Triazolopyrimidinone or triazolopyridinone derivatives, and use thereof

Abstract

The present invention relates to a novel triazolopyrimidinone or triazolopyridinone derivative, a tautomer thereof, a stereoisomer thereof and their mixture, or a pharmaceutically acceptable salt thereof; and a pharmaceutical composition for preventing or treating a tankyrase-related disease, which contains the same as an active ingredient.

Claims

1. A compound represented by Chemical Formula 1, a tautomer thereof, a stereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: ##STR00077## wherein V is N or CH; R.sub.1 is hydrogen, or C.sub.1-6 alkyl; W is CH.sub.2; X is CHR.sub.4; Y is N or C; is a single bond or a double bond, determined by X and Y; l is 1; R.sub.2 is none, hydrogen, or hydroxyl; R.sub.3 is ##STR00078## or heteroaryl; R.sub.4 is none, or hydrogen; m is 0, or 1; n is 0, 1, 2, or 3; each of R.sub.5 is independently halo, C.sub.2-6 alkenyl, C.sub.1-6 hydroxyalkyl, or Z(CH.sub.2).sub.pR.sub.6; p is 0, 1, 2, 3, 4, 5 or 6; Z is O, or none; R.sub.6 is hydroxyl, C.sub.1-6 alkoxy, C.sub.1-3 alkoxy-C.sub.1-3 alkyl, C.sub.5-10 aryl, carboxy, C.sub.1-6 dihydroxyalkyl, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl optionally substituted with hydroxy, heterocyclyl, heteroaryl, O(CO)R.sub.8, (CO)R.sub.8, OR.sub.8, COOR.sub.8, or NR.sub.9R.sub.10; R.sub.8 is hydrogen, C.sub.1-6 alkyl, C.sub.1-6 aminoalkyl, or heterocyclyl; each of R.sub.9 and R.sub.10 is independently hydrogen, C.sub.1-6 alkyl, or C.sub.1-3 alkoxy-C.sub.1-3 alkyl; each of the heteroaryls is a 5- to 10-membered single ring containing one or more nitrogen atom, and each of the heterocyclyls may be a 3- to 10-membered single ring containing one or more heteroatom selected from the group consisting of N, O, and a combination thereof; each of the heterocyclyls may optionally be substituted with one to three substituents selected from the group consisting of C.sub.1-6 alkyl, hydroxyl, and oxo, or amino; and each of the aryls and heteroaryls may optionally be substituted with one to three C.sub.1-6 alkyl.

2. The compound according to claim 1, wherein m is 0; and n is 1, 2 or 3, or a tautomer thereof, a stereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1, wherein m is 0; n is 1, 2 or 3; each of R.sub.5 is independently fluoro, hydroxyethyl, or Z(CH.sub.2).sub.pR.sub.6; Z is O, or none; R.sub.6 is hydroxyl, methoxy, ethoxy, methoxyethyl, C.sub.5-10 aryl, carboxy, 1,2-dihydroxyethyl, 1-chloro-3-hydroxyisopropyl, perfluoromethyl, heterocyclyl, heteroaryl, O(CO)R.sub.8, (CO)R.sub.8, or NR.sub.9R.sub.10; R.sub.8 is hydrogen, methyl, or aminoethyl; each of R.sub.9 and R.sub.10 is independently hydrogen, methyl, ethyl or methoxyethyl; each of the heteroaryls may be a 5- to 10-membered single ring containing one or more nitrogen atom, and each of the heterocyclyls may be a 3- to 10-membered single ring containing one or more heteroatom selected from the group consisting of N, O, and a combination thereof; each of the heterocyclyls may optionally be substituted with one to three substituents selected from the group consisting of methyl, hydroxyl, amino and oxo; and each of the heteroaryls may optionally be substituted with one to three methyl, or a tautomer thereof, a stereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 3, wherein each of the aryls is phenyl or naphthyl; each of the heteroaryls may be selected from the group consisting of tetrazolyl, imidazolyl, pyridinyl, pyridazinyl, pyrimidyl, triazinyl, pyrrolyl, pyrazolyl, triazolyl, or pyrazinyl; and each of the heterocyclyls may be selected from the group consisting of tetrahydropyranyl, tetrahydrofuranyl, dihydrofuranyl, dihydropyranyl, dioxanyl, dioxolanyl, imidazolidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxopiperidinyl, oxopyrrolidinyl and oxooxazolidinyl, or a tautomer thereof, a stereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 4, wherein each of the aryls is phenyl; each of the heteroaryls is tetrazolyl or imidazolyl; and each of the heterocyclyls is tetrahydrofuranyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl, or a tautomer thereof, a stereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 5, wherein each of the heterocyclyls is tetrahydrofuranyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, 4-methylpiperazinyl, 4-methyl-2-oxopiperazinyl, 3-hydroxypyrrolidinyl, 2-hydroxymethylpyrrolidinyl, N-methylpyrrolidinyl, 4-hydroxypiperidinyl, 4-hydroxy-4-methylpiperidinyl, 4-aminopiperidinyl, 2-oxopiperidinyl, or 2,6-dimethylpiperidinyl, or a tautomer thereof, a stereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 1, wherein the compound is selected from a group consisting of 1) 5-(4-(2-fluorophenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one, 2) 5-(4-(2,6-difluoro-4-(2-methoxyethoxy)phenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one, 3) 5-(4-(4-(benzyloxy)-2,6-difluorophenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one, 4) 5-(4-(2,6-difluoro-4-(2-morpholinoethoxy)phenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one, 5) 5-(4-(2,6-difluoro-4-(2-(piperidin-1-yl)ethoxy)phenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one, 6) 5-(4-(4-(2-(dimethylamino)ethoxy)-2,6-difluorophenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one, 7) 5-(4-(2,6-difluoro-4-(2-hydroxyethoxy)phenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one, 8) 2-(3,5-difluoro-4-(4-(3-methyl-7-oxo-6,7-dihydro-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)piperazin-1-yl)phenoxy)ethyl acetate, 9) 5-(4-(2,6-difluoro-4-isopropoxyphenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one, 10) (R)-2-(3,5-difluoro-4-(4-(3-methyl-7-oxo-6,7-dihydro-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)piperazin-1-yl)phenoxy)ethoxy)-1-oxopropan-2-aminium chloride, 11) (S)-2-(3,5-difluoro-4-(4-(3-methyl-7-oxo-6,7-dihydro-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)piperazin-1-yl)phenoxy)ethoxy)-1-oxopropan-2-aminium chloride, 12) 5-(4-(4-(2,3-dihydroxypropoxy)-2,6-difluorophenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one, 13) 5-(4-(2,6-difluoro-4-(morpholinomethyl)phenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one, 14) 5-(4-(2,6-difluoro-4-((4-methylpiperazin-1-yl)methyl)phenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one, 15) 5-(4-(2,6-difluoro-4-(oxetan-3-yloxy)phenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one, 16) 5-(4-(4-(1-chloro-3-hydroxypropan-2-yloxy)-2,6-difluorophenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one, 17) 5-(4-(2,6-difluoro-4-(1-hydroxyethyl)phenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one, 18) 5-(4-(2,6-difluoro-4-(1-methoxyethyl)phenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one, 19) 6-(3,5-difluoro-4-(4-(3-methyl-7-oxo-6,7-dihydro-3H-[1,2,3]triazo[4,5-d]pyrimidin-5-yl)piperazin-1-yl)phenoxy)hexanoic acid, 20) 5-(4-(2,6-difluoro-4-(((2-methoxyethyl)(methyl)amino)methyl)phenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one, 21) 5-(4-(2,6-difluorophenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one, 22) 3-methyl-5-(4-(2,4,6-trifluorophenyl)piperazin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one, 23) 5-(4-(4-(1,2-dihydroxyethyl)-2,6-difluorophenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one, 24) 5-(4-(4-(2,3-dihydroxypropyl)-2,6-difluorophenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one, 25) 5-(4-(2,6-difluoro-4-(2-methoxyethoxy)phenyl)-4-hydroxypiperidin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one, 26) 5-(4-(1H-tetrazol-5-yl)piperidin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one, 27) 5-(4-(2,6-difluoro-4-(2-methoxyethylamino)phenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one, 28) 5-(4-(2,6-difluoro-4-vinylphenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one, 29) 3-methyl-5-(4-(1-methyl-1H-tetrazol-5-yl)piperidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one, 30) 3-methyl-5-(4-(2-methyl-2H-tetrazol-5-yl)piperidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one, 31) 5-(4-(2,6-difluoro-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one, 32) 5-(4-(2,6-difluoro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl) piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one, 33) 5-(4-(2,6-difluoro-4-(3-(piperidin-1-yl)propoxy)phenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one, 34) 5-(4-(4-(bis(2-methoxyethyl)amino)-2,6-difluorophenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one, 35) 5-(4-(2,6-difluoro-4-(2-oxo-2-(piperidin-1-yl)ethoxy)phenyl) piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one, 36) 5-(4-(2,6-difluoro-4-(2-oxo-2-(pyrrolidin-1-yl)ethoxy)phenyl) piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one, 37) 5-(4-(4-(2-aminoethoxy)-2,6-difluorophenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one, 38) 5-(4-(2,6-difluoro-4-(2-(4-methyl-2-oxopiperazin-1-yl) ethoxy)phenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one, 39) 5-(4-(4-(2-(4-aminopiperidin-1-yl)ethoxy)-2,6-difluoro phenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one, 40) 5-(4-(2,6-difluoro-4-(3-methoxypropyl)phenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one, 41) 5-(4-(2,6-difluoro-4-(2-(3-hydroxypyrrolidin-1-yl) ethoxy)phenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one, 42) 5-(4-(2,6-difluoro-4-(2-(4-hydroxypiperidin-1-yl)ethoxy) phenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one, 43) 5-(4-(2,6-difluoro-4-(2-(4-hydroxy-4-methylpiperidin-1-yl)ethoxy)phenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one, 44) 5-(4-(2,6-difluoro-4-(2-methoxyethoxy)phenyl)-5,6-dihydropyridin-1(2H)-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one, 45) 5-(4-(2,6-difluoro-4-(2-methoxyethoxy)phenyl)piperidin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one, 46) 5-(4-(2,6-difluoro-4-(2-(2-oxopiperidin-1-yl)ethoxy)phenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one, 47) 5-(4-(4-(2-ethoxyethoxy)-2,6-difluorophenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one, 48) 5-(4-(4-(2-(cis-2,6-dimethylpiperidin-1-yl)ethoxy)-2,6-difluorophenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one, 49) 5-(4-(4-(2-(4,4-difluoropiperidin-1-yl)ethoxy)-2,6-difluorophenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one, 50) 5-(4-(4-(2-(diethylamino)ethoxy)-2,6-difluorophenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one, 51) 5-(4-(4-(2-(1H-imidazol-1-yl)ethoxy)-2,6-difluorophenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one, 52) 5-(4-(2,6-difluoro-4-((tetrahydrofuran-2-yl)methoxy)phenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one, 53) 6-(4-(2,6-difluoro-4-(2-methoxyethoxy)phenyl)piperazin-1-yl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-4(5H)-one, 54) 6-(4-(2,6-difluoro-4-(2-morpholinoethoxy)phenyl)piperazin-1-yl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-4(5H)-one, 55) 6-(4-(2,6-difluoro-4-(2-(piperidin-1-yl)ethoxy)phenyl)piperazin-1-yl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-4(5H)-one, 56) 6-(4-(4-(2-(dimethylamino)ethoxy)-2,6-difluorophenyl)piperazin-1-yl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-4(5H)-one, 57) 6-(4-(2,6-difluoro-4-(2-hydroxyethoxy)phenyl)piperazin-1-yl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-4(5H)-one, 58) (S)-2-(3,5-difluoro-4-(4-(1-methyl-4-oxo-4,5-dihydro-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)piperazin-1-yl)phenoxy)ethyl2-aminopropanoate hydrochloride, 59) 6-(4-(4-(2,3-dihydroxypropoxy)-2,6-difluorophenyl)piperazin-1-yl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-4(5H)-one, 60) 6-(4-(2,6-difluoro-4-(morpholinomethyl)phenyl)piperazin-1-yl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-4(5H)-one, 61) 6-(4-(2,6-difluoro-4-((4-methylpiperazin-1-yl)methyl)phenyl) piperazin-1-yl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-4(5H)-one, 62) 6-(4-(2,6-difluoro-4-(oxetan-3-yloxy)phenyl)piperazin-1-yl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-4(5H)-one, 63) 6-(4-(2,6-difluoro-4-(1-hydroxyethyl)phenyl)piperazin-1-yl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-4(5H)-one, 64) 6-(4-(2,6-difluoro-4-(1-methoxyethyl)phenyl)piperazin-1-yl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-4(5H)-one, 65) 6-(4-(2,6-difluoro-4-(((2-methoxy ethyl)(methyl)amino)methyl)phenyl)piperazin-1-yl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-4(5H)-one, 66) 1-methyl-6-(4-(2-methyl-2H-tetrazol-5-yl)piperidin-1-yl)-1H-[1,2,3]triazolo[4,5-c]pyridin-4(5H)-one, 67) 6-(4-(2,6-difluoro-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)piperazin-1-yl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-4(5H)-one, 68) 6-(4-(2,6-difluoro-4-(2-(4-methylpiperazin-1-yl) ethoxy)phenyl)piperazin-1-yl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-4(5H)-one, 69) 6-(4-(2,6-difluoro-4-(3-(piperidin-1-yl)propoxy)phenyl)piperazin-1-yl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-4(5H)-one, 70) 6-(4-(2,6-difluoro-4-(2-oxo-2-(pyrrolidin-1-yl)ethoxy) phenyl)piperazin-1-yl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-4(5H)-one, 71) 6-(4-(4-(2-aminoethoxy)-2,6-difluorophenyl)piperazin-1-yl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-4(5H)-one, 72) 6-(4-(4-(2-(4-aminopiperidin-1-yl)ethoxy)-2,6-difluoro phenyl)piperazin-1-yl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-4(5H)-one, and 73) 5-(4-(2,6-difluoro-4-(2-methoxyethoxy)phenyl)piperazin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one, or a tautomer thereof, a stereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising the compound according to claim 1, or a tautomer thereof, a stereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof as an active ingredient, together with at least one pharmaceutically acceptable carrier, diluent, or excipient.

