion type of TNF- α ) and interleukin-1 (IL-I; interleukin-1), etc. Examples of the representing transcription factors at the terminal stage are activating protein- 1 (AP-I), nuclear transcription factor kappa B (NFkB) and nuclear factor of activated T cells (NFAT), etc. There is not much known about the cascade at the intermediate stage, but it appears that regulatory substances such as lipocortin, cyclooxygenase-1, 2, and PLA may be involved in this stage.

[8] As for inflammation factors, TNF- α is the most strong inflammatory cytokine produced mostly in activated macrophages T cells, an stimulate transcription factors such as NK-kB and c-jun/Ap-1 and other inflammatory cytokines such as interleukin- 1 (IL-I), interleukin-6(IL-6) and interleukin-8(IL-8). In fact, TNF- α is associated with various inflammation-related diseases or immune-related diseases such as toxic shock syndrome, acute renal failure, insulin-dependent diabetes, multiple sclerosis, rheumatic arthritis, osteoarthritis, inflammatory bowel disease such as Crohn's disease and ulcerative colitis, etc. TNF- α is also associated with various chronic inflammatory diseases such as psoriatic arthritis, Psoriasis, Ankylosing Spondylitis, Adult-onset Still's Disease, Sjogren's syndrome, Polymyositis, dermatomyositis, vasculitis such as atherosclerosis, Behcet Disease and Wegener's Granulomatosis, etc.

[9] Interleukin-1 is a powerful inflammatory cytokine like TNF- α . It increases gene expression of PLA 2, COX-2 and iNOS, and as a result also increases the production of PAF, PGE and NO thereby inducing inflammatory reactions. Both interleukin-1 α and 1 β are associated with autoimmune diseases such as rheumatic arthritis, insulin- dependent diabetes and the like. Interleukin-1 β, like TNF-α, is also an important mediator of septic shock and its related cardiopulmonary disorders, acute respiratory distress syndrome and multiple organ disorders. Interleukin-6 is a multifunctional cytokine produced in various cells and is associated with multiple myeloma, psoriasis, postmenopausal osteoporosis, CNS trauma, viral and bacterial meningitis, Castleman's disease, glomerulonephritis, certain neuronal diseases such as AIDS dementia complex and Alzheimer's disease and certain leukemia, systemic lupus erythematosus and the like. Interferon- γ (IFN- γ ) is mostly produced by T cells and NK cells and are involved in various inflammatory diseases such as Graft- versus-Host disease, asthma, atopic dermatitis. In addition, interleukin-8 is associated with stroke, myocardial infarction, adult respiratory distress syndrome, trauma concomitant multiple injuries of organs, acute glomerulonephritis, dermatitis, purulent meningitis or other CNS disorders, hemodialysis concomitant syndrome, necrotizing enterocolitis and the like.

[10] Further, prostaglandin serves an important role in inflammatory reactions. The inhibition of prostaglandin, especially the inhibition of synthesis of PGG , PGH , and PGE , has been the critical step in development of anti-inflammatory agents. Prostaglandin synthesis can be prevented by inhibiting cyclooxygenase (COX). Also, since COX is induced by inflammatory cytokines, the synthesis of prostaglandin can be also prevented by inhibiting the synthesis of the cytokines. Therefore, reduction of cytokines as described above can be a good therapeutic method of treatment of in- flammatory reactions and immune reaction-related diseases.

[H]

Disclosure

[12]

[13] The inventors of the present invention have recently succeeded in synthesis of pyridine derivatives with novel structures. They have also discovered that these novel compounds inhibit cytokines, which are involved in inflammatory reactions, and also have an excellent inhibitory effect on the synthesis of TNF- α , interleukin-1, in- terleukin-6, IFN- γ , PGE , More specifically, the inventors of the present invention have found that the novel compounds they synthesized have superior effects in treating inflammation-related diseases, immune-related diseases, chronic inflammatory diseases and also anti-inflammatory and analgesic effects.

[14] Therefore, in an embodiment of the present invention, there are provided novel pyridine derivatives.

[15] In another embodiment of the present invention, there are provided methods of synthesizing the above novel pyridine derivatives.

[16] In a further embodiment of the present invention, there are provided pharmaceutical compositions, comprising the above pyridine derivatives, to be used as therapeutic agents for treatment of cytokines-related diseases such as inflammation- related diseases, immune-related diseases, chronic inflammatory diseases and also as anti-inflammatory and analgesic agent.

[17] The present invention is described in greater detail as set forth hereunder.

[18] In an embodiment of the present invention, there are provided novel pyridine derivatives represented by the following formula 1 or their pharmaceutically acceptable salts:

[19]

[20] wherein R , R , R , R and R can be independently selected from the group consisting of H, halo, cyano, nitro, acyl, hydroxy, amino, C - C low alkyl, C - C low alkenyl, C - C low alkoxy, C - C alkylthio, C - C alkylamino, C - C cy- cloalkylamino, C 4 - C 9 heterocycloalkylamino, arylamino, acylamino, acyloxy, C 1 - C6 alkylsulfinyl, C - C alkylsulfonyl, C - C alkylsulfonylamino, arylsulfinyl,

1 6 1 6 arylsulfonyl, arylsulfonylarnino, aryl, heteroaryl, C - C aralkyl, C - C het- eroaralkyl, aryloxy and heteroaryloxy; or they can independently form a ring by binding with a neighboring substitution group; [21] X is O or S;

[22] Y is O or N-R , wherein R is selected from the group consisting of H, C - C low

6 6 1 6 alkyl, acyl, aryl, heteroaryl, C - C aralkyl and C - C heteroaralkyl; or they can independently form a ring by binding with a neighboring substitution group R ;

[23] the aryl is selected from the group consisting of phenyl, naphthyl and fused phenyl;

[24] the heteroaryl is a 5-membered or 6-membered heterocyclic ring or a fused heterocyclic ring having 1-3 hetero atoms selected from O, N, and S,

[25] the aryl and the heteroaryl can be substituted with 1-4 substitution groups selected from the group consisting of halo, hydroxy, C - C low alkyl, C - C low alkoxy and

1 6 1 6 amino.

[26] The pyridine compounds of the above formula 1 can form pharmaceutically acceptable salts by reacting with acids such as hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, citric acid, fumaric acid, lactic acid, maleic acid, succinic acid, and tartaric acid. The pyridine compounds of the above formula 1 can also form pharmaceutically acceptable salts by reacting with alkali metal ions such as sodium and potassium or ammonium ion. Therefore, the novel compounds of the present invention include pharmaceutically acceptable salts of the pyridine compounds of the above formula 1.

[27] The pyridine compounds of the above formula 1 are preferably as follows:

[28] R R R R and R are selected from the group consisting of H, halo, hydroxy, C

- C low alkyl, C - C low alkoxy, aryloxy, amino, C - C alkylamino, C - C ar- alkylamino, arylamino, acylamino, aryl, heteroaryl, and C - C heteroaralkyl; or they can independently form a ring with a neighboring substitution group;

[29] X is O or S;

[30] Y is O or N-R , wherein R is selected from the group consisting of H, C - C low

6 6 1 6 alkyl, aryl, heteroaryl, C - C aralkyl, and C - C heteroaralkyl; [31] aryl is phenyl;

[32] heteroaryl is selected from the group consisting of furan, thiophene, pyridine, piperidine, piperazine, morpholine, pyrrolidine, and benzodioxol; [33] aryl and heteroaryl are pyridine compounds with 1-4 substitution groups selected from the group consisting of halo, hydroxy, C - C low alkyl, C - C low alkoxy, and

1 6 1 6 amino. [34] The pyridine compounds of the above formula 1 according to the present invention are exemplified as follows: [35] 2H-[2,7]naphthyridine-l-one,

[36] 2-benzyl-2H-[2,7]naphthyridine-l-one, [37] 8-methyl-6-phenyl-2H-[2,7]naphthyridine-l-one,

[38] 2,8-dimethyl-6-phenyl-2H-[2,7]naphthyridine-l-one,

[39] 2-ethyl-8-methyl-6-phenyl-2H-[2,7]naphthyridine-l-one,

[40] 2-benzyl-8-methyl-6-phenyl-2H- [2,7]naphthyridine- 1 -one,

[41] 2-(3,5-difluoro-phenyl)-8-methyl-6-phenyl-2H-[2,7]naphthyridine-l-one,

[42] 2-(3,4-dimethoxy-phenyl)-8-methyl-6-phenyl-2H-[2,7]naphthyridine-l-one,

[43] 2-(4-fluoro-phenyl)-8-methyl-6-phenyl-2H- [2,7]naphthyridine- 1 -one,

[44] 2-(3,5-dichloro-phenyl)-8-methyl-6-phenyl-2H-[2,7]naphthyridine-l-one,

[45] 8-(4-fluoro-phenyl)-6-methyl-2H- [2,7]naphthyridine- 1 -one,

[46] 8-(4-fluoro-phenyl)-2,6-dimethyl-2H- [2,7]naphthyridine- 1 -one,

[47] 2-ethyl-8-(4-fluoro-phenyl)-6-methyl-2H- [2,7]naphthyridine- 1 -one,

[48] 2-(3,5-difluoro-phenyl)-8-(4-fluoro-phenyl)-6-methyl-2 H-[2,7] naphthyridine-

1-one, [49] 2-(3,4-dimethoxy-phenyl)-8-(4-fluoro-phenyl)-6-methyl-2 H-[2,7] naphthyridine-

1-one,

[50] 6-(4-fluoro-phenyl)-8-methyl-2H- [2,7]naphthyridine- 1 -one,

[51 ] 6-(4-fluoro-phenyl)-2,8-dimethyl-2H- [2,7]naphthyridine- 1 -one,

[52] 2-ethyl-6-(4-fluoro-phenyl)-8-methyl-2H- [2,7]naphthyridine- 1 -one,

[53] 2-(3,5-difluoro-phenyl)-6-(4-fluoro-phenyl)-8-methyl-2 H-[2,7] naphthyridine-

1-one, [54] 2-(3,4-dimethoxy-phenyl)-6-(4-fluoro-phenyl)-8-methyl-2 H-[2,7] naphthyridine-

1-one,

[55] 2-(4-fluoro-phenyl)-6-(4-fluoro-phenyl)-8-methyl-2H-[2,7]naphthyridine-l-one,

[56] 2-(3,5-dichloro-phenyl)-6-(4-fluoro-phenyl)-8-methyl-2 H-[2,7]na phthyridine-

1-one,

[57] 6-(3,4-difluoro-phenyl)-8-methyl-2H-[2,7]naphthyridine-l-one,

[58] 6-(3,4-difluoro-phenyl)-2,8-dimethyl-2H-[2,7]naphthyridine-l-one,

[59] 2-ethyl-6-(3,4-difluoro-phenyl)-8-methyl-2H-[2,7]naphthyridine-l-one,

[60] 2-(3,5-difluoro-phenyl)-6-(3,4-difluoro-phenyl)-8-methyl-2 H-[2,7] naphthyridine-

1-one, [61] 2-(3,4-dimethoxy-phenyl)-6-(3,4-difluoro-phenyl)-8-methyl-2 H-[2,7] naph- thyridine-1-one, [62] 2-(4-fluoro-phenyl)-6-(3,4-difluoro-phenyl)-8-methyl-2 H-[2,7] naphthyridine-

1-one, [63] 2-(3,5-dichloro-phenyl)-6-(3,4-difluoro-phenyl)-8-methyl-2 H-[2,7] naphthyridine-

1-one,

[64] 6-ethyl-8-piperidin- 1 -yl-2H- [2,7]naphthyridine- 1 -one,

[65] 6-ethyl-2-methyl-8-piperidin- 1 -yl-2H- [2,7]naphthyridine- 1 -one, [66] 2,6-diethyl-8-piperidin- 1 -yl-2H- [2,7]naphthyridine- 1 -one,

[67] 6-isopropyl-8-piperidin- 1 -yl-2H- [2,7]naphthyridine- 1 -one,

[68] 6-isopropyl-2-methyl-8-piperidin-l-yl-2H-[2,7]naphthyridine-l-one,

[69] 2-ethyl-6-isopropyl-8-piperidin- 1 -yl-2H- [2,7]naphthyridine- 1 -one,

[70] 6-isopropyl-2-methoxymethyl-8-piperidin- 1 -yl-2H-[2,7]naphthyridine- 1 -one,

[71 ] 6-isopropyl-2-(2-methoxy-ethyl)-8-piperidin- 1 -yl-2H- [2,7]naphthyridine- 1 -one,

[72] 2-(4-fluoro-phenyl)-6-isopropyl-8-piperidin- 1 -yl-2H-[2,7]naphthyridine- 1 -one,

[73] 2-(3,4-dimethoxy-phenyl)-6-isopropyl-8-piperidin-l-yl-2 H-[2,7] naphthyridine-

1-one,

[74] 6-tert-butyl-8-piperidin- 1 -yl-2H- [2,7]naphthyridine- 1 -one,

[75] 6-tert-butyl-2-methyl-8-piperidin- 1 -yl-2H-[2,7]naphthyridine- 1 -one,

[76] 6-tert-butyl-2-ethyl-8-piperidin-l-yl-2H-[2,7]naphthyridine-l-one,

[77] 6-tert-butyl-2-(4-fluoro-phenyl)-8-piperidin- 1 -yl-2 H- [2,7]naphthyridine- 1 -one,

[78] 6-tert-butyl-2-(3,4-dimethoxy-phenyl)-8-piperidin-l-yl-2 H-[2,7] naphthyridine-

1-one, [79] 8-(4-fluoro-phenyl)-6-methyl- 1 -oxo-liH- [2,7]naphthyridine-2-2-carboxylic acid methyl ester,

[80] 8-(4-fluoro-phenyl)-6-methyl- 1 -oxo-liH- [2,7]naphthyridine-2-carboxylic acid,

[81] 3- [8-(4-fluoro-phenyl)-6-methyl- 1 -oxo-liH- [2,7]naphthyridine-2-yl]-propionic acid methyl ester,

[82] 3-(4-methoxy-phenyl)-6,8-dimethyl-pyrano[3,4-c]pyridin-l-one,

[83] 3-(4-hydroxy-phenyl)-6,8-dimethyl-pyrano[3,4-c]pyridin-l-one,

[84] 3-(3-methoxy-phenyl)-6,8-dimethyl-pyrano[3,4-c]pyridin-l-one and

[85] S-CS-hydroxy-phenyty-όjS-dimethyl-pyranoP^-cJpyridin-l-one.

