Hydroxyl purine compounds and use thereof

Abstract

Disclosed are a series of hydroxyl purine compounds and the use thereof as PDE2 or TNF inhibitors, in particular, the compounds as shown in formula (I), or tautomers or pharmaceutically acceptable salts thereof. ##STR00001##

Claims

1. A compound as shown in Formula (I), tautomers or pharmaceutically acceptable salts thereof, ##STR00155## wherein, ring B is ##STR00156## optionally substituted with 1 to 3 R groups; L is C.sub.1-3 alkyl optionally substituted with 1 to 2 R groups; ring A is 5- to 6-membered aryl or heteroaryl optionally substituted with 1 or 2 R.sub.1 groups; R.sub.1 is selected from the group consisting of halogen, OH, NH.sub.2, and the following groups optionally substituted with 1 to 3 R.sub.2 groups: C.sub.1-6 alkyl or heteroalkyl, 3- to 6-membered cycloalkyl or heterocycloalkyl, or C.sub.1-6 alkyl or heteroalkyl substituted with 3- to 6-membered cycloalkyl or heterocycloalkyl; R.sub.2 is selected from the group consisting of halogen, OH, NH.sub.2, Me, CF.sub.3, OMe, and OCF.sub.3; the hetero represents heteroatoms selected from the group consisting of O, S, and N, and the numbers of heteroatoms on each heteroalkyl or heterocycloalkyl are each independently selected from the group consisting of 1, 2 and 3; R is selected from the group consisting of halogen, N(R)(R), and C.sub.1-3 alkyl or heteroalkyl optionally substituted with 1 to 3 R groups; and R is selected from the group consisting of H, halogen, NH.sub.2, Me, CF.sub.3, OMe, and OCF.sub.3.

2. The compound, tautomers or pharmaceutically acceptable salts thereof according to claim 1, wherein said R.sub.1 is selected from the group consisting of halogen, OH, NH.sub.2, and the following groups optionally substituted with 1 to 3 R.sub.2 groups: C.sub.1-4 alkyl or heteroalkyl, or C.sub.1-3 alkyl or heteroalkyl substituted with 3- to 5-membered cycloalkyl or heterocycloalkyl.

3. The compound, tautomers or pharmaceutically acceptable salts thereof according to claim 1, wherein R is selected from the group consisting of F, Cl, Br, I, Me, ##STR00157##

4. The compound, tautomers or pharmaceutically acceptable salts thereof according to claim 1, wherein, said ring B is ##STR00158## optionally substituted with 1 to 3 R groups.

5. The compound, tautomers or pharmaceutically acceptable salts thereof according to claim 1, wherein, said L is methylene, ##STR00159## optionally substituted with 1 to 2 R groups.

6. The compound, tautomers or pharmaceutically acceptable salts thereof according to claim 1, wherein said ring A is imidazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, or phenyl, optionally substituted with 1 or 2 R.sub.1 groups.

7. The compound, tautomers or pharmaceutically acceptable salts thereof according to claim 6, wherein said ring A is ##STR00160## optionally substituted with 1 or 2 R.sub.1 groups.

8. The compound, tautomers or pharmaceutically acceptable salts thereof according to claim 6, wherein said structural unit ##STR00161## is selected from the group consisting of: ##STR00162##

9. The compound, tautomers or pharmaceutically acceptable salts thereof according to claim 1, wherein said compound is selected from the group consisting of: TABLE-US-00004 Compound Structure 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74

10. A method for treating central diseases, cardiovascular diseases, or inflammatory diseases, the method comprising administering to a patient in need a therapeutically effective amount of the compound, tautomers or pharmaceutically acceptable salts thereof according to claim 1.

11. The compound, tautomers or pharmaceutically acceptable salts thereof according to claim 1, wherein R.sub.1 is selected from the group consisting of Me, CF.sub.3, Et, CH.sub.2CF.sub.3, ##STR00237##

12. The compound, tautomers or pharmaceutically acceptable salts thereof according to claim 1, wherein, said ring B is selected from the group consisting of: ##STR00238##

13. The compound, tautomers or pharmaceutically acceptable salts thereof according to claim 1, wherein, said L is methylene, ##STR00239##

14. The compound, tautomers or pharmaceutically acceptable salts thereof according to claim 6, wherein said ring A is selected from the group consisting of: ##STR00240##

Description

EXAMPLES

(1) The present invention will be described in detail by way of examples, but is not intended to be a limitation to the present invention.

Example 1

3,7-Dimethyl-1-(oxetan-3-ylmethyl)purin-2,6-dione

(2) ##STR00079##

Step 1

Oxetan-3-yl-methyl methanesulfonate

(3) Oxetan-3-yl-methanol (150 mg, 1.70 mmol) and triethylamine (344 mg, 3.40 mmol) were dissolved in methylene chloride (5 mL), and then methanesulfonyl chloride (390 mg, 3.40 mmol) was added at 0 C. The reaction solution was slowly warmed to room temperature and stirred for 2 hours. The reaction was quenched by adding saturated aqueous sodium bicarbonate solution (10 mL), followed by extraction with methylene chloride (10 mL3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to give oxetan-3-yl-methyl methanesulfonate (200 mg, yellow oily) with a yield of 70%. MS-ESI calculated value: [M+H].sup.+ 167; measured value: 167.

Step 2

3,7-Dimethyl-1-(oxetan-3-yl-methyl)purin-2,6-dione

(4) Oxetan-3-yl-methyl methanesulfonate (200 mg, 1.20 mmol), 3,7-dimethyl-1H-purin-2,6(3H,7H)-dione (216 mg, 1.20 mmol), potassium iodide (20.0 mg, 0.120 mmol) and potassium carbonate (250 mg, 1.81 mmol) were dissolved in N,N-dimethylformamide (10 mL). The reaction solution was heated to 120 C. and stirred for 3 hours, and then cooled to room temperature, followed by filtration. The filtrate was concentrated under reduced pressure and purified by preparative high performance liquid chromatography to give 3,7-dimethyl-1-(oxetan-3-yl-methyl)purin-2,6-dione (100 mg), with a yield of 33%.

(5) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 7.87 (s, 1H), 4.74 (t, J=6.8 Hz, 2H), 4.61 (t, J=6.8 Hz, 2H), 4.30 (d, J=6.8 Hz, 2H), 3.96 (s, 3H), 3.51 (s, 3H), 3.42-3.35 (m, 1H). MS-ESI calculated value: [M+H].sup.+ 251; measured value: 251.

Example 2

1-(3-Fluoro-oxetan-3-yl-methyl)-3,7-dimethyl-3,7-dihydro-purin-2,6-dione

(6) ##STR00080##

Step 1

2-((Benzyloxy)methyl)prop-2-enyl-1-ol

(7) In the condition of 0 C., the tetrahydrofuran solution (20 mL) of 2-methylenepropan-1,3-diol (8.00 g, 90.8 mmol) was added into the tetrahydrofuran solution (180 mL) of sodium hydride (3.63 g, 90.8 mmol) dropwise. The reaction solution was stirred at 0 C. for 1 hour. And tetrabutylammonium iodide (33.5 g, 90.8 mmol) and benzyl bromide (15.5 g, 90.8 mmol) were then added. The reaction mixture was allowed for reaction at room temperature for 3 hours. The reaction solution was cooled to 0 C., quenched by adding water (200 mL), and then extracted with ethyl acetate (100 mL3). The organic phases were combined, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and then separated and purified by silica gel column chromatography (3:1 petroleum ether/ethyl acetate) to give 2-((benzyloxy)methyl)prop-2-enyl-1-ol (7.00, colorless liquid) with a yield of 43%.

(8) .sup.1H NMR: (400 MHz, CDCl.sub.3) 7.38-7.30 (m, 5H), 5.22 (s, 1H), 5.16 (s, 1H), 4.53 (s, 2H), 4.20 (s, 2H), 4.10 (s, 2H).

Step 2

3-(Benzyloxy)-2-(bromomethyl)-2-fluoropropan-1-ol

(9) Under the condition of 0 C., triethylamine hydrofluoride (4.50 g, 27.9 mmol) and bromosuccinimide (3.00 g, 16.8 mmol) were added into the methylene chloride solution (30 mL) of 2-((benzyloxy)methyl)prop-2-enyl-1-ol (2.00 g, 11.2 mmol). The reaction solution was stirred at room temperature for 3 hours. The reaction was quenched by adding water (30 mL), followed by extraction with methylene chloride (30 mL2). The organic phases were combined and then washed successively with saturated aqueous sodium bicarbonate solution and saturated brine. Then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and then separated and purified by silica gel column chromatography (5:1 petroleum ether/ethyl acetate) to give 3-(benzyloxy)-2-(bromomethyl)-2-fluoropropan-1-ol (1.40 g, colorless oil) with a yield of 45%.

(10) .sup.1H NMR: (400 MHz, CDCl.sub.3) 7.38-7.31 (m, 5H), 4.60 (s, 2H), 3.89 (d, J=16.0 Hz, 2H), 3.77 (d, J=16.0 Hz, 2H), 3.70-3.65 (m, 2H).

Step 3

3-((Benzyloxy)methyl)-3-fluoropropylene oxide

(11) In the condition of 0 C., sodium hydride (75.0 mg, 1.88 mmol) were added into the anhydrous tetrahydrofuran solution (2 mL) of 3-(benzyloxy)-2-(bromomethyl)-2-fluoropropan-1-ol (200 mg, 0.721 mmol). The reaction solution was stirred overnight under the condition of room temperature. The reaction was quenched by adding ice-cold water (20 mL), followed by extraction with ethyl acetate (10 mL3). The organic phases were combined, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and then separated and purified by silica gel column chromatography (3:1 petroleum ether/ethyl acetate) to give 3-((benzyloxy)methyl)-3-fluoropropylene oxide (42.0 mg, colorless liquid) with a yield of 30%.

(12) .sup.1H NMR: (400 MHz, CDCl.sub.3) 7.40-7.32 (m, 5H), 4.79 (dd, J=20.0, 8.0 Hz, 2H), 4.64 (s, 2H), 4.60 (dd, J=20.0, 8.0 Hz, 2H), 3.82 (d, J=20.0 Hz, 2H).

Step 4

(3-Fluoro-oxetan-3-yl)methanol

(13) After 3-benzyloxymethyl-3-fluoro-oxetane (190 mg, 0.968 mmol) was dissolved in tetrahydrofuran (10 mL), acetic acid (0.25 mL) and dry palladium-carbon (palladium 10%, water 1%, 20 mg) was added. The reaction solution was allowed for reaction at room temperature for 5 hours under hydrogen atmosphere (30 psi). The reaction solution was filtered to give a (3-fluoro-oxetan-3-yl)methanoltetrahydrofuran solution, which was used directly in the next step.

Step 5

Methyl 3-fluoro-oxetan-3-yl-methanesulfonate

(14) Under the protection of nitrogen, triethylamine (298 mg, 2.94 mmol) and methanesulfonyl chloride (225 mg, 1.96 mmol) were added into the tetrahydrofuran solution of (3-fluoro-oxetan-3-yl)methanol (104 mg, 0.980 mmol) obtained in the previous step. The reaction solution was allowed for reaction at room temperature for 3 hours, followed by adding methylene chloride (30 mL). The reaction solution washed successively with 0.5N hydrochloric acid solution (15 mL) and saturated sodium bicarbonate solution (15 mL). The organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give methyl 3-fluoro-oxetan-3-yl-methanesulfonate (102 mg, yellow oil) with a yield of 57%.

(15) .sup.1H NMR: (400 MHz, CDCl.sub.3) 4.84 (dd, J=18.4, 8.4 Hz, 2H), 4.67-4.51 (m, 4H), 3.09 (s, 3H). M MS-ESI calculated value: [M+H].sup.+ 185; measured value: 185.

Step 6

1-(3-Fluoro-oxetan-3-ylmethyl)-3,7-dimethyl-3,7-dihydro-purin-2,6-dione

(16) Methyl 3-fluoro-oxetan-3-yl-methanesulfonate (100 mg, 0.543 mmol) was dissolved in N,N-dimethylformamide (2 mL), followed by adding 3,7-dimethyl-1H-purin-2,6(3H,7H)-dione (97.8 mg, 0.543 mmol), potassium carbonate (150 mg, 1.09 mmol) and potassium iodide (9.0 mg, 0.054 mmol). The reaction solution was heated to 120 C. and stirred for 3 hours, followed by concentration under reduced pressure. The residue was purified by high performance liquid chromatography to give 1-(3-fluoro-oxetan-3-ylmethyl)-3,7-dimethyl-3,7-dihydro-purin-2,6-dione (28.0 mg) with a yield of 19%.

(17) .sup.1H NMR: (400 MHz, CDCl.sub.3) 7.54 (s, 1H), 4.92 (d, J=9.2 Hz, 1H), 4.86 (d, J=9.2 Hz, 1H), 4.80 (d, J=8.8 Hz, 1H), 4.74 (d, J=8.8 Hz, 1H), 4.54 (d, J=10.0 Hz, 2H), 3.99 (s, 3H), 3.59 (s, 3H). MS-ESI calculated value: [M+H].sup.+ 269; measured value: 269.

Example 3

3,7-Dimethyl-1-((3-methyloxetan-3-yl)methyl)-1H-purin-2,6(3H, 7H)-dione

(18) ##STR00081##

(19) The mixture of 3,7-dimethyl-1H-purin-2,6(3H,7H)-dione (200 mg, 1.10 mmol), 3-(chloromethyl)-3-methyloxetane (198 mg, 1.65 mmol), potassium carbonate (304 mg, 2.20 mmol) and iodomethane (18.0 mg, 0.109 mmol) was dissolved in N,N-dimethylformamide (2 mL). The reaction solution was allowed for reaction in a microwave reactor at 130 C. for 15 minutes. The reaction solution was concentrated under reduced pressure, and then separated and purified by preparative high performance liquid chromatography to give 3,7-dimethyl-1-((3-methyloxetan-3-yl)methyl)-1H-purin-2,6(3H,7H)-dione.

(20) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 7.91 (s, 1H), 4.78 (d, J=6.4 Hz, 2H), 4.23 (d, J=6.4 Hz, 2H), 4.13 (s, 2H), 3.99 (s, 3H), 3.54 (s, 3H), 1.36 (s, 3H). MS-ESI calculated value: [M+H].sup.+ 265; measured value: 265.

Example 4

(21) ##STR00082##

Step 1

(3-Ethyloxetan-3-yl)methyl methanesulfonate

(22) (3-Ethyloxetan-3-yl)methanol (64.0 mg, 0.552 mmol) and triethylamine (111 mg, 1.10 mmol) were dissolved in methylene chloride (20 mL), and methanesulfonyl chloride (94.9 mg, 0.829 mmol) was then added under the condition of 0 C. The reaction solution was stirred at room temperature for 2 hours, and then diluted by adding methylene chloride (20 mL), followed by washing with saturated sodium bicarbonate solution (20 mL2). The organic phases were dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and then separated and purified by silica gel column chromatography (4:1 petroleum ether/ethyl acetate, Rf=0.5) to give (3-ethyloxetan-3-yl)methyl methanesulfonate (100 mg, colorless oil) with a yield of 93%.

(23) MS-ESI calculated value: [M+H].sup.+ 195; measured value: 195.

Step 2

1-((3-Ethyloxetan-3-yl)methyl)3,7-dimethyl-1H-purin-2,6(3H,7H)-dione

(24) (3-Ethyloxetan-3-yl)methyl methanesulfonate (100 mg, 0.520 mmol) was dissolved in N,N-dimethylformamide (20 mL). 3,7-dimethyl-1H-purin-2,6(3H,7H)-dione (92.7 mg, 0.520 mmol), potassium carbonate (107 mg, 0.780 mmol) and potassium iodide (86.3 mg, 0.520 mmol) were added into the reaction solution under the condition of room temperature. The reaction solution was heated to 100 C. and allowed for reaction for 2 hours, followed by dilution by adding ethyl acetate (20 mL). The organic phases were washed with saturated sodium bicarbonate solution (20 mL2), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, followed by purification by preparative high performance liquid chromatography to give 1-((3-ethyloxetan-3-yl)methyl)3,7-dimethyl-1H-purin-2,6(3H,7H)-dione (80.0 mg) with a yield of 56%.

(25) .sup.1H NMR: (400 MHz, CDCl.sub.3) 7.53 (s, 1H), 4.62 (d, J=6.4 Hz, 2H), 4.28 (d, J=6.4 Hz, 2H), 4.06 (s, 2H), 3.98 (s, 3H), 3.58 (s, 3H), 1.82 (q, J=7.2 Hz, 2H), 1.06 (t, J=7.2 Hz, 3H). MS-ESI calculated value: [M+H].sup.+ 279; measured value: 279.

Example 5

1-(2-(2-Ethyloxetan-3-yl)ethyl)-3,7-dimethyl-1H-purin-2,6(3H,7H)-dione

(26) ##STR00083##

Step 1

Methyl 2-(2-(benzyloxy)ethyl)-3-oxopentanoate

(27) Sodium hydride (842 mg, 35.1 mmol) was added into the tetrahydrofuran solution (100 mL) of methyl 3-oxopentanoate (3.04 g, 23.4 mmol) at 0 C. The reaction solution was stirred at 0 C. for 1 hour. The tetrahydrofuran solution (10 mL) of ((2-bromoethoxy)-methyl)-benzene (10.0 g, 46.7 mmol) was added dropwise into the reaction solution at 0 C. The reaction solution was stirred at 70 C. for 24 hours and then cooled to 0 C. Then, the reaction was quenched by adding saturated ammonium chloride solution (20 mL), followed by extraction with ethyl acetate (20 mL3). The organic phases were washed with saturated brine (100 mL3), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The concentrate was separated and purified by silica gel column chromatography (20:1 petroleum ether/ethyl acetate, Rf=0.3) to give methyl 2-(2-(benzyloxy)ethyl)-3-oxopentanoate (3.01 g, colorless oily) with a yield of 49%.

Step 2

Methyl 2-(2-(benzyloxy)ethyl)-3-hydroxypentanoate

(28) Methyl 2-(2-(benzyloxy)ethyl)-3-oxopentanoate (2.50 g, 9.47 mmol) was dissolved in methanol (30 mL), and then lithium borohydride (208 mg, 9.47 mmol) was added under the condition of 0 C. The reaction solution was stirred at 25 C. for 1 hour. The reaction was quenched by adding water (10 mL), and then extracted with ethyl acetate (30 mL3). The organic phases were washed with saturated sodium chloride solution (20 mL3), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and then separated and purified by silica gel column chromatography (3:1 petroleum ether/ethyl acetate, Rf=0.5) to give Methyl 2-(2-(benzyloxy)ethyl)-3-hydroxypentanoate (2.01 g, colorless oil) with a yield of 80%.

(29) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 7.35-7.33 (m, 5H), 4.47 (s, 2H), 3.63-3.61 (m, 3H), 3.52-3.49 (m, 1H), 2.62-2.45 (m, 2H), 2.15-1.85 (m, 2H), 1.57-1.25 (m, 3H), 1.00-0.98 (m, 3H).

Step 3

2-(2-(Benzyloxy)ethyl)pentan-1,3-diol

(30) Under the protection of nitrogen, lithium aluminium hydride (323 mg, 8.27 mmol) was slowly added into the tetrahydrofuran solution (100 mL) of methyl 2-(2-(benzyloxy)ethyl)-3-hydroxypentanoate (2.00 g, 7.52 mmol) at 0 C. The reaction solution was stirred at 0 C. for 1 hour. The reaction solution was cooled to 0 C., and then water (0.33 mL), 15% sodium hydroxide solution (0.33 mL) and water (0.99 mL) were slowly added, successively, followed by filtration. The filtrate was concentrated under reduced pressure to give a product 2-(2-(benzyloxy)ethyl)pentan-1,3-diol (1.50 g, yellow oily) with a yield of 76%.

(31) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 7.36-7.28 (m, 5H), 4.52 (s, 2H), 3.66-3.57 (m, 5H), 1.73-1.69 (m, 5H), 1.00-0.95 (m, 3H).

Step 4

2-(2-(benzyloxy)ethyl)-3-hydroxypentyl methanesulfonate

(32) 2-(2-(Benzyloxy)ethyl)pentan-1,3-diol (1.50 g, 6.30 mmol) and triethylamine (1.91 g, 18.9 mmol) were dissolved in methylene chloride (20 mL), and then methanesulfonyl chloride (846 mg, 7.56 mmol) was added slowly at 0 C. The reaction solution was slowly heated to 25 C. and stirred for 0.5 hour. The reaction was quenched by adding water (20 mL), followed by extraction with methylene chloride (30 mL3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL3), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and then purified by silica gel column chromatography (10:1 petroleum ether/ethyl acetate, Rf=0.4) to give a product 2-(2-(benzyloxy)ethyl)-3-hydroxypentyl methanesulfonate (1.50 g, yellow oil) with a yield of 74%.

(33) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 7.34-7.27 (m, 5H), 4.50 (s, 2H), 4.32-4.26 (m, 2H), 3.60-3.50 (m, 3H), 3.00 (s, 3H), 1.96-1.70 (m, 5H), 0.98-0.94 (m, 3H).