Description

BEST MODE FOR CARRYING OUT THE INVENTION

(1) Hereinafter, the constitution and effect of the present invention will be described in more detail through Examples. However, the following Examples are for illustrative purposes only and the scope of the present invention is not limited by the examples.

Preparation Example 1: 7-Isopropoxy-3-methyl-5-(methylsulfonyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (I-7)

(2) 7-Isopropoxy-3-methyl-5-(methylsulfonyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (I-7) was prepared as an intermediate for synthesis of triazolopyrimidinone derivatives based on the following reaction scheme.

(3) ##STR00010##

1.1. 6-(Methylamino)-2-(methylthio)pyrimidin-4(3H)-one (I-2)

(4) A mixture of 6-amino-thiouracil (10 g, 62 mmol) and methylamine HCl (5 g) in N-methylformamide (40 mL) was heated to reflux for 4 h. After the reaction was completed, the mixture was allowed to cool down to rt and stirred for 0.5 h. Then, water was added, and the precipitate was filtered, washed with water, and dried to afford the N-methyl compound I-1 (5.3 g) as a yellow solid. To a solution of the yellow solid I-1 (5.3 g) and KOH (4.18 g, 74.450 mmol) in water (100 mL) was added dropwise dimethyl sulfate (5.87 mL) at 0 C. over 1 h. After stirring at rt for 16 h, the precipitate was filtered, washed with water, and dried. The residue was purified by column chromatography to afford the desired product I-2 (5.3 g) as a yellow solid.

(5) GC-MS (EI, m/z)=171 (M.sup.+).

1.2. 6-(Methylamino)-2-(methylthio)-5-nitrosopyrimidin-4(3H)-one (I-3)

(6) To a solution of the compound I-2 (5.3 g, 30.954 mmol) in a mixture of water (90 mL) and AcOH (9 mL) was added dropwise a solution of NaNO.sub.2 (5.34 g, 77.385 mmol) in water (25 mL) at 0 C. over 2 h. After stirring at rt for 22 h, the precipitate was filtered, washed with water, and dried to afford the desired product I-3 (5.2 g) as a blue solid.

(7) GC-MS (EI, m/z)=200 (M.sup.+).

1.3. 3-Methyl-5-(methylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one (I-5)

(8) To a preheated (75 C. to 80 C.) 20% S(NH.sub.4).sub.2 in water (110 mL) was added portionwise the compound I-3 (5.2 g, 25.971 mmol) over 1 h. The reaction mixture was heated to reflux for 1 h. The reaction mixture was allowed to cool down to rt, and the precipitate was filtered, washed with MeOH, and dried to afford the intermediate 1-4 as a yellow solid. To a solution of the intermediate 1-4 in 1 N HCl (120 mL) was added dropwise a solution of NaNO.sub.2 (3.05 g, 44.151 mmol) in water (30 mL) at 0 C. over 2 h. After stirring at rt for 3 h, the reaction mixture was filtered to provide the desired product I-5 (4.356 g) as a yellow solid.

(9) GC-MS (EI, m/z)=197 (M.sup.+).

1.4. 7-isopropoxy-3-methyl-5-(methylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (I-6)

(10) A mixture of the compound I-5 (4.356 g, 22.087 mmol), CsF (13.42 g, 88.348 mmol) and 2-iodopropane (6.62 mL, 66.261 mmol) in DMF (50 mL) was heated to 70 C. to 80 C. for 3 h. After cooling down to rt, the mixture was diluted with EtOAc and washed with water. The organic layer was dried over Na.sub.2SO.sub.4, concentrated under reduced pressure, and the residue was purified by column chromatography to afford the desired product I-6 (2.82 g) as a yellow solid.

(11) GC-MS (EI, m/z)=239 (M.sup.+).

1.5. 7-Isopropoxy-3-methyl-5-(methylsulfonyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (I-7)

(12) To a solution of the compound I-6 (2.82 g, 11.784 mmol) in CH.sub.2Cl.sub.2 (35 mL) was added portionwise mCPBA (6.1 g, 35.3 mmol) at 0 C. The reaction mixture was stirred at rt for 4 h, concentrated under reduced pressure. The residue was diluted with EtOAc, washed with saturated NaHCO.sub.3. The organic layer was dried over Na.sub.2SO.sub.4, concentrated under reduced pressure. The residue was diluted with ether and the precipitate was filtered to afford the desired product (2.76 g) as a white solid.

(13) GC-MS (EI, m/z)=271 (M.sup.+).

Preparation Example 2: 3-Methyl-5-(methylsulfonyl)-3,6-dihydro-7H-[1,2,3]triazolo[4,5-d]pyrimidin-7-one (I-7)

(14) To a solution of the compound I-5 in water was added Oxone at rt. After stirring at rt for 3 h, the reaction mixture was diluted with EtOAc and washed with saturated NaHCO.sub.3. The organic layer was dried over Na.sub.2SO.sub.4, concentrated under reduced pressure, the residue was diluted with ether and filtered to afford the desired product as a white solid.

(15) LC-MS (ESI, m/z)=230.2 (M+H.sup.+).

Preparation Example 3: 1-(2,6-Difluoro-4-substituted-phenyl)piperazine hydrochloride (I-3A through I-3E), 4-(2-(3,5-difluoro-4-(piperazin-1-yl)phenoxy)ethyl)morpholine hydrochloride (I-3F) and 2-(3,5-difluoro-4-(piperazin-1-yl)phenoxy)-N,N-dimethylethan-1-amine hydrochloride (I-3G)

(16) ##STR00011##

3.1. 5-(Benzyloxy)-2-bromo-1,3-difluorobenzene

(17) A mixture of 4-bromo-3,5-difluorophenol (7 g, 33.49 mmol), benzyl bromide (4.0 mL, 40.18 mmol) and K.sub.2CO.sub.3 (13.8 g, 100.47 mmol) in DMF (83 mL) was heated at 50 C. to 60 C. under microwave heating condition for 14 h. After cooling down to rt, the reaction mixture was diluted with EtOAc and washed with water. The organic layer was dried over Na.sub.2SO.sub.4, and concentrated under reduced pressure to afford the desired product (9.6 g) as a yellow oil.

(18) LC-MS (ESI, m/z)=299.0 (M+H.sup.+).

3.2. tert-Butyl 4-(4-(benzyloxy)-2,6-difluorophenyl)piperazine-1-carboxylate

(19) A mixture of the compound (1 g, 3.34 mmol) obtained in Preparation Example 3.1 Boc-piperazine (1.49 g, 8.02 mmol), sodium tert-butoxide (898 mg, 9.352 mmol), BINAP (249 mg, 0.4 mmol) and Pd.sub.2(dba).sub.3 (122 mg, 0.133 mmol) in toluene (10 mL) was heated at 130 C. under microwave heating condition for 20 min. After cooling down to rt, the mixture was concentrated under reduced pressure and the residue was purified by column chromatography to afford the desired product (459 mg) as a pink solid.

(20) LC-MS (ESI, m/z)=405.2 (M+H.sup.+).

3.3. tert-Butyl 4-(2,6-difluoro-4-hydroxyphenyl)piperazine-1-carboxylate

(21) To a solution of the compound (200 mg, 0.917 mmol) obtained in Preparation Example 3.2 in MeOH (2.5 mL) was added 10% Pd/C. After stirring at rt for 3 h under hydrogen gas, the reaction mixture was filtered through a Celite pad. The filtrate was concentrated under reduced pressure to afford the desired product (154 mg, 0.489 mmol, 98%) as a white solid.

3.4. tert-Butyl 4-(2,6-difluoro-4-(2-(piperidin-1-yl)ethoxy)phenyl)piperazine-1-carboxylate

(22) A mixture of the phenolic compound (300 mg, 0.954 mmol), 1-(2-chloroethyl)piperidine hydrochloride (211 mg, 1.145 mmol), and K.sub.2CO.sub.3 (527 mg, 3.816 mmol) in DMF (3.0 mL) was heated to 50 C. to 60 C. for 17 h. After cooling down to rt, the mixture was diluted with EtOAc and washed with water. The organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford the desired product (390 mg, 0.917 mmol, yield 96%) as a white solid.

(23) LC-MS (ESI, m/z)=426.2 (M+H.sup.+).

3.5. 1-(2,6-Difluoro-4-(2-(piperidin-1-yl)ethoxy)phenyl)piperazine dihydrochloride

(24) To a solution of the compound (390 mg, 0.917 mmol) obtained in Preparation Example 3.4 in CH.sub.2Cl.sub.2 (1 mL) and MeOH (0.5 mL) was added 4 M HCl (3 mL). After stirring at rt for 4 h, the reaction mixture was concentrated under reduced pressure to afford the desired product I-3B (390 mg) as a white solid.

(25) LC-MS (ESI, m/z)=326.2 (M+H.sup.+).

3.6. 1-(2,6-Difluoro-4-(2-eee(methoxyethoxy)phenyl)piperazine hydrochloride

(26) The compound I-3A was prepared by the following sequence of reactions: O-alkylation used in Preparation Example 3.1 N-arylation used in Preparation Example 3.2 and Boc-group deprotection used in Preparation Example 3.5.

(27) LC-MS (ESI, m/z)=273.2 (M+H.sup.+).

(28) In an analogous manner the following compounds synthesized following the above procedure (Preparation Example 3.4 and 3.5):

3.7. 1-(2,6-Difluoro-4-isopropoxyphenyl)piperazine hydrochloride

(29) From tert-butyl 4-(2,6-difluoro-4-hydroxyphenyl)piperazine-1-carboxylate and 2-iodopropane: 1-(2,6-difluoro-4-isopropoxyphenyl)piperazine hydrochloride was obtained (I-3C).

(30) LC-MS (ESI, m/z)=257.3 (M+H.sup.+).

3.8. 1-(2,6-Difluoro-4-(oxetan-3-yloxy)phenyl)piperazine hydrochloride

(31) From tert-butyl 4-(2,6-difluoro-4-hydroxyphenyl)piperazine-1-carboxylate and oxetan-3-yl 4-methylbenzenesulfonate: 1-(2,6-difluoro-4-(oxetan-3-yloxy)phenyl)piperazine hydrochloride was obtained (I-3D).

(32) LC-MS (ESI, m/z)=271.3 (M+H.sup.+).

3.9. 1-(4-(Benzyloxy)-2,6-difluorophenyl)piperazine hydrochloride

(33) From tert-butyl 4-(2,6-difluoro-4-hydroxyphenyl)piperazine-1-carboxylate and (bromomethyl)benzene: 1-(4-(benzyloxy)-2,6-difluorophenyl)piperazine hydrochloride was obtained (I-3E).

(34) LC-MS (ESI, m/z)=305.3 (M+H.sup.+).

3.10. 4-(2-(3,5-Difluoro-4-(piperazin-1-yl)phenoxy)ethyl)morpholine dihydrochloride

(35) From tert-butyl 4-(2,6-difluoro-4-hydroxyphenyl)piperazine-1-carboxylate and 4-(2-chloroethyl)morpholine hydrochloride: 4-(2-(3,5-difluoro-4-(piperazin-1-yl)phenoxy)ethyl)morpholine dihydrochloride was obtained (I-3F).

(36) LC-MS (ESI, m/z)=328.4 (M+H.sup.+).

3.11. 2-(3,5-Difluoro-4-(piperazin-1-yl)phenoxy)-N,N-dimethylethan-1-amine dihydrochloride

(37) From tert-butyl 4-(2,6-difluoro-4-hydroxyphenyl)piperazine-1-carboxylate and 2-chloro-N,N-dimethylethanamine hydrochloride: 2-(3,5-difluoro-4-(piperazin-1-yl)phenoxy)-N,N-dimethylethan-1-amine dihydrochloride was obtained (I-3G).

(38) LC-MS (ESI, m/z)=286.3 (M+H.sup.+).