[86] [87] In another embodiment of the present invention, there are provided methods of manufacturing novel compounds of pyridine derivatives represented by the above formula 1. [88] Of the pyridine compounds according to the present invention, the compounds of the above formula 1 wherein X=O and Y=N-R can be manufactured by the following

6 reaction scheme 1.

[Reaction Scheme 1 ]

Base

[89] In the above Reaction Scheme 1, R , R , R , R , R and R are respectively the same as defined above.

[90] In a method according to the above reaction scheme 1, the compounds of the above formula 2, used as a starting material, can be easily manufactured by using a known method in the art (J. Org. Chem., Vol. 41, No. 15, 2542, 1976; Pharmazie, 38(9), 591, 1983).

[91] According to the method of the above reaction Scheme 1, the compounds of the above formula 3 can be obtained by reacting the compounds of the above formula 2 with ΛζN-dimethylformamide dimethyl acetal in the presence of an aprotic solvent such as tetrahydrofuran and dimethylformamide. Then, the compounds of the above formula 3 are cyclized in an acidic condition, such as sulfuric acid and acetic acid, to obtain the compounds of the above formula 1, wherein X=O and Y=NH. The compounds of the above formula 1, wherein X=O and Y=NH, are then reacted with a base, such as sodium hydride, potassium hydride, lithium hydride, potassium carbonate, sodium carbonate, and R 6 X (an alkylizing agent wherein R 6 is the same as defined above, and X is a halogen atom) in the presence of an organic solvent such as tetrahydrofuran and dimethylformamide to obtain the compounds of the above formula 1, wherein X=O and Y=N-R

[92]

[93] Further, the following Reaction Scheme 2 briefly shows a method of manufacturing the compounds of the above formula 1, wherein X=Y=O, among the pyridine compounds of the present invention.

[Reaction Scheme 2]

[ ^L94] ^J In the above Reaction Scheme 2,' R l,' R 2,' R 3, R 4, R 5, X and Y are resp fectively J the same as defined above. [95] According to a method of the above Reaction Scheme 2, the compounds of the above formula 1, wherein X=Y=O, can be obtained by reacting the ester compounds of the above formula 4, wherein R is C - C low alkyl, with a base such as sodium

1 6 hydride, potassium hydride, lithium hydride in the presence of an organic solvent such as tetrahydrofuran and dimethylformamide. [96] The following Reaction Scheme 3 briefly shows a method of manufacturing the compounds of the above formula 1, wherein X=S and Y=O or N-R , among the

6 pyridine compounds of the present invention. [Reaction Scheme 3]

Sulfurizing Reagent

(I) (X=O₁ Y=O or N-R₆) (I ) (X=S₁ Y=O Of N-R₆)

[ ^L97] ^J In the above Reaction Scheme 3,' R l,' R 2,' R 3, R 4,' R 5, R 6, X and Y are resp fectively J the same as defined above.

[98] According to a method of the above Reaction Scheme 3, the compounds of the above formula 1, wherein X=S, Y=O or N-R , can be easily obtained by reacting the

6 compounds of the above formula 1, wherein X=O, with an excessive amount of sulfurizing reagent such as Lawesson's reagent at a relatively high temperature. [99] The following Reaction Scheme 4 briefly shows a method of manufacturing the compounds of the above formula 1, wherein X=Y=O, among the pyridine compounds of the present invention.

[Reaction Scheme 4]

[ ^L100] ^J In the above Reaction Scheme 4,' R l,' R 2,' R 3, R 4, R 5, X and Y are resp fectively J the same as defined above.

[101] According to a method of the above Reaction Scheme 4, a compound of the above formula 2 was first dissolved in an anhydrous inert aprotic solvent, and dropwisely added with a base at a temperature from -100 to -40 °C and then stirred. Then, it was dropwisely added with alkyl ester, preferably methyl ester (R COOMe) and allowed to react at a temperature from -78 °C to room temperature for 1-8 hours and finally obtained the compound of the above formula 5. In the above reaction, the aprotic solvent can be selected from tetrahydrofuran(THF), diethyl ether, and dioxane, preferably THF. The base in the above reaction can be selected from lithium bis(trimethylsylyl)amide(LHMDS), potassium bis(trimethylsylyl)amide(KHMDS), lithium diisopropylamide(LDA), sodium hydride(NaH), potassium hydride(KH), lithium hydride(LiH), preferably LHMDS.

[102] Then, the compound of the above formula 5 was cyclized by refluxing it for 6-18 hours in the presence of a concentrated hydrochloric acid and obtained a compound of the above formula 1, wherein X=O and Y=O.

[103] In another embodiment of the present invention, there are provided pharmaceutical compositions comprising the compound of the above formula 1 or its pharmaceutically acceptable salt as an active ingredient for therapeutic treatment.

[104] The pharmaceutical compositions of the present invention can be formulated by menas of a conventional formulation in a form suitable for oral or parenteral administration by further comprising a carrier, an adjuvant or a diluent along with the compound of the above formula 1 or its pharmaceutically acceptable salt. For oral administration, it can be prepared in the form of a tablet, a capsule, a solution, a syrup, a suspension, etc. For parenteral administration, it can be prepared in the form of an intraperitoneal injection, a hypodermic injection, an intramuscular injection, and a transdermal injection.

[105] The effective daily dosage of the pharmaceutical composition of the present invention as an anti-inflammatory and analgesic agent is 0.01 - 1000 mg/day based on adults, but it can be varied depending on the age, body weight, sex, method of administration, health condition, and the seriousness of diseases. Further, it can be administered from one to a few times at regular intervals after consulting with a physician or a pharmacist.

[106] In a further embodiment of the present invention, there are provided pharmaceutical compositions comprising compounds of the above formula 1 or their pharmaceutically acceptable salts which are used as therapeutic agents for treatment and prevention of diseases.

[107] That is, the present invention relates to pharmaceutical compositions comprising compounds of the above formula 1 or their pharmaceutically acceptable salts which have inhibitory effects on synthesis of cytokines thus being useful as therapeutic agent s for treating inflammation-related diseases, immune-related diseases, chronic inflammatory diseases and also an anti-inflammatory and analgesic agent.

[108] The pharmaceutical compositions of the present invention are effective in treating diseases caused by TNF- α , interleukin-1 α , 1 β and IFN- γ . More specifically, the diseases include (a) inflammation-related diseases or immune-related diseases such as rheumatic arthritis, multiple sclerosis, inflammatory bowel disease such as Crohn's disease and ulcerative colitis, Graft-versus-Host disease, systemic lupus erythematosus, toxic shock syndrome, acute renal failure, osteoarthritis and insulin- dependent diabetes; (b) chronic inflammatory diseases such as psoriatic arthritis, psoriasis, Ankylosing Spondylitis, Adult-onset Still's disease, Sjogren's syndrome, polymyositis, dermatomyositis, vasculitis such as atherosclerosis, Behcet disease and Wegener's Granulomatosis; and (c) antiinflammation and analgesic. Further, the pharmaceutical compositions of the present invention are effective in treating immune- related diseases such as glomerulonephritis, dermatitis, asthma, stroke, myocardial infarction, adult respiratory distress syndrome, trauma concomitant multiple injuries of organs, purulent meningitis, necrotizing enterocolitis, hemodialysis concomitant syndrome, septic shock, and postmenopausal osteoporosis.

[109]

Best Mode

[HO]

[111] The present invention is described in greater detail with reference to the following examples, however, they should not be construed as limiting the scope of the present invention.

[112]

[113] Example 1: Synthesis of 2//-[2,7]naphthyridine-l-one

[114] After dissolving 4-methyl-nicotinonitrile (2.0 g, 16.93 mmol) in anhydrous DMF

(20 mL), the mixture was dropwisely added with ΛζN-dimethylformamide dimethyl acetal (4.5 mL, 33.86 mmol) and then stirred at 120 °C for 2 hours under nitrogen atmosphere. The reaction mixture was placed under vacuum concentration, with distilled water and then extracted with EtOAc (100 mL x 2). The resulting organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate, filtered and then concentrated. The resulting residue was dissolved in a mixture of acetic acid (10 mL) and sulfuric acid (10 mL) and then stirred at 110 °C for 1 hour. The reactant was cooled down to room temperature, added with distilled water (200 mL) and then neutralized by slowly adding potassium carbonate while stirring at 0 °C . The resultant was extracted with 20% MeOH/MC (150 mL x 6), and the organic layer was dried with anhydrous sodium sulfate, filtered and then concentrated. The resulting residue was purified by a silica gel column chromatograph (10% MeOH/MC) and obtained a light yellow solid 1.49 g(60%).

[115] ¹ H NMR(300 MHz, DMSO-d₆) δ 6.55(d, IH, J=7.2Hz), 7.43(d, IH, J=7.2Hz),

7.57(d, IH, J=5.4Hz), 8.69(d, IH, J=5.4Hz), 9.30(s, IH), 11.59(brs, IH).

[116]

[117] Example 2: Synthesis of 2-benzyl-2fl-[2,7]naphthyridine-l-one

[118] 2H-[2,7]naphthyridine-l-one (200 mg, 1.368 mmol) was suspended in anhydrous

DMF (6 mL) and then added with NaH (60% dispersion in mineral oil, 82 mg, 2.053 mmol) while stirring at 0 °C under nitrogen atmosphere. The resultant was stirred at room temperautre for 2 hours, dropwisely added with benzyl chloride (0.19 mL, 1.642 mmol) at O °C and then stirred for 2 hours. The reactant was added with a saturated aqueous ammonium chloride solution (5 mL) and distilled water (5 mL) while stirring at 0 °C , and then extracted with EtOAc (30 mL x 2). The resulting organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate, filtered and then concentrated. The resulting residue was purified by a silica gel column chromatograph (5% MeOH/MC) and obtained a white solid [288 mg (89%)].

[119] ¹ H NMR(300 MHz, CDCl₃) δ 5.22(s, 2H), 6.42(d, IH, J=7.2Hz), 7.26-7.39(m, 7

H), 8.72(d, IH, 7=5. IHz), 9.65(s, IH).

[120]

[121] Example 3: Synthesis of 8-methyl-6-phenyl-2fl-[2,7]naphthyridine-l-one

[122] 8-methyl-6-phenyl-2H-[2,7]naphthyridine-l-one [1.91 g(56%)] was obtained as a light yellow solid by using the same method as in Example 1 except that 2,4-dimethyl-6-phenyl-nicotinonitrile(3.01 g, 14.45 mmol) was used instead of 4-methyl-nicotinonitrile.

[123] ^λ Η NMR(300 MHz, DMSO-dp δ 3.02(s, 3H), 6.53(d, IH, J=6.9Hz), 7.36(d, IH,

J=6.9Hz), 7.44-7.55(m, 3H), 7.98(s, IH), 8.16-8.20(m, 2H), 11.35(brs, IH).

[124]

[125] Example 4: Synthesis of 2,8-dimethyl-6-phenyl-2//-[2,7]naphthyridine-l-one

[126] 2,8-dimethyl-6-phenyl-2H-[2,7]naphthyridine-l-one [320 mg(86%)] was obtained as a light yellow solid using the same method in example 2 except that 8-methyl-6-phenyl-2H-[2,7]naphthyridine-l-one (350 mg, 1.481 mmol) and iodomethane (0.11 mL, 1.777 mmol) were used instead of 2H- [2,7] naphthyridine- 1-one and benzyl chloride.