Step 5

3-(2-(Benzyloxy)ethyl)-2-ethyloxetane

(34) Sodium hydride (228 mg, 9.49 mmol) was added into the tetrahydrofuran solution (10 mL) of 2-(2-(benzyloxy)ethyl)-3-hydroxypentyl methanesulfonate (1.50 g, 4.75 mmol) at 0 C. The reaction solution was slowly heated to 25 C. and stirred for 12 hours. The reaction was quenched by adding saturated ammonium chloride solution (5 mL), followed by extraction with ethyl acetate (20 mL3). The organic phases were washed with saturated brine (20 mL3), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The concentrate was separated and purified by silica gel column chromatography (15:1 petroleum ether/ethyl acetate, Rf=0.5) to give 3-(2-(benzyloxy)ethyl)-2-ethyloxetane (800 mg, colorless oily) with a yield of 77%.

(35) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 7.37-7.28 (m, 5H), 4.60-4.58 (m, 1H), 4.57-4.56 (m, 1H), 4.48 (s, 2H), 4.44-4.25 (m, 1H), 3.49-3.44 (m, 2H), 2.77-2.75 (m, 1H), 1.98-1.94 (m, 2H), 1.74-1.63 (m, 2H), 0.92-0.88 (m, 3H).

Step 6

2-(2-Ethyloxetan-3-yl)ethanol

(36) 3-(2-(Benzyloxy)ethyl)-2-ethyloxetane (800 mg, 3.64 mmol) was dissolved in the methylene chloride solution (10 mL), and then ferric trichloride (1.17 g, 7.27 mmol) was added. The reaction solution was stirred at 25 C. for 0.5 hour under the protection of nitrogen and then filtered. The filtrate was concentrated under reduced pressure, and then separated and purified by silica gel column chromatography (3:1 petroleum ether/ethyl acetate, Rf=0.5) to give 2-(2-ethyloxetan-3-yl)ethanol (60.0 mg, colorless oil) with a yield of 13%.

(37) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 3.85-3.82 (m, 3H), 3.77-3.75 (m, 2H), 2.08-2.03 (m, 2H), 1.61-1.52 (m, 3H), 1.05-0.96 (m, 3H).

Step 7

2-(2-ethyloxetan-3-yl)ethyl methanesulfonate

(38) 2-(2-Ethyloxetan-3-yl)ethanol (60.0 mg, 0.463 mmol) and triethylamine (93.0 mg, 0.923 mmol) were dissolved in methylene chloride (2 mL), and then methanesulfonyl chloride (62.2 mg, 0.556 mmol) was added slowly at 0 C. The reaction solution was slowly heated to 25 C. and stirred for 0.5 hour. The reaction was quenched by adding water (5 mL), followed by extraction with methylene chloride (10 mL3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL3), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to give a product 2-(2-ethyloxetan-3-yl)ethyl methanesulfonate (40.0 mg, yellow oil) with a yield of 42%.

Step 8

1-(2-(2-Ethyloxetan-3-yl)ethyl)-3,7-dimethyl-1H-purin-2,6(3H,7H)-dione

(39) 2-(2-Ethyloxetan-3-yl)ethyl methanesulfonate (40.0 mg, 0.192 mmol), 3,7-dimethyl-1H-purin-2,6 (3H,7H)-dione (34.6 mg, 0.192 mmol), potassium iodide (3.5 mg, 0.019 mmol) and potassium carbonate (53.0 mg, 0.384 mmol) were dissolved in anhydrous N,N-dimethylformamide (2 mL). The reaction solution was heated to 120 C., and allowed for reaction for 3 hours. The reaction solution was cooled to 20 C. and then filtered. The filtrate was purified by preparative high performance liquid chromatography to give 1-(2-(2-ethyloxetan-3-yl)ethyl)-3,7-dimethyl-1H-purin-2,6(3H,7H)-dione (3.0 mg) with a yield of 5%.

(40) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 7.52 (s, 1H), 4.17-4.14 (m, 1H), 4.00 (s, 3H), 3.98-3.96 (m, 1H), 3.86-3.85 (m, 2H), 3.59 (s, 3H), 3.58-3.57 (m, 1H), 2.41-2.39 (m, 1H), 1.95-1.94 (m, 1H), 1.85-1.81 (m, 1H), 1.60-1.55 (m, 2H), 1.00-0.96 (m, 3H).

(41) MS-ESI calculated value: [M+H].sup.+ 293; measured value: 293.

Example 6

3,7-Dimethyl-1-[3-(3-methyloxetan-3-yl)propyl]purin-2,6-dione

(42) ##STR00084##

Step 1

Ethyl 3-(3-methyloxetan-3-yl)prop-2-enoate

(43) Ethyl 2-ethoxyethyl phosphate (4.03 g, 17.9 mmol) was dissolved in tetrahydrofuran (20 mL), and then sodium-hydrogen (719 mg, 17.9 mmol) was added at 0 C. After reacting for 0.5 hour, 3-methyloxetan-3-formaldehyde (900 mg, 8.99 mmol) was added, followed by reaction at room temperature for 2 hours. The reaction was quenched by adding saturated ammonium chloride solution (10 mL), followed by extraction with ethyl acetate (20 mL3), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and then separated and purified by silica gel column chromatography (10:1 petroleum ether/ethyl acetate, Rf=0.2) to give ethyl 3-(3-methyloxetan-3-yl)prop-2-enoate (800 mg, yellow oily) with a yield of 52%.

(44) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 7.27 (d, J=16.0 Hz, 1H), 5.93 (d, J=16.0 Hz, 1H), 4.67 (d, J=6.0 Hz, 2H), 4.48 (d, J=6.0 Hz, 2H), 4.20 (q, J=7.2 Hz, 2H), 1.53 (s, 3H), 1.29 (t, J=7.2 Hz, 3H).

(45) MS-ESI calculated value: [M+H].sup.+ 171; measured value: 171.

Step 2

Ethyl 3-(3-methyloxetan-3-yl)ethyl propionate

(46) Ethyl 3-(3-methyloxetan-3-yl)prop-2-enoate (550 mg, 3.23 mmol), wet palladium-carbon (100 mg, 3.23 mmol) were mixed and dissolved in tetrahydrofuran (30 mL), and allowed for reaction under hydrogen (15 psi) atmosphere for 12 hours. The reaction solution was filtered and then the filtrate was concentrated under reduced pressure to give ethyl 3-(3-methyloxetan-3-yl)ethyl propionate (500 mg, yellow oily) with a yield of 90%.

(47) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 4.45 (d, J=6.0 Hz, 2H), 4.33 (d, J=6.0 Hz, 2H), 4.14 (q, J=7.2 Hz, 2H), 2.35 (t, J=4.8 Hz, 2H), 1.98 (t, J=4.8 Hz, 2H), 1.31 (s, 3H), 1.25 (t, J=7.2 Hz, 3H).

(48) MS-ESI calculated value: [M+H]*173; measured value: 173.

Step 3

3-(3-Methyloxetan-3-yl)propan-1-ol

(49) Ethyl 3-(3-methyloxetan-3-yl)ethyl propionate (550 mg, 3.19 mmol) was dissolved in tetrahydrofuran (10 mL), and then lithium aluminum hydride (242 mg, 6.38 mmol) was added at 0 C., followed by reaction for 1 hour. The reaction was quenched by adding water (10 mL), followed by extraction with ethyl acetate (10 mL3). The resultant was dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to give 3-(3-methyloxetan-3-yl)propan-1-ol (250 mg, colorless oily) with a yield of 60%.

(50) MS-ESI calculated value: [M+H].sup.+ 131; measured value: 131.

Step 4

3-(3-Methyloxetan-3-yl)propyl methanesulfonate

(51) 3-(3-Methyloxetan-3-yl)propan-1-ol (250 mg, 1.92 mmol) and triethylamine (583 mg, 5.76 mmol) were dissolved in methylene chloride (5 mL), and then methanesulfonyl chloride (659 mg, 5.76 mmol) was added at 0 C. The reaction solution was slowly warmed to room temperature and stirred for 2 hours. The reaction was quenched by adding aqueous sodium bicarbonate solution (10 mL), followed by extraction with methylene chloride (10 mL3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to give 3-(3-methyloxetan-3-yl)propyl methansulfonate (200 mg, yellow oily) with a yield of 50%.

(52) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 4.47 (d, J=6.0 Hz, 2H), 4.37 (d, J=6.0 Hz, 2H), 4.28 (t, J=6.4 Hz, 2H), 3.09 (s, 3H), 1.71-1.50 (m, 4H), 1.31 (s, 3H). MS-ESI calculated value: [M+H].sup.+ 209; measured value: 209.

Step 5

3,7-Dimethyl-1-[3-(3-methyloxetan-3-yl)propyl]purin-2,6-dione

(53) 3-(3-Methyloxetan-3-yl)propyl methansulfonate (200 mg, 0.960 mmol), 3,7-dimethyl-1H-purin-2,6(3H,7H)-dione (173 mg, 0.960 mmol), potassium iodide (15.9 mg, 0.0960 mmol) and potassium carbonate (265 mg, 1.92 mmol) were dissolved in N,N-dimethylformamide (10 mL). The reaction solution was heated to 120 C. and stirred for 3 hours, and then cooled to room temperature, followed by filtration. The filtrate was concentrated under reduced pressure and purified by preparative high performance liquid chromatography to give 3,7-dimethyl-1-[3-(3-methyloxetan-3-yl)propyl]purin-2,6-dione (50.0 mg) with a yield of 18%.

(54) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 7.89 (s, 1H), 4.46 (d, J=6.0 Hz, 2H), 4.36 (d, J=6.0 Hz, 2H), 4.03-3.95 (m, 5H), 3.55 (s, 3H), 1.74-1.61 (m, 4H), 1.31 (s, 3H). MS-ESI calculated value: [M+H].sup.+ 293; measured value: 293.

Example 7

3,7-Dimethyl-1-((tetrahydrofuran-2-yl)methyl)-1H-purin-2,6(3H,7H)-dione

(55) ##STR00085##

(56) The mixture of 3,7-dimethyl-1H-purin-2,6(3H,7H)-dione (538 mg, 2.99 mmol), 2-(chloromethyl)tetrahydrofuran (300 mg, 2.49 mmol), potassium carbonate (688 mg, 4.98 mmol) and iodomethane (41.0 mg, 0.25 mmol) was dissolved in N,N-dimethylformamide (3 mL). The reaction solution was heated to 130 C. and allowed for reaction for 3 hours. The reaction solution was concentrated under reduced pressure, and then was separated and purified by preparative high performance liquid chromatography to give 3,7-dimethyl-1-((tetrahydrofuran-2-yl)methyl)-1H-purin-2,6(3H,7H)-dione (50.0 mg) with a yield of 8%.

(57) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 7.87 (s, 1H), 4.36-4.28 (m, 1H), 4.23-4.16 (m, 1H), 3.97 (s, 3H), 3.93-3.83 (m, 2H), 3.76-3.69 (m, 1H), 3.53 (s, 3H), 2.07-1.86 (m, 3H), 1.79-1.69 (m, 1H).

(58) MS-ESI calculated value: [M+H].sup.+ 265; measured value: 265.

Example 8

(59) ##STR00086##

Step 1

(Tetrahydrofuran-3-yl)methyl methanesulfonate

(60) (Tetrahydrofuran-3-yl)methanol (56.0 mg, 0.552 mmol) and triethylamine (111 mg, 1.10 mmol) were dissolved in methylene chloride (20 mL), and then methanesulfonyl chloride (94.9 mg, 0.829 mmol) was added under the condition of 0 C. The reaction solution was stirred at room temperature for 2 hours, and then diluted by adding methylene chloride (20 mL), followed by washing with saturated sodium bicarbonate solution (20 mL2), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and then separated and purified by silica gel column chromatography (4:1 petroleum ether/ethyl acetate, Rf=0.5) to give (tetrahydrofuran-3-yl)methyl methanesulfonate (90.0 mg, colorless oil) with a yield of 90%.

(61) MS-ESI calculated value: [M+H].sup.+ 181; measured value: 181.

Step 2

3,7-Dimethyl-1-((tetrahydrofuran-3-yl)methyl)-1H-purin-2,6(3H,7H)-dione

(62) (Tetrahydrofuran-3-yl)methyl methanesulfonate (90.0 mg, 0.510 mmol) was dissolved in N,N-dimethylformamide (20 mL). 3,7-Dimethyl-1H-purin-2,6(3H,7H)-dione (92.7 mg, 0.520 mmol), potassium carbonate (107 mg, 0.780 mmol) and potassium iodide (86.3 mg, 0.520 mmol) were added into the reaction solution under the condition of room temperature. The reaction solution was heated to 100 C. and allowed for reaction for 2 hours, followed by dilution by adding ethyl acetate (20 mL). The organic phases were washed with saturated sodium bicarbonate (20 mL2), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, followed by purification by preparative high performance liquid chromatography to give 3,7-dimethyl-1-((tetrahydrofuran-3-yl)methyl)-1H-purin-2,6(3H,7H)-dione (80.0 mg) with a yield of 60%.

(63) .sup.1H NMR: (400 MHz, CDCl.sub.3) 7.49 (s, 1H), 3.95-3.93 (m, 1H), 3.88 (s, 3H), 3.86 (m, 2H), 3.66-3.60 (m, 2H), 3.46-3.45 (m, 1H), 3.42 (s, 3H), 2.62-2.57 (m, 1H), 1.86-1.82 (m, 1H), 1.63-1.58 (m, 1H). MS-ESI calculated value: [M+H].sup.+ 265; measured value: 265.

Example 9

3,7-Dimethyl-1-[2-(2-methyltetrahydrofuran-3-yl)ethyl]purin-2,6-dione

(64) ##STR00087##

Step 1

2-(2-Methyl-3-ylidene)ethyl acetate

(65) Ethyl-2-ethoxyethyl phosphate (2.24 g, 9.98 mmol) was dissolved in tetrahydrofuran (20 mL), and then sodium-hydrogen (399 mg, 9.98 mmol) was added at 0 C. After reacting for 0.5 hour, 2-methyltetrahydrofuran-3-one (500 mg, 4.99 mmol) was added, followed by reaction at room temperature for 2 hours. The reaction was quenched by adding saturated ammonium chloride solution (10 mL), followed by extraction with ethyl acetate (30 mL3), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and then separated and purified by silica gel column chromatography (10:1 petroleum ether/ethyl acetate, Rf=0.6) to give 2-(2-methyl-3-ylidene)ethyl acetate (400 mg, yellow oily) with a yield of 47%.

(66) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 5.76 (s, 1H), 4.45-4.42 (m, 1H), 4.19 (q, J=7.2 Hz, 2H), 4.12-4.09 (m, 1H), 3.80-3.76 (m, 1H), 3.17-3.11 (m, 1H), 2.98-2.92 (m, 1H), 1.34 (d, J=6.0 Hz, 3H), 1.28 (t, J=7.2 Hz, 3H). MS-ESI calculated value: [M+H].sup.+ 171; measured value: 171.

Step 2

2-(2-methyltetrahydrofuran-3-yl)ethyl acetate

(67) 2-(2-Methyl-3-ylidene)ethyl acetate (1.70 g, 9.99 mmol), wet palladium-carbon (100 mg, 3.23 mmol) were mixed and dissolved in tetrahydrofuran (30 mL), and allowed for reaction under hydrogen (15 psi) atmosphere for 12 hours. The reaction solution was filtered and then the filtrate was concentrated under reduced pressure to give ethyl 2-(2-methyltetrahydrofuran-3-yl)ethyl acetate (1.50 g, yellow oily) with a yield of 87%.

(68) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 84.17 (q, J=7.2 Hz, 2H), 3.92-3.55 (m, 3H), 2.62-2.10 (m, 4H), 1.72-1.64 (m, 1H), 1.32-1.22 (m, 6H). MS-ESI calculated value: [M+H].sup.+ 173; measured value: 173.

Step 3

2-(2-Methyltetrahydrofuran-3-yl)ethanol

(69) 2-(2-Methyltetrahydrofuran-3-yl)ethyl acetate (250 mg, 1.45 mmol) was dissolved in tetrahydrofuran (10 mL), and then lithium aluminum hydride (61.0 mg, 1.61 mmol) was added at 0 C., followed by reaction for 1 hour. The reaction was quenched by adding water (10 mL), followed by extraction with ethyl acetate (10 mL3). The resultant was dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to give 2-(2-methyltetrahydrofuran-3-yl)ethanol (180 mg, colorless oily) with a yield of 95%.

(70) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 3.96-3.51 (m, 5H), 2.26-2.08 (m, 2H), 1.77-1.62 (m, 2H), 1.48-1.35 (m, 1H), 1.31-1.13 (m, 3H). MS-ESI calculated value: [M+H].sup.+ 131; measured value: 131.

Step 4

2-(2-Methyltetrahydrofuran-3-yl)ethyl methanesulfonate

(71) 2-(2-Methyltetrahydrofuran-3-yl)ethanol (180 mg, 1.38 mmol) and triethylamine (280 mg, 2.77 mmol)) were dissolved in methylene chloride (5 mL), and then methanesulfonyl chloride (310 mg, 2.71 mmol) was added at 0 C. The reaction solution was slowly warmed to room temperature and stirred for 2 hours. The reaction was quenched by adding aqueous sodium bicarbonate solution (10 mL), followed by extraction with methylene chloride (10 mL3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to give 2-(2-methyltetrahydrofuran-3-yl)ethyl methanesulfonate (200 mg, yellow oily) with a yield of 69%.

(72) MS-ESI calculated value: [M+H].sup.+ 209; measured value: 209.

Step 5

3,7-Dimethyl-1-[2-(2-methyltetrahydrofuran-3-yl)ethyl]purin-2,6-dione

(73) 2-(2-Methyltetrahydrofuran-3-yl)ethyl methanesulfonate (200 mg, 0.960 mmol), 3,7-dimethyl-1H-purin-2,6(3H,7H)-dione (173 mg, 0.960 mmol), potassium iodide (16.0 mg, 0.0960 mmol) and potassium carbonate (200 mg, 1.45 mmol) were dissolved in N,N-dimethylformamide (10 mL). The reaction solution was heated to 120 C. and stirred for 3 hours, and then cooled to room temperature, followed by filtration. The filtrate was concentrated under reduced pressure, and then purified by preparative high performance liquid chromatography to give 3,7-dimethyl-1-[2-(2-methyltetrahydrofuran-3-yl)ethyl]purin-2,6-dione (20.0 mg) with a yield of 7%.

(74) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 7.86 (s, 1H), 4.13-4.03 (m, 3H), 3.99 (s, 3H), 3.95-3.44 (m, 2H), 3.52 (s, 3H), 2.22-1.65 (m, 4H), 1.60-1.53 (m, 1H), 1.25-1.02 (m, 3H). MS-ESI calculated value: [M+H].sup.+ 293; measured value: 293.

Example 10

3,7-Dimethyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-purin-2,6-(3H,7H)-dione

(75) ##STR00088##

Step 1

(Tetrahydro-2H-pyran-4-yl)methyl methanesulfonate

(76) Tetrahydropyran-4-ylmethanol (500 mg, 4.30 mmol) and triethylamine (870 mg, 8.60 mmol) were dissolved in methylene chloride (10 mL), and then methanesulfonyl chloride (985 mg, 8.60 mmol) was added at 0 C., followed by reaction at 25 C. for 1 hour. The reaction was quenched by adding water (10 mL), followed by extraction with methylene chloride (10 mL3), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to give (tetrahydro-2H-pyran-4-yl)methyl methanesulfonate (700 mg, yellow oily) with a yield of 84%.

(77) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 4.10 (d, J=6.4 Hz, 2H), 3.99-3.96 (m, 2H), 3.48-3.42 (m, 2H), 3.09 (s, 3H), 2.05-2.03 (m, 1H), 1.72-1.67 (m, 2H), 1.43-1.39 (m, 2H). MS-ESI calculated value: [M+H].sup.+ 195; measured value: 195.

Step 2

3,7-Dimethyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-purin-2,6-(3H,7H)-dione

(78) (Tetrahydro-2H-pyran-4-yl)methyl methanesulfonate (700 mg, 3.60 mmol), 3,7-dimethyl-1H-purin-2,6-(3H,7H)-dione (649 mg, 3.60 mmol), potassium iodide (119 mg, 0.720 mmol) and potassium carbonate (995 mg, 7.20 mmol) were dissolved in N,N-dimethylformamide (20 mL). The reaction solution was heated to 120 C. and stirred for 3 hours, and then cooled to room temperature, followed by filtration. The filtrate was concentrated under reduced pressure. The residue was washed with methanol (10 mL) to give 3,7-dimethyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-purin-2,6-(3H,7H)-dione (200 mg) with a yield of 20%.

(79) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 7.88 (s, 1H), 3.99 (s, 3H), 3.96-3.91 (m, 4H), 3.54 (s, 3H), 3.40-3.36 (m, 2H), 2.10-2.07 (m, 1H), 1.60-1.56 (m, 2H), 1.46-1.40 (m, 2H). MS-ESI calculated value: [M+H].sup.+ 279; measured value: 279.