Preparation Example 4: 4-(3,5-Difluoro-4-(piperazin-1-yl)benzyl)morpholine dihydrochloride

4.1. tert-Butyl 4-(2,6-difluoro-4-formylphenyl)piperazine-1-carboxylate

(39) A mixture of 3,4,5-trifluorobenzaldehyde (2 g, 12.493 mmol), Boc-piperazine (2.33 g, 12.493 mmol) and K.sub.2CO.sub.3 (3.45 g, 24.986 mmol) in DMF (4 mL) was heated to 110 C. to 120 C. for 18 h. After cooling down to rt, the mixture was diluted with EtOAc and washed with water. The organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified by column chromatography to afford the desired product (2.7 g) as a yellow solid.

(40) LC-MS (ESI, m/z)=327.1 (M+H.sup.+).

4.2. tert-Butyl 4-(2,6-difluoro-4-(morpholinomethyl)phenyl)piperazine-1-carboxylate

(41) A mixture of the compound (500 mg, 1.532 mmol) obtained in Preparation Example 4.1 morpholine (0.27 mL, 3.064 mmol), and Ti(OiPr).sub.4 (0.91 mL, 3.064 mmol) in MeOH (5 mL) was stirred at rt for 17 h. NaCNBH.sub.3 (193 mg, 3.064 mmol) was added to the reaction mixture at 0 C. After stirring at rt for 3 h, the mixture was concentrated under reduced pressure, and the residue was diluted with EtOAc and filtered through a Celite pad. The organic layer was washed with water, dried over Na.sub.2SO.sub.4, and concentrated under reduced pressure. The residue was purified by column chromatography to afford the desired product (272 mg) as a yellow oil.

(42) LC-MS (ESI, m/z)=398.2 (M+H.sup.+).

4.3. 4-(3,5-Difluoro-4-(piperazin-1-yl)benzyl)morpholine dihydrochloride

(43) Using the compound obtained in Preparation Example 4.2 the desired product was prepared by following a similar method to that described in Preparation Example 3.5.

(44) LC-MS (ESI, m/z)=298.1 (M+H.sup.+).

Preparation Example 5: 1-(3,5-Difluoro-4-(piperazin-1-yl)phenyl)ethanol hydrochloride

5.1. tert-Butyl 4-(2,6-difluoro-4-(1-hydroxyethyl)phenyl)piperazine-1-carboxylate

(45) To a solution of the compound (600 mg, 1.839 mmol) obtained in Preparation Example 4.1 in THF (5 mL) was added dropwise 1.6 M MeLi in diethyl ether (1.26 mL, 2.023 mmol) at 78 C. for 2 h. The reaction mixture was slowly warmed to rt. After the reaction mixture was quenched with a few drops of water and concentrated under reduced pressure. The residue was diluted with EtOAc and washed with water. The organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure, and the residue was purified by column chromatography to afford the desired product (503 mg) as a yellow solid.

(46) LC-MS (ESI, m/z)=342.2 (M+H.sup.+).

5.2. 1-(3,5-Difluoro-4-(piperazin-1-yl)phenyl)ethanol hydrochloride

(47) The compound (250 mg, 0.730 mmol) obtained in Preparation Example 5.1 was deprotected by 4 M HCl (4 mL) by following a similar method to that described in Preparation Example 3.5 to afford the desired product (226 mg, quant) as a yellow solid.

(48) LC-MS (ESI, m/z)=243.1 (M+H.sup.+).

Preparation Example 6: 1-(2,6-Difluoro-4-(1-methoxyethyl)phenyl)piperazine hydrochloride

6.1. tert-Butyl 4-(2,6-difluoro-4-(1-methoxyethyl)phenyl)piperazine-1-carboxylate

(49) To a solution of the compound (250 mg, 0.730 mmol) obtained in Preparation Example 5.1 in THF (2.5 mL) was added NaH (53 mg, 1.095 nmmol, 55% in mineral oil) at 0 C. The reaction mixture was stirred for 10 min and dimethyl sulfate was added dropwise to the reaction mixture at 0 C. After stirring at rt for 1 h, the reaction mixture was concentrated under reduced pressure and the residue was diluted with EtOAc. The organic layer was washed with water, dried over Na.sub.2SO.sub.4, and concentrated under reduced pressure. The residue was purified by column chromatography to afford the desired product (294 mg) as a colorless oil.

(50) LC-MS (ESI, m/z)=356.2 (M+H.sup.+).

6.2. 1-(2,6-Difluoro-4-(1-methoxyethyl)phenyl)piperazine hydrochloride

(51) Using the compound (294 mg, 0.730 mmol) obtained in Preparation Example 6.1 the compound (198 mg) was prepared by following a similar method to that described in Preparation Example 3.5.

(52) LC-MS (ESI, m/z)=257.1 (M+H.sup.+).

Preparation Example 7: 4-(2,6-Difluoro-4-(2-methoxyethoxy)phenyl)piperidin-4-ol hydrochloride

7.1. tert-Butyl 4-(2,6-difluoro-4-(2-methoxyethoxy)phenyl)piperazin-4-hydroxypiperidine-1-carboxylate

(53) To a solution of 2-bromo-1,3-difluoro-5-(2-methoxyethoxy)benzene (600 mg, 2.246 mmol) in ether (20 mL) was added dropwise 2.5 M n-BuLi in hexane (0.98 mL, 2.47 mmol) at 78 C. over 10 min. After stirring at 78 C. for 30 min a solution of Boc-piperidone (537 mg, 2.69 mmol) in ether (4 mL) was added dropwise to the reaction mixture at 78 C. over 20 min. The reaction mixture was allowed to warm to rt, quenched with water (15 mL), and diluted with ether. The organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford the desired product (1.01 g) as a yellow oil.

(54) LC-MS (ESI, m/z)=388.2 (M+H.sup.+).

7.2. 4-(2,6-Difluoro-4-(2-methoxyethoxy)phenyl)piperidin-4-ol hydrochloride

(55) Using the desired product obtained in Preparation Example 7.1 the compound (370 mg) was prepared by following a similar method to that described in Preparation Example 3.5.

(56) LC-MS (ESI, m/z)=288.1 (M+H.sup.+).

Preparation Example 8: 4-(1H-tetrazol-5-yl)piperidine hydrochloride

8.1. tert-Butyl 4-(1H-tetrazol-5-yl)piperidine-1-carboxylate

(57) A mixture of tert-butyl 4-cyanopiperidine-1-carboxylate (1 g, 4.75 mmol), sodium azide (923 mg, 14.26 mmol), and ammonium chloride (763 g, 14.26 mmol) in DMF (9.4 mL) was heated to 140 C. for 20 h. After cooling down to rt, the reaction mixture was diluted with EtOAc, washed with 0.5 N HCl and brine. The organic layer was dried over Na.sub.2SO.sub.4, and concentrated under reduced pressure. The residue was diluted with ether and the precipitate was filtered to afford the desired product (764 mg).

(58) LC-MS (ESI, m/z)=254.1 (M+H.sup.+).

8.2. 4-(1H-tetrazol-5-yl)piperidine hydrochloride

(59) Using the compound obtained in Preparation Example 8.1 the compound was prepared by following a similar method to that described in Preparation Example 3.5.

(60) LC-MS (ESI, m/z)=154.1 (M+H.sup.+).

Preparation Examples 9 and 10

3-(3,5-Difluoro-4-(piperazin-1-yl)phenyl)propane-1,2-diol hydrochloride (A) and 1-(3,5-difluoro-4-(piperazin-1-yl)phenyl)ethane-1,2-diol hydrochloride (B)

(61) ##STR00012##

9.1. 1-(4-(2,6-Difluoro-4-nitrophenyl)piperazin-1-yl)ethan-1-one

(62) A mixture of 3,4,5-Trifluoronitrobenzene and N-acetylpiperazine in MeCN was heated to 60 C. for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography.

(63) LC-MS (ESI, m/z)=287.2 (M+H.sup.+).

9.2. 1-(4-(2,6-Difluoro-4-aminophenyl)piperazin-1-yl)ethan-1-one

(64) The compound obtained in Preparation Example 9.1 was hydrogenated by Pd/C under hydrogen gas to afford the desired product.

(65) LC-MS (ESI, m/z)=256.2 (M+H.sup.+).

9.3. 1-(4-(4-Bromo-2,6-difluorophenyl)piperazin-1-yl)ethan-1-one

(66) The amine group of the compound obtained in Preparation Example 9.2 was replaced by bromide through the Sandmeyer reaction.

(67) LC-MS (ESI, m/z)=319.0 (M+H.sup.+).

9.4. 1-(4-(4-Allyl-2,6-difluorophenyl)piperazin-1-yl)ethan-1-one

(68) An allyl group was introduced to the compound obtained in Preparation Example 9.3 via the Stille coupling reaction using Pd(PPh.sub.3).sub.4, allylSnBu.sub.3, and DMF (100 C., 18 h). Then, the desired product was purified by column chromatography.

(69) LC-MS (ESI, m/z)=281.3 (M+H.sup.+).

9.5. 3-(3,5-Difluoro-4-(piperazin-1-yl)phenylpropane-1,2-diol hydrochloride (A)

(70) The allylic compound obtained in Preparation Example 9. was dihydroxylated by OSO.sub.4. Then, the desired product was afforded by removing the N-acetyl group of the dihydroxylated compound under acidic conditions.

(71) LC-MS (ESI, m/z)=273.3 (M+H.sup.+).

10.1. 1-(4-(4-Vinyl-2,6-difluorophenyl)piperazin-1-yl)ethan-1-one

(72) The vinyl group was introduced via the Stille coupling reaction employed in Preparation Example 9.3 using (vinyl)SnBu.sub.3.

(73) LC-MS (ESI, m/z)=267.3 (M+H.sup.+).

10.2. 1-(3,5-Difluoro-4-(piperazin-1-yl)phenyl)ethane-1,2-diol hydrochloride (B)

(74) The vinylic compound obtained in Preparation Example 10.1 was dihydroxylated by OsO.sub.4. Then, the compound B was obtained by removing the N-acetyl group of the dihydroxylated compound under acidic conditions.

(75) LC-MS (ESI, m/z)=259.2 (M+H.sup.+).

Preparation Example 11: 3,5-Difluoro-N-(2-methoxyethyl)-4-(piperazin-1-yl)aniline hydrochloride (I-i)

11.1. tert-Butyl 4-(2,6-difluoro-4-nitrophenyl)piperazine-1-carboxylate

(76) To a solution of 1,2,3-trifluoro-5-nitrobenzene (1 g, 5.65 mmol) in MeCN (11 mL) was added Boc-piperazine (2.63, 14.12 mmol) at rt. The reaction mixture was stirred at 60 C. for 3 h. After cooling down to rt, the mixture was diluted with EtOAc and washed with water. The organic layer was dried over Na.sub.2SO.sub.4, and concentrated under reduced pressure. The residue was purified by column chromatography to afford the desired product (1.93 g, quant) as a yellow solid.

(77) LC-MS (ESI, m/z)=344.1 (M+H.sup.+).

11.2. tert-Butyl 4-(4-amino-2,6-difluorophenyl)piperazine-1-carboxylate

(78) The compound (1.75 g, 5.09 mmol) obtained in Preparation Example 11.1 was hydrogenated by Pd/C under hydrogen gas to afford the desired product (1.57 g) as a yellow solid.

(79) LC-MS (ESI, m/z)=314.1 (M+H.sup.+).

11.3. tert-Butyl 4-(2,6-difluoro-4-(2-methoxyethylamino)phenyl)piperazine-1-carboxylate

(80) To a solution of the compound (1.57 g, 5.01 mmol) obtained in Preparation Example 11.2 in DMF was added portionwise NaH (437 mg, 10.02 mmol, 55% in mineral oil) at 0 C. over 30 min. A solution of 1-bromo-2-methoxyethane (835 mg, 6.01 mmol) in DMF (3 mL) was added dropwise to the reaction mixture at 0 C. After stirring overnight at rt, the mixture was quenched with iced water and diluted with EtOAc. The organic layer was washed with water, dried over Na.sub.2SO.sub.4, and concentrated under reduced pressure. The residue was purified by column chromatography to afford the desired product (140 mg, quant) as a yellow oil.

(81) LC-MS (ESI, m/z)=372.2 (M+H.sup.+).

11.4. 3,5-Difluoro-N-(2-methoxyethyl)-4-(piperazin-1-yl)aniline hydrochloride

(82) The desired product (110 mg) was afforded as a white solid by deprotecting the compound (140 mg, 0.376 mmol) obtained in Preparation Example 11.3 using 4 M HCl.

(83) LC-MS (ESI, m/z)=272.1 (M+H.sup.+).