[127] ^λ Η NMR(300 MHz, CDCl₃) δ 3.20(s, 3H), 3.58(s, 3H), 6.42(d, IH, J=7.2Hz),

7.24(d, IH, J=7.2Hz), 7.41-7.52(m, 3H), 7.57(s, IH), 8.08-8.12(m, 2H).

[128]

[129] Example 5: Synthesis of 2-ethyl-8-methyl-6-phenyl-2//-[2,7] naphthyridine-

1-one

[130] 2-ethyl-8-methyl-6-phenyl-2H-[2,7]naphthyridine-l-one [265 mg (96%)] was obtained as a white solid by using the same method as in Example 2 except that 8-methyl-6-phenyl-2H-[2,7]naphthyridine-l-one (1.95 g, 8.25 mmol) and ethyl bromide (0.74 mL, 9.904 mmol) were used instead of 2H-[2,7]naphthyridine-l-one and benzyl chloride.

[131] ^λ Η NMR(300 MHz, CDCl₃) δ 1.39 (t, 3H, J=7.2Hz), 3.20 (s, 3H), 4.03 (q, 2H, J

=7.2Hz), 6.43 (d, IH, J=7.5Hz), 7.24 (d, IH, J=7.5Hz), 7.41-7.52 (m, 3H), 7.56 (s, IH), 8.08-8.12 (m, 2H).

[132] [133] Example 6: Synthesis of 2-benzyl-8-methyl-6-phenyl-2£-^r-[2,7] naphthyridine-

1-one

[ 134] 2-benzyl-8-methyl-6-phenyl-2H- [2,7]naphthyridine- 1 -one [265 mg (96%)] was obtained as a white solid using the same method as in Example 2 except that 8-methyl-6-phenyl-2H-[2,7]naphthyridine-l-one (200 mg, 0.846 mmol) was used instead of 2H-[2,7]naphthyridine-l-one.

[135] ^λ Η NMR(300 MHz, CDCl₃) δ 3.21 (s, 3H), 5.19(s, 2H), 6.41(d, IH, /=7.5Hz),

7.24(d, IH, /=7.5Hz), 7.27-7.39(m, 5H), 7.40-7.52(m, 3H), 7.56(s, IH), 8.08-8.12(m, 2H).

[136]

[ 137] Example 7: Synthesis of 2-(3,5-difluoro-phenyl)-8-methyl-6-phenyl-2/y-[2,7] naphthyridine-1-one

[138] 8-methyl-6-phenyl-2H-[2,7]naphthyridine-l-one (200 mg, 0.846 mmol), CuI (32 mg, 0.169 mmol), K 3 PO 4 (359 mg, 1.692 mmol) were suspended in 1,4-dioxane (3 mL), dropwisely added with 3,5-difluoroiodobenzene(0.12 mL, 1.016 mmol), N,N - dimethylethylene diamine (0.036 mL, 0.338 mmol) and then refluxed for 15 hours under nitrogen atmosphere. The resultant was cooled down to room temperature, added with distilled water (50 mL) and then extracted with EtOAc (50 mL). The resulting organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by a silica gel column chromatograph (20% EtOAc/Ηexanes) and obtained a white solid [212 mg(72%)].

[139] ^λ Η NMR(300 MHz, CDCl₃) δ 3.16(s, 3H), 6.53(d, IH, J=7.2Hz), 6.88-6.95(m,

IH), 6.98-7.06(m, 2H), 7. 27(d, IH, J=I. 2Hz), 7.43-7.55(m, 3H), 7.63(s, IH), 8.11-8.15(m, 2H).

[140]

[141] Example 8: Synthesis of 2-(3,4-dimethoxy-phenyl)-8-methyl-6-phenyl-2ff-[2,7] naphthyridine-1-one

[142] 2-(3,4- dimethoxy-phenyl)-8-methyl-6-phenyl-2H-[2,7]naphthyridine-l-one [253 mg (80%)] was obtained as a white solid using the same method as in Example 7 except that 4-bromoveratrol (0.15 mL, 1.016 mmol) was used instead of 3,5-difluoroiodobenzene was obtained as a white solid.

[143] ^λ Η NMR(300 MHz, CDCl₃) δ 3.18(s, 3H), 3.92(s, 3H), 3.93 (s, 3H), 6.48(d, IH, J

=7.2Hz), 6.92-6.99(m, 3H), 7.32(d, IH, J=7.2Hz), 7.42-7.54(m, 3H), 7.62(s, IH), 8.11-8.15(m, 2H).

[144]

[145] Example 9: Synthesis of 2-(4-fluoro-phenyl)-8-methyl-6-phenyl-2f-^r-[2,7] naph- thyridine-1-one [146] 2-(4-fluoro-phenyl)-8-methyl-6-phenyl-2H-[2,7]naphthyridine-l-one [185 mg

(66%)] was obtained as a white solid using the same method as in Example 7 except that l-fluoro-4-iodobenzene (0.12 mL, 1.016 mmol) was used instead of 3,5-difluoroiodobenzene.

[147] ^λ Η NMR(300 MHz, CDCl₃) δ 3.17(s, 3H), 6.51(d, IH, J=7.2Hz), 7.17-7.25(m, 2

H), 7.29(d, IH, J=7.2Hz), 7.37-7.54(m, 5H), 7.63(s, IH), 8.11-8.15(m, 2H).

[148]

[149] Example 10: Synthesis of 2-(3,5-dicMoro-phenyl)-8-methyl-6-phenyl-2ff-[2,7] naphthyridine-1-one

[150] 2-(3,5-dichloro-phenyl)-8-methyl-6-phenyl-2H-[2,7]naphthyridine-l-one [217 mg

(67%)] was obtained as a white solid using the same method as in Example 7 except that 3,5-dichloroiodobenzene (277 mg, 1.016mmol) was used instead of 3,5-difluoroiodobenzene.

[151] ^λ Η NMR(300 MHz, CDCl₃) δ 3.16 (s, 3H), 6.52(d, IH, J =7.5Hz), 7.24(d, IH, J

=7.5Hz), 7.37(d, 2H, J=1.8Hz), 7.44-7.55(m, 4H), 7.63(s, IH), 8.11-8.15(m, 2H).

[152]

[153] Example 11: Synthesis of 8-(4-fluoro-phenyl)-6-methyl-2//-[2,7] naph- thyridine-1-one

[ 154] 8-(4-fluoro-phenyl)-6-methyl-2H- [2,7]naphthyridine- 1 -one [3.68 g (80%)] was obtained as a light yellow solid using the same method as in Example 1 except that 2-(4-fluoro -phenyl)-4,6-dimethyl-nicotinonitrile(4.1 g, 18.122 mmol) was used instead of 4-methyl-nicotinonitrile.

[155] ^λ Η NMR(300 MHz, DMSO-d₆) δ 2.54(s, 3H), 6.48(d, IH, J=7.2Hz), 7.1 l-7.19(m,

2H), 7.36(d, IH, J=7.2Hz), 7.39-7.46(m, 3H).

[156]

[157] Example 12: Synthesis of 8-(4-fluoro-phenyl)-2,6-dimethyl-2f7-[2,7] naph- thyridine-1-one

[158] 8-(4-fluoro-phenyl)-2,6-dimethyl-2H-[2,7]naphthyridine-l-one [368mg (87%)] was obtained as a white solid using the same method as in Example 2 except that 8-(4- fluoro-phenyl)-6-methyl-2H-[2,7]naphthyridine-l-one(400 mg, 1.573 mmol) and iodomethane (0.12 mL, 1.888 mmol) were used instead of 2H-[2,7] naphthyridine- 1-one and benzyl chloride.

[159] ^λ Η NMR(300 MHz, CDCl₃) δ 2.66 (s, 3H), 3.47(s, 3H), 6.39(d, IH, J=7.5Hz),

7.08-7.16(m, 2H), 7.18(s, IH), 7.25(d, IH, J=7.5Hz), 7.40-7.46(m, 2 H).

[160]

[161] Example 13: Synthesis of 2-ethyl-8-(4-fluoro-phenyl)-6-methyl-2//-[2,7] naph- thyridine-1-one

[ 162] 2-ethyl-8-(4-fluoro-phenyl)-6-methyl-2H- [2,7]naphthyridine- 1 -one [394 mg (93 %) ] was obtained as a white solid using the same method as in Example 2 except that

8-(4-fluoro-phenyl)-6-methyl-2H-[2,7]naphthyridine-l-one (380 mg, 1.495 mmol) and bromoethane (0.13 mL, 1.794 mmol) were used instead of 2H-[2,7] naphthyridine-

1-one and benzyl chloride. [163] ^λ Η NMR(300 MHz, CDCl₃) δ 1.29(t, 3H, J=7.2Hz), 2.66(s, 3H), 3.94(q, 2H, J

=7.2Hz), 6.40(d, IH, J=7.2Hz), 7.07-7.15(m, 2H), 7.17(s, IH), 7.25(d, IH, J =7.2Hz),

7.41-7.48(m, 2H). [164] [165] Example 14: Synthesis of

2-(3,5-difluoro-phenyl)-8-(4-fluoro-phenyl)-6-methyl-2f-^r-[2,7]naphthyridine-l-one [ 166] 2-(3,5-difluoro-phenyl)-8-(4-fluoro-phenyl)-6-methyl-2H- [2,7]naphthyridine- 1 -one

[272 mg (94%)] was obtained as a white solid using the same method as in Example 7 except that 8-(4-fluoro-phenyl)-6-methyl-2H-[2,7]naphthyridine-l-one (200 mg, 0.787 mmol) was used instead of 8-methyl-6-phenyl-2H-[2,7]naphthyridine-l-one. [167] ^λ Η NMR(300 MHz, CDCl₃) δ 2.70(s, 3H), 6.50(d, IH, J=7.2Hz), 6.80-6.88(m,

IH), 6.88-6.97(m, 2H), 7.04-7.12(m, 2H), 7.24(s, IH), 7.28 (d, IH, J=I 2 Hz),

7.41-7.47(m, 2 H). [168] [169] Example 15: Synthesis of

2-(3,4-dimethoxy-phenyl)-8-(4-fluoro-phenyl)-6-methyl-2f-^r-[2,7]naphthyridine-l- one [170] 2-(3,4-dimethoxy-phenyl)-8-(4-fluoro-phenyl)-6-methyl-2 H-[2,7] naphthyridine-

1-one [301 mg (98%)] was obtained as a light yellow solid using the same method as in Example 7 except that 8-(4-fluoro-phenyl)-6-methyl-2H-[2,7]naphthyridine-l-one

(200 mg, 0.787 mmol) and 4-bromoveratrol (0.14 mL, 0.944 mmol) were used instead of 8-methyl-6-phenyl-2Η-[2,7]naphthyridine-l-one and 3,5-difluoroiodobenzene. [171] ^λ H NMR(300 MHz, CDCl₃) δ 2.69(s, 3H), 3.85(s, 3H), 3.88(s, 3H), 6.44(d, IH, J

=7.2Hz), 6.80-6.9 l(m, 3H), 7.02-7.09(m, 2H), 7.23(s, IH), 7.32(d, IH, J=7.2Hz),

7.41-7.48(m, 2H). [172] [173] Example 16: Synthesis of 6-(4-fluoro-phenyl)-8-methyl-2ff-[2,7] naph- thyridine-1-one [ 174] 6-(4-fluoro-phenyl)-8-methyl-2H- [2,7]naphthyridine- 1 -one [2.03 g (63 %)] was obtained as a light yellow solid using the same method as in Example 1 except that

6-(4-fluoro-phenyl)-2,4-dimethyl-nicotinonitrile (3.0 g, 13.260 mmol) was used instead of 4-methyl-nicotinonitrile. [175] ^λ Η NMR(300 MHz, DMSO-dp δ 3.01(s, 3H), 6.52(d, IH, J=7.2Hz), 7.31-7.37(m,

3H), 7.97(s, IH), 8.21-8.26(m, 2H), 11.35(brs, IH). [176]

[177] Example 17: Synthesis of 6-(4-fluoro-phenyl)-2,8-dimethyl-2ff-[2,7] naph- thyridine-1-one

[178] 6-(4-fluoro-phenyl)-2,8-dimethyl-2H-[2,7]naphthyridine-l-one [253 mg (96%)] was obtained as a white solid using the same method as in Example 2 except that 6-(4-fluoro-phenyl)-8-methyl-2H-[2,7]naphthyridine-l-one (250 mg, 0.983 mmol) and iodomethane (0.074 mL, 1.180 mmol) were used instead of 2H- [2,1] naphthyridine- 1-one and benzyl chloride.