Example 11

3,7-Dimethyl-1-((4-methyltetrahydro-2H-pyran-4-yl)methyl)-1H-purin-2,6-(3H,7H)-dione

3,7-Dimethyl-1-(2-(3-methyltetrahydrofuran-3-yl)ethyl)-1H-purin-2,6-(3H,7H)-dione

(80) ##STR00089##

Step 1

Methyl 4-methyltetrahydro-2H-pyran-4-carboxylate

(81) Methyl tetrahydro-2H-pyran-4-carboxylate (2.50 g, 17.3 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL), and then lithium diisopropylamide solution (2M n-hexane solution, 10.4 mL, 20.8 mmol) was slowly added dropwise at 78 C. under the protection of nitrogen. The reaction solution was stirred at 78 C. for 1 hour. Iodomethane (4.92 g, 34.7 mmol) was added slowly, and stirred for 1 hour. The reaction was quenched by adding water (20 mL). The reaction solution was extracted with ethyl acetate (50 mL3). The organic phases were combined, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and then purified by silica gel column chromatography (10:1 petroleum ether/ethyl acetate, Rf=0.4) to give methyl 4-methyltetrahydro-2H-pyran-4-carboxylate (1.20 g, yellow oil) with a yield of 44%.

(82) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 3.79-3.75 (m, 2H), 3.71 (s, 3H), 3.48-3.42 (m, 2H), 2.06-2.02 (m, 2H), 1.51-1.44 (m, 2H), 1.20 (s, 3H).

Step 2

(4-Methyltetrahydro-2H-pyran-4-yl)methanol

(83) Methyl 4-methyltetrahydro-2H-pyran-4-carboxylate (1.20 g, 7.59 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and then lithium aluminum hydride (576 mg, 15.2 mmol) was added at 0 C. The reaction solution was heated to 25 C. and stirred for 1 hour. The reaction was quenched by adding water (20 mL), followed by extraction with ethyl acetate (50 mL3). The resultant was dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and then purified by silica gel column chromatography (1:1 petroleum ether/ethyl acetate, Rf=0.2) to give (4-methyltetrahydro-2H-pyran-4-yl)methanol (700 mg, yellow oil) with a yield of 71%.

(84) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 3.75-3.71 (m, 2H), 3.68-3.66 (m, 2H), 3.33 (s, 2H), 1.62-1.55 (m, 2H), 1.31-1.26 (m, 2H), 1.03 (s, 3H).

Step 3

(4-Methyltetrahydro-2H-pyran-4-yl)methyl methanesulfonate

(85) (4-Methyltetrahydro-2H-pyran-4-yl)methanol (700 mg, 5.38 mmol) was dissolved in methylene chloride (10 mL), and then triethylamine (1.09 g, 10.8 mmol) and methanesulfonyl chloride (739 mg, 6.46 mmol) were added at 0 C. The reaction solution was allowed for reaction at 0 C. for 2 hours. The reaction was quenched by adding saturated aqueous sodium bicarbonate solution (10 mL), followed by extraction with methylene chloride (50 mL3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL3), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to give (4-methyltetrahydro-2H-pyran-4-yl)methyl methanesulfonate (700 mg, yellow oil) with a yield of 63%.

(86) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 4.08 (s, 2H), 3.73-3.71 (m, 2H), 3.68-3.65 (m, 2H), 3.08 (s, 3H), 1.66-1.59 (m, 2H), 1.39-1.35 (m, 2H), 1.12 (s, 3H).

Step 4

3,7-Dimethyl-1-((4-methyltetrahydro-2H-pyran-4-yl)methyl)-1H-purin-2,6-(3H,7H)-dione

3,7-Dimethyl-1-(2-(3-methyltetrahydrofuran-3-yl)ethyl)-1H-purin-2,6-(3H,7H)-dione

(87) (4-Methyltetrahydro-2H-pyran-4-yl)methyl methanesulfonate (300 mg, 1.44 mmol), 3,7-dimethyl-1H-purin-2,6-(3H,7H)-dione (259 mg, 1.44 mmol), potassium iodide (23.9 mg, 0.144 mmol) and potassium carbonate (239 mg, 1.73 mmol) were dissolved in anhydrous N,N-dimethylformamide (10 mL). The reaction solution was heated to 130 C. and allowed for microwave reaction for 2 hours. The reaction solution was cooled to 20 C. and then filtered. The filtrate was purified by preparative high performance liquid chromatography to give 3,7-dimethyl-1-((4-methyltetrahydro-2H-pyran-4-yl)methyl)-1H-purin-2,6-(3H,7H)-dione (Isomer 1) (80.0 mg) with a yield of 19%, and 3,7-dimethyl-1-(2-(3-methyltetrahydrofuran-3-yl)ethyl)-1H-purin-2,6-(3H,7H)-dione (Isomer 2) (90.0 mg) with a yield of 24%.

(88) 3,7-Dimethyl-1-((4-methyltetrahydro-2H-pyran-4-yl)methyl)-1H-purin-2,6-(3H,7H)-dione. .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 7.87 (s, 1H), 3.97 (s, 3H), 3.96 (s, 2H), 3.78-3.74 (m, 2H), 3.66-3.64 (m, 2H), 3.33 (s, 3H), 1.68-1.62 (m, 2H), 1.35-1.31 (m, 2H), 1.02 (s, 3H). MS-ESI calculated value: [M+H].sup.+ 293; measured value: 293.

(89) 3,7-Dimethyl-1-(2-(3-methyltetrahydrofuran-3-yl)ethyl)-1H-purin-2,6-(3H,7H)-dione. .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 7.87 (s, 1H), 4.04-3.99 (m, 2H), 3.92 (s, 3H), 3.90-3.89 (m, 2H), 3.61-3.33 (m, 5H), 1.97-1.93 (m, 1H), 1.77-1.70 (m, 3H), 1.02 (s, 3H). MS-ESI calculated value: [M+H].sup.+ 293; measured value: 293.

Example 12

1-((4-Ethyltetrahydro-2H-pyran-4-yl)methyl)-3,7-dimethyl-1H-purin-2,6-(3H,7H)-dione

1-(2-(3-Ethyltetrahydro-furan-3-yl)ethyl)-3,7-dimethyl-1H-purin-2,6-(3H,7H)-dione

(90) ##STR00090##

Step 1

Methyl 4-ethyltetrahydro-2H-pyran-4-carboxylate

(91) Methyl tetrahydro-2H-pyran-4-carboxylate (2.50 g, 17.3 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL), and then lithium diisopropylamide solution (2M n-hexane solution, 10.4 mL, 20.8 mmol) was slowly added dropwise at 78 C. under the protection of nitrogen. The reaction solution was stirred at 78 C. for 1 hour. Iodoethane (5.41 g, 34.7 mmol) was added slowly and stirred for 1 hour. The reaction was quenched by adding water (20 mL). The reaction solution was extracted with ethyl acetate (50 mL3). The organic phases were combined, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and then purified by silica gel column chromatography (10:1 petroleum ether/ethyl acetate, Rf=0.4) to give methyl 4-ethyltetrahydro-2H-pyran-4-carboxylate (1.00 g, yellow oily) with a yield of 33%.

(92) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 3.84-3.81 (m, 2H), 3.73 (s, 3H), 3.47-3.40 (m, 2H), 2.10-2.06 (m, 2H), 1.53-1.28 (m, 2H), 0.85-0.81 (m, 2H), 1.20 (t, J=7.2 Hz, 3H).

Step 2

(4-Ethyltetrahydro-2H-pyran-4-yl)methanol

(93) Methyl 4-ethyltetrahydro-2H-pyran-4-carboxylate (1.00 g, 5.81 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and then lithium aluminum hydride (220 mg, 5.81 mmol) was added at 0 C. The reaction solution was heated to 25 C. and then stirred for 1 hour. The reaction was quenched by adding water (20 mL), followed by extraction with ethyl acetate (50 mL3). The resultant was dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and then purified by silica gel column chromatography (1:1 petroleum ether/ethyl acetate, Rf=0.2) to give (4-ethyltetrahydro-2H-pyran-4-yl)methanol (600 mg, yellow oil) with a yield of 72%.

(94) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 3.75-3.66 (m, 4H), 3.45 (s, 2H), 1.54-1.50 (m, 4H), 1.42-1.38 (m, 2H), 0.88-0.84 (m, 3H).

Step 3

(4-Ethyltetrahydro-2H-pyran-4-yl)methyl methanesulfonate

(95) (4-Ethyltetrahydro-2H-pyran-4-yl)methanol (600 mg, 4.16 mmol) was dissolved in methylene chloride (10 mL), and then triethylamine (843 mg, 8.32 mmol) and methanesulfonyl chloride (572 mg, 4.99 mmol) were added at 0 C. The reaction solution was allowed for reaction at 0 C. for 2 hours. The reaction was quenched by adding saturated aqueous sodium bicarbonate solution (10 mL), followed by extraction with methylene chloride (50 mL3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL3), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to give (4-ethyltetrahydro-2H-pyran-4-yl)methyl methanesulfonate (600 mg, yellow oil) with a yield of 65%.

(96) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 4.12 (s, 2H), 3.71-3.69 (m, 4H), 3.11 (s, 3H), 1.61-1.52 (m, 4H), 1.28-1.24 (m, 2H), 0.93-0.89 (m, 3H).

Step 4

1-((4-Ethyltetrahydro-2H-pyran-4-yl)methyl)-3,7-dimethyl-1H-purin-2,6-(3H,7H)-dione

1-(2-(3-Ethyltetrahydro-furan-3-yl)ethyl)-3,7-dimethyl-1H-purin-2,6-(3H, 7H)-dione

(97) (4-Ethyltetrahydro-2H-pyran-4-yl)methyl methanesulfonate (300 mg, 1.35 mmol), 3,7-dimethyl-1H-purin-2,6-(3H,7H)-dione (243 mg, 1.35 mmol), potassium iodide (22.4 mg, 0.135 mmol) and potassium carbonate (224 mg, 1.62 mmol) were dissolved in anhydrous N,N-dimethylformamide (10 mL). The reaction solution was heated to 130 C. and allowed for microwave reaction for 2 hours. The reaction solution was cooled to 20 C. and then filtered. The filtrate was purified by preparative high performance liquid chromatography to give 1-((4-ethyltetrahydro-2H-pyran-4-yl)methyl)-3,7-dimethyl-1H-purin-2,6-(3H,7H)-dione (Isomer 1) (120 mg) with a yield of 29%, and 1-(2-(3-ethyltetrahydro-furan-3-yl)ethyl)-3,7-dimethyl-1H-purin-2,6-(3H,7H)-dione (Isomer 2) (80.0 mg) with a yield of 19%.

(98) 1-((4-Ethyltetrahydro-2H-pyran-4-yl)methyl)-3,7-dimethyl-1H-purin-2,6-(3H,7H)-dione. .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 7.88 (s, 1H), 4.03 (s, 2H), 3.98 (s, 3H), 3.73-3.72 (m, 2H), 3.65-3.63 (m, 2H), 3.53 (s, 3H), 1.62-1.52 (m, 4H), 1.52-1.43 (m, 2H), 0.98-0.94 (m, 3H). MS-ESI calculated value: [M+H].sup.+ 307; measured value: 307.

(99) 1-(2-(3-Ethyltetrahydro-furan-3-yl)ethyl)-3,7-dimethyl-1H-purin-2,6-(3H,7H)-dione. .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 7.87 (s, 1H), 4.00-3.98 (m, 5H), 3.87-3.86 (m, 2H), 3.63-3.61 (m, 2H), 3.56 (s, 3H), 1.90-1.80 (m, 1H), 1.75-1.72 (m, 3H), 1.58-1.54 (m, 2H), 1.05-1.01 (m, 3H). MS-ESI calculated value: [M+H].sup.+ 307; measured value: 307.

Example 13

3,7-Dimethyl-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-purin-2,6(3H,7H)-dione

(100) ##STR00091##

(101) 4-(2-Bromoethyl)tetrahydro-2H-pyran (200 mg, 1.00 mmol), 3,7-dimethyl-1H-purin-2,6(3H,7H)-dione (186 mg, 1.00 mmol), potassium iodide (17.0 mg, 0.100 mmol) and potassium carbonate (414 mg, 3.00 mmol) were dissolved in N,N-dimethylformamide (4 mL). The reaction solution was heated to 130 C. and allowed for reaction for 3 hours, and then the reaction solution was than cooled to 25 C. The reaction was quenched by adding saturated brine, followed by extraction with ethyl acetate (50 mL3). The organic phases were dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and then purified by high performance preparative plate (ethyl acetate, Rf=0.5) to give a product 3,7-dimethyl-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-purin-2,6(3H,7H)-dione (224 mg) with a yield of 77%.

(102) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 7.86 (s, 1H), 4.06-4.01 (m, 2H), 3.97 (s, 3H), 3.92 (dd, J=12, 3.2 Hz, 2H), 3.53 (s, 3H), 3.44-3.38 (m, 2H), 1.73 (d, J=12.8 Hz, 2H), 1.61-1.55 (m, 3H), 1.38-1.24 (m, 2H). MS-ESI calculated value: [M+H].sup.+ 293; measured value: 293.

Example 14

1-[2-((2S,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-ethyl]-3,7-dimethyl-1H-2,6(3H,7H)-dione

(103) ##STR00092##

Step 1

2-Methyl-2H-pyran-4(3H)-one

(104) (E)-((4-Methoxy-1,3-dien-2-yl)oxy)trimethylsilane (5.00 g, 29.0 mmol) and acetaldehyde (55.0 g, 58.0 mmol) were dissolved in anhydrous diethyl ether (50 mL), and then boron trifluoride diethyl ether (4.33 g, 30.5 mmol) were added at 78 C. The reaction was conducted at 78 C. for 2.5 hours while stirring, and then quenched by adding saturated ammonium chloride solution (40 mL). The reaction solution was extracted with ethyl acetate (20 mL3), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and then separated and purified by silica gel column chromatography (10:1 petroleum ether/ethyl acetate, Rf=0.6) to give 2-methyl-2H-pyran-4(3H)-one (1.25 g, yellow oil) with a yield of 38%.

(105) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 7.75 (d, J=6.4 Hz, 1H), 5.65 (d, J=6.4 Hz, 1H), 4.63-4.58 (m, 1H), 2.59-2.45 (m, 2H), 1.46 (d, J=3.2 Hz, 3H).

Step 2

(2S,6S)-2,6-dimethyl-tetrahydro-pyran-4-one

(106) Methyllithium (1.6M diethyl ether solution, 20.9 mL, 33.4 mmol) was dissolved in anhydrous diethyl ether solution (30 mL) at 0 C., and then copper iodide (4.25 g, 22.3 mmol) was added under the protection of nitrogen. The reaction solution was allowed for reaction at 0 C. for 0.5 hour. The diethyl ether solution (5 mL) of 2-methyl-2H-pyran-4(3H)-one (1.25 g, 11.2 mmol) was added slowly. The reaction solution was heated to 20 C. and then stirred for 3 hours. The reaction was quenched by adding saturated ammonium chloride solution (20 mL), followed by extraction with ethyl acetate (20 mL3), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and then separated and purified by silica gel column chromatography (10:1 petroleum ether/ethyl acetate, Rf=0.3) to give (2S,6S)-2,6-dimethyl-tetrahydro-pyran-4-one (400 mg, yellow solid) with a yield of 29%.

(107) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 4.36-4.31 (m, 2H), 2.58-2.53 (m, 2H), 2.28-2.25 (m, 2H), 1.25 (d, J=6.0 Hz, 6H).

Step 3

(2,6-Dimethyl-tetrahydro-pyran-4-ylidene)-ethyl acetate

(108) Triphenylphosphine ethyl acetate (3.26 g, 9.37 mmol) was dissolved in anhydrous toluene (10 mL), and then ((2S,6S)-2,6-dimethyl-tetrahydro-pyran-4-one (400 mg, 3.13 mmol) was added. The reaction solution was heated to 110 C., allowed for reaction for 72 hours, and then cooled to 20 C. The reaction was quenched by adding water (50 mL), followed by extraction with ethyl acetate (20 mL3), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and then purified by silica gel column chromatography (10:1 petroleum ether/ethyl acetate, Rf=0.7) to give (2,6-dimethyl-tetrahydro-pyran-4-ylidene)-ethyl acetate (200 mg, yellow oil) with a yield of 32%.

(109) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 5.77 (s, 1H), 4.14-4.07 (m, 4H), 2.98-2.97 (m, 1H), 2.84-2.82 (m, 1H), 2.44-2.40 (m, 1H), 2.11-2.09 (m, 1H), 1.28-1.25 (m, 3H), 1.18-1.16 (m, 6H).

Step 4

(2,6-Dimethyl-tetrahydro-pyran-4-yl)-ethyl acetate

(110) (2,6-Dimethyl-tetrahydro-pyran-4-ylidene)-ethyl acetate (200 mg, 1.01 mmol) was dissolved in ethyl acetate solution (20 mL), and then wet palladium-carbon (10%, 20.0 mg) was added. The reaction solution was stirred at 25 C. for 2 hours under hydrogen pressure. The reaction solution was filtered and then the filtrate was concentrated under reduced pressure to give (2,6-dimethyl-tetrahydro-pyran-4-yl)-ethyl acetate (150 mg, yellow oil) with a yield of 75%.

(111) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 4.20-4.10 (m, 3H), 3.83-3.82 (m, 1H), 2.28-2.21 (m, 3H), 1.72-1.69 (m, 1H), 1.58-1.55 (m, 1H), 1.31-1.30 (m, 1H), 1.28-1.26 (m, 6H), 1.12-1.11 (m, 1H), 1.02-1.01 (m, 3H).

Step 5

2-(2,6-Dimethyl-tetrahydro-pyran-4-yl)-ethanol

(112) (2,6-Dimethyl-tetrahydro-pyran-4-yl)-ethyl acetate (150 mg, 0.750 mmol) was dissolved in anhydrous tetrahydrofuran (2 mL), and then lithium aluminum hydride (57.0 mg, 1.50 mmol) was added at 0 C. The reaction solution was heated to 25 C. and then stirred for 1 hour. The reaction was quenched by adding water (10 mL), followed by extraction with ethyl acetate (10 mL3), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and purified by preparative TLC plate (3:1 petroleum ether/ethyl acetate, Rf=0.5) to give 2-(2,6-dimethyl-tetrahydro-pyran-4-yl)-ethanol (70.0 mg, yellow oil) with a yield of 86%.

(113) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 4.20-4.18 (m, 1H), 3.83-3.81 (m, 1H), 3.64-3.61 (m, 2H), 1.99-1.98 (m, 1H), 1.70-1.68 (m, 1H), 1.55-1.53 (m, 1H), 1.47-1.42 (m, 3H), 1.31-1.29 (m, 3H), 1.13-1.11 (m, 3H), 0.85-0.82 (m, 1H).

Step 6

2-((2S,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)ethyl methanesulfonate

(114) 2-(2,6-Dimethyl-tetrahydro-pyran-4-yl)-ethanol (150 mg, 0.949 mmol) was dissolved in methylene chloride (5 mL), and then triethylamine (287 mg, 2.85 mmol) and methanesulfonyl chloride (213 mg, 1.90 mmol) were added at 0 C. The reaction solution was allowed for reaction at 25 C. for 2 hours. The reaction was quenched by adding saturated aqueous sodium bicarbonate solution (10 mL), followed by extraction with methylene chloride (10 mL3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to give 2-((2S,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)ethyl methanesulfonate (200 mg, yellow oil) with a yield of 90%.

(115) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 4.33-4.30 (m, 2H), 4.23-4.20 (m, 1H), 3.85-3.82 (m, 1H), 3.08 (s, 3H), 2.03-2.14 (m, 1H), 1.68-1.67 (m, 1H), 1.65-1.63 (m, 2H), 1.58-1.56 (m, 1H), 1.41-1.39 (m, 1H), 1.31-1.29 (m, 3H), 1.14-1.12 (m, 3H), 0.89-0.86 (m, 1H).

Step 7

1-[2-((2S,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-ethyl]-3,7-dimethyl-1H-2,6 (3H,7H)-dione

(116) 2-((2S,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)ethyl methanesulfonate (100 mg, 0.424 mmol), 3,7-dimethyl-3,7-dihydro-purin-2,6-dione (83.9 mg, 0.466 mmol), potassium iodide (7.4 mg, 0.047 mmol) and potassium carbonate (109 mg, 0.790 mmol) were dissolved in N,N-dimethylformamide (3 mL). The reaction solution was heated to 120 C. and allowed for reaction for 3 hours. The reaction solution was then cooled to 20 C. and filtered. The filtrate was separated and purified by preparative high performance liquid chromatography to give 1-[2-((2S,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-ethyl]-3,7-dimethyl-1H-2,6(3H,7H)-dione (40.0 mg) with a yield of 30%.

(117) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 8.14 (s, 1H), 4.21-4.18 (m, 1H), 4.07-4.05 (m, 2H), 4.01 (s, 3H), 3.82-3.81 (m, 1H), 3.54 (s, 3H), 1.85-1.66 (m, 1H), 1.55-1.51 (m, 2H), 1.40-1.39 (m, 2H), 1.29-1.28 (m, 1H), 1.27-1.26 (m, 3H), 1.12-1.11 (m, 3H), 0.89-0.86 (m, 1H). MS-ESI calculated value: [M+H].sup.+ 321; measured value: 321.