Preparation Example 12: 2-(3,5-Difluoro-4-(piperazin-1-yl)phenoxy)-1-(substituted-1-yl)ethanone hydrochloride (I-12A and I-12B), 1-(2,6-difluoro-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)piperazine hydrochloride (I-12C), 1-(2-(3,5-difluoro-4-(piperazin-4-yl)phenoxy)ethyl)-substituted hydrochloride (I-12D and I-12F), 1-(4-(2-azidoethoxy)-2,6-difluorophenyl)piperazine hydrochloride (I-12E), benzyl 1-(2-(3,5-difluoro-4-(piperazin-1-yl)phenoxy)ethyl)piperidin-4-ylcarbamate hydrochloride (I-12G) and 1-(2-(3,5-difluoro-4-(piperazin-1-yl)phenoxy)ethyl)piperidin-2-one (I-12H)

(84) ##STR00013##

12.1. tert-Butyl 4-(2,6-difluoro-4-(2-oxo-2-(pyrrolidin-1-yl)ethoxy)phenyl)piperazin-1-carboxylate

(85) To a solution of pyrrolidine (377.8 mg, 5.313 mmol) in THF (2.5 mL) was added dropwise a solution of 2-chloroacetyl chloride (300 mg, 2.656 mmol) in THF (2.5 mL) at 0 C. over 5 min. After stirring at rt for 15 h, the reaction mixture was diluted with EtOAc and washed with water. The organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford the desired product (438 mg) as a yellow oil. A mixture of 2-chloro-1-(pyrrolidin-1-yl)ethanone (169 mg, 1.145 mmol), the compound (300 mg, 0.954 mmol) obtained in Preparation Example 3.3 and K.sub.2CO.sub.3 (527 mg, 3.816 mmol) in DMF (3.2 mL) was stirred at rt for 17 h. The reaction mixture was diluted with EtOAc and washed with water. The organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford the desired product (346 mg) as a white solid.

12.2. 2-(3,5-Difluoro-4-(piperazin-1-yl)phenoxy)-1-(pyrrolidin-1-yl)ethanone hydrochloride (I-12A)

(86) To a solution of tert-butyl 4-(2,6-difluoro-4-(2-oxo-2-(pyrrolidin-1-yl)ethoxy)phenyl)piperazin-1-carboxylate (336 mg, 0.790 mmol) in CH.sub.2Cl.sub.2 (0.5 mL) was added 4 M HCl (2 mL). The mixture was stirred at rt for 3 h and concentrated under reduced pressure. The residue was diluted with ether and the precipitate was filtered to afford the desired product (295 mg) as a white solid.

(87) LC-MS (ESI, m/z)=326.1 (M+H.sup.+).

12.3. tert-Butyl 4-(2,6-difluoro-4-(2-oxo-2-(piperidin-1-yl)ethoxy)phenyl)piperazin-1-carboxylate

(88) The desired product was prepared in analogously with the procedure in Preparation Example 12.1. The pyrrolidine motif was replaced with the piperidine to afford the desired product.

(89) LC-MS (ESI, m/z)=440.2 (M+H.sup.+).

12.4. 2-(3,5-Difluoro-4-(piperazin-1-yl)phenoxy)-1-(piperidin-1-yl)ethanone hydrochloride (I-12B)

(90) The compound (336 mg, 0.790 mmol) obtained in Preparation Example 12.3 was deprotected by 4 M HCl to afford the desired product (243 mg) as a white solid.

(91) LC-MS (ESI, m/z)=340.1 (M+H.sup.+).

12.5. tert-Butyl 4-(4-(2-(benzyloxy)ethoxy)-2,6-difluorophenyl)piperazin-1-carboxylate

(92) A mixture of the compound (1 g, 3.181 mmol) obtained in Preparation Example 3.3 benzyl-2-bromoethylamine (851 mg, 3.818 mmol) and K.sub.2CO.sub.3 (1.32 g, 9.544 mmol) in DMF (6.4 mL) was heated to 70 C. to 80 C. for 2 h. After cooling down to rt, the reaction mixture was diluted with EtOAc and washed with brine. The organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford the desired product (1.427 g) as a yellow oil.

(93) LC-MS (ESI, m/z)=449.2 (M+H.sup.+).

12.6. tert-Butyl 4-(2,6-difluoro-4-(2-hydroxyethoxy)phenyl)piperazin-1-carboxylate

(94) To a solution of the compound (1.427 g, 3.181 mmol) obtained in Preparation Example 12.5 in MeOH (10.6 mL) was added 10% Pd/C (428 mg). After stirring at rt for 2 h under hydrogen gas. The mixture was filtered through a Celite pad and the filtrate was concentrated under reduced pressure to afford the desired product (1.14 g) as a pale yellow solid.

(95) LC-MS (ESI, m/z)=359.1 (M+H.sup.+).

12.7. tert-Butyl 4-(2,6-difluoro-4-(2-(tosyloxy)ethoxy)phenyl)piperazin-1-carboxylate

(96) A mixture of the compound (1.14 g, 3.181 mmol) obtained in Preparation Example 12.6 4-methylbenzyl-1-sulfonyl chloride (909.8 mg, 4.722 mmol), TEA (804.8 mg, 7.953 mmol) and DMAP (97.2 mg, 0.057 mmol) in CH.sub.2Cl.sub.2 (10.6 mL) was stirred at rt for 3 h. The mixture was diluted with EtOAc, washed with 0.5 N HCl and saturated NaHCO.sub.3. The organic layer was dried over Na.sub.2SO.sub.4, concentrated under reduced pressure to afford the desired product (1.44 g) as a white solid.

(97) LC-MS (ESI, m/z)=513.2 (M+H.sup.+).

12.8. tert-Butyl 4-(2,6-difluoro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)piperazin-1-carboxylate

(98) To a solution of the compound (368 mg, 0.718 mmol) obtained in Preparation Example 12.7 1-methylpiperazine (143.8 mg, 1.436 mmol) in DMF (2.4 mL) was heated to 50 C. to 60 C. for 15 h. After cooling down to rt, the mixture was diluted with EtOAc and washed with water. The organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford the desired product (270 mg) as a yellow oil.

12.9. 1-(2-(3,5-Difluoro-4-(piperazin-1-yl)phenoxy)ethyl)-4-methylpiperazine dihydrochloride (I-12D)

(99) The compound (270 mg, 0.613 mmol) obtained in Preparation Example 12.8 was deprotected with 4 M HCl to afford the desired product (253 mg) as a white solid.

(100) LC-MS (ESI, m/z)=341.2 (M+H.sup.+).

12.10. 1-(2-(3,5-Difluoro-4-(piperazin-1-yl)phenoxy)ethyl)-4-pyrrolidine dihydrochloride (I-12C)

(101) The desired product was synthesized by following the reaction conditions used in Preparation Examples 12.8 and 12.9.

(102) LC-MS (ESI, m/z)=312.2 (M+H.sup.+).

12.11. 1-(4-(2-Azidoethoxy)-2,6-difluorophenyl)piperazine hydrochloride (I-12E)

(103) The desired product was synthesized by following the reaction conditions used in Preparation Examples 12.8 and 12.9.

(104) LC-MS (ESI, m/z)=284.1 (M+H.sup.+).

12.12. 1-(2-(3,5-Difluoro-4-(piperazin-1-yl)phenoxy)ethyl)-4-methylpiperazin-2-one hydrochloride (I-12F)

(105) The desired product was synthesized by following reaction conditions similar to those used in Preparation Examples 12.8 and 12.9.

(106) LC-MS (ESI, m/z)=355.2 (M+H.sup.+).

12.13. Benzyl 1-(2-(3,5-difluoro-4-(piperazin-1-yl)phenoxy)ethyl)piperidin-4-ylcarbamate dihydrochloride (I-12G)

(107) The desired product was synthesized by following the reaction conditions used in Preparation Examples 12.8 and 12.9.

(108) LC-MS (ESI, m/z)=475.2 (M+H.sup.+).

12.14. 1-(2-(3,5-Difluoro-4-(piperazin-1-yl)phenoxy)ethyl)piperidin-2-one (I-12H)

(109) The desired product was synthesized by following the reaction conditions used in Preparation Examples 12.8 and 12.9.

(110) LC-MS (ESI, m/z)=340.2 (M+H.sup.+).

Preparation Example 13: 1-(2,6-Difluoro-4-(3-methoxypropyl)phenyl)piperazine hydrochloride (I-13A)

(111) ##STR00014##

13.1. tert-Butyl 4-(2,6-difluoro-4-(2-oxo-2-(pyrrolidin-1-yl)ethoxy)phenyl)piperazin-1-carboxylate

(112) To a solution of (2-methoxyethyl)triphenylphosphonium bromide (1.424 g, 3.549 mmol) in THF (10 mL) was added dropwise 2.5 M n-BuLi in hexane (1.42 mL) at 0 C. for 0.5 h. A solution of the compound (772 mg, 2.366 mmol) obtained in Preparation Example 4.1 in THF (2 mL) was added dropwise to the reaction mixture at 0 C. After stirring at rt for 18 h, the reaction mixture was quenched with a few drops of MeOH, and diluted with EtOAc. The organic layer was washed with water, dried over Na.sub.2SO.sub.4, concentrated under reduced pressure. The residue was purified by column chromatography to afford the desired product (239 mg, 0.649 mmol) as a colorless oil.

(113) LC-MS (ESI, m/z)=369.2 (M+H.sup.+).

13.2. 1-(2,6-Difluoro-4-(3-methoxypropyl)phenyl)piperazine hydrochloride (I-13A)

(114) To a solution of the compound (239 mg, 0.165 mmol) obtained in Preparation Example 13.1 in MeOH (4 mL) was added 10% Pd/C (120 mg). After stirring at rt for 1 h under hydrogen gas, the mixture was filtered through a Celite pad. The filtrate was concentrated under reduced pressure to afford the intermediate (164 mg, 0.434 mmol) as a colorless oil. The obtained intermediate was deprotected using 4 M HCl to afford the desired product (164 mg) as a white solid.

(115) LC-MS (ESI, m/z)=271.1 (M+H.sup.+).

Preparation Example 14: 1-(2-(3,5-Difluoro-4-(piperazin-1-yl)phenoxy)ethyl)pyrrolidin-3-ol hydrochloride (I-14A), 1-(2-(3,5-difluoro-4-(piperazin-1-yl)phenoxy)ethyl)piperidin-4-ol hydrochloride (I-14B) and 1-(2-(3,5-difluoro-4-piperazin-1-yl)phenoxy)ethyl)-4-methylpiperidin-4-ol hydrochloride (I-14C)

(116) ##STR00015##

14.1. tert-Butyl 4-(4-(2-bromomethoxy)-2,6-difluorophenyl)piperazin-1-carboxylate

(117) To a mixture of tert-butyl 4-(2,6-difluoro-4-hydroxyphenyl)piperazin-1-carboxylate (3.14 g, 10 mmol) and K.sub.2CO.sub.3 (4.2 g, 30 mmol) in MeCN (50 mL) was added 1,2-dibromoethane (3.8 g, 20 mmol). The reaction mixture was heated to reflux for 12 h. After cooling down to rt, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography to afford the desired product (3.5 g) as a white solid.

14.2. 1-(2-(3,5-Difluoro-4-(piperazin-1-yl)phenoxy)ethyl)pyrrolidin-3-ol hydrochloride (I-14A)

(118) The compound (0.42 g, 1.00 mmol) obtained in Preparation Example 14.1 was reacted with 3-hydroxypyrrolidine (0.13 g, 1.5 mmol) to afford an aminated intermediate. The intermediate was treated with 4 M HCl to remove the Boc-group of piperidine to afford the desired product (0.3 g).

14.3. 1-(2-(3,5-Difluoro-4-(piperazin-1-yl)phenoxy)ethyl)piperidin-4-ol hydrochloride (I-14B)

(119) The desired product was synthesized by following the reaction conditions used in Preparation Examples 14.1 and 14.2.

14.4. 1-(2-(3,5-Difluoro-4-(piperazin-1-yl)phenoxy)ethyl)-4-methylpiperidin-4-ol hydrochloride (I-14C)

(120) The desired product was synthesized by following the reaction conditions used in Preparation Examples 14.1 and 14.2.

Preparation Example 15: 4-(Benzyloxy)-6-chloro-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridine (I-15) as an intermediate

(121) ##STR00016##

15.1. tert-Butyl 2,6-dichloropyridin-4-ylcarbamate

(122) A mixture of 2,6-dichloropyridin-4-amine (2.1 g, 12.833 mmol), (Boc).sub.2O (3.09 g, 14.172 mmol), and DMAP (393.5 mg, 3.221 mmol) in THF (64.4 mL) was heated to 60 C. to 70 C. for 23 h. After cooling down to rt, the mixture was concentrated under reduced pressure. The residue was diluted with EtOAc, washed with saturated NH.sub.4Cl solution and dried over Na.sub.2SO.sub.4. The organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography to afford the desired product (2.04 g) as a white solid.

(123) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 10.336 (s, 1H), 7.473 (s, 2H), 1.408 (s, 9H).

15.2. tert-Butyl 2,6-Dichloropyridin-4-yl(methyl)carbamate

(124) To a mixture of NaH (639.3 mg, 14.651 mmol, 55% in mineral oil) in DMF (20 mL) was added dropwise a solution of the compound (2.57 g, 9.767 mmol) obtained in Preparation Example 15.1 in DMF (20 mL) at 0 C. over 10 min. After stirring for 30 min, a solution of MeI (0.67 mL, 10.774 mmol) in DMF (8 mL) was added dropwise to the reaction mixture at 0 C. After stirring at rt for 1 h, the mixture was cooled down to 0 C., added water and diluted with EtOAc. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified by column chromatography to afford the desired product (2.5 g) as a yellow oil.