[179] ^λ Η NMR(300 MHz, CDCl₃) δ 3.18(s, 3H), 3.58(s, 3H), 6.40 (d, IH, J=I.2 Hz),

7.13-7.21 (m, 2H), 7.24(d, IH, J=7.2Hz), 7.52(s, IH), 8.07-8.14(m, 2H).

[180]

[181] Example 18: Synthesis of 2-ethyl-6-(4-fluoro-phenyl)-8-methyl-2I/-[2,7] naph- thyridine-1-one

[182] 2-ethyl- 6-(4-fluoro-phenyl)-8-methyl-2H-[2,7]naphthyridine-l-one [260 mg

(94%)] was obtained as a white solid using the same method as in Example 2 except that 6-(4-fluoro-phenyl)-8-methyl-2H-[2,7]naphthyridine-l-one (250 mg, 0.983 mmol) and bromoethane (0.088 mL, 1.180 mmol) were used instead of 2H- [2,1] naph- thyridine-1-one and benzyl chloride.

[183] ^λ Η NMR(300 MHz, CDCl₃) δ 1.39(t, 3H, J=7.2Hz), 3.18(s, 3H), 4.03(q, 2H, J

=7.2Hz), 6.42(d, IH, J=7.2Hz), 7.13-7.21(m, 2H), 7.24(d, IH, J=7.2Hz), 7.51(s, IH), 8.07-8.14(m, 2H).

[184]

[ 185] Example 19: Synthesis of

2-(3,5-difluoro-phenyl)-6-(4-fluoro-phenyl)-8-methyl-2ff-[2,7]naphthyridine-l-one

[ 186] 2-(3,5-difluoro-phenyl)-6-(4-fluoro-phenyl)-8-methyl-2H- [2,7]naphthyridine- 1 -one

[276 mg (96%)] was obtained as a white solid using the same method as in Example 7 except that 6-(4-fluoro-phenyl)-8-methyl-2H-[2,7]naphthyridine-l-one (200 mg, 0.787 mmol) was used instead of 8-methyl-6-phenyl-2H-[2,7]naphthyridine-l-one.

[187] ^λ Η NMR(300 MHz, CDCl₃) δ 3.15 (s, 3H), 6.52(d, IH, J=7.2Hz), 6.8 9-6.96(m,

IH), 6.98- 7.06(m, 2H), 7.15-7.23(m, 2H), 7.27(d, IH, J=7.2Hz), 7.58(s, IH), 8.10-8.17(m, 2H).

[188]

[ 189] Example 20: Synthesis of

2-(3,4-dimethoxy-phenyl)-6-(4-fluoro-phenyl)-8-methyl-2i7-[2,7]naphthyridine-l- one

[190] 2-(3,4-dimethoxy-phenyl)-6-(4-fluoro-phenyl)-8-methyl-2 H-[2,7] naphthyridine-

1-one [297 mg (97 %)] was obtained as a white solid using the same method as in Example 7 except that 6 -(4-fluoro-phenyl)-8-methyl-2H-[2,7]naphthyridine-l-one (200 mg, 0.787 mmol) and 4- bromoveratrol (0.14 mL, 0.944 mmol) were used instead of 8-methyl-6-phenyl-2H-[2,7]naphthyridine-l-one and 3,5-difluoroiodobenzene. [191] ^λ Η NMR(300 MHz, CDCl₃) δ 3.16 (s, 3H), 3.92(s, 3H), 3.94 (s, 3H), 6.47(d, IH, J

=7.2Hz), 6.92-7.00(m, 3H), 7.15-7.23 (m, 2H), 7.33(d, IH, J=7.2Hz), 7.58(s, IH),

8.10-8.17(m, 2H). [192] [193] Example 21 : Synthesis of 2-(4-fluoro-phenyl)-6-(4-fluoro-phenyl)-8-methyl-2ff

-[2,7]naphthyridine-l-one [ 194] 2-(4-fluoro- phenyl)-6-(4-fluoro-phenyl)-8-methyl-2H- [2,7]naphthyridine- 1 -one

[264 mg (96%)] was obtained as a white solid using the same method as in Example 7 except that 6-(4-fluoro-phenyl)-8-methyl-2H-[2,7]naphthyridine-l-one(200 mg, 0.787 mmol) and l-fluoro-4-iodobenzene (0.11 mL, 0.944 mmol) were used instead of

8-methyl-6-phenyl-2H-[2,7]naphthyridine-l-one and 3,5-difluoroiodobenzene. [195] ^λ Η NMR(300 MHz, CDCl₃) δ 3.15 (s, 3H), 6.50(d, IH, J=7.5Hz), 7.15-7.25(m,

4H), 7.30(d, IH, J=7.5Hz), 7.37-7.44(m, 2H), 7.58(s, IH), 8.10-8.17(m, 2H). [196] [197] Example 22: Synthesis of

2-(3,5-dichloro-phenyl)-6-(4-fluoro-phenyl)-8-methyl-2f-^r-[2,7]naphthyridine-l-on e [198] 2-(3,5-dichloro-phenyl)-6-(4-fluoro-phenyl)-8-methyl-2 H-[2,7] naphthyridine-

1-one [295 mg (94%)] was obtained as a white solid using the same method as in

Example 7 except that 6-(4-fluoro-phenyl)-8-methyl-2H-[2,7]naphthyridine-l-one (200 mg, 0.787 mmol) and 3,5-dichloroiodobenzene(258 mg, 0.944 mmol) were used instead of 8-methyl-6-phenyl-2H-[2,7]naphthyridine-l-one and

3,5-difluoroiodobenzene. [199] ^λ Η NMR(300 MHz, CDCl₃) δ 3.15(s, 3H), 6.52(d, IH, J=7.5Hz), 7.16-7.23(m,

2H), 7.25(d, IH, J=7.5Hz), 7.37(d, 2H, J=I.8Hz), 7.46(t, IH, J=I.8Hz), 7.58(s, IH),

8.11-8.17(m, 2H). [200] [201] Example 23: Synthesis of 6-(3,4-difluoro-phenyl)-8-methyl-2f7-[2,7] naph- thyridine-1-one [202] 6-(3,4-difluoro-phenyl)-8-methyl-2H-[2,7]naphthyridine-l-one [2.42 g (68%)] was obtained as a light yellow solid using the same method as in Example 1 except that

6-(3,4-difluoro-phenyl)-2,4-dimethyl-nicotinonitrile (3.3g, 13.51 lmmol) was used instead of 4-methyl-nicotinonitrile. [203] ^λ Η NMR(300 MHz, DMSO-dp δ 3.01(s, 3H), 6.50(d, IH, J=6.9Hz), 7.38(d, IH, J

=6.9Hz), 7.53-7.62(m, IH), 8.03-8.09 (m, 2H), 8.17-8.24(m, IH), 11.40(brs, IH). [204] [205] Example 24: Synthesis of 6-(3,4-difluoro-phenyl )-2,8-dimethyl-2//-[2,7] naph- thyridine-1-one

[206] 6-(3,4-difluoro-phenyl)-2,8-dimethyl-2H-[2,7]naphthyridine-l-one [250 mg (95%)] was obtained as a light yellow solid using the same method as in Example 2 except that 6-(3,4-difluoro-phenyl)-8-methyl-2H-[2,7]naphthyridine-l-one (250 mg, 0.918 mmol) and iodomethane (0.069 mL, 1.102 mmol) were used instead of 2H-[2,7] naph- thyridine-1-one and benzyl chloride.

[207] ^λ Η NMR(300 MHz, CDCl₃) δ 3.18 (s, 3H), 3.58(s, 3H), 6.41(d, IH, J=7.2Hz),

7.22-7.31(m, 2H), 7.51(s, IH), 7.81-7.87(m, IH), 7.96-8.03(m, IH).

[208]

[209] Example 25: Synthesis of 2-ethyl-6-(3,4-difluoro-phenyl)-8-methyl-2//-[2,7] naphthyridine-1-one

[210] 2-ethyl-6-(3,4-difluoro-phenyl)-8-methyl-2H-[2,7]naphthyridine-l-one [245 mg

(89%)] was obtained as a light yellow solid using the same method as in Example 2 except that 6-(3,4-difluoro-phenyl)-8-methyl-2H-[2,7]naphthyridine-l-one (250 mg, 0.918 mmol) and bromoethane (0. 082 mL, 1.102 mmol) were used instead of 2H-[2,7] naphthyridine-1-one and benzyl chloride.

[211] ^λ Η NMR(300 MHz, CDCl₃) δ 1.40(t, 3H, J=7.2Hz), 3.18(s, 3H), 4.04(q, 2H, J

=7.2Hz), 6.43(d, IH, J=7.2Hz), 7.22-7.31(m, 2H), 7.51(s, IH), 7.81-7.87(m, IH), 7.96-8.03(m, IH).

[212]

[213] Example 26: Synthesis of

2-(3,5-difluoro-phenyl)-6-(3,4-difluoro-phenyl)-8-methyl-2ff-[2,7]naphthyridine-l -one

[214] 2-(3,5-difluoro-phenyl)-6-(3,4-difluoro-phenyl)-8-methyl-2 H-[2,7] naphthyridine-

1-one [267 mg (95%)] was obtained as a white solid using the same method as in Example 7 except that 6-(3,4-difluoro-phenyl)-8-methyl-2H-[2,7]naphthyridine-l-one (200 mg, 0.735 mmol) was used instead of 8-methyl-6-phenyl-2Η-[2,7] naphthyridine- 1-one.

[215] ^λ H NMR(300 MHz, CDCl₃) δ 3.14 (s, 3H), 6.53(d, IH, J=7.2Hz), 6.89-6.97(m, 1

H), 6.98-7.06(m, 2H), 7.24-7.33(m, 2H), 7.57(s, IH), 7.85-7.90(m, IH), 7.99-8.07(m, IH).

[216]

[217] Example 27: Synthesis of

2-(3,4-dimethoxy-phenyl)-6-(3,4-difluoro-phenyl)-8-methyl-2f-^r-[2,7]naphthyridine -1-one

[218] 2-(3,4-dimethoxy-phenyl)-6-(3,4-difluoro-phenyl)-8-methyl-2 H-[2,7] naph- thyridine- 1-one [292 mg (97%)] was obtained as a white solid using the same method as in Example 7 except that 6-(3,4-difluoro-phenyl)-8-methyl-2H-[2,7] naphthyridine-

1-one (200 mg, 0.735 mmol) and 4-bromoveratrol (0.13 mL, 0.882 mmol) were used instead of 8-methyl-6-phenyl-2H-[2,7]naphthyridine-l-one and

3,5-difluoroiodobenzene. [219] ^λ Η NMR(300 MHz, CDCl₃) δ 3.16 (s, 3H), 3.92(s, 3H), 3.94 (s, 3H), 6.48(d, IH, J

=7.2Hz), 6.92-7.00(m, 3H), 7.24 -7.33(m, IH), 7.35 (d, IH, J=7.2Hz), 7.57(s, IH),

7.85-7.90(m, IH), 7.99-8.06(m, IH). [220] [221] Example 28: Synthesis of

2-(4-fluoro-phenyl)-6-(3,4-difluoro-phenyl)-8-methyl-2f-^r-[2,7]naphthyridine-l-one [222] 2-(4-fluoro-phenyl)-6-(3,4-difluoro-phenyl)-8-methyl-2 H-[2,7] naphthyridine-

1-one [252 mg (94%)] was obtained as a white solid using the same method as in

Example 7 except that 6-(3,4-difluoro-phenyl)-8-methyl-2H-[2,7]naphthyridine-l-one

(200 mg, 0.735 mmol) and l-fluoro-4-iodobenzene (0.10 mL, 0.882 mmol) were used instead of 8-methyl-6-phenyl-2H-[2,7]naphthyridine-l-one and

3,5-difluoroiodobenzene. [223] ^λ Η NMR(300 MHz, CDCl₃) δ 3.15 (s, 3H), 6.50(d, IH, J=7.2Hz), 7.17-7.33(m,

4H), 7.36-7.43(m, 2H), 7.57(s, IH), 7.85-7.90(m, IH), 7.99-8.06(m, IH). [224] [225] Example 29: Synthesis of

2-(3,5-dichloro-phenyl)-6-(3,4-difluoro-phenyl)-8-methyl-2ff-[2,7]naphthyridine-l

-one [226] 2-(3,5-dichloro-phenyl)-6-(3,4-difluoro-phenyl)-8-methyl-2H-[2,7] naphthyridine-

1-one [302 mg (98%)] was obtained as a white solid using the same method as in

(200 mg, 0.735 mmol) and 3,5-dichloroiodobenzene (241 mg, 0.882 mmol) were used instead of 8-methyl-6-phenyl-2H-[2,7]naphthyridine-l-one and

3,5-difluoroiodobenzene. [227] ^λ Η NMR(300 MHz, CDCl₃) δ 3.14(s, 3H), 6.52(d, IH, J=7.2Hz), 7.24-7.33(m, 2