Example 15

1-(2-(3-Ethyltetrahydro-2H-pyran-4-yl)ethyl)-3,7-dimethyl-1H-purin-2,6-(3H,7H)-dione

(118) ##STR00093##

Step 1

3-Ethyldihydro-2H-pyran-4-(3H)-one

(119) Dihydro-2H-pyran-4-(3H)-one (5.00 g, 50.0 mmol) and hexamethylphosphoramide (8.95 g, 50.0 mmol) were dissolved in tetrahydrofuran (50 mL) and then lithium diisopropylamide (50 mL, 2.0 M tetrahydrofuran solution, 100 mmol) was slowly added dropwise under the condition of 78 C., followed by stirred for 30 minutes under the condition of 78 C. Iodoethane (16.2 g, 75.0 mmol) was added into the reaction solution under the condition of 0 C. and then stirred for 2 hours. Water (15 mL) was added into the reaction solution, which was then extracted with ethyl acetate (40 mL3). The organic phases were combined and washed with saturated sodium chloride (20 mL2), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and then separated and purified by silica gel column chromatography (10:1 petroleum ether/ethyl acetate, Rf=0.5) to give 3-ethyldihydro-2H-pyran-4-(3H)-one (1.20 g, colorless oil) with a yield of 19%.

(120) .sup.1H NMR: (400 MHz, CDCl.sub.3) 4.15-4.11 (m, 2H), 3.77-3.76 (m, 1H), 3.47-3.42 (m, 1H), 2.45-2.40 (m, 3H), 1.80-1.78 (m, 2H), 0.91 (t, J=7.2 Hz, 3H). MS-ESI calculated value: [M+H].sup.+ 129; measured value: 129.

Step 2

Ethyl 2-(3-ethyldihydro-2H-pyran-4(3H)-ylidene)ethyl acetate

(121) 3-Ethyldihydro-2H-pyran-4(3H)-one (600 mg, 4.68 mmol) and ethyl 2-(diethoxyphosphoryl)ethyl acetate (1.15 g, 5.15 mmol) were dissolved in tetrahydrofuran (30 mL). Sodium hydride (224 mg, 9.36 mmol) was added into the reaction solution under the condition of 0 C. After stirring at room temperature for 30 minutes, water (10 mL) was added into the reaction solution under the condition of 0 C. The reaction solution was diluted by adding ethyl acetate (30 mL). The organic phases were washed with water (20 mL2), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and then separated and purified by silica gel column chromatography (10:1 petroleum ether/ethyl acetate, Rf 0.7) to give ethyl 2-(3-ethyldihydro-2H-pyran-4(3H)-ylidene)ethyl acetate (800 mg, yellow oil) with a yield of 86%.

(122) MS-ESI calculated value: [M+H].sup.+ 199; measured value: 199.

Step 3

2-(3-Ethyltetrahydro-2H-pyran-4-yl)ethyl acetate

(123) Ethyl 2-(3-ethyldihydro-2H-pyran-4(3H)-ylidene)ethyl acetate (800 mg, 4.04 mmol) was dissolved in methanol (40 mL), and wet palladium-carbon (10%, 0.02 g) was then added under the condition of room temperature. The reaction system was subjected to hydrogen replacement for 3 times and then allowed for reaction at room temperature for 2 hours. The reaction solution was filtered, followed by concentration to give 2-(3-ethyltetrahydro-2H-pyran-4-yl)ethyl acetate (600 mg, yellow oil) with a yield of 74%. MS-ESI calculated value: [M+H].sup.+ 201; measured value: 201.

Step 4

2-(3-Ethyltetrahydro-2H-pyran-4-yl)ethanol

(124) 2-(3-Ethyltetrahydro-2H-pyran-4-yl)ethyl acetate (600 mg, 3.00 mmol) was dissolved in tetrahydrofuran (30 mL), and then lithium aluminium hydride (170 mg, 4.50 mmol) was added under the condition of 0 C. After stirring at room temperature for 2 hours, water (0.2 mL), 15% sodium hydroxide (0.2 mL) and water (0.6 mL) were added into the reaction solution, respectively, followed by stirring for 20 minutes. The reaction solution was diluted by adding ethyl acetate (30 mL). The organic phase was washed with water (20 mL2), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to give 2-(3-ethyltetrahydro-2H-pyran-4-yl)ethanol (400 mg, yellow oil) with a yield of 84%.

(125) MS-ESI calculated value: [M+H].sup.+ 159; measured value: 159.

Step 5

2-(3-Ethyltetrahydro-2H-pyran-4-yl)ethyl methanesulfonate

(126) 2-(3-Ethyltetrahydro-2H-pyran-4-yl)ethanol (474 mg, 3.00 mmol) and triethylamine (455 mg, 4.50 mmol) were dissolved in methylene chloride (30 mL). methanesulfonyl chloride (412 mg, 3.60 mmol) was added into the reaction solution under the condition of 0 C., followed by stirring at 0 C. for 2 hours. The reaction solution was diluted by adding methylene chloride (30 mL). The organic phase was washed with water (20 mL2), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to give 2-(3-ethyltetrahydro-2H-pyran-4-yl)ethyl methanesulfonate (600 mg, yellow oil) with a yield of 85%. MS-ESI calculated value: [M+H].sup.+ 237; measured value: 237.

Step 6

1-(2-(3-Ethyltetrahydro-2H-pyran-4-yl)ethyl)-3,7-dimethyl-1H-purin-2,6-(3H,7H)-dione

(127) 2-(3-Ethyltetrahydro-2H-pyran-4-yl)ethyl methanesulfonate (400 mg, 1.69 mmol) and 3,7-dimethyl-1H-purin-2,6-(3H,7H)-dione (305 mg, 1.69 mmol) were dissolved in N,N-dimethylformamide (20 mL), and then potassium carbonate (467 mg, 3.38 mmol) and potassium iodide (28.0 mg, 0.169 mmol) were added under the condition of room temperature. The reaction solution was stirred for 2 hours under the condition of 100 C. The reaction solution was then cooled to room temperature for concentration and diluted by adding ethyl acetate (30 mL). The organic phase was washed with water (20 mL2), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, followed by purification by preparative high performance liquid chromatography to give 1-(2-(3-ethyltetrahydro-2H-pyran-4-yl)ethyl)-3,7-dimethyl-1H-purin-2,6-(3H,7H)-dione (200 mg) with a yield of 37%.

(128) .sup.1H NMR: (400 MHz, CDCl.sub.3) 7.49 (s, 1H), 3.97-3.95 (m, 5H), 3.83-3.77 (m, 2H), 3.43 (s, 3H), 3.42-3.35 (m, 2H), 1.79-1.41 (m, 8H), 0.91-0.82 (m, 3H). MS-ESI calculated value: [M+H].sup.+ 321; measured value: 321.

Example 16

1-(2-(2-Methyltetrahydro-2H-pyran-4-yl)ethyl)-3,7-dimethyl-1H-purin-2,6(3H,7H)-dione

(129) ##STR00094##

Step 1

2-(2-Methyltetrahydro-2H-pyran-4-yl)ethyl methanesulfonate

(130) 2-(2-Methyltetrahydro-2H-pyran-4-yl)ethanol (100 mg, 0.630 mmol) and N,N-diisopropylethylamine (122 mg, 0.940 mmol) were dissolved in methylene chloride (20 mL), and then methanesulfonyl chloride (86.9 mg, 0.750 mmol) was added at 0 C. After stirring at 25 C. for 0.5 hour, the reaction solution was diluted by adding methylene chloride (20 mL), and washed with saturated sodium bicarbonate (30 mL2). The organic phases were dried over anhydrous sodium sulfate for concentration to give 2-(2-methyltetrahydro-2H-pyran-4-yl)ethyl methanesulfonate (180 mg, yellow oil) with a yield of 100%.

Step 2

1-(2-(2-Methyltetrahydro-2H-pyran-4-yl)ethyl)-3,7-dimethyl-1H-purin-2,6(3H,7H)-dione

(131) 2-(2-Methyltetrahydro-2H-pyran-4-yl)ethyl methanesulfonate (180 mg, 0.760 mmol) was dissolved in N,N-dimethylformamide (10 mL), and then 3,7-dimethyl-1H-purin-2,6(3H,7H)-dione (146 mg, 0.800 mmol), potassium iodide (13.0 mg, 0.0800 mmol) and potassium carbonate (211 mg, 1.60 mmol) were added into the reaction solution under the condition of 25 C. The reaction solution was heated to 120 C., allowed for reaction for 2 hours, and then diluted by adding ethyl acetate (30 mL), followed by washing with saturated sodium bicarbonate (20 mL2). The organic phases were dried over anhydrous sodium sulfate for concentration to obtain a yellow oil, which was separated and purified by high performance liquid chromatography to give 1-(2-(2-methyltetrahydro-2H-pyran-4-yl)ethyl)-3,7-dimethyl-1H-purin-2,6(3H,7H)-dione (50.0 mg) with a yield of 20%.

(132) .sup.1H NMR: (400 MHz, Methanol-d.sub.4) 7.87 (s, 1H), 4.05-3.96 (m, 6H), 3.54-3.19 (m, 5H), 1.80-1.45 (m, 8H), 0.98-0.92 (m, 4H). MS-ESI calculated value: [M+H].sup.+ 321; measured value: 321.

Example 17

3,7-Dimethyl-1-(2-morpholinoethyl)-purin-2,6-dione

(133) ##STR00095##

(134) At room temperature, potassium carbonate (138 mg, 1.03 mmol) and potassium iodide (86.3 mg, 0.517 mmol) were added into the acetonitrile solution (2 mL) of the mixture of 1-(3-chloropropyl)-3,7-dimethyl-purin-2,6(3H,7H)-dione (71.9 mg, 0.826 mmol) and morpholine (50.0 mg, 0.207 mmol). The reaction solution was stirred at 90 C. for 4 hours. The reaction was quenched by adding water (5 mL), followed by extraction with ethyl acetate (5 mL3). The organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The concentrate was separated and purified by preparative high performance liquid chromatography to give 3,7-dimethyl-1-(2-morpholinoethyl)-purin-2,6-dione (15.0 mg) with a yield of 25%. .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 7.86 (s, 1H), 4.16 (t, J=6.4 Hz, 2H), 3.97 (s, 3H), 3.68-3.65 (m, 4H), 3.52 (s, 3H), 2.65-2.57 (m, 6H). MS-ESI calculated value: [M+H].sup.+ 294; measured value: 294.

Example 18

((-4-Methoxyphenyl)methyl)-3,7-dimethyl-1H-purin-2,6-(3H,7H)-dione

(135) ##STR00096##

Step 1

4-Methoxycyclohexanecarboxylate

(136) 4-Methoxycyclohexanecarboxylic acid (300 mg, 1.90 mmol) was dissolved in methanol (7 mL), and then thionyl chloride (1.13 g, 9.50 mmol) was added slowly at 0 C. The reaction solution was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure to give a crude product 4-methoxycyclohexanecarboxylate (283 mg, yellow oily) with a yield of 86%.

(137) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 3.65 (s, 3H), 3.41-3.35 (m, 1H), 3.30 (s, 3H), 2.44-2.38 (m, 1H), 1.84-1.75 (m, 4H), 1.67-1.54 (m, 4H)

Step 2

(4-Methoxycyclohexyl)methanol

(138) Lithium aluminum hydride (92.8 mg, 2.45 mmol) was slowly added into the tetrahydrofuran (7 mL) containing methyl-4-methoxycyclohexanecarboxylic acid (280 mg, 1.63 mmol) at 0 C. under the protection of nitrogen. The reaction solution was stirred at room temperature for 4 hours, and then cooled to 0 C. in an ice-water bath. Water (0.1 mL), 15% sodium hydroxide (0.1 mL) and water (0.3 mL) was slowly added successively. The reaction solution was heated to room temperature, and then stirred for half an hour, followed by filtration. The filter cake was washed with tetrahydrofuran (8 mL2) and the filtrate was concentrated under reduced pressure to give (4-methoxycyclohexyl)methanol (213 mg, yellow oily) with a yield of 91%. .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 3.49-3.45 (m, 1H), 3.39-3.37 (m, 2H), 3.32 (s, 3H), 1.95-1.80 (m, 3H), 1.56-1.48 (m, 4H), 1.36-1.27 (m, 2H).

Step 3

(4-Methoxycyclohexyl)methyl methanesulfonate

(139) (4-Methoxycyclohexyl)methanol (210 mg, 1.46 mmol) and triethylamine (443 mg, 4.38 mmol) were dissolved in methylene chloride (7 mL), and then methanesulfonyl chloride (250 mg, 2.19 mmol) was added slowly at 0 C. The reaction solution was stirred overnight at room temperature, followed by adding water, and extraction with methylene chloride (50 mL3). The organic phases were washed with saturated brine (25 mL2), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to give a product which was then purified by silica gel column chromatography (5:1 petroleum ether/ethyl acetate, Rf=0.4) to give a product (4-methoxycyclohexyl)methyl methanesulfonate (240 mg, yellow oily) with a yield of 74%. .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 4.07 (d, J=6.4 Hz, 2H), 3.51-3.47 (m, 1H), 3.32 (s, 3H), 3.07 (s, 3H), 1.98-1.92 (m, 2H), 1.85-1.78 (m, 1H), 1.63-1.36 (m, 6H).

Step 4

1((-4-Methoxycyclohexyl)methyl)-3,7-dimethyl-1H-purin-2,6-(3H,7H)-dione

(140) (4-Methoxycyclohexyl)methyl methanesulfonate (240 mg, 1.08 mmol), 3,7-dimethyl-1H-purin-2,6-(3H,7H)-dione (233 mg, 1.30 mmol) and potassium iodide (17.9 mg, 0.108 mmol) were dissolved in N,N-dimethylformamide (5 mL), and then potassium carbonate (298 mg, 2.16 mmol) was added. The reaction solution was heated and refluxed at 130 C. for 4 hours. Then, the reaction solution was cooled to room temperature and then filtered. The filtrate was concentrated under reduced pressure to give a product which was then purified by preparative high performance liquid chromatography to give a product 1((-4-methoxycyclohexyl)methyl)-3,7-dimethyl-1H-purin-2,6-(3H,7H)-dione (67.0 mg) with a yield of 20%. .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 7.88 (s, 1H), 3.99 (s, 3H), 3.89 (d, J=7.2 Hz, 2H), 3.54 (s, 3H), 3.47-3.42 (m, 1H), 3.32 (s, 3H), 1.94-1.87 (m, 3H), 1.47-1.39 (m, 6H). MS-ESI calculated value: [M+H].sup.+ 307; measured value: 307.

Example 19

3-Methyl-1-((3-methyloxetan-3-yl)methyl)-7-(2,2,2-trifluoroethyl)-1H-purin-2,6(3H,7H)-dione

(141) ##STR00097##

Step 1

3-Methyl-1-((3-methyloxetan-3-yl)methyl)-7-(2,2,2-trifluoroethyl)-1H-purin-2,6 (3H,7H)-dione

(142) 3-Methyl-7-(2,2,2-trifluoroethyl)-1H-purin-2,6(3H,7H)-dione (200 mg, 0.806 mmol), 3-(chloromethyl)-3-methyloxetane (97.2 mg, 0.806 mmol) and potassium iodide (13.4 mg, 0.0806 mmol) were dissolved in N,N-dimethylformamide (5 mL), and then potassium carbonate (223 mg, 1.61 mmol) was added. The reaction solution was heated and refluxed at 130 C. for 2.5 hours. Then, the reaction solution was cooled to 25 C. and then filtered. The filtrate was concentrated under reduced pressure to give a product which was then purified by preparative high performance liquid chromatography to give a product 3-methyl-1-((3-methyloxetan-3-yl)methyl)-7-(2,2,2-trifluoroethyl)-1H-purin-2,6(3H,7H)-dione (48.0 mg) with a yield of 18%. .sup.1H NMR: (400M Hz, Methonal-d.sub.4) 8.09 (s, 1H), 5.25-5.18 (m, 2H), 4.75 (d, J=6.4 Hz, 2H), 4.23 (d, J=6.4 Hz, 2H), 4.15 (s, 2H), 3.56 (s, 3H), 1.35 (s, 3H).

(143) MS-ESI calculated value: [M+H].sup.+ 333; measured value: 333.

Example 20

1-(2-((2R,6R)-2,6-dimethyltetrahydro-2H-pyran-4-yl)ethyl)-3-methyl-7-(2,2,2-trifluoroethyl)-1H-purin-2,6 (3H,7H)-dione

(144) ##STR00098##

(145) 3-Methyl-7-(2,2,2-trifluoroethyl)-1H-purin-2,6(3H,7H)-dione (100 mg, 0.4 mmol), potassium iodide (7.0 mg, 0.040 mmol) and potassium carbonate (165 mg, 1.20 mmol) were dissolved in N,N-dimethylformamide (3 mL). The reaction solution was heated to 130 C. and allowed for reaction for 1 hour. 2-((2S,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)ethyl methanesulfonate (50.0 mg, 0.200 mmol) was then added, and the reaction was continued at 130 C. 2.5 hours. The reaction solution was filtered directly and the filtrate was concentrated under reduced pressure. The crude product obtained was purified by preparative high performance liquid chromatography to give a product 1-(2-((2R,6R)-2,6-dimethyltetrahydro-2H-pyran-4-yl)ethyl)-3-methyl-7-(2,2,2-trifluoroethyl)-1H-purin-2,6 (3H,7H)-dione (68.0 mg) with a yield of 87%. .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 8.08 (s, 1H), 5.27-5.21 (m, 2H), 4.22-4.15 (m, 1H), 4.10-4.03 (m, 2H), 3.80-3.75 (m, 1H), 3.57 (s, 3H), 1.95-1.30 (m, 7H) 1.28 (d, J=6.8 Hz, 3H), 1.12 (d, J=6.8 Hz, 3H). MS-ESI calculated value: [M+H].sup.+ 389; measured value: 389.

Example 21

1-(2-((2R,6R)-2,6-dimethyltetrahydro-2H-pyran-4-yl)ethyl)yl-7-isopropyl-3-methyl-1H-purin-2,6(3H,7H)-dione

(146) ##STR00099##

(147) 2-((2S,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)ethyl methanesulfonate (100 mg, 0.424 mmol), 7-isopropyl-3-methyl-1H-purin-2,6(3H,7H)-dione (100 mg, 0.466 mmol), potassium iodide (7.4 mg, 0.047 mmol) and potassium carbonate (109 mg, 0.790 mmol) were dissolved in anhydrous N,N-dimethylformamide (3 mL). The reaction solution was heated to 120 C. and stirred for 3 hours. The reaction solution was cooled to 20 C. and then filtered. The filtrate was separated and purified by preparative high performance liquid chromatography to give 1-(2-((2R,6R)-2,6-dimethyltetrahydro-2H-pyran-4-yl)ethyl)yl-7-isopropyl-3-methyl-1H-purin-2,6(3H,7H)-dione (70.0 mg) with a yield of 46%.

(148) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 8.92 (s, 1H), 5.21-5.15 (m, 1H), 4.21-4.09 (m, 1H), 4.08-4.06 (m, 2H), 4.05-4.04 (m, 1H), 3.58 (s, 3H), 1.86-1.80 (m, 1H), 1.68-1.66 (m, 2H), 1.65-1.64 (m, 6H), 1.57-1.55 (m, 2H), 1.54-1.52 (m, 1H), 1.30-1.28 (m, 3H), 1.13-1.12 (m, 3H), 0.90-0.87 (m, 1H).

(149) MS-ESI calculated value: [M+H].sup.+ 349; measured value: 349.

Example 22

7-(Cyclopropylmethyl)-3-methyl-1-((3-methyloxetan-3-yl)methyl)-1H-purin-2,6(3H,7H)-dione

(150) ##STR00100##

Step 1

7-(Cyclopropylmethyl)-3-methyl-1-((3-methyloxetan-3-yl)methyl)-1H-purin-2,6 (3H,7H)-dione

(151) 7-(Cyclopropylmethyl)-3-methyl-1H-purin-2,6(3H,7H)-dione (250 mg, 1.14 mmol), 3-(chloromethyl)-3-methyloxetane (137 mg, 1.14 mmol) and potassium iodide (18.9 mg, 0.114 mmol) were dissolved in N,N-dimethylformamide (5 mL), and then potassium carbonate (315 mg, 2.28 mmol) was added. The reaction solution was heated and refluxed at 130 C. for 2.5 hours. Then, the reaction solution was cooled to 25 C. and then filtered. The filtrate was concentrated under reduced pressure to give a product which was then purified by preparative high performance liquid chromatography to give a product 7-(cyclopropylmethyl)-3-methyl-1-((3-methyloxetan-3-yl)methyl)-1H-purin-2,6(3H, 7H)-dione (55.0 mg) with a yield of 16%. .sup.1H NMR: (400M Hz, Methonal-d.sub.4) 8.01 (s, 1H), 4.76 (d, J=6.4 Hz, 2H), 4.24-4.18 (m, 4H), 4.14 (s, 2H), 3.55 (s, 3H), 1.39-1.33 (m, 4H), 0.62-0.56 (m, 2H), 0.48-0.43 (m, 2H). MS-ESI calculated value: [M+H].sup.+ 305; measured value: 305.