(125) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 7.578 (s, 1H), 3.262 (s, 1H), 1.474 (s, 9H).

15.3. 2,6-Dichloro-N-methyl-3-nitropyridin-4-amine

(126) To a solution of the compound (2.671 g, 9.417 mmol) obtained in Preparation Example 15.2 in concentrated sulfuric acid (9.4 mL) was added dropwise 60% to 62% nitric acid (0.8 mL, 10.359 mmol) at 0 C. over 10 min. The reaction mixture was stirred at rt for 3 h and iced water was slowly added to the solution. The precipitate was filtered to afford the desired product (1.6 g) as a yellow solid.

(127) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 7.752 (q, J=4.2 Hz, 1H), 6.979 (s, 1H), 2.821 (d, J=4.5 Hz, 1H).

15.4. 2,6-Dichloro-N4-methylpyridin-3,4-diamine

(128) To a solution of the compound (1.6 g, 7.206 mmol) obtained in Preparation Example 15.3 in MeOH (6 mL) and EtOAc (6 mL) was added 5% Pd/C (160 mg). After stirring at rt for 4 h under hydrogen gas, the mixture was filtered through a Celite pad. The filtrate was concentrated under reduced pressure, and the residue was washed with 20% EtOAc in n-hexane (20 mL) to afford the desired product (1.06 g) as a brown solid.

(129) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 6.334 (s, 1H), 6.276 (q, J=3.9 Hz, 1H), 4.879 (brs, 2H), 2.771 (d, J=4.8 Hz, 1H).

15.5. 4,6-Dichloro-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridine

(130) To a solution of the compound (1.06 g, 5.519 mmol) obtained in Preparation Example 15.4 in 1 N HCl (22 mL) was added dropwise a solution of sodium nitrite (647 mg, 9.382 mmol) in water (5 mL) at 0 C. over 20 min. After stirring at rt for 1 h, the reaction mixture was filtered and the precipitate was washed with water to afford the desired product (983 mg) as a brown solid.

(131) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 8.239 (s, 1H), 4.327 (s, 3H).

15.6. 4-(Benzyloxy)-6-chloro-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridine (I-15)

(132) To a mixture of NaH (644.7 mg, 14.776 mmol, 55% in mineral oil) in DMF (16 mL) was added dropwise a solution of benzylalcohol (1.53 mL, 14.776 mmol) in DMF (16 mL). The mixture was stirred at 0 C. for 30 min. A solution of the compound (2 g, 9.851 mmol) obtained in Preparation Example in 15.5 in THF (16 mL) was added dropwise to the reaction mixture was quenched with iced water and diluted with EtOAc. The organic layer was washed with brine and dried over Na.sub.2SO.sub.4. The filtrate was concentrated under reduced pressure and the residue was washed with n-hexane to afford the desired product (2.56 g) as a yellow solid.

(133) LC-MS (ESI, m/z)=330.3 (M+H.sup.+).

Example 1: 5-(4-(2-Fluorophenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one

(134) To a microwave reaction vial were added the compound (I-7) obtained in Preparation Example 2, 1-(2-fluorophenyl)piperazine as amine, diisopropylethylamine (DIPEA), and isopropyl alcohol (2 mL). The reaction mixture was heated at 150 C. under microwave heating condition for 30 min. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography to afford the desired product.

(135) LC-MS (ESI, m/z)=464.2 (M+H.sup.+).

Example 2: 5-(4-(2,6-Difluoro-4-(2-methoxyethoxy)phenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one

(136) Step 1:

(137) A sealed tube was charged with the compound I-7 (300 mg, 1.1 mmol), the compound I-3A (409 mg, 1.32 mmol), EtOH (2 mL), and DIPEA (0.29 mL, 1.65 mmol). The reaction mixture was heated to reflux for 2 h, concentrated under reduced pressure and the residue was diluted with EtOAc. The organic layer was washed with water, dried over Na.sub.2SO.sub.4, and concentrated under reduced pressure. The residue was purified by column chromatography to afford the desired product (427 mg) as a white solid.

(138) LC-MS (ESI, m/z)=464.2 (M+H.sup.+).

(139) Step 2:

(140) To a solution of the compound (427 mg, 0.921 mmol) obtained in Step 1 in AcOH (6 mL) and 35% HCl (1.5 mL) was heated to 60 C. to 70 C. for 2 h. The mixture was concentrated under reduced pressure and the residue adjusted to pH 5 to pH 6 by dropwise addition of 2 N NaOH. The precipitate was filtered and purified by column chromatography to afford the desired product (307 mg) as a white solid.

(141) LC-MS (ESI, m/z)=422.1 (M+H.sup.+).

Example 3: 5-(4-(4-(Benzyloxy)-2,6-difluorophenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one

(142) Following the general procedure of Example 1, the desired product was afforded using the previously obtained amine (I-3E).

(143) LC-MS (ESI, m/z)=454.4 (M+H.sup.+).

Example 4: 5-(4-(2,6-Difluoro-4-(2-morpholinoethoxy)phenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one

(144) Following the general procedure of Example 1, the desired product was afforded using the previously obtained amine (I-3F).

(145) LC-MS (ESI, m/z)=477.5 (M+H.sup.+).

Example 5

5-(4-(2,6-Difluoro-4-(2-(piperidin-1-yl)ethoxy)phenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one

(146) Following the general procedure of Example 1, the desired product was afforded using the previously obtained amine (I-3B).

(147) LC-MS (ESI, m/z)=475.5 (M+H.sup.+).

Example 6

5-(4-(4-(2-(Dimethylamino)ethoxy)-2,6-difluorophenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one

(148) Following the general procedure of Example 1, the desired product was afforded using the previously obtained amine (I-3G).

(149) LC-MS (ESI, m/z)=435.1 (M+H.sup.+).

Example 7: 5-(4-(2,6-Difluoro-4-(2-hydroxyethoxy)phenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one

(150) To a microwave reaction vial were added the compound I-7, (1-(4-(2-(benzyloxy)ethoxy)-2,6-difluorophenyl)piperazine hydrochloride prepared using a similar method to that described in Preparation Example 3.6, DIPEA, and isopropyl alcohol (2 mL). The reaction mixture was heated at 150 C. under microwave heating condition for 30 min. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography. After sequential deprotection of the isopropyl group in the same manner as described in Step 2 of Example 2 and the O-benzyl group via catalyst hydrogenation as described in Preparation Example 3.3 the desired product was afforded.

(151) LC-MS (ESI, m/z)=408.1 (M+H.sup.+).

Example 8: 2-(3,5-Difluoro-4-(4-(3-methyl-7-oxo-6,7-dihydro-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)piperazin-1-yl)phenoxy)ethyl acetate

(152) The desired product was afforded as a byproduct during the deprotection step in Example 7.

(153) LC-MS (ESI, m/z)=450.1 (M+H.sup.+).

Example 9: 5-(4-(2,6-Difluoro-4-isopropoxyphenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one

(154) Following the general procedure of Example 1, the desired product was afforded using the previously obtained amine (I-3C).

(155) LC-MS (ESI, m/z)=406.1 (M+H.sup.+).

Example 10: (R)-2-(3,5-difluoro-4-(4-(3-methyl-7-oxo-6,7-dihydro-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)piperazin-1-yl)phenoxy)ethyl2-aminopropanoate hydrochloride

(156) The compound obtained in Example 7 was coupled with Boc-D-Ala-OH in the presence of a coupling reagent (PyBOP) followed by Boc deprotection to afford the desired product.

(157) LC-MS (ESI, m/z)=479.2 (M+H.sup.+).

Example 11: (S)-2-(3,5-difluoro-4-(4-(3-methyl-7-oxo-6,7-dihydro-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)piperazin-1-yl)phenoxy)ethyl2-aminopropanoate hydrochloride

(158) The desired product was synthesized in the same manner as described in Example 10 using Boc-L-Ala-OH.

(159) LC-MS (ESI, m/z)=479.2 (M+H.sup.+).

Example 12

5-(4-(4-(2,3-Dihydroxypropoxy)-2,6-difluorophenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one

(160) Following the general procedure of Step 1 in Example 2, the intermediate compound was afforded using the previously obtained amine (I-3E). The resulting compound was hydrogenated using Pd/C to provide the phenolic compound, which was further reacted with (2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate to afford the protected target compound.

(161) After simultaneous removal of the isopropyl and dioxolanyl groups using a method similar to that described in Step 2 of Example 2, the desired product was afforded.

(162) LC-MS (ESI, m/z)=438.1 (M+H.sup.+).

Example 13: 5-(4-(2,6-Difluoro-4-(morpholinomethyl)phenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one

(163) The desired product was synthesized in the same manner as described in Example 2 using the amine synthesized following a similar method to that described in Preparation Example 4.

(164) LC-MS (ESI, m/z)=447.2 (M+H.sup.+).

Example 14

5-(4-(2,6-Difluoro-4-((4-methylpiperazin-1-yl)methyl)phenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one

(165) The desired product was synthesized in the same manner as described in Example 2 using the amine synthesized following a similar method to that described in Preparation Example 4.

(166) LC-MS (ESI, m/z)=460.2 (M+H.sup.+).

Example 15: 5-(4-(2,6-Difluoro-4-(oxetan-3-yloxy)phenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one

(167) Following the general procedure of Example 2, the desired product was afforded using the previously obtained amine (I-3E).

(168) LC-MS (ESI, m/z)=420.1 (M+H.sup.+).

Example 16

5-(4-(4-(1-Chloro-3-hydroxypropan-2-yloxy)-2,6-difluorophenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one

(169) The desired product was synthesized in the same manner as described in Example 15 using the amine produced as a byproduct during the synthesis of the compound I-3D in Preparation Example 3.

(170) LC-MS (ESI, m/z)=456.1 (M+H.sup.+).

Example 17: 5-(4-(2,6-Difluoro-4-(1-hydroxyethyl)phenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one

(171) Following the general procedure of Example 2, the desired product was synthesized using the compound obtained in Preparation Example 5.

(172) LC-MS (ESI, m/z)=392.1 (M+H.sup.+).

Example 18: 5-(4-(2,6-Difluoro-4-(1-methoxyethyl)phenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one

(173) Following the general procedure of Example 2, the desired product was synthesized using the compound obtained in Preparation Example 6.

(174) LC-MS (ESI, m/z)=406.2 (M+H.sup.+).

Example 19: 6-(3,5-Difluoro-4-(4-(3-methyl-7-oxo-6,7-dihydro-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)piperazin-1-yl)phenoxy)hexanoic acid

(175) The compound obtained in Preparation Example 3.3 was alkylated using ethyl 5-bromopentanoate and the Boc group was removed. The resulting amine compound reacted with the compound I-7 following a similar method to that described in Example 2 to afford the desired product.

(176) LC-MS (ESI, m/z)=478.2 (M+H.sup.+).

Example 20

5-(4-(2,6-Difluoro-4-(((2-methoxyethyl)(methyl)amino)methyl)phenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one

(177) Following the general procedure of Example 2, the desired product was afforded using the amine compound obtained in Preparation Example 4.

(178) LC-MS (ESI, m/z)=449.2 (M+H.sup.+).

Example 21: 5-(4-(2,6-Difluorophenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one

(179) Following the general procedure of Example 1, the desired product was afforded using the amine prepared in the same manner as described in Preparation Examples 3.2 and 3.5.

(180) LC-MS (ESI, m/z)=348.1 (M+H.sup.+).

Example 22: 3-Methyl-5-(4-(2,4,6-trifluorophenyl)piperazin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one

(181) Following the general procedure of Example 1, the desired product was afforded using the amine prepared in the same manner as described in Preparation Examples 3.2 and 3.5.

(182) LC-MS (ESI, m/z)=366.3 (M+H.sup.+).

Example 23: 5-(4-(4-(1,2-Dihydroxyethyl)-2,6-difluorophenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one

(183) Following the general procedure of Example 1, the desired product was afforded using the amine prepared in Preparation Example 10 (B).

(184) LC-MS (ESI, m/z)=408.3 (M+H.sup.+).

Example 24: 5-(4-(4-(2,3-Dihydroxypropyl)-2,6-difluorophenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one

(185) Following the general procedure of Example 1, the desired product was afforded using the amine prepared in Preparation Example 9 (A).

(186) LC-MS (ESI, m/z)=422.4 (M+H.sup.+).

Example 25: 5-(4-(2,6-Difluoro-4-(2-methoxyethoxy)phenyl)-4-hydroxypiperidin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one

(187) Following the general procedure of Example 1, the desired product was afforded using the amine prepared in Preparation Example 7.

(188) LC-MS (ESI, m/z)=437.3 (M+H.sup.+).

Example 26: 5-(4-(1H-tetrazol-5-yl)piperidin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one

(189) Following the general procedure of Example 1, the desired product was afforded using the amine prepared in Preparation Example 8.

(190) LC-MS (ESI, m/z)=303.1 (M+H.sup.+).

Example 27: 5-(4-(2,6-Difluoro-4-(2-methoxyethylamino)phenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one

(191) Following the general procedure of Example 1, the desired product was afforded using the amine prepared in Preparation Example 11.