H), 7.37(d, 2H, J=1.8Hz), 7.46(t, IH, J=1.8Hz), 7.57(s, IH), 7.85-7.90(m, IH),

8.00-8.07(m, IH). [228] [229] Example 30: Synthesis of 6-ethyl-8-piperidin-l-yl-2//-[2,7] naphthyridine-

1-one [230] 6-ethyl-8-piperidin- 1 -yl-2H- [2,7]naphthyridine- 1 -one [0.92 g (41 %)] obtained as a yellow solid using the same method as in Example 1 except that

6-ethyl-4-methyl-3,4,5,6-tetrahydro-2H-[l,2] nonpyridinyl-3-carbonitrile (2.0g,

8.721mmol) was used instead of 4-methyl-nicotinonitrile. [231] ^λ H NMR(300 MHz, CDCl₃) δ 1.28(t, 3H, /=7.5Hz), 1.64-1.69(m, 2H),

1.75-1.81(m, 4H), 2.71(q, 2H, /=7.5Hz), 3.46-3.49(m, 4H), 6.27(d, IH, /=7.2Hz),

6.58(s, IH), 7.13(d, IH, /=7.2Hz), 10.65(brs, IH). [232] [233] Example 31: Synthesis of 6-ethyl-2-methyl-8-piperidin-l -yl-2//-[2,7] naph- thyridine-1-one [234] 6-ethyl-2-methyl-8-piperidin- 1 -yl-2H- [2,7]naphthyridine- 1 -one [ 170 mg (81 %)] was obtained as a light yellow solid using the same method as in Example 2 except that

6-ethyl-8-piperidin-l-yl-2H-[2,7]naphthyridine-l-one (200 mg, 0.777 mmol) and iodomethane (0.058 mL, 0.932 mmol) were used instead of 2H-[2,7] naphthyridine-

1-one and benzyl chloride. [235] ^λ Η NMR(300 MHz, CDCl₃) δ 1.27(t, 3H, J=7.5Hz), 1.62-1.67(m, 2H),

1.73-1.80(m, 4H), 2.69(q, 2H, J=7.5Hz), 3.41-3.44(m, 4H), 3.51(s, 3H), 6.20(d, IH, J

=7.2Hz), 6.53(s, IH), 7.1 l(d, IH, J=7.2Hz). [236] [237] Example 32: Synthesis of 2,6-diethyl-8-piperidin-l-yl-2//-[2,7] naphthyridine-

1-one [238] 2,6-diethyl-8-piperidin-l-yl-2H-[2,7]naphthyridine-l-one [168 mg (76 %)] was obtained as a light yellow solid using the same method as in Example 2 except that

6-ethyl-8- piperidin-l-yl-2H-[2,7]naphthyridine-l-one (200 mg, 0.777 mmol) and bromoethane (0.070 mL, 0.932 mmol) were used instead of 2H-[2,7] naphthyridine-

1-one and benzyl chloride. [239] ^λ Η NMR(300 MHz, CDCl₃) δ 1.26(t, 3H, J=7.5Hz), 1.33(t, 3H, J=7.2Hz), 1.61 -

1.67(m, 2H), 1.72-1.79(m, 4H), 2.69(q, 2H, J=7.5Hz), 3.42-3.46(m, 4H), 3.97(q, 2H, J

=7.2Hz), 6.21(d, IH, J=7.2Hz), 6.51(s, IH), 7.1 l(d, IH, J=7.2Hz). [240] [241] Example 33: Synthesis of 6-isopropyl-8-piperidin-l-yl-2//-[2,7] naphthyridine-

1-one [242] 6-isopropyl-8-piperidin-l-yl-2H-[2,7]naphthyridine-l-one [51 mg (46 %)] was obtained as a light yellow solid using the same method as in Example 1 except that

6-isopropyl-4-methyl-3,4,5,6-tetrahydro-2H-[l,2]nonpyridinyl-3-carbonitrile (100 mg,

0.411 mmol) was used instead of 4-methyl-nicotinonitrile. [243] ^λ Η NMR(300 MHz, CDCl₃) δ 1.27(d, 6H, J=6.9Hz), 1.63- 1.68(m, 2H),

1.74-1.80(m, 4H), 2.88-2.97(m, IH), 3.47-3.51(m, 4H), 6.29 (d, IH, 7=6.9 Hz), 6.58(s,

IH), 7.14(d, IH, J =6.9Hz), 10.98(brs, IH). [244] [245] Example 34: Synthesis of 6-isopropyl-2-methyl-8-piperidin-l-yl-2fr-[2,7] naph- thyridine-1-one [246] 6-isopropyl-2-methyl-8-piperidin-l-yl-2H-[2,7]naphthyridine-l-one [241 mg

(92%)] was obtained as a light yellow solid using the same method as in Example 2 except that 6-isopropyl-8-piperidin-l-yl-2H-[2,7]naphthyridine-l-one (250 mg, 0.921 mmol) and iodomethane (0.069 mL, 1.105 mmol) were used instead of 2H- [2,7] naph- thyridine-1-one and benzyl chloride.

[247] ^λ Η NMR(300 MHz, CDCl₃) δ 1.26(d, 6H, J=6.6Hz), 1.63- 1.67(m, 2H),

1.73-1.79(m, 4H), 2.86-2.95(m, IH), 3.42-3.46(m, 4H), 3.51(s, IH), 6.21 (d, IH, J =7.2Hz), 6.53(s, IH), 7.1 l(d, IH, J=7.2Hz).

[248]

[249] Example 35: Synthesis of 2-ethyl-6-isopropyl-8-piperidin-l-yl-2H-[2,7] naph- thyridine-1-one

[250] 2-ethyl-6-isopropyl-8-piperidin-l-yl-2H-[2,7]naphthyridine-l-one [246 mg (89%)] was obtained as a light yellow solid using the same method as in Example 2 except that 6-isopropyl-8-piperidin-l-yl-2H-[2,7]naphthyridine-l-one (250 mg, 0.921 mmol) and bromoethane (0.082 mL, 1.105 mmol) were used instead of 2H-[2,7] naphthyridine- 1-one and benzyl chloride.

[251] ¹ H NMR(300 MHz, CDCl₃) δ 1.26(d, 6H, J=6.9Hz), 1.33(t, 3H, J=7.2Hz),

1.61-1.67(m, 2H), 1.72-1.78(m, 4H), 2.86-2.95(m, IH), 3.44-3.48(m, 4H), 3.97(q, 2H, J=7.2Hz), 6.23 (d, IH, J=7.2Hz), 6.51(s, IH), 7.1 l(d, IH, J=7.2Hz).

[252]

[253] Example 36: Synthesis of 6-isopropyl-2-methoxymethyl-8-piperidin-l-yl-2ff -

[2,7]naphthyridine-l-one

[254] 6-isopropyl-2-methoxymethyl-8-piperidin- 1 -yl-2H-[2,7]naphthyridine- 1 -one [ 185 mg (64%)] was obtained as a light yellow oil using the same method as in Example 2 except that 6-isopropyl-8-piperidin-l-yl-2H-[2,7]naphthyridine-l-one (250 mg, 0.921 mmol) and chloromethyl methyl ether (0.084 mL, 1.105 mmol) were used instead of 2 H-[2,7]naphthyridine-l-one and benzyl chloride.

[255] ^λ Η NMR(300 MHz, CDCl₃) δ 1.26(d, 6H, J=6.9Hz), 1.61-1.75(m, 6H),

2.86-2.96(m, IH), 3.37(s, 3H), 3.46-3.49(m, 4H), 5.32(s, 2H), 6. 25(d, IH, J=7.2Hz), 6.50(s, IH), 7.18(d, IH, J=7.2Hz).

[256]

[257] Example 37: Synthesis of 6-isopropyl-2-(2-methoxy-ethyl)-8-piperidin-l-yl-2ff

-[2,7]naphthyridine-l-one

[258] 6-isopropyl-2-(2-methoxy-ethyl)-8-piperidin- 1 -yl-2H- [2,7]naphthyridine- 1 -one

[279 mg (92%)] was obtained as a light yellow oil using the same method as in Example 2 except that 6-isopropyl-8-piperidin-l-yl-2H-[2,7]naphthyridine-l-one (250 mg, 0.921 mmol) and 2-chloroethyl methyl ether (0.101 mL, 1.105 mmol) were used instead of 2H-[2,7]naphthyridine-l-one and benzyl chloride. [259] ^λ H NMR(300 MHz, CDCl₃) δ 1.26(d, 6H, /=6.6Hz), 1.62-1.67(m, 2H), 1.71-1.7

7(m, 4H), 2.86-2.95(m, IH), 3.30(s, 3H), 3.43-3.47(m, 4H), 3.67(t, 2H, 7=5. IHz), 4.09(t, 2H, J=5.1Hz), 6.19(d, IH, J=7.2Hz), 6.52(s, IH), 7.18(d, IH, J=7.2Hz).

[260]

[261] Example 38: Synthesis of 2-(4-fluoro-phenyl)-6-isopropyl-8-piperidin-l-yl-2£-^r -

[2,7]naphthyridine-l-one

[262] 2-(4-fluoro-phenyl)-6-isopropyl-8-piperidin- 1 -yl-2H-[2,7]naphthyridine- 1 -one

[260 mg (97 %)] was obtained as a white solid using the same method as in Example 7 except that 6-isopropyl-8-piperidin-l-yl-2H-[2,7]naphthyridine-l-one (200 mg, 0.737 mmol) and l-fluoro-4-iodobenzene (0.10 mL, 0.884 mmol) were used instead of 8-methyl-6-phenyl-2H-[2,7]naphthyridine-l-one and 3,5-difluoroiodobenzene.

[263] ^λ Η NMR(300 MHz, CDCl₃) δ 1.28(d, 6H, J=6.9Hz), 1.59- 1.70(m, 6H),

2.89-2.98(m, IH), 3.46-3.50(m, 4H), 6.28 (d, IH, J=7.5Hz), 6.54(s, IH), 7.12-7.19(m, 3H), 7.31-7.38(m, 2H).

[264]

[265] Example 39: Synthesis of

2-(3,4-dimethoxy-phenyl)-6-isopropyl-8-piperidin-l-yl-2£-^r-[2,7]naphthyridine-l-o ne

[266] 2-(3,4-dimethoxy-phenyl)-6-isopropyl-8-piperidin-l-yl-2 H-[2,7] naphthyridine-

1-one [265 mg (88%)] was obtained as a white solid using the same method as in Example 7 except that 6-isopropyl-8-piperidin-l-yl-2H-[2,7]naphthyridine-l-one (200 mg, 0.737 mmol) and 4-bromoveratrol (0.13 mL, 0.884 mmol) were used instead of 8-methyl-6-phenyl-2H-[2,7]naphthyridine-l-one and 3,5-difluoroiodobenzene.

[267] ^λ Η NMR(300 MHz, CDCl₃) δ 1.28(d, 6H, J=6.6Hz), 1.61-1.70(m, 6H),

2.89-2.98(m, IH), 3.47-3.51(m, 4H), 3.87(s, 3H), 3.91(s, 3H), 6. 26(d, IH, J=7.2Hz), 6.54(s, IH), 6.87-6.95(m, 3H), 7.17 (d, IH, J=7.2Hz).

[268]

[269] Example 40: Synthesis of 6-te/f-butyl-8-piperidin-l-yl-2/7-[2,7] naphthyridine-

1-one

[270] 6-tert-butyl-8-piperidin-l-yl-2H-[2,7]naphthyridine-l-one [1.25 g (42 %)] was obtained as a light yellow solid using the same method as in Example 1 except that 6- tert-butyl-4-methyl-3,4,5,6-tetrahydro-2H-[l,2]nonpyridinyl-3-carbonitrile (2.7 g, 10.491 mmol) was used instead of 4-methyl-nicotinonitrile.

[271] ^λ Η NMR(300 MHz, CDCl₃) δ 1.33(s, 9H), 1.63-1.68(m, 2H), 1.73-1.77(m, 4H),

3.48-3.52(m, 4H), 6. 31(d, IH, J=7.2Hz), 6.71(s, IH), 7.15(d, IH, J=7.2Hz), 10.92(brs, IH).

[272]

[273] Example 41 : Synthesis of 6-terf-butyl-2-methyl-8-piperidin- 1 -yl-2H- [2,7] naph- thyridine-1-one

[274] 6-tert-butyl-2-methyl-8-piperidin-l-yl-2H-[2,7]naphthyridine-l-one [197 mg

(94%)] was obtained as a light yellow solid using the same method as in Example 2 except that 6-tert-butyl-8-piperidin-l-yl-2H-[2,7]naphthyridine-l-one (200 mg, 0.701 mmol) and iodomethane (0.066 mL, 1.051 mmol) were used instead of 2H- [2,7] naph- thyridine-1-one and benzyl chloride.