Example 23

7-(Cyclopropylmethyl-1-(2-((2R,6R)-2,6-dimethyltetrahydro-2H-pyran-4-yl)ethyl-3-methyl-1H-purin-2,6(3H,7H)-dione

(152) ##STR00101##

(153) ((2S,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)ethyl methanesulfonate (100 mg, 0.424 mmol) and 7-(cyclopropylmethyl)-3-methyl-1H-purin-2,6(3H,7H)-dione (102 mg, 0.466 mmol) were dissolved in N,N-dimethylformamide (3 mL), and then potassium carbonate (109 mg, 0.790 mmol) and potassium iodide (7.4 mg, 0.047 mmol) were added under the protection of nitrogen. The reaction solution was heated to 120 C. and stirred for 3 hours. After being cooled to 20 C., the mixture was filtered. The filtrate was separated and purified by preparative high performance liquid chromatography to give 7-(cyclopropylmethyl)-1-(2-((2R,6R)-2,6-dimethyltetrahydro-2H-pyran-4-yl)ethyl)-3-methyl-1H-purin-2,6(3H,7H)-dione (70.0 mg) with a yield of 46%.

(154) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 8.02 (s, 1H), 4.25-4.21 (m, 3H), 4.20-4.19 (m, 2H), 4.08-4.02 (m, 1H), 3.55 (s, 3H), 1.87-1.80 (m, 1H), 1.66-1.56 (m, 2H), 1.54-1.50 (m, 2H), 1.42-1.40 (m, 2H), 1.29-1.27 (m, 3H), 1.13-1.12 (m, 3H), 0.89-0.86 (m, 1H), 0.63-0.60 (m, 2H), 0.49-0.47 (m, 2H).

(155) MS-ESI calculated value: [M+H].sup.+ 361; measured value: 361.

Example 24

7-(Cyclopropylmethyl)-1-((4-methoxycyclohexyl)methyl)-3-methyl-purin-2,6-dione

(156) ##STR00102##

Step 1

7-(Cyclopropylmethyl)-1-((4-methoxycyclohexyl)methyl)-3-methyl-purin-2,6-dione

(157) (4-Methoxycyclohexyl)methyl methanesulfonate (30.0 mg, 0.135 mmol), 7-(cyclopropylmethyl)-3-methyl-purin-2,6-dione (26.8 mg, 0.121 mmol), potassium iodide (2.2 mg, 0.014 mmol) and potassium carbonate (37.3 mg, 0.269 mmol) were dissolved in N,N-dimethylformamide (5 mL). The reaction solution was heated to 120 C. and stirred for 3 hours, and then cooled to room temperature, followed by filtration. The filtrate was concentrated under reduced pressure, and the residue was then purified by preparative high performance liquid chromatography to give 7-(cyclopropylmethyl)-1-((4-methoxycyclohexyl)methyl)-3-methyl-purin-2,6-dione (20.0 mg) with a yield of 43%. .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 8.01 (s, 1H), 4.20 (d, J=7.2 Hz, 2H), 3.88 (d, J=16.0 Hz, 2H), 3.56 (s, 3H), 3.34 (s, 3H), 3.17-3.14 (m, 1H), 2.09-2.06 (m, 2H), 1.75-1.73 (m, 3H), 1.41-1.39 (m, 1H), 1.34-1.10 (m, 4H), 0.63-0.61 (m, 2H), 0.48-0.47 (m, 2H).

(158) MS-ESI calculated value: [M+H].sup.+ 347; measured value: 347.

Example 25

7-Isobutyl-3-methyl-1-((3-methyloxetan-3-yl)methyl)-1H-purin-2,6(3H,7H)-dione

(159) ##STR00103##

Step 1

7-Isobutyl-3-methyl-1-((3-methyloxetan-3-yl)methyl)-1H-purin-2,6(3H,7H)-dione

(160) 7-Isobutyl-3-methyl-1H-purin-2,6(3H,7H)-dione (200 mg, 0.900 mmol), 3-(chloromethyl)-3-methyloxetane (109 mg, 0.900 mmol) and potassium iodide (14.9 mg, 0.0900 mmol) were dissolved in N,N-dimethylformamide (5 mL), and then potassium carbonate (249 mg, 1.80 mmol) was added. The reaction solution was heated and refluxed at 130 C. for 2.5 hours. Then, the reaction solution was cooled to 25 C. and then filtered. The filtrate was concentrated under reduced pressure to give a product which was then purified by preparative high performance liquid chromatography to give a product 7-isobutyl-3-methyl-1-((3-methyloxetan-3-yl)methyl)-1H-purin-2,6(3H,7H)-dione (34.0 mg) with a yield of 12%. .sup.1H NMR: (400M Hz, Methonal-d.sub.4) 7.95 (s, 1H), 4.75 (d, J=1.2 Hz, 2H), 4.22 (d, J=6.4 Hz, 2H), 4.15-4.12 (m, 4H), 3.55 (s, 3H), 2.23-2.12 (m, 1H), 1.35 (s, 3H), 0.92 (d, J=6.8 Hz, 6H). MS-ESI calculated value: [M+H].sup.+ 307; measured value: 307.

Example 26

1-(2-((2R,6R)-2,6-dimethyltetrahydro-2H-pyran-4-yl)ethyl)-7-isobutyl-3-methyl-1H-purin-2,6(3H, 7H)-dione

(161) ##STR00104##

(162) 7-Isobutyl-3-methyl-1H-purin-2,6(3H,7H)-dione (90.0 mg, 0.400 mmol), potassium iodide (7.0 mg, 0.040 mmol) and potassium carbonate (165 mg, 1.20 mmol) were dissolved in N,N-dimethylformamide (3 mL). The reaction solution was heated to 130 C. and allowed for reaction for 1 hour. 2-((2S,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)ethyl methanesulfonate (50.0 mg, 0.200 mmol) was then added, and the reaction was continued at 130 C. for 2.5 hours. The reaction solution was filtered directly and the filtrate was concentrated under reduced pressure. The crude product obtained was purified by preparative high performance liquid chromatography to give a product 1-(2-((2R,6R)-2,6-dimethyltetrahydro-2H-pyran-4-yl)ethyl)-7-isobutyl-3-methyl-1H-purin-2,6(3H, 7H)-dione (71.0 mg) with a yield of 97%.

(163) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 7.93 (s, 1H), 4.24-3.98 (m, 5H), 3.86-3.78 (m, 1H), 3.55 (s, 3H), 2.26-2.16 (m, 1H), 1.79-1.77 (m, 1H), 1.72-1.65 (m, 1H), 1.60-1.47 (m, 2H), 1.45-1.38 (m, 1H), 1.28 (d, J=6.8 Hz, 3H), 1.12 (d, J=6.8 Hz, 3H), 0.94-0.88 (m, 8H). MS-ESI calculated value: [M+H].sup.+ 363; measured value: 363.

Example 27

4-Methyl-6-((3-methyloxetan-3-yl)methyl)-1-(2,2,2-trifluoroethyl)-pyrazolo[4,3-d]pyrimidin-5,7-dione

(164) ##STR00105## ##STR00106##

Step 1

Methyl 4-nitro-pyrazol-5-carboxylate

(165) 4-Nitro-pyrazol-5-carboxylic acid (45.0 g, 286 mmol) was dissolved in methanol (700 mL), and then thionyl chloride (102 g, 859 mmol) was added dropwise at 0 C. The reaction solution was allowed for reaction at 25 C. while stirring for 18 hours. The reaction solution was concentrated under reduced pressure to give methyl 4-nitro-pyrazol-5-carboxylate (49.0 g, white solid) with a yield of 100%. .sup.1H NMR: (400 MHz, CDCl.sub.3) 8.53 (s, 1H), 4.06 (s, 3H). MS-ESI calculated value: [M+H].sup.+ 172; measured value: 172.

Step 2

Methyl 4-nitro-1-(2,2,2-trifluoroethyl)-pyrazol-5-carboxylate

(166) Methyl 4-nitro-pyrazol-5-carboxylate (25.0 g, 146 mmol) was dissolved in N,N-dimethylformamide (350 mL), and then sodium hydride (6.43 g, 161 mmol) was added in batches at 0 C. After reaction at 0 C. while stirring for 1 hour, 2,2,2-trifluoroethyl trifluoromethanesulfonate (33.9 g, 146 mmol) was added dropwise. The reaction solution was allowed for reaction at 25 C. while stirring for 18 hours. Then, water (1.2 L) was added into the reaction solution, and the reaction solution was extracted with ethyl acetate (300 mL2). The organic phases were combined, washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, and the filtered. The filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (5:1 petroleum ether/ethyl acetate, Rf=0.3) to give methyl 4-nitro-1-(2,2,2-trifluoroethyl)-pyrazol-5-carboxylate (8.00 g, colorless oil) with a yield of 22%. .sup.1H NMR: (400 MHz, CDCl.sub.3) 8.13 (s, 1H), 5.06 (q, J=8.0 Hz, 2H), 4.04 (s, 3H). MS-ESI calculated value: [M+H].sup.+ 254; measured value: 254.

Step 3

Methyl 4-amino-1-(2,2,2-trifluoroethyl)-pyrazol-5-carboxylate

(167) Methyl 4-nitro-1-(2,2,2-trifluoroethyl)-pyrazol-5-carboxylate (7.50 g, 29.6 mmol) was dissolved in methanol (100 mL), and then dry palladium-carbon (palladium 10%, water 1%, 750 mg) was added. The reaction solution was allowed for reaction at room temperature for 3 hours under 40 psi hydrogen pressure. The reaction solution was filtered and then the filtrate was concentrated under reduced pressure to give methyl 4-amino-1-(2,2,2-trifluoroethyl)-pyrazol-5-carboxylate (6.30 g, similar white solid) with a yield of 95%.

(168) .sup.1H NMR: (400 MHz, CDCl.sub.3) 7.25 (s, 1H), 5.10 (q, J=8.4 Hz, 2H), 4.21 (s, 2H), 3.94 (s, 3H).

(169) MS-ESI calculated value: [M+H].sup.+ 224; measured value: 224.

Step 4

Methyl 4-(2,2,2-trifluoroacetamide)-1-(2,2,2-trifluoroethyl)-pyrazol-5-carboxylate

(170) Methyl 4-amino-1-(2,2,2-trifluoroethyl)-pyrazol-5-carboxylate (6.30 g, 28.2 mmol) was dissolved in methylene chloride (100 mL), and then trifluoroacetic anhydride (8.89 g, 42.4 mmol) was added dropwise under the protection of nitrogen. The reaction solution was stirred at room temperature for 2 hours. The reaction was quenched by adding saturated sodium bicarbonate solution (100 mL), followed by extraction with methylene chloride (100 mL) and washing with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give methyl 4-(2,2,2-trifluoroacetamide)-1-(2,2,2-trifluoroethyl)-pyrazol-5-carboxylate (9.20 g crude product, yellow oil). .sup.1H NMR: (400 MHz, CDCl.sub.3) 9.66 (s, 1H), 8.45 (s, 1H), 5.18 (q, J=8.0 Hz, 2H), 4.06 (s, 3H). MS-ESI calculated value: [M+H].sup.+ 320; measured value: 320.

Step 5

Methyl 4-(2,2,2-trifluoro-N-methylacetamide)-1-(2,2,2-trifluoroethyl)-pyrazol-5-carboxylate

(171) Methyl 4-(2,2,2-trifluoroacetamide)-1-(2,2,2-trifluoroethyl)-pyrazol-5-carboxylate (9.20 g, 28.8 mmol) was dissolved in N,N-dimethylformamide (50 mL), and then potassium carbonate (5.98 g, 43.3 mmol) was added. The reaction solution was heated to 80 C., allowed for reaction for 1 hour, and then cooled to room temperature, followed by adding iodomethane (6.14 g, 43.2 mmol). The reaction solution was stirred at room temperature for 18 hours. Water (300 mL) was added into the reaction solution, followed by extraction with ethyl acetate (100 mL3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure to give methyl 4-(2,2,2-trifluoro-N-methylacetamide)-1-(2,2,2-trifluoroethyl)-pyrazol-5-carboxylate (9.80 g crude product, yellow oil). .sup.1H NMR: (400 MHz, CDCl.sub.3) 7.65 (s, 1H), 5.45-5.15 (m, 2H), 3.93 (s, 3H), 3.29 (s, 3H). MS-ESI calculated value: [M+H].sup.+ 334; measured value: 334.

Step 6

4-[(Tert-butoxycarbonyl)(methyl)amino]-1-(2,2,2-trifluoroethyl)-pyrazol-5-carboxylic acid

(172) Methyl 4-(2,2,2-trifluoro-N-methylacetamide)-1-(2,2,2-trifluoroethyl)-pyrazol-5-carboxylate (9.90 g, 29.7 mmol) was dissolved in tetrahydrofuran (40 mL) and water (40 mL), and then lithium hydroxide monohydrate (6.23 g, 0.149 mol) was added, allowing for reaction at room temperature while stirring for 18 hours. After adding di-tert-butyl dicarbonate (13.0 g, 59.4 mmol), the reaction solution was allowed for reaction at room temperature for 6 hours. The reaction solution was concentrated under reduced pressure, followed by adjusting the pH value to pH=4 with 2N hydrochloric acid solution, and then filtered. The filter cake was dried to give 4-[(tert-butoxycarbonyl)(methyl)amino]-1-(2,2,2-trifluoroethyl)-pyrazol-5-carboxylic acid (8.00 g, white solid) with a yield of 83%. .sup.1H NMR: (400 MHz, CDCl.sub.3) 7.58 (s, 1H), 5.25 (q, J=8.0 Hz, 2H), 3.27 (s, 3H), 1.42 (s, 9H). MS-ESI calculated value: [M+H].sup.+ 324; measured value: 324.

Step 7

4-[(Tert-butoxycarbonyl)(methyl)amino]-1-(2,2,2-trifluoroethyl)-pyrazol-5-carboxamide

(173) 4-[Tert-butoxycarbonyl(methyl)amino]-2-(2,2,2-trifluoroethyl)pyrazole-5-carboxylic acid, 2-(7-azobenzotriazole)-tetramethyluronium hexafluorophosphate (13.8 g, 36.2 mmol) and ammonium chloride (2.98 g, 55.7 mmol) were dissolved in methylene chloride (120 mL), and then triethylamine (4.23 g, 41.8 mmol) was added dropwise at room temperature. The reaction solution was stirred at room temperature for 18 hours. Then, water (100 mL) was added into the reaction solution, followed by extraction with methylene chloride (100 mL2). The organic phases were combined, washed successively with saturated sodium bicarbonate (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, the residue was treated with ethanol (20 mL) to give 4-[(tert-butoxycarbonyl)(methyl)amino]-1-(2,2,2-trifluoroethyl)-pyrazol-5-carboxamide (6.00 g, white solid) with a yield of 67%. .sup.1H NMR: (400 MHz, CDCl.sub.3) 7.54 (s, 1H), 5.25 (q, J=8.0 Hz, 2H), 3.22 (s, 3H), 1.48 (s, 9H). MS-ESI calculated value: [M+H].sup.+ 323; measured value: 323.

Step 8

4-(Methylamino)-2-(2,2,2-trifluoroethyl)pyrazole-5-carboxamide

(174) 4-[(Tert-butoxycarbonyl)(methyl)amino]-1-(2,2,2-trifluoroethyl)-pyrazol-5-carboxamide (5.00 g, 15.51 mmol) was dissolved in hydrochloric acid-ethyl acetate (50 mL). After reacting at room temperature while stirring for 18 hours, the reaction solution was concentrated under reduced pressure. The residue was dissolved by methanol (50 mL), and then potassium carbonate (5.36 g, 38.8 mmol) was added. The reaction solution was stirred at room temperature for 2 hours, and then concentrated under reduced pressure. The residue was extracted with methylene chloride (100 mL) and filtered. The filtrate was spin-dried to give 4-(methylamino)-2-(2,2,2-trifluoroethyl)pyrazole-5-carboxamide (2.90 g, white solid) with a yield of 84%. .sup.1H NMR: (400 MHz, Methanol-d.sub.4) 7.93 (s, 1H), 5.26 (q, J=8.4 Hz, 2H), 3.13 (s, 3H).

(175) MS-ESI calculated value: [M+H].sup.+ 223; measured value: 223.

Step 9

4-Methyl-1-(2,2,2-trifluoroethyl)-pyrazolo[4,3-d]pyrimidin-5,7-dione

(176) 4-(Methylamino)-2-(2,2,2-trifluoroethyl)pyrazole-5-carboxamide (2.70 g, 12.2 mmol) and 1,1-carbonyldiimidazole (3.94 g, 24.3 mmol) were dissolved in N,N-dimethylformamide (20 mL). The reaction solution was heated to 140 C. and allowed for reaction for 1 hour. After cooling to room temperature, water (100 mL) was added into the reaction solution. The solid was precipitated and collected by filtration. The filter cake was dried to give 4-methyl-1-(2,2,2-trifluoroethyl)-pyrazolo[4,3-d]pyrimidin-5,7-dione (1.80 g, white solid) with a yield of 60%. .sup.1H NMR: (400 MHz, DMSO-d.sub.6) 11.56 (s, 1H), 7.95 (s, 1H), 5.35 (q, J=8.8 Hz, 2H), 3.33 (s, 3H). MS-ESI calculated value: [M+H].sup.+ 249; measured value: 249.

Step 10

4-Methyl-6-((3-methyloxetan-3-yl)methyl)-1-(2,2,2-trifluoroethyl)-pyrazolo[4,3-d]pyrimidin-5,7-dione

(177) 4-Methyl-1-(2,2,2-trifluoroethyl)pyrazolo[4,3-d]pyrimidin-5,7-dione (70.0 mg, 0.282 mmol) was dissolved in N,N-dimethylformamide (2 mL), and then 3-(chloromethyl)-3-methyl-oxetane (40.8 mg, 0.338 mmol), potassium carbonate (78.0 mg, 0.564 mmol) and potassium iodide (56.2 mg, 0.338 mmol) were added. The reaction solution was heated to 120 C. and then stirred for 1 hour. The reaction solution was cooled to room temperature, and the filtered. The filtrate was concentrated under reduced pressure, the residue was purified by high performance liquid chromatography to give 4-methyl-6-[(3-methyloxetan-3-yl)methyl]-1-(2,2,2-trifluoroethyl)pyrazolo[4,3-d]pyrimidin-5,7-di one (30.0 mg) with a yield of 32%. .sup.1H NMR: (400 MHz, CDCl.sub.3) 7.57 (s, 1H), 5.21 (q, J=8.0 Hz, 2H), 4.72 (d, J=6.0 Hz, 2H), 4.26 (d, J=6.0 Hz, 2H), 4.16 (s, 2H), 3.52 (s, 3H), 1.40 (s, 3H).

(178) MS-ESI calculated value: [M+H].sup.+ 333; measured value: 333.

Example 28

6-((3-Ethyloxetan-3-yl)methyl)-4-methyl-1-(2,2,2-trifluoroethyl)-pyrazolo[4,3-d]pyrimidin-5,7-dione

(179) ##STR00107##

Step 1

(3-Ethyloxetan-3-yl)methyl methanesulfonate

(180) (3-Ethyloxetan-3-yl)methanol (1.00 g, 8.61 mmol) and triethylamine (1.74 g, 17.2 mmol) were dissolved in anhydrous methylene chloride (15 mL), and then methanesulfonyl chloride (1.28 g, 11.2 mmol) was slowly added at 0 C. under the protection of nitrogen. The reaction solution was stirred at 0 C. for 1 hour. The reaction was quenched by adding saturated sodium bicarbonate solution (50 mL), followed by extraction with methylene chloride (20 mL2). The organic phases were combined, washed with saturated sodium chloride solution (50 mL2), dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to give (3-ethyloxetan-3-yl)methyl methanesulfonate (1.30 g, yellow oily) with a yield of 78%. MS-ESI calculated value: [M+H].sup.+ 195; measured value: 195.

Step 2

6-((3-Ethyloxetan-3-yl)methyl)-4-methyl-1-(2,2,2-trifluoroethyl)-pyrazolo[4,3-d]pyrimidin-5,7-dione

(181) 4-Methyl-1-(2,2,2-trifluoroethyl)pyrazolo[4,3-d]pyrimidin-5,7-dione (30.0 mg, 0.121 mmol), (3-ethyloxetan-3-yl)methyl methanesulfonate (35.2 mg, 0.181 mmol), potassium carbonate (33.2 mg, 0.242 mmol) and potassium iodide (4.0 mg, 0.024 mmol) were dissolved in N,N-dimethylformamide (10 mL). The reaction solution was heated to 120 C. and stirred for 3 hours. The reaction solution was cooled to room temperature, and poured into water (30 mL), followed by extraction with ethyl acetate (20 mL3). The organic phases were combined, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrate and the crude product was separated and purified by preparative high performance liquid chromatography to give 6-((3-ethyloxetan-3-yl)methyl)-4-methyl-1-(2,2,2-trifluoroethyl)-pyrazolo[4,3-d]pyrimidin-5,7-dione (10 mg) with a yield of 24%. .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 7.86 (s, 1H), 5.37-5.31 (m, 2H), 4.64 (d, J=6.4 Hz, 2H), 4.30 (d, J=6.4 Hz, 2H), 4.14 (s, 2H), 3.54 (s, 3H), 1.84-1.79 (m, 2H), 1.07 (t, J=7.2 Hz, 3H). MS-ESI calculated value: [M+H].sup.+ 347; measured value: 347.