(192) LC-MS (ESI, m/z)=421.3 (M+H.sup.+).

Example 28: 5-(4-(2,6-Difluoro-4-vinylphenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one

(193) Following the general procedure of Example 1, the desired product was afforded using the amine which was prepared by the Boc removal from the compound obtained in Preparation Example 10.1.

(194) LC-MS (ESI, m/z)=374.3 (M+H.sup.+).

Example 29: 3-Methyl-5-(4-(1-methyl-1H-tetrazol-5-yl)piperidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one

(195) After adding Cs.sub.2CO.sub.3, MeI and THF to the compound obtained in Preparation Example 8.1, the reaction mixture was heated to 80 C. for 2 h. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography to provide the Boc-protected amine. After the removal of the Boc group, the resulting amine was reacted with the compound I-7 in the same manner as described in Example 2 to afford the desired product.

(196) LC-MS (ESI, m/z)=317.1 (M+H.sup.+).

Example 30: 3-Methyl-5-(4-(2-methyl-2H-tetrazol-5-yl)piperidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one

(197) The compound obtained in Preparation Example 8.1, was reacted with the compound I-7 in the same manner as described in Example 29 to afford the desired product.

(198) LC-MS (ESI, m/z)=317.1 (M+H.sup.+).

Example 31

5-(4-(2,6-Difluoro-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one

(199) Following the general procedure of Example 2, the desired product was afforded using the amine prepared in Preparation Example 12.10.

(200) LC-MS (ESI, m/z)=461.2 (M+H.sup.+).

Example 32

5-(4-(2,6-Difluoro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one

(201) Following the general procedure of Example 2, the desired product was afforded using the amine (I-12D) prepared in Preparation Example 12.9.

(202) LC-MS (ESI, m/z)=490.2 (M+H.sup.+).

Example 33

5-(4-(2,6-Difluoro-4-(3-(piperidin-1-yl)propoxy)phenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one

(203) tert-Butyl 4-(2,6-difluoro-4-(2-hydroxypropoxy)phenyl)piperazine-1-carboxylate was subjected to tosylation (TsCl, TEA, DMAP and CH.sub.2Cl.sub.2), substitution with piperidine (piperidine, K.sub.2CO.sub.3 and DMF), and then deprotection of the Boc group to provide the desired amine. The resulting amine was reacted with the compound I-7 in the same manner as described in Example 2 to afford the desired product.

(204) LC-MS (ESI, m/z)=489.3 (M+H.sup.+).

Example 34

5-(4-(4-(Bis(2-methoxyethyl)amino)-2,6-difluorophenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one

(205) Following the general procedure of Example 1, the desired product was afforded using the amine which was prepared as a byproduct during the reaction in Preparation Example 11.

(206) LC-MS (ESI, m/z)=479.2 (M+H.sup.+).

Example 35: 5-(4-(2,6-Difluoro-4-(2-oxo-2-(piperidin-1-yl)ethoxy)phenyl) piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one

(207) Following the general procedure of Example 2, the desired product was afforded using the amine (I-12B) prepared in Preparation Example 12.4.

(208) LC-MS (ESI, m/z)=489.2 (M+H.sup.+).

Example 36: 5-(4-(2,6-Difluoro-4-(2-oxo-2-(pyrrolidin-1-yl)ethoxy)phenyl) piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one

(209) Following the general procedure of Example 2, the desired product was afforded using the amine (I-12A) prepared in Preparation Example 12.2.

(210) LC-MS (ESI, m/z)=475.2 (M+H.sup.+).

Example 37: 5-(4-(4-(2-Aminoethoxy)-2,6-difluorophenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one

(211) Step 1:

(212) To a sealed tube was added the compound I-7, the compound I-12E (200 mg, 0.485 mmol), EtOH (1.72 mL), and DIPEA (0.180 mL, 1.032 mmol). The reaction mixture was heated to 60 C. to 65 C. for 16 h. After cooling down to rt, the mixture was concentrated under reduced pressure and the residue was diluted with EtOAc. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to afford the desired product (211 mg) as a yellow oil.

(213) LC-MS (ESI, m/z)=475.2 (M+H.sup.+).

(214) Step 2:

(215) To a solution of the compound (210 mg, 0.443 mmol) obtained in Step 1 in MeOH (1.5 mL) was added 10% Pd/C (42 mg) at rt. After stirring at rt for 2 h under hydrogen gas, the mixture was filtered through a Celite pad. The filtrate was concentrated under reduced pressure to afford the desired product (99 mg) as a white solid.

(216) LC-MS (ESI, m/z)=449.2 (M+H.sup.+).

(217) Step 3:

(218) To a solution of the compound (97 mg, 0.216 mmol) obtained in Step 2 in AcOH (2 mL) and 35% HCl solution (0.5 mL) was heated to 60 C. to 70 C. for 2 h. The mixture was concentrated under reduced pressure and the residue was adjusted to pH 5 to pH 6 by adding 2 N NaOH dropwise. The precipitate was filtered with CH.sub.2Cl.sub.2 to afford the desired product (59 mg) as a white solid.

(219) LC-MS (ESI, m/z)=407.2 (M+H.sup.+).

Example 38: 5-(4-(2,6-Difluoro-4-(2-(4-methyl-2-oxopiperazin-1-yl)ethoxy)phenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one

(220) Following the general procedure of Example 2, the desired product was afforded using the amine (I-12F) prepared in Preparation Example 12.12.

(221) LC-MS (ESI, m/z)=504.3 (M+H.sup.+).

Example 39: 5-(4-(4-(2-(4-Aminopiperidin-1-yl)ethoxy)-2,6-difluorophenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one

(222) Following a procedure similar to that described in Example 37, the desired product was afforded using the amine (I-12G) prepared in Preparation Example 12.13.

(223) LC-MS (ESI, m/z)=490.3 (M+H.sup.+).

Example 40: 5-(4-(2,6-Difluoro-4-(3-methoxypropyl)phenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one

(224) Following the general procedure of Example 2, the desired product was afforded using the amine (I-13A) prepared in Preparation Example 13.2.

(225) LC-MS (ESI, m/z)=420.1 (M+H.sup.+).

Example 41: 5-(4-(2,6-Difluoro-4-(2-(3-hydroxypyrrolidin-1-yl)ethoxy)phenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one

(226) Following the general procedure of Example 2, the desired product was afforded using the previously obtained amine (I-14A).

(227) LC-MS (ESI, m/z)=476.8 (M+H.sup.+).

Example 42: 5-(4-(2,6-Difluoro-4-(2-(4-hydroxypiperidin-1-yl)ethoxy)phenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one

(228) Following the general procedure of Example 2, the desired product was afforded using the previously obtained amine (I-14B).

(229) LC-MS (ESI, m/z)=490.9 (M+H.sup.+).

Example 43

5-(4-(2,6-Difluoro-4-(2-(4-hydroxy-4-methylpiperidin-1-yl)ethoxy)phenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one

(230) Following the general procedure of Example 2, the desired product was afforded using the previously obtained amine (I-14C).

(231) LC-MS (ESI, m/z)=504.7 (M+H.sup.+).

Example 44

5-(4-(2,6-Difluoro-4-(2-methoxyethoxy)phenyl)-5,6-dihydropyridin-1(2H)-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one

(232) Following the general procedure of Example 2, the desired product was afforded using the amine prepared in Preparation Example 7.2.

(233) LC-MS (ESI, m/z)=419.2 (M+H.sup.+).

Example 45: 5-(4-(2,6-Difluoro-4-(2-methoxyethoxy)phenyl)piperidin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one

(234) The desired product was afforded by Pd/C-catalyzed hydrogenation of the compound obtained in Example 44.

(235) LC-MS (ESI, m/z)=421.2 (M+H.sup.+).

Example 46

5-(4-(2,6-Difluoro-4-(2-(2-oxopiperidin-1-yl)ethoxy)phenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one

(236) Following the general procedure of Example 2, the desired product was afforded using the amine prepared in Preparation Example 12.14.

(237) LC-MS (ESI, m/z)=489.2 (M+H.sup.+).

Example 47: 5-(4-(4-(2-Ethoxyethoxy)-2,6-difluorophenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one

(238) Following the general procedure of Example 2, the desired product was afforded using 1-(4-(2-ethoxyethoxy)-2,6-difluorophenyl)piperazine hydrochloride.

(239) LC-MS (ESI, m/z)=436.2 (M+H.sup.+).

Example 48

5-(4-(4-(2-(cis-2,6-Dimethylpiperidin-1-yl)ethoxy)-2,6-difluorophenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one

(240) Following the general procedure of Example 2, the desired product was afforded using the amine prepared in the same manner as described in Preparation Examples 3.4 and 3.5.

(241) LC-MS (ESI, m/z)=502.9 (M+H.sup.+).

Example 49

5-(4-(4-(2-(4,4-Difluoropiperidin-1-yl)ethoxy)-2,6-difluorophenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one

(242) Following the general procedure of Example 2, the desired product was afforded using the amine prepared in the same manner as described in Preparation Examples 3.4 and 3.5.

(243) LC-MS (ESI, m/z)=511.1 (M+H.sup.+).

Example 50

5-(4-(4-(2-(Diethylamino)ethoxy)-2,6-difluorophenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one

(244) Following the general procedure of Example 2, the desired product was afforded using the amine prepared in the same manner as described in Preparation Examples 3.4 and 3.5.

(245) LC-MS (ESI, m/z)=462.9 (M+H.sup.+).

Example 51

5-(4-(4-(2-(1H-imidazol-1-yl)ethoxy)-2,6-difluorophenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one

(246) Following the general procedure of Example 2, the desired product was afforded using the amine prepared in the same manner as described in Preparation Examples 3.4 and 3.5.

(247) LC-MS (ESI, m/z)=457.9 (M+H.sup.+).

Example 52

5-(4-(2,6-Difluoro-4-((tetrahydrofuran-2-yl)methoxy)phenyl)piperazin-1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one

(248) Following the general procedure of Example 2, the desired product was afforded using the amine prepared in the same manner as described in Preparation Examples 3.4 and 3.5.

(249) LC-MS (ESI, m/z)=448.1 (M+H.sup.+).

Example 53: 6-(4-(2,6-Difluoro-4-(2-methoxyethoxy)phenyl)piperazin-1-yl)-1-methyl-1H[1,2,3]triazolo[4,5-c]pyridin-4(5H)-one

(250) Step 1:

(251) To a mixture of the compound I-15 (195 mg, 0.710 mmol), the amine I-3A (195 mg, 0.852 mmol), sodium tert-butoxide (204.6 mg, 2.130 mmol), BINAP (44.2 mg, 0.035 mmol), Pd.sub.2(dba).sub.3 (32.5 mg, 0.133 mmol) and 1,4-dioxane was added to a sealed tube and heated to 100 C. to 110 C. for 5.5 h. After cooling down to rt, the mixture was filtered through a Celite pad. The filtrate was diluted with EtOAc and washed with water, dried over Na.sub.2SO.sub.4. The organic layer was filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to afford the desired product (160 mg) as a yellow oil.

(252) LC-MS (ESI, m/z)=564.3 (M+H.sup.+).

(253) Step 2:

(254) To a solution of the compound (104 mg, 0.204 mmol) obtained in Step 1 in MeOH (0.68 mL) and CH.sub.2Cl.sub.2 (0.2 mL) was added 10% Pd/C (20 mg) at rt. After stirring at rt for 1 h under hydrogen gas, the mixture was filtered through a Celite pad. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography to afford the desired product (36.7 mg) as a white solid.

(255) LC-MS (ESI, m/z)=474.3 (M+H.sup.+).

Example 54: 6-(4-(2,6-Difluoro-4-(2-morpholinoethoxy)phenyl)piperazin-1-yl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-4(5H)-one

(256) Following the general procedure of Example 53, the desired product was afforded using the amine (I-3F) prepared in Preparation Example 3.10.

(257) LC-MS (ESI, m/z)=476.3 (M+H.sup.+).

Example 55

6-(4-(2,6-Difluoro-4-(2-(piperidin-1-yl)ethoxy)phenyl)piperazin-1-yl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-4(5H)-one

(258) Following the general procedure of Example 53, the desired product was afforded using the amine (I-3B) prepared in Preparation Example 3.4.

(259) LC-MS (ESI, m/z)=474.3 (M+H.sup.+).

Example 56

6-(4-(4-(2-(Dimethylamino)ethoxy)-2,6-difluorophenyl)piperazin-1-yl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-4(5H)-one

(260) Following the general procedure of Example 53, the desired product was afforded using the amine (I-3G) prepared in Preparation Example 3.11.

(261) LC-MS (ESI, m/z)=434.2 (M+H.sup.+).

Example 57: 6-(4-(2,6-Difluoro-4-(2-hydroxyethoxy)phenyl)piperazin-1-yl)-1-methyl-1H[1,2,3]triazolo[4,5-c]pyridin-4(5H)-one

(262) Following the general procedure of Example 53, the desired product was afforded using (1-(4-(2-(benzyl)ethoxy)-2,6-difluorophenyl)piperazine hydrochloride synthesized in the same manner as described in Preparation Example 3.6.