[275] ^λ Η NMR(300 MHz, CDCl₃) δ 1.32(s, 9H), 1.61-1.67(m, 2H), 1.71-1.79(m, 4H),

3.44-3.47(m, 4H), 3.52(s, 3H), 6.24(d, IH, J=7.2Hz), 6.66(s, IH), 7.1 l(d, IH, J =7.2Hz).

[276]

[277] Example 42: Synthesis of 6-te/t-butyl-2-ethyl-8-piperidin-l-yl-2ff-[2,7] naph- thyridine-1-one

[278] 6-tert-butyl-2-ethyl-8-piperidin-l-yl-2H-[2,7]naphthyridine-l-one [196 mg (89%)] was obtained as a white solid using the same method as in Example 2 except that 6-tert -butyl-8-piperidin-l-yl-2H-[2,7]naphthyridine-l-one (200 mg, 0.701 mmol) and bromoethane (0.078 mL, 1.051 mmol) were used instead of 2H-[2,7] naphthyridine- 1-one and benzyl chloride.

[279] ^λ Η NMR(300 MHz, CDCl₃) δ 1.32 (s, 9H), 1.33(t, 3H, J=7.2Hz), 1.61-1.66(m,

2H), 1.71-1.77(m, 4H), 3.4 5-3.49(m, 4H), 3.98(q, 2H, J=7.2Hz), 6.26(d, IH, J =7.2Hz), 6.65(s, IH), 7.1 l(d, IH, J=7.2Hz).

[280]

[281] Example 43: Synthesis of 6-te/f-butyl-2-(4-fluoro-phenyl)-8-piperidin-l-yl-2f7 -

[2,7]naphthyridine-l-one

[282] 6-tert-butyl-2-(4-fluoro-phenyl)-8-piperidin- 1 -yl-2 H- [2,7]naphthyridine- 1 -one

[220 mg (9 2%)] was obtained as a white solid using the same method as in Example 7 except that 6-tert-butyl-8-piperidin-l-yl-2H-[2,7]naphthyridine-l-one (180 mg, 0.631 mmol) and l-fluoro-4-iodobenzene (0.087 mL, 0.757 mmol) were used instead of 8-methyl-6-phenyl-2H-[2,7]naphthyridine-l-one and 3,5-difluoroiodobenzene.

[283] ^λ Η NMR(300 MHz, CDCl₃) δ 1.34(s, 9H), 1.60-1.69(m, 6H), 3.47-3.50(m, 4H),

6.31(d, IH, J=7.5Hz), 6.68(s, IH), 7.11-7.19(m, 3H), 7.32-7.39(m, 2H).

[284]

[285] Example 44: Synthesis of 6-tert - butyl-2-(3,4-dimethoxy-phenyl)-8-piperidin-l-yl-2f-^r-[2,7]naphthyridine-l-one

[286] 6-tert-butyl-2-(3,4-dimethoxy-phenyl)-8-piperidin-l-yl-2 H-[2,7] naphthyridine-

1-one [253 mg (95%)] was obtained as a white solid using the same method as in Example 7 except that 6-tert-butyl-8-piperidin-l-yl-2H-[2,7]naphthyridine-l-one (180 mg, 0.631 mmol) and 4-bromoveratrol (0.11 mL, 0.757 mmol) were used instead of 8-methyl-6-phenyl-2H-[2,7]naphthyridine-l-one and 3,5-difluoroiodobenzene. [287] ^λ H NMR(300 MHz, CDCl₃) δ 1.34(s, 9H), 1.61-1.70(m, 6H), 3.49-3.52(m, 4H),

3.87(s, 3H), 3.92(s, 3H), 6. 29(d, IH, /=7.2Hz), 6.68 (s, IH), 6.88-6.95(m, 3H), 7.17(d, IH, /=7.2Hz).

[288]

[289] Example 45: Synthesis of 8-(4-fluoro-phenyl)-6-methyl-l-oxo-l//7-[2,7] naph- thyridine-2-2-carboxylic acid methyl ester

[290] Triethylamine (4.67 mL) and methylchloroformate (1.55 mL) were added to a suspension of 6-(4-fluoro phenyl)-8-methyl-2H-[2,7]naphthyridine-l-one (1.7 g, 6.69 mmol) and methylenechloride (30 mL) and then stirred for 2 hours. The resulting solvent was dried under reduced pressure and the residue remaining thereof was purified by 20% ethylacetate/methylenechloride column chromatograph and obtained 8-(4-fluoro-phenyl)-6-methyl-l-oxo-llΗ-[2,7]naphthyridine-2-2-carboxylic acid methyl ester [527 mg (25%)] as a white solid.

[291] ' H NMR(300 MHz, CDCl₃) δ 7.75(d, J=8.1Hz, IH), 7.74-7.44(m, 2H),

7.15-7.09(m, 2H), 6.38(d, J=7.8Hz, IH), 4.00(s, 3H), 2.67(s, 3H).

[292]

[293] Example 46: Synthesis of 8-(4-fluoro-phenyl)-6-methyl-l-oxo-l//7-[2,7] naph- thyridine-2-carboxylic acid

[294] Lithium hydroxide hydrate (39mg) was added to an aqueous methanol/water (2 mL/2 mL) solution of 8-(4-fluoro-phenyl)-6-methyl-l-oxo-liH-[2,7] naphthyridine- 2-2-carboxylic acid methyl ester (250 mg, 0.80 mmol) and stirred for 2 hours. The mixtures was adjusted to a pΗ 5 with 1 M HCl, added with distilled water and then stored in a refrigerator for 2 hours. The resulting solid was filtered, dried under vacuum and the final product was obtained as a white solid [122 mg (51%)].

[295] ^λ Η NMR(300Mz, DMSO-d₆) δ 11.22(br s, 1Η), 7.45-7.35(m, 4Η), 7.18-7.12(m,

2H), 6.49(d, J=7.2Hz, IH), 2.53(s, 3H).

[296]

[297] Example 47: Synthesis of 3-[8-(4-fluoro-phenyl)-6-methyl-l-oxo-l//y-[2,7] naph thy ridine-2-yl] -propionic acid methyl ester

[298] Sodium hydroxide (25 mg) was added to a suspension of

6-(4-fluoro-phenyl)-8-methyl-2H-[2,7]naphthyridine-l-one (1.7 g, 6.69 mmol), methyl acrylate (2.88 mL), and tetrahydrofuran (30 mL), and then stirred for 2 hours. The mixture was further added with sodium hydroxide (25 mg), stirred for 2 hours and then added again with sodium hydroxide (25 mg) and stirred for 1 hour. The resulting solution was neutralized with 1 M HCl, added with distilled water and then extracted with ethylacetate. The resulting organic layer was washed with water and a saturated saline solution, dried with anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by 10% ethylacetate/methylenechloride chromatograph and the final product was obtained as a violet solid [1.64 g(72%)]. ¹ H NMR(300 MHz, CDCl₃) δ 7.46-7.42(m, 3H), 7.17-7.08(m, 3H), 6.38(d, J =12Ηz, IH), 4.14(t, /=6.3Hz, 2H), 3.65(s, 3H), 4.14(t, /=6.2Hz, 2H), 2.65(s, 3H).

[300]

[301] Example 48: Synthesis of 4-[2-(4-methoxy-phenyl)-2-oxo-ethyl] -

2,6-dimethyl-nicotinonitrile

[302] 2,4,6-trimethyl-nicotinonitrile (700 mg, 4.788 mmol) was dissolved in anhydrous

THF (10 mL), dropwisely added with LHMDS (IM THF solution, 10 mL, 10.055 mmol) while stirring at -78 °C under nitrogen atmosphere and then stirred for 1 hour. Then, the mixture was dropwisely added with methyl 4-methoxybenzoatel (875 mg, 5.267 mmol), which was dissolved in anhydrous THF (5 mL), and stirred for 30 minutes at -78 °C and 1 hour at 0 °C . The reaction mixture was added with a saturated aqueous ammonium chloride solution (10 mL) and distilled water (10 mL) while stirring and extracted with methylenechloride (60 mL x 2). The resulting organic layer was dried with anhydrous sodium sulfate, filtered and then concentrated. The resulting residue was purified with a silica gel column chromatograph (50% EtOAc/Hexanes) and obtained the final product as a yellow solid [1.237 g (92%)].

[303] ^λ H NMR(300 MHz, CDCl₃) δ 2.57(s, 3H), 2.76(s, 3H), 3.90(s, 3H), 4.42(s, 2H),

6.96-7.01(m, 2H), 7.03(s, IH), 7.99-8.04(m, 2H).

[304]

[305] Example 49: Synthesis of 3-(4-methoxy-phenyl)-6,8-dimethyl-pyrano[3,4-c] pyridin-1-one

[306] 4-[2-(4-methoxy-phenyl)-2-oxo-lethyl]-2,6-dimethyl-nicotinonitrile (800 mg, 2.854 mmol) was dissolved in cone. HCl (12 mL) and refluxed under heat for 15 hours. The reaction mixture was concentrated under vacuum, neutralized at 0 °C by dropwisely adding a saturated aqueous sodium carbonate , added with distilled water (20 mL) and then extracted with 10% MeOH/CHCl (80 mL x 2). The resulting organic layer was dried with anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by a silica gel column chromatograph (3% MeOH/MC) and obtained the final product as a yellow solid [742 mg (92 %)].

[307] ^λ H NMR(300 MHz, CDCl₃) δ 2.60(s, 3H), 3.01(s, 3H), 3.88(s, 3H), 6.66(s, IH),

6.96-7.01(m, 3H), 7.80-7.85(m, 2H).

[308]

[309] Example 50: Synthesis of 3-(4-hydroxy-phenyl)-6,8-dimethyl-pyrano[3,4-c] pyridin-1-one

[310] 3-(4-methoxy-phenyl)-6,8-dimethyl-pyrano[3,4-c]pyridin-l-one (400 mg, 1.422 mmol) was dissolved in anhydrous methylenechloride (10 mL), dropwisely added with BBr (IM methylenechloride solution, 2.8 mL, 2.844 mmol) while stirring at -78 °C under nitrogen atmosphere, slowly increased to room temperature and then stirred for 15 hours . The reaction mixture was added with a saturated aqueous sodium carbonate (20 mL) and distilled water (20 mL) while stirring at 0 °C and then extracted with 10% MeOH/CHCl (100 mL x 4). The resulting organic layer was dried with anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by a silica gel column chromatograph (5% MeOH/MC) and obtained the final product as a yellow solid 195 mg(51%).

[311] ¹ H NMR(300 MHz, DMSO-d₆) δ 2.50(s, 3H), 2.83(s, 3H), 6.88-6.93(m, 2H),

7.13(s, IH), 7.21(s, IH), 7.73-7.78(m, 2H), 10.18(brs, IH).

[312]

[313] Example 51: Synthesis of 4-[2-(3-methoxy-phenyl)-2-oxo-ethyl] -

2,6-dimethyl-nicotinonitrile

[314] 4-[2-(3-methoxy- phenyl)-2-oxo-lethyl]-2,6-dimethyl-nicotinonitrile [1.219 g

(91%)] was obtained as a yellow solid by using the same method as in Example 48 except that methyl 3-methoxybenzoatel (0.76 mL, 5.267 mmol) was used instead of methyl 4-methoxybenzoatel.

[315] ^λ H NMR(300 MHz, CDCl₃) δ 2.57(s, 3H), 2.77(s, 3H), 3.87(s, 3H), 4.46(s, 2H),

7.02(s, IH), 7.16-7.20(m, IH), 7.40-7.46(m, IH), 7.53-7.54(m, IH), 7.60-7.64(m, IH).

[316]

[317] Example 52: Synthesis of 3-(3-methoxy-phenyl)-6,8-dimethyl-pyrano[3,4-c] pyridin-1-one

[318] 3-(3-methoxy-phenyl)-6,8-dimethyl-pyrano[3,4-c]pyridin-l-one [588 mg (73%)] was obtained as a yellow solid by using the same method as in Example 49 except that 4-[2-(3-methoxy-phenyl)-2-oxo-lethyl]-2,6-dimethyl-nicotinonitrile (800 mg, 2.854 mmol) was used instead of 4-[2-(4-methoxy-phenyl)-2-oxo-lethyl] - 2,6-dimethyl-nicotinonitrile.

[319] ^λ H NMR(300 MHz, CDCl₃) δ 2.62(s, 3H), 3.02(s, 3H), 3.89(s, 3H), 6.77(s, IH),

7.00-7.03(m, 2H), 7.36-7.47(m, 3H).