Example 29

4-Methyl-6-((tetrahydrofuran-3-yl)methyl)-1-(2,2,2-trifluoroethyl)-pyrazolo[4,3-d]pyrimidin-5,7-dione

(182) ##STR00108##

Step 1

4-Methyl-6-((tetrahydrofuran-3-yl)methyl)-1-(2,2,2-trifluoroethyl)-pyrazolo[4,3-d]pyrimidin-5,7-dione

(183) Tetrahydrofuran-3-yl-methyl methanesulfonate (30.0 mg, 0.166 mmol), 4-methyl-1-(2,2,2-trifluoroethyl)pyrazolo[4,3-d]pyrimidin-5,7-dione (41.3 mg, 0.166 mmol), potassium carbonate (46.0 mg, 0.333 mmol) and potassium iodide (5.5 mg, 0.033 mmol) were dissolved in N,N-dimethylformamide (5 mL). The reaction solution was heated to 120 C. and stirred for 3 hours. Then, the reaction solution was cooled to room temperature, and poured into water (20 mL), followed by extraction with ethyl acetate (20 mL3). The organic phases were combined, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated and then separated and purified by preparative high performance liquid chromatography to give 4-methyl-6-((tetrahydrofuran-3-yl)methyl)-1-(2,2,2-trifluoroethyl)-pyrazolo[4,3-d]pyrimidin-5,7-dione (10.0 mg) with a yield of 18%. .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 7.83 (s, 1H), 5.38-5.30 (m, 2H), 4.10-4.04 (m, 2H), 3.92-3.87 (m, 1H), 3.78-3.75 (m, 2H), 3.64-3.62 (m, 1H), 3.52 (s, 3H), 2.76-2.72 (m, 1H), 2.04-2.01 (m, 1H), 1.79-1.72 (m, 1H). MS-ESI calculated value: [M+H].sup.+ 333; measured value: 333.

Example 30

6-((3-Ethyloxetan-3-yl)methyl)-4-methyl-1-(2,2,2-trifluoroethyl)-pyrazolo[4,3-d]pyrimidin-5,7-dione

(184) ##STR00109##

Step 1

(Tetrahydropyran-4-yl)methyl methanesulfonate

(185) Tetrahydropyran-4-ylmethanol (1.00 g, 8.61 mmol) and triethylamine (1.74 g, 17.2 mmol) were dissolved in anhydrous methylene chloride (20 mL), and then methanesulfonyl chloride (1.28 g, 11.2 mmol) was slowly added at 0 C. under the protection of nitrogen. The reaction solution was stirred at 0 C. for 1 hour. The reaction was quenched by adding saturated sodium bicarbonate solution (50 mL), followed by extraction with methylene chloride (20 mL2). The organic phases were combined, washed with saturated sodium chloride solution (50 mL2), dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to give (tetrahydropyran-4-yl)methyl methanesulfonate (1.30 g, yellow oily) with a yield of 78%. MS-ESI calculated value: [M+H].sup.+ 195; measured value: 195.

Step 2

4-Methyl-6-((tetrahydropyran-4-yl)methyl)-1-(2,2,2-trifluoroethyl)-pyrazolo[4,3-d]pyrimidin-5,7-dione

(186) 4-Methyl-1-(2,2,2-trifluoroethyl)pyrazolo[4,3-d]pyrimidin-5,7-dione (30.0 mg, 0.121 mmol), (tetrahydropyran-4-yl)methyl methanesulfonate (35.2 mg, 0.181 mmol), potassium carbonate (33.2 mg, 0.242 mmol) and potassium iodide (4.0 mg, 0.024 mmol) were dissolved in N,N-dimethylformamide (10 mL). The reaction solution was heated to 120 C. and stirred for 3 hours. The reaction solution was cooled to room temperature, and poured into water (30 mL), followed by extraction with ethyl acetate (20 mL3). The organic phases were combined, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated and then separated and purified by preparative high performance liquid chromatography to give 4-methyl-6-((tetrahydropyran-4-yl)methyl)-1-(2,2,2-trifluoroethyl)-pyrazolo[4,3-d]pyrimidin-5,7-dione (10.0 mg) with a yield of 24%. .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 7.80 (s, 1H), 5.33-5.27 (m, 2H), 3.93-3.89 (m, 4H), 3.49 (s, 3H), 3.36-3.34 (m, 2H), 2.08-2.05 (m, 1H), 1.57-1.53 (m, 2H), 1.44-1.37 (m, 2H). MS-ESI calculated value: [M+H].sup.+ 347; measured value: 347.

Example 31

4-Methyl-6-(2-(tetrahydropyran-4-yl)ethyl)-1-(2,2,2-trifluoroethyl)-pyrazolo[4,3-d]pyrimidin-5,7-dione

(187) ##STR00110##

Step 1

4-Methyl-6-(2-(tetrahydropyran-4-yl)ethyl)-1-(2,2,2-trifluoroethyl)-pyrazolo[4,3-d]pyrimidin-5,7-dione

(188) 2-Tetrahydropyran-4-yl-ethyl methanesulfonate (50.0 mg, 0.240 mmol), 4-methyl-1-(2,2,2-trifluoroethyl)pyrazolo[4,3-d]pyrimidin-5,7-dione (59.6 mg, 0.240 mmol), potassium carbonate (66.4 mg, 0.480 mmol) and potassium iodide (7.9 mg, 0.048 mmol) were dissolved in N,N-dimethylformamide (5 mL). The reaction solution was heated to 120 C. and stirred for 3 hours. Then, the reaction solution was cooled to room temperature, and poured into water (20 mL), followed by extraction with ethyl acetate (20 mL3). The organic phases were combined, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated and the crude product was separated and purified by preparative high performance liquid chromatography to give 4-methyl-6-(2-(tetrahydropyran-4-yl)ethyl)-1-(2,2,2-trifluoroethyl)-pyrazolo[4,3-d]pyrimidin-5,7-dione (20.0 mg) with a yield of 23%. .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 7.82 (s, 1H), 5.36-5.27 (m, 2H), 4.08-4.05 (m, 2H), 3.95-3.91 (m, 2H), 3.51 (s, 3H), 3.44-3.41 (m, 2H), 1.76-1.73 (m, 2H), 1.60-1.58 (m, 3H), 1.37-1.30 (m, 2H). MS-ESI calculated value: [M+H].sup.+ 361; measured value: 361.

Example 32

6-((4-Methoxycyclohexyl)methyl)-4-methyl-1-(2,2,2-trifluoroethyl)-pyrazolo[4,3-d]pyrimidin-5,7-dione

(189) ##STR00111##

Step 1

6-((4-Methoxycyclohexyl)methyl)-4-methyl-1-(2,2,2-trifluoroethyl)-pyrazolo[4,3-d]pyrimidin-5,7-dione

(190) 4-Methyl-1-(2,2,2-trifluoroethyl)pyrazolo[4,3-d]pyrimidin-5,7-dione (50.0 mg, 0.201 mmol), ((4-methoxycyclohexyl)methyl methanesulfonate (44.8 mg, 0.201 mmol), potassium carbonate (55.7 mg, 0.403 mmol) and potassium iodide (6.7 mg, 0.040 mmol) were dissolved in N,N-dimethylformamide (5 mL). The reaction solution was heated to 120 C. and stirred for 3 hours. Then, the reaction solution was cooled to room temperature, and poured into water (20 mL), followed by extraction with ethyl acetate (20 mL3). The organic phases were combined, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated and then was separated and purified by preparative high performance liquid chromatography to give 6-((4-methoxycyclohexyl)methyl)-4-methyl-1-(2,2,2-trifluoroethyl)-pyrazolo[4,3-d]pyrimidin-5,7-dione (20.0 mg) with a yield of 26%. .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 7.82 (s, 1H), 5.36-5.30 (m, 2H), 3.89 (d, J=6.8 Hz, 2H), 3.51 (s, 3H), 3.39 (s, 3H), 3.21-3.15 (m, 1H), 2.09-2.08 (m, 2H), 1.81-1.73 (m, 3H), 1.16-1.10 (m, 4H). MS-ESI calculated value: [M+H].sup.+ 375; measured value: 375.

Example 33

1-(Cyclopropylmethyl)-4-methyl-6-((3-methyloxetan-3-yl)methyl)-pyrazolo[4,3-d]pyrimidin-5,7-dione

(191) ##STR00112## ##STR00113##

Step 1

Methyl 1-(cyclopropylmethyl)-4-nitro-pyrazol-5-carboxylate

(192) Methyl 4-nitro-pyrazol-5-carboxylate (22.0 g, 129 mmol) was dissolved in N,N-dimethylformamide (350 mL), and then sodium hydride (5.66 g, 141 mmol) was added in batches at 0 C. The reaction solution was stirred at 0 C. for 1 hour, and then sodium iodide was added (21.2 g, 141 mmol), and bromomethylcyclopropane (19.1 g, 141 mmol) was added dropwise. The reaction solution was stirred at 25 C. for 18 hours. Water (1.2 L) was added into the reaction solution, followed by extraction with ethyl acetate (300 mL2). The organic phases were combined, washed with saturated brine (500 mL), dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (5:1 petroleum ether/ethyl acetate, Rf=0.3) to give methyl 1-(cyclopropylmethyl)-4-nitro-pyrazol-5-carboxylate (5.00 g, colorless oil) with a yield of 17%. .sup.1H NMR: (400 MHz, CDCl.sub.3) 8.04 (s, 1H), 4.14 (d, J=7.6 Hz, 2H), 4.03 (s, 3H), 1.40-1.23 (m, 1H), 0.75-0.55 (m, 2H), 0.47-0.34 (m, 2H). MS-ESI calculated value: [M+H].sup.+ 226; measured value: 226.

Step 2

Methyl 4-amino-1-(cyclopropylmethyl)-pyrazol-5-carboxylate

(193) Methyl 1-(cyclopropylmethyl)-4-nitro-pyrazol-5-carboxylate (5.00 g, 22.2 mmol) was dissolved in methanol (70 mL), and then dry palladium-carbon (palladium 10%, water 1%, 500 mg) was added. The reaction was conducted at room temperature for 3 hours under 40 psi hydrogen pressure. The reaction solution was filtered and then the filtrate was concentrated under reduced pressure to give methyl 4-amino-1-(cyclopropylmethyl)-pyrazol-5-carboxylate (4.30 g, similar white solid) with a yield of 99%. .sup.1H NMR: (400 MHz, CDCl.sub.3) 7.11 (s, 1H), 4.27 (d, J=7.6 Hz, 2H), 4.11 (s, 2H), 3.91 (s, 3H), 1.46-1.21 (m, 1H), 0.53-0.43 (m, 2H), 0.41-0.32 (m, 2H). MS-ESI calculated value: [M+H].sup.+ 196; measured value: 196.

Step 3

Methyl 1-(cyclopropylmethyl)-4-(2,2,2-trifluoroacetamido)-pyrazol-5-carboxylate

(194) Methyl 4-amino-1-(cyclopropylmethyl)-pyrazol-5-carboxylate (4.30 g, 22.0 mmol) was dissolved in methylene chloride (40 mL), and then trifluoroacetic anhydride (6.94 g, 33.1 mmol) was added dropwise under the protection of nitrogen. The reaction solution was stirred at room temperature for 2 hours. The reaction was quenched by adding saturated sodium bicarbonate solution (50 mL), followed by extraction with methylene chloride (40 mL) and washing with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give methyl 1-(cyclopropylmethyl)-4-(2,2,2-trifluoroacetamido)-pyrazol-5-carboxylate (6.30 g, colorless oil) with a yield of 98%.

(195) .sup.1H NMR: (400 MHz, CDCl.sub.3) 9.72 (s, 1H), 8.28 (s, 1H), 4.37 (d, J=7.2 Hz, 2H), 4.09 (s, 3H), 1.39-1.23 (m, 1H), 0.60-0.48 (m, 2H), 0.45-0.37 (m, 2H). MS-ESI calculated value: [M+H].sup.+ 292; measured value: 292.

Step 4

Methyl 1-(cyclopropylmethyl)-4-(2,2,2-trifluoro-N-methylacetamido)-pyrazol-5-carboxylate

(196) Methyl 1-(cyclopropylmethyl)-4-(2,2,2-trifluoroacetamido)-pyrazol-5-carboxylate (6.20 g, 21.3 mmol) was dissolved in N,N-dimethylformamide (50 mL), and then potassium carbonate (4.41 g, 31.9 mmol) was added. The reaction solution was heated to 80 C. and allowed for reaction for 1 hour. The reaction solution was cooled to room temperature, and then iodomethane (4.53 g, 31.9 mmol) was added. The reaction solution was stirred at room temperature for 18 hours. Water (300 mL) was added into the reaction solution, followed by extraction with ethyl acetate (100 mL3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to give methyl 1-(cyclopropylmethyl)-4-(2,2,2-trifluoro-N-methylacetamido)-pyrazol-5-carboxylate (6.44 g, yellow oil) with a yield of 99%. .sup.1H NMR: (400 MHz, CDCl.sub.3) 7.50 (s, 1H), 4.43 (d, J=7.2 Hz, 2H), 3.90 (s, 3H), 3.28 (s, 3H), 1.43-1.27 (m, 1H), 0.60-0.47 (m, 2H), 0.45-0.33 (m, 2H). MS-ESI calculated value: [M+H].sup.+ 306; measured value: 306.

Step 5

4-[Tert-butoxycarbonyl)(methyl)amino]1-(cyclopropylmethyl)-pyrazol-5-carboxylic acid

(197) Methyl 1-(cyclopropylmethyl)-4-(2,2,2-trifluoro-N-methylacetamido)-pyrazol-5-carboxylate (6.40 g, 21.0 mmol) was dissolved in tetrahydrofuran (30 mL) and water (30 mL), and then lithium hydroxide monohydrate (4.40 g, 105 mmol) was added. The reaction solution was allowed for reaction at room temperature while stirring for 18 hours. Di-tert-butyl dicarbonate (9.15 g, 41.9 mmol) was added, and the reaction solution was allowed for reaction at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, followed by adjusting the pH value to pH=4 with 2N hydrochloric acid solution, and then filtered. The filter cake was dried to give 4-((tert-butoxycarbonyl)(methyl)amino)-1-(cyclopropylmethyl)-pyrazol-5-carboxylic acid (4.50 g, white solid) with a yield of 73%. .sup.1H NMR: (400 MHz, CDCl.sub.3) 7.46 (s, 1H), 4.38 (d, J=6.8 Hz, 2H), 3.21 (s, 3H), 1.58-1.25 (m, 10H), 0.60-0.47 (m, 2H), 0.45-0.37 (m, 2H). MS-ESI calculated value: [M+H].sup.+ 296; measured value: 296.

Step 6

Tert-butyl (5-Carbamoyl-1-(cyclopropylmethyl)-pyrazol-4-yl)(methyl) carbamate

(198) 4-[Tert-butoxycarbonyl)(methyl)amino]1-(cyclopropylmethyl)-pyrazol-5-carboxylic acid (3.40 g, 11.5 mmol), 2-(7-azabenzotriazole)-tetramethyluronium hexafluorophosphate (5.69 g, 15.0 mmol) and ammonium chloride (1.23 g, 23.0 mmol) were dissolved in methylene chloride (120 mL), and then triethylamine (1.75 g, 17.3 mmol) was added dropwise at room temperature. The reaction solution was stirred at room temperature for 18 hours. Water (50 mL) was added into the reaction solution, followed by extraction with methylene chloride (500 mL2). The organic phases were combined, washed successively with saturated sodium bicarbonate (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, the residue was treated with ethanol (20 mL) to give tert-butyl (5-carbamoyl-1-(cyclopropylmethyl)-pyrazol-4-yl)(methyl) carbamate (3.00 g, crude product, yellow oil). MS-ESI calculated value: [M+H].sup.+ 295; measured value: 295.

Step 7

1-(Cyclopropylmethyl)-4-(methylamino)-pyrazol-5-carboxamide

(199) Tert-butyl (5-Carbamoyl-1-(cyclopropylmethyl)-pyrazol-4-yl)(methyl) carbamate (3.30 g, 11.2 mmol) was dissolved in hydrochloric acid-ethyl acetate (25 mL). After reacting at room temperature while stirring for 18 hours, the reaction solution was concentrated under reduced pressure. The residue was dissolved by methanol (40 mL), and then potassium carbonate (3.10 g, 22.4 mmol) was added, followed by stirring at room temperature for 2 hours. The reaction solution was filtered and the filtrate was concentrated under reduced pressure. The residue was extracted with methylene chloride (60 mL), followed by filtration. The filtrate was spin-dried and the residue was beaten with methylene chloride (15 mL), followed by filtration to give 1-(cyclopropylmethyl)-4-(methylamino)-pyrazol-5-carboxamide (1.45 g, white solid) with a yield of 67%. .sup.1H NMR: (400 MHz, CDCl.sub.3) 7.34 (s, 2H), 7.17 (s, 1H), 4.62-4.47 (m, 1H), 4.21 (d, J=6.8 Hz, 2H), 2.65 (d, J=5.6 Hz, 3H), 1.22-1.10 (m, 1H), 0.43-0.34 (m, 2H), 0.31-0.23 (m, 2H).

(200) MS-ESI calculated value: [M+H].sup.+ 195; measured value: 195.

Step 8

1-(Cyclopropylmethyl)-4-methyl-pyrazolo[4,3-d]pyrimidin-5,7-dione

(201) 1-(Cyclopropylmethyl)-4-(methylamino)-pyrazol-5-carboxamide (1.45 g, 7.47 mmol) was dissolved in N,N-dimethylformamide (10 mL), and then sodium hydride (627 mg, 15.7 mmol) was added in batches at 0 C. The reaction solution was stirred at 0 C. for 1 hour under the protection of nitrogen. After adding 1,1-carbonyldiimidazole (1.82 g, 11.2 mmol), the reaction solution was heated to 75 C. and allowed for reaction for 2 hours and then cooled to room temperature. The reaction was quenched by adding water (80 mL), followed by filtration. The filter cake wad dried to give 1-(cyclopropylmethyl)-4-methyl-pyrazolo[4,3-d]pyrimidin-5,7-dione (1.60 g, white solid) with a yield of 97%. .sup.1H NMR: (400 MHz, DMSO-d.sub.6) 11.35 (s, 1H), 7.72 (s, 1H), 4.29 (d, J=6.8 Hz, 2H), 3.32 (s, 3H), 1.17-1.07 (m, 1H), 0.54-0.32 (m, 4H). MS-ESI calculated value: [M+H].sup.+ 221; measured value: 221.

Step 9

1-(Cyclopropylmethyl)-4-methyl-6-((3-methyloxetan-3-yl)methyl)-pyrazolo[4,3-d]pyrimidin-5,7-dione

(202) 1-(Cyclopropylmethyl)-4-methyl-pyrazolo[4,3-d]pyrimidin-5,7-dione (62.1 mg, 0.282 mmol) was dissolved in N,N-dimethylformamide (2 mL), and then 3-(chloromethyl)-3-methyl-oxetane (40.8 mg, 0.338 mmol), potassium carbonate (78.0 mg, 0.564 mmol) and potassium iodide (56.2 mg, 0.338 mmol) were added. The reaction solution was heated to 120 C. and then stirred for 1 hour. The reaction solution was cooled to room temperature and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography to give 1-(cyclopropylmethyl)-4-methyl-6-((3-methyloxetan-3-yl)methyl)-pyrazolo[4,3-d]pyrimidin-5,7-dione (46.0 mg) with a yield of 54%. .sup.1H NMR: (400 MHz, CDCl.sub.3) 7.42 (s, 1H), 4.73 (d, J=6.4 Hz, 2H), 4.43 (d, J=6.8 Hz, 2H), 4.26 (d, J=6.4 Hz, 2H), 4.14 (s, 2H), 3.50 (s, 3H), 1.41 (s, 3H), 1.40-1.28 (m, 1H), 0.60-0.52 (m, 2H), 0.51-0.38 (m, 2H). MS-ESI calculated value: [M+H].sup.+ 305; measured value: 305.

Example 34

1-(Cyclopropylmethyl)-6-((3-ethyloxetan-3-yl)methyl)-4-methyl-pyrazolo[4,3-d]pyrimidin-5,7-dione

(203) ##STR00114##

Step 1

1-(Cyclopropylmethyl)-6-((3-ethyloxetan-3-yl)methyl)-4-methyl-pyrazolo[4,3-d]pyrimidin-5,7-dione

(204) (3-Ethyloxetan-3-yl)methyl methanesulfonate (34.4 mg, 0.177 mmol), 1-(cyclopropylmethyl)-4-methyl-pyrazolo[4,3-d]pyrimidin-5,7-dione (30.0 mg, 0.136 mmol), potassium iodide (2.3 mg, 0.014 mmol) and potassium carbonate (56.5 mg, 0.408 mmol) were dissolved in N,N-dimethylformamide (3 mL). The reaction solution was heated to 120 C. and stirred for 3 hours, and then cooled to room temperature, followed by filtration. The filtrate was concentrated under reduced pressure, and the residue was then purified by preparative high performance liquid chromatography to give 1-(cyclopropylmethyl)-6-((3-ethyloxetan-3-yl)methyl)-4-methyl-pyrazolo[4,3-d]pyrimidin-5,7-dione (21.0 mg) with a yield of 48%. .sup.1H NMR: (400 MHz, CDCl.sub.3) 7.44 (s, 1H), 4.62 (d, J=6.4 Hz, 2H), 4.44 (d, J=7.6 Hz, 2H), 4.30 (d, J=6.8 Hz, 2H), 4.10 (s, 2H), 3.52 (s, 3H), 1.88-1.83 (m, 2H), 1.37-1.36 (m, 1H), 1.11-1.07 (m, 3H), 0.56-0.46 (m, 4H). MS-ESI calculated value: [M+H].sup.+ 319; measured value: 319.