(263) LC-MS (ESI, m/z)=407.1 (M+H.sup.+).

Example 58: (S)-2-(3,5-difluoro-4-(4-(1-methyl-4-oxo-4,5-dihydro-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)piperazin-1-yl)phenoxy)ethyl2-aminopropanoate hydrochloride

(264) The compound obtained in Example 52 was coupled with Boc-L-Ala-OH in the presence of a coupling reagent (PyBOP) followed by Boc deprotection to afford the desired product.

(265) LC-MS (ESI, m/z)=478.2 (M+H.sup.+).

Example 59

6-(4-(4-(2,3-Dihydroxypropoxy)-2,6-difluorophenyl)piperazin-1-yl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-4(5H)-one

(266) The compound I-15 was reacted with 1-(4-(tert-butyldimethylsilyloxy)-2,6-difluorophenyl)piperazine in the same manner as described in Step 1 of Example 53, followed by TBS deprotection and alkylation with (2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate to afford the corresponding alkylated compound. The resulting compound was treated with TFA to remove the protecting group and further reacted in the same manner as described in Step 2 of Example 53 to afford the desired product.

(267) LC-MS (ESI, m/z)=473.2 (M+H.sup.+).

Example 60: 6-(4-(2,6-Difluoro-4-(morpholinomethyl)phenyl)piperazin-1-yl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-4(5H)-one

(268) Following the general procedure of Example 53, the desired product was afforded using the amine prepared in Preparation Example 4.

(269) LC-MS (ESI, m/z)=446.2 (M+H.sup.+).

Example 61: 6-(4-(2,6-Difluoro-4-((4-methylpiperazin-1-yl)methyl)phenyl)piperazin-1-yl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-4(5H)-one

(270) Following the general procedure of Example 53, the desired product was afforded using the amine prepared in the same manner as described in Preparation Example 4.

(271) LC-MS (ESI, m/z)=459.2 (M+H.sup.+).

Example 62: 6-(4-(2,6-Difluoro-4-(oxetan-3-yloxy)phenyl)piperazin-1-yl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-4(5H)-one

(272) Following the general procedure of Example 53, the desired product was afforded using the amine (I-3D) prepared in Preparation Example 3.8.

(273) LC-MS (ESI, m/z)=419.1 (M+H.sup.+).

Example 63: 6-(4-(2,6-Difluoro-4-(1-hydroxyethyl)phenyl)piperazin-1-yl)-1-methyl-1H[1,2,3]triazolo[4,5-c]pyridin-4(5H)-one

(274) The compound obtained in Preparation Example 5.1 was subjected to O-benzylation, followed by Boc deprotection to provide the desired amine product. The resulting amine was reacted with the compound I-15 in the same manner as described in Example 53 to afford the desired product.

(275) LC-MS (ESI, m/z)=391.1 (M+H.sup.+).

Example 64: 6-(4-(2,6-Difluoro-4-(1-methoxyethyl)phenyl)piperazin-1-yl)-1-methyl-1H[1,2,3]triazolo[4,5-c]pyridin-4(5H)-one

(276) Following the general procedure of Example 53, the desired product was afforded using the amine prepared in Preparation Example 6.

(277) LC-MS (ESI, m/z)=405.1 (M+H.sup.+).

Example 65: 6-(4-(2,6-Difluoro-4-(((2-methoxyethyl)(methyl)amino)methyl)phenyl)piperazin-1-yl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-4(5H)-one

(278) Following the general procedure of Example 53, the desired product was afforded using the amine prepared in the same manner as described in Preparation Example 4.

(279) LC-MS (ESI, m/z)=448.2 (M+H.sup.+).

Example 66: 1-Methyl-6-(4-(2-methyl-2H-tetrazol-5-yl)piperidin-1-yl)-1H-[1,2,3]triazolo[4,5-c]pyridin-4(5H)-one

(280) Cs.sub.2CO.sub.3, MeI and THF were added to the compound obtained in Preparation Example 8.1, the resulting mixture was heated to 80 C. for 2 h. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography to provide the Boc-protected amine. After the removal of the Boc group, the resulting amine was reacted with the compound I-15 in the same manner as described in Example 53 to afford the desired product.

(281) LC-MS (ESI, m/z)=316.1 (M+H.sup.+).

Example 67

6-(4-(2,6-Difluoro-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)piperazin-1-yl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-4(5H)-one

(282) Following the general procedure of Example 53, the desired product was afforded using the amine (I-12C) prepared in Preparation Example 12.10.

(283) LC-MS (ESI, m/z)=460.2 (M+H.sup.+).

Example 68: 6-(4-(2,6-Difluoro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)piperazin-1-yl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-4(5H)-one

(284) Following the general procedure of Example 53, the desired product was afforded using the amine (I-12D) prepared in Preparation Example 12.9.

(285) LC-MS (ESI, m/z)=489.3 (M+H.sup.+).

Example 69

6-(4-(2,6-Difluoro-4-(3-(piperidin-1-yl)propoxy)phenyl)piperazin-1-yl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-4(5H)-one

(286) Tert-Butyl 4-(2,6-difluoro-4-(2-hydroxypropoxy)phenyl)piperazine-1-carboxylate compound was subjected to tosylation (TsCl, TEA, DMAP and CH.sub.2Cl.sub.2), substitution with piperidine (piperidine, K.sub.2CO.sub.3 and DMF), and then deprotection of the Boc group to provide the desired amine. The resulting amine compound was reacted with the compound I-15 in the same manner as described in Example 53 to afford the desired product.

(287) LC-MS (ESI, m/z)=488.3 (M+H.sup.+).

Example 70: 6-(4-(2,6-Difluoro-4-(2-oxo-2-(pyrrolidin-1-yl)ethoxy)phenyl)piperazin-1-yl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-4(5H)-one

(288) Following the general procedure of Example 53, the desired product was afforded using the amine (I-12A) prepared in Preparation Example 12.2.

(289) LC-MS (ESI, m/z)=474.2 (M+H.sup.+).

Example 71: 6-(4-(4-(2-Aminoethoxy)-2,6-difluorophenyl)piperazin-1-yl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-4(5H)-one

(290) Following the general procedure of Example 53, the desired product was afforded using the amine (I-12E) prepared in Preparation Example 12.11.

(291) LC-MS (ESI, m/z)=406.2 (M+H.sup.+).

Example 72: 6-(4-(4-(2-(4-Aminopiperidin-1-yl)ethoxy)-2,6-difluorophenyl)piperazin-1-yl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-4(5H)-one

(292) Following the general procedure of Example 53, the desired product was afforded using the amine (I-12G) prepared in Preparation Example 12.13.

(293) LC-MS (ESI, m/z)=489.3 (M+H.sup.+).

Example 73: 5-(4-(2,6-Difluoro-4-(2-methoxyethoxy)phenyl)piperazin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one

(294) Step 1:

(295) To a solution of 2,6-dichloropyrimidin-4-amine (1 g, 6.098 mmol) and 4-dimethylaminopyridine (149 mg, 1.220 mmol) in CH.sub.2Cl.sub.2 (12 mL) was added ditert-butyl dicarbonate (2.66 g, 12.196 mmol). After stirring at rt for 24 h, the reaction mixture was concentrated and the residue was diluted with EtOAc, washed with water and dried over Na.sub.2SO.sub.4. The organic layer was concentrated to afford the residue which was used to the next reaction without further purification.

(296) To a mixture of NaH (330 mg, 6.744 mmol, 55% in mineral oil) in DMF (10 mL) was added dropwise benzylalcohol (0.7 mL, 6.744 mmol) at 0 C. for 30 min. A solution of the crude product (2.047 g, 5.620 mmol) in DMF (6 mL) was added dropwise to the reaction mixture at 0 C. for 10 min. After stirring at rt for 1 h, the reaction mixture was diluted with EtOAc, washed with brine and dried over Na.sub.2SO.sub.4. The organic layer was filtered, concentrated under reduced pressure and the residue was purified by column chromatography to afford the desired product (1.494 g, 3.427 mmol) as a yellow oil.

(297) LC-MS (ESI, m/z)=436.1 (M+H.sup.+).

(298) Step 2:

(299) A mixture of the compound (1.42 g, 3.258 mmol) obtained in Step 1, the compound I-3A (1.21 g, 3.910 mmol), sodium tert-butoxide (626 mg, 6.516 mmol), BINAP (203 mg, 0.326 mmol) and Pd.sub.2(dba).sub.3 (149 mg, 0.163 mmol) in 1,4-dioxane was added to a sealed tube and heated to 100 C. to 110 C. for 17 h. After cooling down to rt, the mixture was filtered through a Celite pad and the residue was diluted with EtOAc. The organic layer was washed with water, dried over Na.sub.2SO.sub.4, and concentrated under reduced pressure. The residue was purified by column chromatography to afford the desired product (371 mg, 0.654 mmol) as a yellow oil.

(300) LC-MS (ESI, m/z)=572.3 (M+H.sup.+).

(301) Step 3:

(302) To a solution of tert-butyl 6-(benzyloxy)-2-(4-(2,6-difluoro-4-(2-methoxyethoxy)phenyl)piperazin-1-yl)pyrimidin-4-ylcarbamate (374 mg, 0.654 mmol) in MeOH (2.2 mL) was added 10% Pd/C. After stirring at rt for 5.5 h under hydrogen gas, the reaction mixture was filtered through a Celite pad. The filtrate was concentrated, and desired product was obtained as a white solid (230 mg, 0.478 mmol) which was used to the next reaction without further purification.

(303) LC-MS (ESI, m/z)=482.2 (M+H.sup.+).

(304) Step 4:

(305) The desired product (154 mg) was afforded as an orange solid from the compound (210 mg) obtained in Step 3 following in the same manner as described in Preparation Example 3.5.

(306) LC-MS (ESI, m/z)=382.1 (M+H.sup.+).

(307) Step 5:

(308) The desired product (145 mg) was afforded as a brown solid from the compound (154 mg) obtained in Step 4 following the same manner as described in the Preparation Example 1.2.

(309) LC-MS (ESI, m/z)=411.1 (M+H.sup.+).

(310) Step 6:

(311) The desired product (21.7 mg) was afforded as a yellow solid from the compound (145 mg) obtained in Step 5 following the same manner as described in the Preparation Example 1.3.

(312) LC-MS (ESI, m/z)=408.2 (M+H.sup.+).

Example 74: Analysis of Activity of Tankyrase 1

(313) Activities of novel compounds synthesized according to Examples 1 to 72 against tankyrase 1 were analyzed using a Trevigen kit (Cat. No. 4700-096-K). Poly PAR histone protein-coated 96-well plate, anti-PAR monoclonal antibody and goat anti-mouse IgG-HRP were used for measurement of absorbance by ELISA method. Specifically, 20 I-PAR assay buffer was diluted to 1 by adding water, and 50 L of the diluted buffer was added to each well of the 96-well plate followed by reacting at rt for 30 min. Then, the supernatant was completely removed from each well and 10 L of 1 I-PAR assay buffer and 15 L of assay substrate were added to each well along with 1 L of a 50 solution of inhibitors to be tested, which were the compounds obtained in the Examples 1 to 72. 10 mUnits/L of tankyrase 1 enzyme was diluted 50-fold with 1 I-PAR assay buffer and 25 L of the diluted enzyme was added to each well and reacted while stirring at rt for 30 min. One without any compound of the present invention was used as a positive control and another containing 1 I-PAR assay buffer with the same volume instead of tankyrase 1 enzyme was used as a negative control. Upon completion of the reaction, 200 L of PBSX, which was prepared by adding 0.1% triton X-100 to PBS, was added and removed and this washing process was repeated twice. Washing was repeated twice more using PBS in the same manner. 5 antibody diluent was diluted with distilled water to 1 concentration, 50 L of the diluted goat anti-mouse IgG-HRP to 1/2000 was added to each well and reacted while stirring at rt for 30 min. Washes were carried out twice using PBSX and PBS, respectively. After adding 50 L of TACS-sapphire to each well of the plate, the plate was blocked from light to react for 10 min to 15 min and the color of the reaction solution turned blue. To stop the reaction, 50 L of 0.2N HCl was added to turn the solution yellow. Finally, the absorbance of the resulting solution was measured at 450 nm.