[320]

[321] Example 53: Synthesis of 3-(3-hydroxy-phenyl)-6,8-dimethyl-pyrano[3,4-c] pyridin-1-one

[322] 3-(3-hydroxy-phenyl)-6,8-dimethyl-pyrano[3,4-c]pyridine -1-one [188 mg (57%)] was obtained as a yellow solid by using the method same as in Example 50 except that 3-(3-methoxy- phenyl)-6,8-dimethyl-pyrano[3,4-c]pyridin-l-one (350 mg, 1.244 mmol) was used instead of 3-(4-methoxy-phenyl)-6,8-dimethyl-pyrano[3,4-c] pyridin- 1-one.

[323] ^λ H NMR(300 MHz, DMSO-dp δ 2.53(s, 3H), 2.86(s, 3H), 6.90-6.94(m, IH),

7.28-7.38(m, 5H), 9.82(brs, IH). [324]

[325] The compounds of the above formula 1 can be formulated in various types depending on the purpose. The followings are only a few exemplary formulations of the compounds of the above formula 1 of the present invention and they should not be construed as limiting the scope of the present invention. [326]

[327] Formulation 1 : Manufacture of Tablets (Direct Pressure)

[328] An active ingredient (5.0 mg) was sifted, mixed with lactose (14.1 mg) ,

Crospovidone USNF (0.8 mg ) and magnesium stearate (0.1 mg ), and then pressed to be formed into a tablet. [329]

[330] Formulation 2 : Manufacture of Tablets (Wet Granulation)

[331] An active ingredient (5.0 mg) was sifted, mixed with lactose (16.0 mg ) and starch

(4.0 mg) . Polysolvate (80 0.3 mg ) was dissolved in purified water and then added to the mixture for granulation. After drying, the mixture was added with colloidal silicon dioxide (2.7 mg ) and magnesium stearate (2.0 mg ). The resulting granules were formed into a tablet by pressing. [332]

[333] Formulation 3 : Manufacture of Drugs in Powders and Capsules

[334] An active ingredient (5.0 mg) was sifted, and then mixed with lactose (14.8 mg) , polyvinyl pyrrolidone (10.0 mg) and magnesium stearate (0.2 mg ) to be formed into powders. The powders were encapsulated into hard No. 5 gelatin capsules by using a suitable apparatus. [335]

[336] Experimental Example 1: Test of Inhibitory Effects of Cytokines

[337] 1) Test of Inhibitory Effects against Cytokines in Human Whole Blood

[338] Venous blood (20 mL) was collected respectively from each of 5 healthy men and women volunteers who had never been administered with any anti-inflammatory drugs during the past 2 weeks and added with heparin, respectively. Then, 1 mL of each sample was transferred into a test tube and a test substance was added into the test tub e. The mixture was preincubated for 1 hour at 37 °C , added with LPS (lipopoly saccharide) (I m g/mL) and reacted at the above temperature for 4 hours and then centrifuged for 10 minutes at 4 °C at the rate of 3000 rpm. Each of thus prepared plasma was collected and then the amount of TNF- α in plasma was measured using human TNF- α ELISA kit based on the amount of recombinant human TNF- α. Here, anti-human TNF- α monoclone IgG antibody-coated plate was used. For the test of IL- 1 α , the amount of IL-I α in plasma, obtained by treating as described above, was measured using human IL-I α ELISA kit based on the amount of recombinant human IL-I α. Here, anti-human IL-I α monoclone antibody-coated plate was used. Likewise, for the test of PGE , the amount of PGE in plasma, obtained by treating as described above, was measured using human PGE ELISA kit based on the amount of recombinant human PGE . Here, anti-human PGE monoclone antibody-coated plate was used. From the above tests, the respective inhibitory rate against the expression of each cytokine was obtained. The results were compared with the activity of In- domethacin, a commercially available anti-inflammatory and analgesic agent, and are shown in the following table 1.

[339] [ Table 1 1

[340] According to the above table 1, in the test of inhibitory activity of compounds against cytokines in human whole blood, pyridine compounds of the present invention showed 2-3 times more superior inhibitory effects against the synthesis of TNF- α and IL-I α, as compared with Indomethacin, the commercially available anti-inflammatory and analgesic agent.

[341] [342] 2) Test of Inhibitory Effects against Cytokines in Animal Models [343] Sprague-Dawley rats with body weight of 180-200 g were fasted for 24 hours (free water feeding) before the test. First, the rats were orally administered with a test substance at a concentration of 40 mg/kg, and 1 hour after that, they were abdominally administered with LPS (1 mg/kg). Rats were sacrificed 2 hours later. Blood samples were collected from their abdominal veins, stored at room temperature for 2 hours and then centrifuged for 2 minutes at 12,000 rpm. Each of the prepared plasma was collected and then the amount of TNF- α in plasma was measured using rat TNF- α ELISA kit based on the amount of recombinant rat TNF- α. Here, anti-rat TNF- α monoclone IgG antibody-coated plate was used. For the test of IL-I α , the amount of IL-I α in plasma, obtained by treating as described above, was measured using rat IL-I α ELISA kit based on the amount of recombinant rat IL-I α. Here, anti-rat IL-I α monoclone antibody-coated plate was used. Likewise, for the test of IL-6, the amount of IL-6 in plasma, obtained by treating as described above, was measured using rat IL- 6 ELISA kit based on the amount of recombinant rat IL-6 . Here, anti-rat IL-6 monoclone antibody-coated plate was used. Further, for the test of INF- γ , the amount of INF- γ in plasma, obtained by treating as described above, was measured using rat INF- γ ELISA kit based on the amount of recombinant rat INF- γ. Here, anti-rat INF- γ monoclone antibody-coated plate was used.

[344] From the above tests, the respective inhibitory rate against the expression of each cytokine was obtained. The inhibitory effects of the compounds of the present invention against the TNF- α were compared with BIRB-796, a TNF- α inhibitory substance under phase II clinical trial, while the other acitivities of the compounds were compared with the activity of Indomethacin, a commercially available antiinflammatory and analgesic agent, and the results are shown in the following table 2 and table 3.

[345] [ Table 2 1

[346] [347] [ Table 3 1

[348] According to the above table 2, the compounds of the present invention showed superior inhibitory effects against the synthesis of TNF-α in an animal model, as compared with BIRB-796. Further, from the above table 3, it is apparent that the compounds of the present invention have superior inhibitory effects against the synthesis of IL-I α, IL-6, as compared with Indomethacin.

[349] [350] 3) Test of Inhibitory Effects against Cellular Cytokines [351] General reagents used were purchased from Sigma- Aldrich chem. Co. and cytokines inhibitory activities were tested according to the methods described below.

[352] Cell culture-related media and reagents were purchased from GIBCO BRL (USA), and mouse TNF- α ELISA kit was purchased from R&D system ( USA ). As for apparatuses, ELISA reader (Spectra max-Plus 384, Molecular Device, USA ) was used.

[353] Murine macrophage cell line RAW 264.7 was obtained from Korea Tissue Culture Center (KTCC). The cell line was cultured in 10% FBS-containing DMEM in a cell culturing apparatus kept at 37 °C , 5% CO with appropriate gas and humidity. First, murine RAW 264.7 cell line was cultured in 10% FBS-containing DMEM for 24 hours, and the cells were aliquoted into each well of a 96 well plate at the concentration of 5 x 10⁵/mL with 200 μ L per each well and cultured for 24 hours. Then, test substances were treated at various concentrations and reacted at 37 °C for 1 hour . Lipopolysaccharide (LPS) (1 μ g/mL) was added thereto and reacted at 37 °C for 12 hours . The supernatant was recovered and the amount of mouse TNF- α in the medium was measured by using ELISA kit. The activities were compared with that of thalidomide, a control substance, and the results are shown in the following table 4. [354] [ Table 4 l

[355] According to the above Table 4, the pyridine compounds of the present invention generally showed excellent inhibitory activities against the synthesis of TNF- α in RAW 264.7 cells. In particular, the compounds of Examples 3, 4, 5 and 6 showed superior activities as compared with the control substance.

[356] [357] Experimental Example 2: Antiinflammatory and Analgesic Effects in Animal Model

[358] 1) Test of Croton oil-induced Ear Edema [359] Male ICR ( Institute of Cancer Research ) mice with body weight of 20 - 3O g were divided into a group of 6 per each concentration and used for the test. One hour after orally administering a test compound, croton-oil (acetone solution) was applied to one of the ears of each mouse. Four hours after that, the thickness of the swollen ear in a treated group was compared with that of untreated ear and the average rate of increase in thickness of the treated ear was calculated and then the inhibitory rate by comparing with that of a placebo group was calculated. The result is shown in the following Table 5. [360] [ Table 5 1

[361]

[362] 2) Test of Arachidonic Acid-Induced Ear Edema [363] Male ICR ( Institute of Cancer Research ) mice with body weight of 20 - 3O g were divided into a group of 6 per each concentration and used for the test. One hour after orally administering a test compound, arachidonic acid (acetone solution) was applied to the right ear of each mouse. One hour after that, the thickness of the swollen ear in a treated group was compared with that of untreated ear and calculated the average rate of increase in thickness of the treated ear and then calculated the inhibitory rate by comparing with that of a placebo group. The result is shown in the following Table 6.

[364] [ Table 6 1

[365] [366] 3^*) Writhing Test [367] Male ICR ( Institute of Cancer Research ) mice with body weight of 20 - 3O g were divided into a group of 10 per each concentration and used for the test. One hour after orally administering a test compound, acetic acid (distilled water) was abdominally administered. Mice were observed for 10 minutes to count the number of writhing and then compared with that of a placebo group thereby calculating the inhibitory rate. The result is shown in the following Table 7.

[368] [ Table 7 1

[369] According to the above tables 5 and 6 regarding the anti-inflammatory effects of the compounds of the present invention in animal model, the pyridine compounds of the present invention showed equal or better effects at concentrations of 2 mg/kg, 10 mg/kg and 50 mg/kg as compared with Celecoxib (100 mg/kg), a commercially available anti-inflammatory analgesic. Further, in the above Table 7 of writhing test, the pyridine compounds of the present invention showed a similar level of efficacies as that of Celecoxib (100 mg/kg).

[370] [371] Experimental Example 3: Therapeutic Effects in Disease Animals [372] 1) Therapeutic Effect in Animal Model with Behcet Disease [373] The rear side of ICR mice were scarred by scratching with an injection needle and then inoculated with 1.0 x 10⁶ palque-forning units (pfu)/mL of Herpes simplex virus type 1 (F strain). Ten days after the inoculation, the mice were inoculated again in the same manner. Inoculated mice showed symptoms within 3-4 days. Major symptoms selected were oral cavity, progenitalis, skin ulcer and ocular complication, and accidents selected were gastrointestinal tract rating, Behcet arthritis, and neuropathy. Of the above symptoms, when there is an event that at least one major symptom and at least one accident are observed at the same time it was diagnose as 'Behcet disease'. The mice diagnosed as having Behcet disease were subjected to treatment. Simulated gastric fluid was used as a vehicle of a drug. Each test group consisted of 6 mice diagnosed as having Behcet disease. The compounds of Example 4 and BIRB-796 and thalidomide as control group compounds were administered for 5 days and their therapeutic effects were observed. The mice were observed continuously to identify the presence of any symptoms for a period of 8 weeks and the results are shown in the following Table 8. [374] [ Table 8 1

[375] From the above Table 8, it is apparent that the compounds of Example 4 have symptom-improving effect equivalent in level to that of thalidomide while they are superior to that of BIRB-796.

[376] [377] 2) Therapeutic Effects in Animal Model with Asthma [378] Of the compounds of the present invention, the inhibitory effects of compounds in Examples 3 and 4 against the airway inflammation were evaluated by their influence on leukocytosis and eosinophilia to bronchopulmonaries, which are induced when sensitized mice were exposed to antigens, as set forth hereunder and the result is shown in the following Table 9.

[379] Six week old B ALB/c female mice (SLC, JAPAN) were sensitized by in- traperitoneally administering with 0.2 mL of a mixed solution of consisting of 10 m g of ovalbumin and alum at days 0, 7 and 14. Eight and ten days after the sensitization, respectively, 0.7% ovalbumin was prepared into an aerosol by using an highly pressed air and sprayed for 50 minutes to induce airway infection. Twenty four hours after the airway infection, bronchopulmonaries were washed with 1.5 mL of phosphate buffer solution (PBS) and then the washed solution was collected. The number of leukocytosis and eosinophilia present in the above washed solution was counted, respectively. Test compounds were orally administered 3 times 7-10 days after the final sensitization.

[380] [ Table 9 1

[381] As shown in the above Table 9, the compounds of Examples 3 and 4 of the present invention had superior inhibitory effects in asthma model to BIRB-796, a control compound. Further, the compounds of Example 3 of the present invention had a similar level of effect to that of rolipram, a positive control compound.

[382]

[383] 3) Therapeutic Effect on Septic Shock Model

[384] Uninfected male Balb/c mice with body weight of 15-20 g were obtained 1 week prior to the experiment and allowed to adapt to a standard pen at 25 °C .