Example 35

1-(Cyclopropylmethyl)-4-methyl-6-((tetrahydrofuran-3-yl)methyl)-pyrazolo[4,3-d]pyrimidin-5,7-dione

(205) ##STR00115##

Step 1

1-(Cyclopropylmethyl)-4-methyl-6-((tetrahydrofuran-3-yl)methyl)-pyrazolo[4,3-d]pyrimidin-5,7-dione

(206) (Tetrahydrofuran-3-yl)methyl methanesulfonate (53.1 mg, 0.295 mmol), 1-(cyclopropylmethyl)-4-methyl-pyrazolo[4,3-d]pyrimidin-5,7-dione (50.0 mg, 0.227 mmol) and potassium carbonate (94.1 mg, 0.681 mmol) were dissolved in N,N-dimethylformamide (5 mL), and then potassium iodide (3.8 mg, 0.023 mmol) was added. The reaction solution was stirred at 120 C. for 3 hours. The reaction solution was filtered directly and the filtrate was concentrated under reduced pressure. The crude product obtained was purified by preparative high performance liquid chromatography to give a product 1-(cyclopropylmethyl)-4-methyl-6-((tetrahydrofuran-3-yl)methyl)-pyrazolo[4,3-d]pyrimidin-5,7-di one (36.0 mg) with a yield of 52%. .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 7.63 (s, 1H), 4.41 (d, J=7.2 Hz, 2H), 3.95-3.90 (m, 1H), 3.87-3.82 (m, 1H), 3.77-3.72 (m, 1H), 3.61-3.54 (m, 2H), 3.45-3.42 (m, 1H), 3.14 (s, 3H), 2.59-2.52 (m, 1H), 1.87-1.79 (m, 1H), 1.62-1.53 (m, 1H), 1.22-1.12 (m, 1H), 0.36-0.25 (m, 4H). MS-ESI calculated value: [M+H].sup.+ 305; measured value: 305.

Example 36

1-(Cyclopropylmethyl)-4-methyl-6-((tetrahydropyran-4-yl)methyl)-pyrazolo[4,3-d]pyrimidin-5,7-dione

(207) ##STR00116##

Step 1

1-(Cyclopropylmethyl)-4-methyl-6-((tetrahydropyran-4-yl)methyl)-pyrazolo[4,3-d]pyrimidin-5,7-dione

(208) (Tetrahydropyran-4-yl)methyl methanesulfonate (34.4 mg, 0.177 mmol), 1-(cyclopropylmethyl)-4-methyl-pyrazolo[4,3-d]pyrimidin-5,7-dione (30.0 mg, 0.136 mmol), potassium iodide (2.3 mg, 0.014 mmol) and potassium carbonate (56.5 mg, 0.408 mmol) were dissolved in N,N-dimethylformamide (3 mL). The reaction solution was heated to 120 C. and stirred for 3 hours, and then cooled to room temperature, followed by filtration. The filtrate was concentrated under reduced pressure, and the residue was then purified by preparative high performance liquid chromatography to give 1-(cyclopropylmethyl)-4-methyl-6-((tetrahydropyran-4-yl)methyl)-pyrazolo[4,3-d]pyrimidin-5,7-dione (30.0 mg) with a yield of 69%. .sup.1H NMR: (400 MHz, CDCl.sub.3) 7.42 (s, 1H), 4.45 (d, J=7.6 Hz, 2H), 4.00-3.95 (m, 4H), 3.49 (s, 3H), 3.39-3.33 (m, 2H), 2.10-2.06 (m, 1H), 1.48-1.40 (m, 5H), 0.57-0.48 (m, 4H). MS-ESI calculated value: [M+H].sup.+ 319; measured value: 319.

Example 37

1-(Cyclopropylmethyl)-4-methyl-6-(2-(tetrahydropyran-4-yl)ethyl)-pyrazolo[4,3-d]pyrimidin-5,7-dione

(209) ##STR00117##

Step 1

1-(Cyclopropylmethyl)-4-methyl-6-(2-(tetrahydropyran-4-yl)ethyl)-pyrazolo[4,3-d]pyrimidin-5,7-dione

(210) 2-(Tetrahydropyran-4-yl)ethyl methanesulfonate (50.0 mg, 0.227 mmol), 1-(cyclopropylmethyl)-4-methyl-pyrazolo[4,3-d]pyrimidin-5,7-dione (47.3 mg, 0.227 mmol), potassium iodide (3.8 mg, 0.023 mmol) and potassium carbonate (62.3 mg, 0.454 mmol) were dissolved in N,N-dimethylformamide (3 mL). The reaction solution was heated to 120 C. and stirred for 3 hours, and then cooled to room temperature, followed by filtration. The filtrate was concentrated under reduced pressure, and the residue was then purified by preparative high performance liquid chromatography to give 1-(cyclopropylmethyl)-4-methyl-6-(2-(tetrahydropyran-4-yl)ethyl)-pyrazolo[4,3-d]pyrimidin-5,7-dione (20.0 mg) with a yield of 27%. .sup.1H NMR: (400 MHz, CDCL.sub.3) 7.40 (s, 1H), 4.43 (d, J=7.2 Hz, 2H), 4.08-4.05 (m, 2H), 3.98-3.94 (m, 2H), 3.49 (s, 3H), 3.38 (t, J=1.6 Hz, 2H), 1.73-1.69 (m, 2H), 1.62-1.59 (m, 4H), 1.39-1.36 (m, 2H), 0.55-0.46 (m, 4H). MS-ESI calculated value: [M+H].sup.+ 333; measured value: 333.

Example 38

1-(Cyclopropylmethyl)-6-((4-methoxycyclohexyl)methyl)-4-methyl-pyrazolo[4,3-d]pyrimidin-5,7-dione

(211) ##STR00118##

Step 1

1-(Cyclopropylmethyl)-6-((4-methoxycyclohexyl)methyl)-4-methyl-pyrazolo[4,3-d]pyrimidin-5,7-dione

(212) (4-Methoxycyclohexyl)methyl methanesulfonate (30.0 mg, 0.135 mmol), 1-(cyclopropylmethyl)-4-methyl-pyrazolo[4,3-d]pyrimidin-5,7-dione (26.8 mg, 0.121 mmol), potassium iodide (2.2 mg, 0.014 mmol) and potassium carbonate (37.3 mg, 0.269 mmol) were dissolved in N,N-dimethylformamide (5 mL). The reaction solution was heated to 120 C. and stirred for 3 hours, and then cooled to room temperature, followed by filtration. The filtrate was concentrated under reduced pressure, and the residue was then purified by preparative high performance liquid chromatography to give 1-(cyclopropylmethyl)-6-((4-methoxycyclohexyl)methyl)-4-methyl-pyrazolo[4,3-d]pyrimidin-5,7-dione (16.0 mg) with a yield of 34%. .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 7.64 (s, 1H), 4.42 (d, J=6.8 Hz, 2H), 3.89 (d, J=6.8 Hz, 2H), 3.50 (s, 3H), 3.35 (s, 3H), 3.20-3.15 (m, 1H), 2.10-2.06 (m, 2H), 1.76-1.73 (m, 3H), 1.38-1.36 (m, 1H), 1.16-1.12 (m, 4H), 0.55-0.46 (m, 4H). MS-ESI calculated value: [M+H].sup.+ 347; measured value: 347.

Example 39

1-Methyl-3-((3-methyloxetan-3-yl)methyl)pyrido[2,3-d]pyrimidin-2,4-dione

(213) ##STR00119##

Step 1

2-(Methylamino)nicotinonitrile

(214) 2-Chloro-3-cyanopyridine (30.0 g, 216 mmol) was added into 40% methylamine aqueous solution (300 mL), which was heated to 80 C. and then stirred for 2 hours. The reaction solution was concentrated by reduced pressure distillation. The solid obtained by filtration was washed with water (30 mL3) and then dried to give 2-(methylamino)nicotinonitrile (22.3 g, pale yellow solid) with a yield of 76%. .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 8.25-8.22 (m, 1H), 7.79-7.74 (m, 1H), 6.65-6.59 (m, 1H), 2.96 (s, 3H).

Step 2

2-(Methylamino)pyridin-3-carboxamide

(215) 2-(Methylamino)nicotinonitrile (600 mg, 4.51 mmol), potassium carbonate (1.87 mg, 0.130 mmol), hydrogen peroxide (0.1 mL) were dissolved in dimethyl sulfoxide (10 mL), followed by reaction at room temperature for 1 hour. The reaction was quenched by adding water (10 mL). The reaction solution was extracted with ethyl acetate (10 mL3), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure and then purified by silica gel preparative plate (1:1 petroleum ether/ethyl acetate, Rf=0.2) to give 2-(methylamino)pyridin-3-carboxamide (500 mg, white solid) with a yield of 73%. .sup.1H NMR: (400 MHz, DMSO-d.sub.6) 8.45-8.40 (br, 1H), 8.28 (d, J=2.0 Hz, 1H), 7.95-7.93 (m, 2H), 7.35-7.30 (br, 1H), 6.53 (dd, J=7.6, 2.0 Hz, 1H), 3.03 (d, J=4.8 Hz, 3H). MS-ESI calculated value: [M+H].sup.+ 152; measured value: 152.

Step 3

1-Methylpyrido[2,3-d]pyrimidin-2,4(1H,3H)-dione

(216) 2-(Methylamino)pyridin-3-carboxamide (100 mg, 0.661 mmol) and phenyl isocyanate (157 mg, 1.32 mmol) were dissolved in toluene (10 mL), followed by stirring at 110 C. for 12 hours. The reaction was quenched by adding water (10 mL). The reaction solution was filtered to give 1-methylpyrido[2,3-d]pyrimidin-2,4(1H,3H)-dione (20.0 mg, yellow solid) with a yield of 17%.

(217) .sup.1H NMR: (400 MHz, DMSO-d.sub.6) 11.72 (s, 1H), 8.72 (d, J=2.0 Hz, 1H), 8.31 (d, J=7.6 Hz, 1H), 7.29 (dd, J=7.6, 2.0 Hz, 1H), 3.48 (s, 3H). MS-ESI calculated value: [M+H].sup.+ 178; measured value: 178.

Step 4

(218) 1-Methylpyrido[2,3-d]pyrimidin-2,4-dione (70.0 mg, 0.395 mmol) was dissolved in N,N-dimethylformamide (2 mL), and then 3-(chloromethyl)-3-methyl-oxetane (52.4 mg, 0.435 mmol), potassium carbonate (109 mg, 0.790 mmol) and potassium iodide (78.7 mg, 0.474 mmol) were added. The reaction solution was heated to 120 C. and then stirred for 1 hour. The reaction solution was cooled to room temperature and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography to give 1-methyl-3-((3-methyloxetan-3-yl)methyl)pyrido[2,3-d]pyrimidin-2,4-dione (44.0 mg) with a yield of 43%. .sup.1H NMR: (400 MHz, CDCl.sub.3) 8.69 (d, J=2.0 Hz, 1H), 8.46 (d, J=5.6 Hz, 1H), 7.27-7.18 (m, 1H), 4.76 (d, J=6.8 Hz, 2H), 4.28 (d, J=6.8 Hz, 2H), 4.23 (s, 2H), 3.73 (s, 3H), 1.41 (s, 3H). MS-ESI calculated value: [M+H].sup.+ 262; measured value: 262.

Example 40

3-((3-Ethyloxetan-3-yl)methyl)-1-methylpyrido[2,3-d]pyrimidin-2,4-dione

(219) ##STR00120##

Step 1

3-((3-Ethyloxetan-3-yl)methyl)-1-methylpyrido[2,3-d]pyrimidin-2,4-dione

(220) 1-Methylpyrido[2,3-d]pyrimidin-2,4-dione (30.0 mg, 0.169 mmol), (3-ethyloxetan-3-yl)methyl methanesulfonate (49.3 mg, 0.254 mmol), potassium carbonate (46.8 mg, 0.338 mmol) and potassium iodide (5.6 mg, 0.034 mmol) were dissolved in N,N-dimethylformamide (10 mL). The reaction solution was heated to 120 C. and stirred for 3 hours. The reaction solution was cooled to room temperature, and poured into water (30 mL), followed by extraction with ethyl acetate (20 mL3). The organic phases were combined, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated and then separated and purified by preparative high performance liquid chromatography to give 3-((3-ethyloxetan-3-yl)methyl)-1-methylpyrido[2,3-d]pyrimidin-2,4-dione (10.0 mg) with a yield of 21%. .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 8.74-8.73 (m, 1H), 8.48-8.46 (m, 1H), 7.35-7.32 (m, 1H), 4.67 (d, J=6.8 Hz, 2H), 4.32 (d, J=6.8 Hz, 2H), 4.20 (s, 2H), 3.72 (s, 3H), 1.84-1.79 (m, 2H), 1.08 (t, J=7.2 Hz, 3H). MS-ESI calculated value: [M+H].sup.+ 276; measured value: 276.

Example 41

1-Methyl-3-(tetrahydrofuran-3-ylmethyl)pyrido[2,3-d]pyrimidin-2,4-dione

(221) ##STR00121##

Step 1 1-Methyl-3-(tetrahydrofuran-3-ylmethyl)pyrido[2,3-d]pyrimidin-2,4-dione

(222) Tetrahydrofuran-3-yl-methyl methanesulfonate (30.0 mg, 0.166 mmol), 1-methylpyrido[2,3-d]pyrimidin-2,4-dione (29.5 mg, 0.166 mmol), potassium carbonate (46.0 mg, 0.333 mmol) and potassium iodide (5.5 mg, 0.033 mmol) were dissolved in N,N-dimethylformamide (5 mL). The reaction solution was heated to 120 C. and stirred for 3 hours. Then, the reaction solution was cooled to room temperature, and poured into water (20 mL), followed by extraction with ethyl acetate (20 mL3). The organic phases were combined, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated and then was separated and purified by preparative high performance liquid chromatography to give 1-methyl-3-(tetrahydrofuran-3-ylmethyl)pyrido[2,3-d]pyrimidin-2,4-dione (10.0 mg) with a yield of 23%. .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 8.65-8.63 (m, 1H), 8.46-8.41 (m, 1H), 7.33-7.30 (m, 1H), 4.14-4.12 (m, 2H), 4.09-4.07 (m, 1H), 3.79-3.75 (m, 2H), 3.69 (s, 3H), 3.65-3.62 (m, 1H), 2.79-2.75 (m, 1H), 2.06-2.01 (m, 1H), 1.78-1.75 (m, 1H). MS-ESI calculated value: [M+H].sup.+ 262; measured value: 262.

Example 42

1-Methyl-3-((tetrahydropyran-4-yl)methyl)pyrido[2,3-d]pyrimidin-2,4-dione

(223) ##STR00122##

Step 1

1-Methyl-3-((tetrahydropyran-4-yl)methyl)pyrido[2,3-d]pyrimidin-2,4-dione

(224) 1-Methylpyrido[2,3-d]pyrimidin-2,4-dione (30.0 mg, 0.169 mmol), tetrahydropyran-4-yl-methyl methanesulfonate (49.4 mg, 0.254 mmol), potassium carbonate (46.8 mg, 0.338 mmol) and potassium iodide (5.6 mg, 0.034 mmol) were dissolved in N,N-dimethylformamide (10 mL). The reaction solution was heated to 120 C. and stirred for 3 hours. The reaction solution was cooled to room temperature, and poured into water (30 mL), followed by extraction with ethyl acetate (20 mL3). The organic phases were combined, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated and then separated and purified by preparative high performance liquid chromatography to give 1-methyl-3-((tetrahydropyran-4-yl)methyl)pyrido[2,3-d]pyrimidin-2,4-dione (10.0 mg, yellow oily) with a yield of 21%. .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 8.71-8.69 (m, 1H), 8.48-8.40 (m, 1H), 7.33-7.30 (m, 1H), 3.99-3.91 (m, 4H), 3.69 (s, 3H), 3.39-3.33 (m, 2H), 2.13-2.10 (m, 1H), 1.62-1.58 (m, 2H), 1.44-1.40 (m, 2H). MS-ESI calculated value: [M+H].sup.+ 276; measured value: 276.

Example 43

1-Methyl-3-(2-(tetrahydropyran-4-yl)ethyl)pyrido[2,3-d]pyrimidin-2,4-dione

(225) ##STR00123##

Step 1

1-Methyl-3-(2-(tetrahydropyran-4-yl)ethyl)pyrido[2,3-d]pyrimidin-2,4-dione

(226) 2-Tetrahydropyran-4-yl-ethyl methanesulfonate (50.0 mg, 0.240 mmol), 1-methylpyrido[2,3-d]pyrimidin-2,4-dione (42.5 mg, 0.240 mmol), potassium carbonate (66.4 mg, 0.480 mmol) and potassium iodide (7.9 mg, 0.048 mmol) were dissolved in N,N-dimethylformamide (5 mL). The reaction solution was heated to 120 C. and stirred for 3 hours. Then, the reaction solution was cooled to room temperature, and poured into water (20 mL), followed by extraction with ethyl acetate (20 mL3). The organic phases were combined, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated and then was separated and purified by preparative high performance liquid chromatography to give 1-methyl-3-(2-(tetrahydropyran-4-yl)ethyl)pyrido[2,3-d]pyrimidin-2,4-dione (20.0 mg) with a yield of 29%. .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 8.72-8.71 (m, 1H), 8.47-8.45 (m, 1H), 7.34-7.31 (m, 1H), 4.14-4.10 (m, 2H), 3.96-3.93 (m, 2H), 3.70 (s, 3H), 3.43-3.40 (m, 2H), 1.78-1.75 (m, 2H), 1.66-1.62 (m, 3H), 1.38-1.32 (m, 2H). MS-ESI calculated value: [M+H].sup.+ 290; measured value: 290.

Example 44

3-((4-Methoxycyclohexyl)methyl)-1-methylpyrido[2,3-d]pyrimidin-2,4-dione

(227) ##STR00124##

Step 1

3-((4-Methoxycyclohexyl)methyl)-1-methylpyrido[2,3-d]pyrimidin-2,4-dione

(228) 1-Methylpyrido[2,3-d]pyrimidin-2,4-dione (50.0 mg, 0.282 mmol), (4-methoxycyclohexyl)methyl methanesulfonate (62.7 mg, 0.282 mmol), potassium carbonate (78.0 mg, 0.564 mmol) and potassium iodide (9.4 mg, 0.056 mmol) were dissolved in N,N-dimethylformamide (5 mL). The reaction solution was heated to 120 C. and stirred for 3 hours. The reaction solution was cooled to room temperature, and then poured into water (20 mL), followed by extraction with ethyl acetate (20 mL3). The organic phases were combined, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated and then was separated and purified by preparative high performance liquid chromatography to give 3-((4-methoxycyclohexyl)methyl)-1-methylpyrido[2,3-d]pyrimidin-2,4-dione (20.0 mg) with a yield of 23%. .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 8.73-8.71 (m, 1H), 8.47-8.45 (m, 1H), 7.34-7.31 (m, 1H), 3.95 (d, J=6.8 Hz, 2H), 3.71 (s, 3H), 3.36 (s, 3H), 3.20-3.16 (m, 1H), 2.10-2.08 (m, 2H), 1.84-1.76 (m, 3H), 1.21-1.08 (m, 4H). MS-ESI calculated value: [M+H].sup.+ 304; measured value: 304.

Example 45

1-Methyl-3-((3-epoxypropan-3-yl)methyl)pyrido[3,4-d]pyrimidin-2,4-dione

(229) ##STR00125##

Step 1

3-(Methylamino)isonicotinic acid

(230) 3-Fluoroisonicotinic acid (3.00 g, 21.3 mmol) was dissolved in dioxane (6 mL), and then 30% methylamine aqueous solution (22.0 g, 213 mmol) was added. The reaction solution was heated to 140 C. and then stirred for 14 hours. Concentrated hydrochloric acid (12N, 3 mL) was added to adjust the pH value to pH=3, followed by filtration. The filter cake was dried to give 3-(methylamino)isonicotinic acid (3.00 g, yellow solid) with a yield of 93%. .sup.1H NMR: (400 MHz, DMSO-d.sub.6) 8.46 (s, 1H), 7.89 (s, 1H), 7.69 (d, J=4.8 Hz, 1H), 7.50 (d, J=4.8 Hz, 1H), 2.80 (s, 3H).

Step 2

3-(Methylamino)isonicotinamide

(231) 3-(Methylamino)isonicotinic acid (4.00 g, 26.3 mmol), 1-hydroxybenzotriazole (10.7 g, 78.9 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (15.1 g, 78.9 mmol) and ammonium chloride (5.63 g, 105 mmol) were dissolved in N,N-dimethylformamide (5 mL). The reaction solution was stirred at 25 C. for 24 hours. The reaction was quenched by adding water (100 mL). The mixture was extracted with isopropanol/chloroform (1:3) (50 mL2). The organic phases were combined, concentrated under reduced pressure. Methylene chloride/methanol (10:1, 30 mL) was added into the residue and then stirred for 10 minutes, followed by filtration. The filter cake was dried to give 3-(methylamino)isonicotinamide (3.50 g, yellow solid) with a yield of 88%. .sup.1H NMR: (400 MHz, DMSO-d.sub.6) 8.09 (s, 2H), 7.80 (d, J=5.2 Hz, 1H), 7.62-7.61 (m, 1H), 7.52-7.48 (m, 1H), 7.43 (d, J=5.2 Hz, 1H), 2.84 (d, J=5.2 Hz, 3H).