(314) TABLE-US-00001 TABLE 1 TNKS1 (IC.sub.50) Comp. R group IUPAC name (nM) 1 5-(4-(2-fluorophenyl)piperazin-1-yl)-3- methyl-3H-[1,2,3]triazolo[4,5- d]pyrimidin-7(6H)-one 66.74 2 5-(4-(2,6-difluoro-4-(2- methoxyethoxy)phenyl)piperazin-1-yl)- 3-methyl-3H-[1,2,3]triazolo[4,5- d]pyrimidin-7(6H)-one 29.94 3 0 5-(4-(4-(benzyloxy)-2,6- difluorophenyl)piperazin-1-yl)-3- methyl-3H-[1,2,3]triazolo[4,5- d]pyrimidin-7(6H)-one 207 4 5-(4-(2,6-difluoro-4-(2- morpholinoethoxy)phenyl)piperazin-1- yl)-3-methyl-3H-[1,2,3]triazolo[4,5- d]pyrimidin-7(6H)-one 38.57 5 5-(4-(2,6-difluoro-4-(2-(piperidin-1- yl)ethoxy)phenyl)piperazin-1-yl)-3- methyl-3H-[1,2,3]triazolo[4,5- d]pyrimidin-7(6H)-one 14.25 6 5-(4-(4-(2-(dimethylamino)ethoxy)- 2,6-difluorophenyl)piperazin-1-yl)-3- methyl-3H-[1,2,3]triazolo[4,5- d]pyrimidin-7(6H)-one 16.3 7 5-(4-(2,6-difluoro-4-(2- hydroxyethoxy)phenyl)piperazin-1-yl)- 3-methyl-3H-[1,2,3]triazolo[4,5- d]pyrimidin-7(6H)-one 43.96 8 2-(3,5-difluoro-4-(4-(3-methyl-7-oxo- 6,7-dihydro-3H-[1,2,3]triazolo[4,5- d]pyrimidin-5-yl)piperazin-1- yl)phenoxy)ethyl acetate 46.9 9 5-(4-(2,6-difluoro-4-isopropoxyphenyl) piperazin-1-yl)-3-methyl-3H-[1,2,3] triazolo[4,5-d]pyrimidin-7(6H)-one 60.91 10 (R)-2-(3,5-difluoro-4-(4-(3-methyl-7- oxo-6,7-dihydro-3H-[1,2,3]triazolo[4,5-d] pyrimidin-5-yl)piperazin-1-yl) phenoxy)ethoxy)-1-oxopropan-2- aminium chloride 32.05 11 (S)-2-(3,5-difluoro-4-(4-(3-methyl-7- oxo-6,7-dihydro-3H-[1,2,3]triazolo[4,5-d] pyrimidin-5-yl)piperazin-1-yl) phenoxy)ethoxy)-1-oxopropan-2- aminium chloride 14.54 12 5-[4-(4-(2,3-dihydroxypropoxy)-2,6- difluorophenyl)piperazin-1-yl)-3- methyl-3H-[1,2,3]triazolo[4,5-d] pyrimidin-7(6H)-one 12.94 13 0 5-(4-(2,6-difluoro-4-(morpholinomethyl) phenyl)piperazin-1-yl)-3-methyl-3H- [1,2,3]triazolo[4,5-d]pyrimidin-7(6H)- one 28.01 14 5-(4-(2,6-difluoro-4-((4-methyl piperazin-1-yl)methyl)phenyl)piperazin- 1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d] pyrimidin-7(6H)-one 41.49 15 5-(4-(2,6-difluoro-4-(oxetan-3-yloxy) phenyl)piperazin-1-yl)-3-methyl-3H- [1,2,3]triazolo[4,5-d]pyrimidin-7(6H)- one 24.7 16 5-(4-(4-(1-chloro-3-hydroxypropan-2- yloxy)-2,6-difluorophenyl)piperazin- 1-yl)-3-methyl-3H-[1,2,3]triazolo[4,5- d]pyrimidin-7(6H)-one 28.58 17 5-(4-(2,6-difluoro-4-(1-hydroxyethyl) phenyl)piperazin-1-yl)-3-methyl-3H- [1,2,3]triazolo[4,5-d]pyrimidin-7(6H)- one 17.58 18 5-(4-(2,6-difluoro-4-(1-methoxyethyl) phenyl)piperazin-1-yl)-3-methyl-3H- [1,2,3]triazolo[4,5-d]pyrimidin-7(6H)- one 29.97 19 6-(3,5-difluoro-4-(4-(3-methyl-7-oxo- 6,7-dihydro-3H-[1,2,3]triazo[4,5-d] pyrimidin-5-yl)piperazin-1-yl) phenoxy)hexanoic acid 79.97 20 5-(4-(2,6-difluoro-4-(((2-methoxyethyl) (methyl)amino)methyl)phenyl)piperazin- 1-yl)-3-methyl-3H-[1,2(3]triazolo [4,5-d]pyrimidin-7(6H)-one 83.12 21 5-(4-(2,6-difluorophenyl)piperazin-1- yl)-3-methyl-3H-[1,2,3]triazolo[4,5-d] pyrimidin-7(6H)-one 8.90 22 3-methyl-5-(4-(2,4,6-trifluorophenyl) piperazin-1-yl)-3H-[1,2,3]triazolo[4,5- d]pyrimidin-7(6H)-one 49.68 25 0 5-(4-(2,6-difluoro-4-(2-methoxy ethoxy)phenyl)-4-hydroxy piperidin-1-yl)-3-methyl-3H- [1,2,3]triazolo[4,5-d]pyrimidin- 7(6H)-one 33.12 26 5-(4-(1H-tetrazol-5-yl)piperidin- 1-yl)-3-methyl-3H-[1,2,3]triazolo [4,5-d]pyrimidin-7(6H)-one 411.5 32 5-(4-(2,6-difluoro-4-(2-(4-methyl piperazin-1-yl)ethoxy)phenyl) piperazin-1-yl)-3-methyl-3H- [1,2,3]triazolo[4,5-d]pyrimidin- 7(6H)-one 119.5 33 5-(4-(2,6-difluoro-4-(3-(piperidin- 1-yl)propoxy)phenyl)piperazin-1- yl)-3-methyl-3H-[1,2,3]triazolo [4,5-d]pyrimidin-7(6H)-one 51.3 34 5-(4-(4-(bis(2-methoxyethyl) amino)-2,6-difluorophenyl) piperazin-1-yl)-3-methyl-3H- [1,2,3]triazolo[4,5-d]pyrimidin- 7(6H)-one 67.73 35 5-(4-(2,6-difluoro-4-(2-oxo-2- (piperidin-1-yl)ethoxy)phenyl) piperazin-1-yl)-3-methyl-3H- [1,2,3]triazolo[4,5-d]pyrimidin- 7(6H)-one 48.69 36 5-(4-(2,6-difluoro-4-(2-oxo-2- (pyrrolidin-1-yl)ethoxy)phenyl) piperazin-1-yl)-3-methyl-3H- [1,2,3]triazolo[4,5-d]pyrimidin- 7(6H)-one 39.55 37 5-(4-(4-(2-aminoethoxy)-2,6- difluorophenyl)piperazin-1-yl)- 3-methyl-3H-[1,2,3]triazolo [4,5-d]pyrimidin-7(6H)-one 28.09 38 5-(4-(2,6-difluoro-4-(2-(4- methyl-2-oxopiperazin-1-yl) ethoxy)phenyl)piperazin-1-yl)- 3-methyl-3H-[1,2,3]triazolo [4,5-d]pyrimidin-7(6H)-one 43 39 5-(4-(4-(2-(4-aminopiperidin- 1-yl)ethoxy)-2,6-difluoro phenyl)piperazin-1-yl)-3- methyl-3H-[1,2,3]triazolo [4,5-d]pyrimidin-7(6H)-one 22.74 40 0 5-(4-(2,6-difluoro-4-(3- methoxypropyl)phenyl) piperazin-1-yl)-3-methyl-3H- [1,2,3]triazolo[4,5-d] pyrimidin-7(6H)-one 93.1 41 5-(4-(2,6-difluoro-4-(2-(3- hydroxypyrrolidin-1-yl) ethoxy)phenyl)piperazin-1-yl)- 3-methyl-3H-[1,2,3]triazolo [4,5-d]pyrimidin-7(6H)-one 71.27 42 5-(4-(2,6-difluoro-4-(2-(4- hydroxypiperidin-1-yl)ethoxy) phenyl)piperazin-1-yl)-3- methyl-3H-[1,2,3]triazolo [4,5-d]pyrimidin-7(6H)-one 51.37 43 5-(4-(2,6-difluoro-4-(2-(4- hydroxy-4-methylpiperidin-1- yl)ethoxy)phenyl)piperazin-1- yl)-3-methyl-3H-[1,2,3] triazolo[4,5-d]pyrimidin- 7(6H)-one 50.86 44 5-(4-(2,6-difluoro-4-(2-methoxy ethoxy)phenyl)-5,6-dihydropyridin- 1(2H)-yl)-3-methyl-3H-[1,2,3] triazolo[4,5-d]pyrimidin-7(6H)-one 52.93 45 5-(4-(2,6-difluoro-4-(2-methoxy ethoxy)phenyl)piperidin-1-yl)-3- methyl-3H-[1,2,3]triazolo[4,5-d] pyrimidin-7(6H)-one 37.61 53 6-(4-(2,6-difluoro-4-(2-methoxy ethoxy)phenyl)piperazin-1-yl)-1- methyl-1H-[1,2,3]triazolo[4,5- c]pyridin-4(5H)-one 22.71 54 6-(4-(2,6-difluoro-4-(2-morpholino ethoxy)phenyl)piperazin-1-yl)-1- methyl-1H-[1,2,3]triazolo[4,5- c]pyridin-4(5H)-one 10.96 55 6-(4-(2,6-difluoro-4-(2-(piperidin- 1-yl)ethoxy)phenyl)piperazin-1-yl)- 1-methyl-1H-[1,2,3]triazolo[4,5- c]pyridin-4(5H)-one 29.29 56 0 6-(4-(4-(2-(dimethylamino)ethoxy)- 2,6-difluorophenyl)piperazin-1- yl)-1-methyl-1H-[1,2,3]triazolo[4,5- c]pyridin-4(5H)-one 27.5 57 6-(4-(2,6-difluoro-4-(2-hydroxy ethoxy)phenyl)piperazin-1-yl)-1- methyl-1H-[1,2,3]triazolo[4,5- c]pyridin-4(5H)-one 7.976 58 (S)-2-(3,5-difluoro-4-(4-(1-methyl- 4-oxo-4,5-dihydro-1H-[1,2,3] triazolo[4,5-c]pyridin-6-yl) piperazin-1-yl)phenoxy)ethyl 2- aminopropanoate hydrochloride 13.36 59 6-(4-(4-(2,3-dihydroxypropoxy)- 2,6-difluorophenyl)piperazin-1-yl)- 1-methyl-1H-[1,2,3]triazolo[4,5- c]pyridin-4(5H)-one 15.96 60 6-(4-(2,6-difluoro-4-(morpholino methyl)phenyl)piperazin-1-yl)-1- methyl-1H-[1,2,3]triazolo[4,5- c]pyridin-4(5H)-one 25.78 61 6-(4-(2,6-difluoro-4-((4-methyl piperazin-1-yl)methyl)phenyl) piperazin-1-yl)-1-methyl-1H-[1,2,3] triazolo[4,5-c]pyridin-4(5H)-one 28.23 62 6-(4-(2,6-difluoro-4-(oxetan-3- yloxy)phenyl)piperazin-1-yl)-1- methyl-1H-[1,2,3]triazolo[4,5-c] pyridin-4(5H)-one 22.14 63 6-(4-(2,6-difluoro-4-(1-hydroxy ethyl)phenyl)piperazin-1-yl)-1- methyl-1H-[1,2,3]triazolo[4,5-c] pyridin-4(5H)-one 27.33 64 6-(4-(2,6-difluoro-4-(1-methoxy ethyl)phenyl)piperazin-1-yl)-1- methyl-1H-[1,2,3]triazolo[4,5-c] pyridin-4(5H)-one 31.16 65 6-(4-(2,6-difluoro-4-(((2-methoxy ethyl)(methyl)amino)methyl)phenyl) piperazin-1-yl)-1-methyl-1H-[1,2,3] triazolo[4,5-c]pyridin-4(5H)-one 40.23 66 0 1-methyl-6-(4-(2-methyl-2H- tetrazol-5-yl)piperidin-1-yl)-1H- [1,2,3]triazolo[4,5-c]pyridin-4(5H)- one 330.7 67 6-(4-(2,6-difluoro-4-(2-(pyrrolidin- 1-yl)ethoxy)phenyl)piperazin-1-yl)- 1-methyl-1H-[1,2,3]triazolo[4,5-c] pyridin-4(5H)-one 18.57 68 6-(4-(2,6-difluoro-4-(2-(4- methylpiperazin-1-yl) ethoxy)phenyl)piperazin-1-yl)- 1-methyl-1H-[1,2,3]triazolo [4,5-c]pyridin-4(5H)-one 14.23 69 6-(4-(2,6-difluoro-4-(3- (piperidin-1-yl)propoxy) phenyl)piperazin-1-yl)-1- methyl-1H-[1,2,3]triazolo[4,5- c]pyridin-4(5H)-one 19.1 70 6-(4-(2,6-difluoro-4-(2-oxo- 2-(pyrrolidin-1-yl)ethoxy) phenyl)piperazin-1-yl)-1- methyl-1H-[1,2,3]triazolo[4,5- c]pyridin-4(5H)-one 15.58 71 6-(4-(4-(2-aminoethoxy)-2,6- difluorophenyl)piperazin-1-yl)- 1-methyl-1H-[1,2,3]triazolo [4,5-c]pyridin-4(5H)-one 24.9 72 6-(4-(4-(2-(4-aminopiperidin- 1-yl)ethoxy)-2,6-difluoro phenyl)piperazin-1-yl)-1- methyl-1H-[1,2,3]triazolo[4,5- c]pyridin-4(5H)-one 7.312