[385] The endotoxin of E. coli serotype 0111 :B4 ( Sigma , USA ) was mixed with a physiological saline solution by vortexing and prepared into a homogenized solution. The compound of the present invention was orally administered to mice at a concentration of 100 g/kg, and 1 hour after the above administration, the above prepared LPS endotoxin (40 mg/kg) was abdominally injected of the mice. Twenty four hours, forty eight hours and seventy two hours after the endotoxin administration, respectively, the mortality of the mice were observed and the results are shown in the following Table 10.

[386] [ Table 10 1

[387] From the above Table 10, it is apparent that the compounds of the present invention have similar level of effects in septic shock animal model to that of a control compound.

[388]

Industrial Applicability

[389]

[390] From the foregoing, it is evident that the pyridine derivatives of the present invention represented by the above formula 1, have excellent inhibitory effects on the synthesis of cytokines, which are involved in inflammatory reactions, especially the synthesis of TNF- α , IL-I α , IL-6, INF- γ , and PGE Further, the pyridine derivatives of the present invention have superior anti-inflammatory and analgesic effects to Indomethacin or Celecoxib, commercially available anti-inflammatory analgesics.

[391] Therefore, the pyridine derivatives of the present invention represented by the above formula 1 are useful for the treatment of various diseases associated with synthesis of cytokines such as inflammation-related diseases, immune-related diseases, chronic inflammatory diseases and also as an anti-inflammatory analgesic.

Claims

[1] A compound represented by the following formula 1 or its pharmaceutically acceptable salts:

wherein R , R , R , R and R can be independently selected from the group

1 2 3 4 5 consisting of H, halo, cyano, nitro, acyl, hydroxy, amino, C -C low alkyl, C -

1 6 2

C low alkenyl, C -C low alkoxy, C -C alkylthio, C -C alkylamino, C -C

6 ^J \ 6 ^J \ 6 ^J 1 10 "^ ' 4 9 cycloalkylamino, C -C heterocycloalkylamino, arylamino, acylamino, acyloxy,

4 9

C -C alkylsulfinyl, C -C alkylsulfonyl, C -C alkylsulfonylamino, arylsulfinyl, arylsulfonyl, arylsulfonylamino, aryl, heteroaryl, C -C aralkyl, C

- C heteroaralkyl, aryloxy and heteroaryloxy; or they can independently form a ring by binding with a neighboring substitution group;

X is O or S;

Y is O or N-R , wherein R is selected from the group consisting of H, C - C

6 6 1 6 low alkyl, acyl, aryl, heteroaryl, C -C aralkyl and C -C heteroaralkyl; or they can independently form a ring by binding with a neighboring substitution group R₅; said aryl is selected from the group consisting of phenyl, naphthyl and fused phenyl; said heteroaryl is a 5-membered or 6-memebred heterocyclic ring or a fused heterocyclic ring having 1-3 hetero atoms selected from O, N, and S, said aryl and heteroaryl can be substituted with 1-4 substitution groups selected from the group consisting of halo, hydroxy, C -C low alkyl, C -C low alkoxy

1 6 1 6 and amino.

[2] In claim 1, said R R R R and R are selected from the group consisting of H, halo, hydroxy, C -C low alkyl, C -C low alkoxy, aryloxy, amino, C -C

1 6 1 6 1 6 alkylamino, C -C aralkylamino, arylamino, acylamino, aryl, heteroaryl, and C

- C heteroaralkyl; or they can independently form a ring with a neighboring substitution group; said X is O or S; said Y is O or N-R , wherein R is selected from the group consisting of H, C -

6 6 1

C low alkyl, aryl, heteroaryl, C -C aralkyl, and C -C heteroaralkyl; said aryl is phenyl; said heteroaryl is selected from the group consisting of furan, thiophene, pyridine, piperidine, piperazine, morpholine, pyrrolidine, and benzodioxol; said aryl and heteroaryl are aryl or heteroaryl substituted with 1-4 substitution groups selected from the group consisting of halo, hydroxy, C - C low alkyl, C

1 6 1

- C low alkoxy, and amino.

6

[3] In claim 1, the compounds represented by the formula 1 is selected from the group consisting of: 2H- [2,7]naphthyridine- 1 -one, 2-benzyl-2H- [2,7]naphthyridine- 1 -one, 8-methyl-6-phenyl-2H-[2,7]naphthyridine-l-one, 2,8-dimethyl-6-phenyl-2H- [2,7]naphthyridine- 1 -one, 2-ethyl-8-methyl-6-phenyl-2H-[2,7]naphthyridine-l-one, 2-benzyl-8-methyl-6-phenyl-2H- [2,7]naphthyridine- 1 -one, 2-(3,5-difluoro-phenyl)-8-methyl-6-phenyl-2H-[2,7]naphthyridine-l-one, 2-(3,4-dimethoxy-phenyl)-8-methyl-6-phenyl-2H-[2,7]naphthyridine-l-one, 2-(4-fluoro-phenyl)-8-methyl-6-phenyl-2H- [2,7]naphthyridine- 1 -one, 2-(3,5-dichloro-phenyl)-8-methyl-6-phenyl-2H-[2,7]naphthyridine-l-one, 8-(4-fluoro-phenyl)-6-methyl-2H- [2,7]naphthyridine- 1 -one, 8-(4-fluoro-phenyl)-2,6-dimethyl-2H- [2,7]naphthyridine- 1 -one, 2-ethyl-8-(4-fluoro-phenyl)-6-methyl-2H- [2,7]naphthyridine- 1 -one, 2-(3,5-difluoro-phenyl)-8-(4-fluoro-phenyl)-6-methyl-2 H-[2,7] naphthyridine- 1-one,

2-(3,4-dimethoxy-phenyl)-8-(4-fluoro-phenyl)-6-methyl-2 H-[2,7] naphthyridine- 1-one,

6-(4-fluoro-phenyl)-8-methyl-2H- [2,7]naphthyridine- 1 -one, 6-(4-fluoro-phenyl)-2,8-dimethyl-2H- [2,7]naphthyridine- 1 -one, 2-ethyl-6-(4-fluoro-phenyl)-8-methyl-2H- [2,7]naphthyridine- 1 -one, 2-(3,5-difluoro-phenyl)-6-(4-fluoro-phenyl)-8-methyl-2 H-[2,7] naphthyridine- 1-one,

2-(3,4-dimethoxy-phenyl)-6-(4-fluoro-phenyl)-8-methyl-2 H-[2,7] naphthyridine- 1-one,

2-(4-fluoro-phenyl)-6-(4-fluoro-phenyl)-8-methyl-2H-[2,7]naphthyridine-l-one, 2-(3,5-dichloro-phenyl)-6-(4-fluoro-phenyl)-8-methyl-2 H-[2,7] naphthyridine- 1-one,

6-(3,4-difluoro-phenyl)-8-methyl-2H- [2,7]naphthyridine- 1 -one, 6-(3,4-difluoro-phenyl)-2,8-dimethyl-2H-[2,7]naphthyridine-l-one, 2-ethyl-6-(3,4-difluoro-phenyl)-8-methyl-2H-[2,7]naphthyridine-l-one, 2-(3,5-difluoro-phenyl)-6-(3,4-difluoro-phenyl)-8-methyl-2 H-[2,7] naph- thyridine-1-one,

2-(3,4-dimethoxy-phenyl)-6-(3,4-difluoro-phenyl)-8-methyl-2 H-[2,7] naph- thyridine-1-one,

2-(4-fluoro-phenyl)-6-(3,4-difluoro-phenyl)-8-methyl-2 H-[2,7] naphthyridine- 1-one,

2-(3,5-dichloro-phenyl)-6-(3,4-difluoro-phenyl)-8-methyl-2 H-[2,7] naph- thyridine-1-one,

6-ethyl-8-piperidin- 1 -yl-2H- [2,7]naphthyridine- 1 -one, 6-ethyl-2-methyl-8-piperidin- 1 -yl-2H- [2,7]naphthyridine- 1 -one, 2,6-diethyl-8-piperidin- 1 -yl-2H- [2,7]naphthyridine- 1 -one, 6-isopropyl-8-piperidin- 1 -yl-2H- [2,7]naphthyridine- 1 -one, 6-isopropyl-2-methyl-8-piperidin- 1 -yl-2H- [2,7]naphthyridine- 1 -one, 2-ethyl-6-isopropyl-8-piperidin- 1 -yl-2H- [2,7]naphthyridine- 1 -one, 6-isopropyl-2-methoxymethyl-8-piperidin- 1 -yl-2H-[2,7]naphthyridine- 1 -one, 6-isopropyl-2-(2-methoxy-ethyl)-8-piperidin- 1 -yl-2H- [2,7]naphthyridine- 1 -one, 2-(4-fluoro-phenyl)-6-isopropyl-8-piperidin- 1 -yl-2H-[2,7]naphthyridine- 1 -one, 2-(3,4-dimethoxy-phenyl)-6-isopropyl-8-piperidin-l-yl-2 H-[2,7] naphthyridine- 1-one,

6-tert-butyl-8-piperidin- 1 -yl-2H- [2,7]naphthyridine- 1 -one, 6-tert-butyl-2-methyl-8-piperidin- 1 -yl-2H-[2,7]naphthyridine- 1 -one, 6-tert-butyl-2-ethyl-8-piperidin- 1 -yl-2H- [2,7]naphthyridine- 1 -one, 6-tert-butyl-2-(4-fluoro-phenyl)-8-piperidin- 1 -yl-2 H- [2,7]naphthyridine- 1 -one, 6-tert-butyl-2-(3,4-dimethoxy-phenyl)-8-piperidin-l-yl-2 H-[2,7] naphthyridine- 1-one,

8-(4-fluoro-phenyl)-6-methyl- 1 -oxo-liH- [2,7]naphthyridine-2-2-carboxylic acid methyl ester,

8-(4-fluoro-phenyl)-6-methyl- 1 -oxo-liH- [2,7]naphthyridine-2-carboxylic acid, 3-[8-(4-fluoro-phenyl)-6-methyl-l-oxo-liH-[2,7]naphthyridine-2-yl]-propionic acid methyl ester,

3-(4-methoxy-phenyl)-6, 8-dimethyl-pyrano [3 ,4-c]pyridin- 1 -one, 3-(4-hydroxy-phenyl)-6,8-dimethyl-pyrano[3,4-c]pyridin-l-one, 3-(3-methonapxy-phenyl)-6,8-dimethyl-pyrano[3,4-c]pyridin-l-one, S-CS-hydroxy-phenyty-όjS-dimethyl-pyranoP^-clpyridin-l-one and their pharmaceutically acceptable salts. [4] A pharmaceutical composition comprising a compound represented by the following formula 1 or its pharmaceutically acceptable salt having an inhibitory effect on cytokine synthesis

wherein R , R , R , R , R , X and Y are same as defined in claim 1.

1 2 3 4 5

[5] In claim 4, said cytokine is TNF- α .

[6] A therapeutic agent for treatment of inflammation-related diseases comprising a compound represented by the following formula 1 or its pharmaceutically acceptable salt:

wherein R , R , R , R , R , X and Y are same as defined in claim 1.

1 2 3 4 5

[7] In claim 6, said inflammation-related diseases are selected from the group consisting of rheumatic arthritis, multiple sclerosis, Crohn's disease, ulcerative colitis, Graft-versus-Host disease, systemic lupus erythematosus, toxic shock syndrome, acute renal failure, osteoarthritis and insulin-dependent diabetes.

[8] An anti-inflammatory and analgesic agent comprising a compound represented by the following formula 1 or its pharmaceutically acceptable salt:

wherein R , R , R , R , R , X and Y are same as defined in claim 1.

1 2 3 4 5

[9] A therapeutic agent for treatment of immune-related diseases comprising a compound represented by the following formula 1 or its pharmaceutically acceptable salt:

wherein R , R , R , R , R , X and Y are same as defined in claim 1.

1 2 3 4 5

[10] In claim 9, said immune-related diseases are selected from the group consisting of glomerulonephritis, dermatitis, asthma, stroke, myocardial infarction, acute respiratory syndrome, trauma concomitant multiple injuries of organs, purulent meningitis, necrotizing enterocolitis, hemodialysis concomitant syndrome, Septic shock, and postmenopausal osteoporosis.

[H] A therapeutic agent for treatment of chronic inflammatory diseases comprising a compound represented by the following formula 1 or its pharmaceutically acceptable salt:

wherein R , R , R , R , R , X and Y are same as defined in claim 1.

1 2 3 4 5

[12] In claim 11, said chronic inflammatory diseases are selected from the group consisting of Psoriatic arthritis, Psoriasis, Ankylosing Spondylitis, Adult-onset Still's Disease, Sjogren's syndrome, Polymyositis, Dermatomyositis, and vasculitis comprising atherosclerosis, Behcet Disease and Wegener's Granulomatosis.