Step 3

1-Methylpyrido[3,4-d]pyrimidin-2,4-dione

(232) Under the condition of 0 C., sodium hydride (1.80 g, 45.0 mmol) was added into the N,N-dimethylformamide solution (50 mL) of 3-(methylamino)isonicotinamide (3.40 g, 22.5 mmol). The reaction solution was stirred at 0 C. for 1 hour. Then carbonyldiimidazole (5.47 g, 33.7 mmol) was added. The reaction mixture was allowed for reaction at room temperature for 1 hour. The reaction solution was cooled to 0 C., quenched by adding water (20 mL). The white solid was precipitated and then filtered. The filter cake was dried to give 1-methylpyrido[3,4-d]pyrimidin-2,4-dione (3.50 g, yellow solid) with a yield of 95%. .sup.1H NMR: (400 MHz, DMSO-d.sub.6) 11.83 (s, 1H), 8.86 (s, 1H), 8.48 (d, J=4.8 Hz, 1H), 7.82 (d, J=4.8 Hz, 1H), 3.49 (s, 3H).

Step 4

1-Methyl-3-((3-epoxypropan-3-yl)methyl)pyrido[3,4-d]pyrimidin-2,4-dione

(233) 3-(Chloromethyl)-3-methyl-oxetane (22.5 mg, 0.186 mmol), 1-methylpyrido[3,4-d]pyrimidin-2,4-dione (30.0 mg, 0.169 mmol), potassium iodide (2.8 mg, 0.017 mmol) and potassium carbonate (46.8 mg, 0.338 mmol) were dissolved in N,N-dimethylformamide (5 mL). The reaction solution was heated to 120 C. and stirred for 3 hours, and then cooled to room temperature, followed by filtration. The filtrate was concentrated under reduced pressure, and the residue was then purified by preparative high performance liquid chromatography to give 1-methyl-3-((3-epoxypropan-3-yl)methyl)pyrido[3,4-d]pyrimidin-2,4-dione (10.0 mg) with a yield of 19%. .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 8.88 (s, 1H), 8.53 (d, J=5.2 Hz, 1H), 8.03 (d, J=5.2 Hz, 1H), 4.78 (d, J=6.4 Hz, 2H), 4.28-4.26 (m, 4H), 3.69 (s, 3H), 1.38 (s, 3H). MS-ESI calculated value: [M+H].sup.+ 262; measured value: 262.

Example 46

3-((3-Ethyloxetan-3-yl)methyl)-1-methylpyrido[3,4-d]pyrimidin-2,4-dione

(234) ##STR00126##

Step 1

3-((3-Ethyloxetan-3-yl)methyl)-1-methylpyrido[3,4-d]pyrimidin-2,4-dione

(235) (3-Ethyloxetan-3-yl)methyl methanesulfonate (36.2 mg, 0.186 mmol), 1-methylpyrido[3,4-d]pyrimidin-2,4-dione (30.0 mg, 0.169 mmol), potassium iodide (2.8 mg, 0.017 mmol) and potassium carbonate (46.8 mg, 0.338 mmol) were dissolved in N,N-dimethylformamide (5 mL). The reaction solution was heated to 120 C. and stirred for 3 hours, and then cooled to room temperature, followed by filtration. The filtrate was concentrated under reduced pressure, and the residue was then purified by preparative high performance liquid chromatography to give 3-((3-ethyloxetan-3-yl)methyl)-1-methylpyrido[3,4-d]pyrimidin-2,4-dione (11.0 mg) with a yield of 22%. .sup.1H NMR: (400 MHz, CDCl.sub.3) 8.79 (s, 1H), 8.60 (d, J=4.8 Hz, 1H), 8.01 (d, J=4.8 Hz, 1H), 4.62 (d, J=6.8 Hz, 2H), 4.32 (d, J=6.4 Hz, 2H), 4.20 (s, 2H), 3.71 (s, 3H), 1.85-1.79 (m, 2H), 1.10-1.07 (m, 3H). MS-ESI calculated value: [M+H].sup.+ 276; measured value: 276.

Example 47

1-Methyl-3-((tetrahydrofuran-3-yl)methyl)pyrido[3,4-d]pyrimidin-2,4-dione

(236) ##STR00127##

Step 1

1-Methyl-3-((tetrahydrofuran-3-yl)methyl)pyrido[3,4-d]pyrimidin-2,4-dione

(237) 3-(Tetrahydrofuran-3-yl)methyl methanesulfonate (33.6 mg, 0.186 mmol), 1-methylpyrido[3,4-d]pyrimidin-2,4-dione (30.0 mg, 0.169 mmol), potassium iodide (2.8 mg, 0.017 mmol) and potassium carbonate (46.8 mg, 0.338 mmol) were dissolved in N,N-dimethylformamide (5 mL). The reaction solution was heated to 120 C. and stirred for 3 hours, and then cooled to room temperature, followed by filtration. The filtrate was concentrated under reduced pressure, and the residue was then purified by preparative high performance liquid chromatography to give 1-methyl-3-((tetrahydrofuran-3-yl)methyl)pyrido[3,4-d]pyrimidin-2,4-dione (21.0 mg) with a yield of 45%. .sup.1H NMR: (400 MHz, CDCl.sub.3) 8.78 (s, 1H), 8.60 (d, J=4.8 Hz, 1H), 8.03 (d, J=4.8 Hz, 1H), 4.23-4.21 (m, 2H), 3.85-3.81 (m, 3H), 3.71 (s, 3H), 3.66-3.65 (m, 1H), 2.81-2.77 (m, 1H), 2.05-2.00 (m, 1H), 1.81-1.77 (m, 1H). MS-ESI calculated value: [M+H].sup.+ 262; measured value: 262.

Example 48

1-Methyl-3-((tetrahydropyran-4-yl)methyl)pyrido[3,4-d]pyrimidin-2,4-dione

(238) ##STR00128##

Step 1

1-Methyl-3-((tetrahydropyran-4-yl)methyl)pyrido[3,4-d]pyrimidin-2,4-dione

(239) (Tetrahydropyran-4-yl)methyl methanesulfonate (36.2 mg, 0.186 mmol), 1-methylpyrido[3,4-d]pyrimidin-2,4-dione (30.0 mg, 0.169 mmol), potassium iodide (2.8 mg, 0.017 mmol) and potassium carbonate (46.8 mg, 0.338 mmol) were dissolved in N,N-dimethylformamide (5 mL). The reaction solution was heated to 120 C. and stirred for 3 hours, and then cooled to room temperature, followed by filtration. The filtrate was concentrated under reduced pressure, and the residue was then purified by preparative high performance liquid chromatography to give 1-methyl-3-((tetrahydropyran-4-yl)methyl)pyrido[3,4-d]pyrimidin-2,4-dione (10.0 mg) with a yield of 21%. .sup.1H NMR: (400 MHz, CDCl.sub.3) 8.76 (s, 1H), 8.58 (d, J=4.8 Hz, 1H), 8.01 (d, J=4.8 Hz, 1H), 4.03 (d, J=7.2 Hz, 2H), 3.99-3.95 (m, 2H), 3.70 (s, 3H), 3.37-3.18 (m, 2H), 2.13-2.09 (m, 1H), 1.57-1.48 (m, 4H). MS-ESI calculated value: [M+H].sup.+ 276; measured value: 276.

Example 49

1-Methyl-3-(2-(tetrahydropyran-4-yl)ethyl)pyrido[3,4-d]pyrimidin-2,4-dione

(240) ##STR00129##

Step 1

1-Methyl-3-(2-(tetrahydropyran-4-yl)ethyl)pyrido[3,4-d]pyrimidin-2,4-dione

(241) 2-(Tetrahydropyran-4-yl)ethyl methanesulfonate (38.8 mg, 0.186 mmol), 1-methylpyrido[3,4-d]pyrimidin-2,4-dione (30.0 mg, 0.169 mmol), potassium iodide (2.8 mg, 0.017 mmol) and potassium carbonate (46.8 mg, 0.338 mmol) were dissolved in N,N-dimethylformamide (5 mL). The reaction solution was heated to 120 C. and stirred for 3 hours, and then cooled to room temperature, followed by filtration. The filtrate was concentrated under reduced pressure, and the residue was then purified by preparative high performance liquid chromatography to give 1-methyl-3-(2-(tetrahydropyran-4-yl)ethyl)pyrido[3,4-d]pyrimidin-2,4-dione (10.0 mg) with a yield of 20%. .sup.1H NMR: (400 MHz, CDCl.sub.3) 9.17 (s, 1H), 8.62-8.60 (m, 1H), 8.43-8.41 (m, 1H), 4.16-4.13 (m, 2H), 3.99-3.95 (m, 2H), 3.77 (s, 3H), 3.42-3.36 (m, 2H), 1.72-1.64 (m, 5H), 1.43-1.34 (m, 2H). MS-ESI calculated value: [M+H].sup.+ 290; measured value: 290.

Example 50

3-((4-Methoxycyclohexyl)methyl)-1-methylpyrido[3,4-d]pyrimidin-2,4-dione

(242) ##STR00130##

Step 1

3-((4-Methoxycyclohexyl)methyl)-1-methylpyrido[3,4-d]pyrimidin-2,4-dione

(243) (4-Methoxycyclohexyl)methyl methanesulfonate (41.4 mg, 0.186 mmol), 1-methylpyrido[3,4-d]pyrimidin-2,4-dione (30.0 mg, 0.169 mmol), potassium iodide (2.8 mg, 0.017 mmol) and potassium carbonate (46.8 mg, 0.338 mmol) were dissolved in N,N-dimethylformamide (5 mL). The reaction solution was heated to 120 C. and stirred for 3 hours, and then cooled to room temperature, followed by filtration. The filtrate was concentrated under reduced pressure, and the residue was then purified by preparative high performance liquid chromatography to give 3-((4-methoxycyclohexyl)methyl)-1-methylpyrido[3,4-d]pyrimidin-2,4-dione (10.0 mg) with a yield of 19%. .sup.1H NMR: (400 MHz, CDCl.sub.3) 8.76 (s, 1H), 8.58 (d, J=4.8 Hz, 1H), 8.01 (d, J=4.8 Hz. 1H), 3.99 (d, J=7.2 Hz, 2H), 3.69 (s, 3H), 3.35 (s, 3H), 3.15-3.11 (m, 1H), 2.08-1.97 (m, 2H), 1.86-1.82 (m, 3H), 1.23-1.10 (m, 4H). MS-ESI calculated value: [M+H].sup.+ 304; measured value: 304.

Example 51

1-Methyl-3-((3-methylpyridin-3-yl)methyl)pyrido[4,3-d]pyrimidin-2,4-dione

(244) ##STR00131##

Step 1

4-(Methylamino)nicotinic acid

(245) 4-Chloronicotinic acid (7.00 g, 44.3 mmol) was dissolved in dioxane (14 mL), and then 30% methylamine aqueous solution (55.2 g, 444 mmol) was added. The reaction solution was heated in microwave to 100 C. and stirred for 50 minutes. Hydrochloric acid solution (4N, 5 mL) was added to adjust the pH value to pH=3, followed by filtration. The filter cake was dried to give 4-(methylamino)nicotinic acid (5.00 g, white solid) with a yield of 74%. .sup.1H NMR: (400 MHz, DMSO-d.sub.6) 8.52 (s, 1H), 8.13 (d, J=6.8 Hz, 1H), 6.78 (d, J=6.8 Hz, 1H), 2.95 (d, J=4.4 Hz, 3H).

Step 2

4-(Methylamino)nicotinamide

(246) 4-(Methylamino)nicotinic acid (5.20 g, 34.2 mmol), 1-hydroxybenzotriazole (27.7 g, 205 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (39.3 g, 205 mmol) and ammonium chloride (14.6 g, 273 mmol) were dissolved in N,N-dimethylformamide (50 mL). The reaction solution was stirred at 25 C. for 8 hours. The reaction was quenched by adding water (100 mL). The mixture was extracted with isopropanol/chloroform (1:3) (30 mL5). The organic phases were combined, and concentrated under reduced pressure. The residue was added into methylene chloride/methanol (10:1, 50 mL) and then stirred for 10 minutes, followed by filtration. The filter cake was dried to give 4-(methylamino)nicotinamide (4.70 g, white solid) with a yield of 91%. .sup.1H NMR: (400 MHz, DMSO-d.sub.6) 9.67 (d, J=7.6 Hz, 1H), 8.77 (s, 1H), 8.52 (s, 1H), 8.30-8.28 (m, 1H), 7.87 (s, 1H), 7.01 (d, J=7.6 Hz, 1H), 3.01 (s, 3H).

Step 3

1-Methylpyrido[4,3-d]pyrimidin-2,4-dione

(247) Under the condition of 0 C., sodium hydride (1.52 g, 63.5 mmol) was added into the N,N-dimethylformamide solution (50 mL) of 4-(methylamino)nicotinamide (4.80 g, 31.8 mmol). The reaction solution was stirred at 0 C. for 1 hour. Carbonyldiimidazole (7.72 g, 47.6 mmol) was then added. The reaction mixture was allowed for reaction at 75 C. for 2 hours. The reaction solution was cooled to room temperature, quenched by adding water (50 mL). Hydrochloric acid solution (12N, 5 mL) was added to adjust the pH value to pH=3. The white solid was precipitated and then filtered. The filter cake was dried to give 1-methylpyrido[4,3-d]pyrimidin-2,4-dione (3.50 g, yellow solid) with a yield of 95%. .sup.1H NMR: (400 MHz, DMSO-d.sub.6) 11.76 (s, 1H), 8.97 (s, 1H), 8.69 (d, J=6.0 Hz, 1H), 7.38 (d, J=6.0 Hz, 1H), 3.39 (s, 3H).

Step 4

1-Methyl-3-((3-methylpyridin-3-yl)methyl)pyrido[4,3-d]pyrimidin-2,4-dione

(248) 3-(Chloromethyl)-3-methyloxetane (26.5 mg, 0.220 mmol), 1-methylpyrido[4,3-d]pyrimidin-2,4-dione (30.0 mg, 0.169 mmol) and potassium carbonate (70.2 mg, 0.508 mmol) were dissolved in N,N-dimethylformamide (3 mL), and then potassium iodide (2.8 mg, 0.017 mmol) was added. The reaction solution was stirred at 120 C. for 3 hours. The reaction solution was filtered directly and the filtrate was concentrated under reduced pressure. The crude product obtained was purified by preparative high performance liquid chromatography to give a product 1-methyl-3-((3-methylpyridin-3-yl)methyl)pyrido[4,3-d]pyrimidin-2,4-dione (22.0 mg) with a yield of 48%. .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 9.14 (s, 1H), 8.71 (d, J=6.4 Hz, 1H), 7.44 (d, J=6.4 Hz, 1H), 4.79 (d, J=6.0 Hz, 2H), 4.27 (d, J=6.0 Hz, 2H), 4.25 (s, 2H), 3.61 (s, 3H), 1.38 (s, 3H). MS-ESI calculated value: [M+H].sup.+ 262; measured value: 262.

Example 52

3-((3-Ethyloxetan-3-yl)methyl)-1-methylpyrido[4,3-d]pyrimidin-2,4-dione

(249) ##STR00132##

Step 1

3-((3-Ethyloxetan-3-yl)methyl)-1-methylpyrido[4,3-d]pyrimidin-2,4-dione

(250) (3-Ethyloxetan-3-yl)methyl methanesulfonate (42.7 mg, 0.220 mmol), 1-methylpyrido[4,3-d]pyrimidin-2,4-dione (30.0 mg, 0.169 mmol) and potassium carbonate (70.2 mg, 0.508 mmol) were dissolved in N,N-dimethylformamide (3 mL), and then potassium iodide (2.8 mg, 0.017 mmol) was added. The reaction solution was stirred at 120 C. for 3 hours. The reaction solution was filtered directly and the filtrate was concentrated under reduced pressure. The crude product obtained was purified by preparative high performance liquid chromatography to give a product 3-((3-ethyloxetan-3-yl)methyl)-1-methylpyrido[4,3-d]pyrimidin-2,4-dione (20.0 mg) with a yield of 42%. .sup.1H NMR: (400 MHz, CDCl.sub.3) 9.29 (s, 1H), 8.75 (d, J=6.0 Hz, 1H), 7.09 (d, J=6.0 Hz, 1H), 4.61 (d, J=6.4 Hz, 2H), 4.31 (d, J=6.4 Hz, 2H), 4.17 (s, 2H), 3.59 (s, 3H), 1.83-1.78 (q, J=7.6 Hz, 2H), 1.07 (t, J=7.6 Hz, 3H). MS-ESI calculated value: [M+H].sup.+ 276; measured value: 276.

Example 53

1-Methyl-3-((tetrahydrofuran-3-yl)methyl)pyrido[4,3-d]pyrimidin-2,4-dione

(251) ##STR00133##

Step 1

1-Methyl-3-((tetrahydrofuran-3-yl)methyl)pyrido[4,3-d]pyrimidin-2,4-dione

(252) (Tetrahydrofuran-3-yl)methyl methanesulfonate (39.6 mg, 0.220 mmol), 1-methylpyrido[4,3-d]pyrimidin-2,4-dione (30.0 mg, 0.169 mmol) and potassium carbonate (70.2 mg, 0.508 mmol) were dissolved in N,N-dimethylformamide (3 mL), and then potassium iodide (2.8 mg, 0.017 mmol) was added. The reaction solution was stirred at 120 C. for 3 hours. The reaction solution was filtered directly and the filtrate was concentrated under reduced pressure. The crude product obtained was purified by preparative high performance liquid chromatography to give a product 1-methyl-3-((tetrahydrofuran-3-yl)methyl)pyrido[4,3-d]pyrimidin-2,4-dione (20.0 mg) with a yield of 43%. .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 9.11 (s, 1H), 8.68 (d, J=6.0 Hz, 1H), 7.42 (d, J=6.0 Hz, 1H), 4.17-4.04 (m, 2H), 3.96-3.91 (m, 1H), 3.81-3.73 (m, 2H), 3.65-3.61 (m, 1H), 3.60 (s, 3H), 2.81-2.71 (m, 1H), 2.08-2.00 (m, 1H), 1.81-1.73 (m, 1H). MS-ESI calculated value: [M+H].sup.+ 262; measured value: 262.

Example 54

1-Methyl-3-((tetrahydropyran-4-yl)methyl)pyrido[4,3-d]pyrimidin-2,4-dione

(253) ##STR00134##

Step 1

1-Methyl-3-((tetrahydropyran-4-yl)methyl)pyrido[4,3-d]pyrimidin-2,4-dione

(254) (Tetrahydropyran-4-yl)methyl methanesulfonate (42.7 mg, 0.220 mmol), 1-methylpyrido[4,3-d]pyrimidin-2,4-dione (30.0 mg, 0.169 mmol) and potassium carbonate (70.2 mg, 0.508 mmol) were dissolved in N,N-dimethylformamide (3 mL), and then potassium iodide (2.8 mg, 0.017 mmol) was added. The reaction solution was stirred at 120 C. for 3 hours. The reaction solution was filtered directly and the filtrate was concentrated under reduced pressure. The crude product obtained was purified by preparative high performance liquid chromatography to give a product 1-methyl-3-((tetrahydropyran-4-yl)methyl)pyrido[4,3-d]pyrimidin-2,4-dione (19.0 mg) with a yield of 40%. .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 9.12 (s, 1H), 8.69 (d, J=6.0 Hz, 1H), 7.42 (d, J=6.0 Hz, 1H), 3.99 (d, J=7.2 Hz, 2H), 3.96-3.92 (m, 2H), 3.60 (s, 3H), 3.37-3.33 (m, 2H), 2.13-2.11 (m, 1H), 1.63-1.59 (m, 2H), 1.47-1.37 (m, 2H). MS-ESI calculated value: [M+H].sup.+ 276; measured value: 276.

Example 55

1-Methyl-3-(2-(tetrahydropyran-4-yl)ethyl)pyrido[4,3-d]pyrimidin-2,4-dione

(255) ##STR00135##

Step 1

1-Methyl-3-(2-(tetrahydropyran-4-yl)ethyl)pyrido[4,3-d]pyrimidin-2,4-dione

(256) 2-(Tetrahydropyran-4-yl)ethyl methanesulfonate (35.2 mg, 0.169 mmol), 1-methylpyrido[4,3-d]pyrimidin-2,4-dione (30.0 mg, 0.169 mmol) and potassium carbonate (70.2 mg, 0.508 mmol) were dissolved in N,N-dimethylformamide (3 mL), and then potassium iodide (2.8 mg, 0.017 mmol) was added. The reaction solution was stirred at 120 C. for 3 hours. The reaction solution was filtered directly and the filtrate was concentrated under reduced pressure. The crude product obtained was purified by preparative high performance liquid chromatography to give a product 1-methyl-3-(2-(tetrahydropyran-4-yl)ethyl)pyrido[4,3-d]pyrimidin-2,4-dione (25.0 mg) with a yield of 51%. .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 9.12 (s, 1H), 8.69 (d, J=6.4 Hz, 1H), 7.43 (d, J=6.4 Hz, 1H), 4.10 (t, J=7.4 Hz, 2H), 3.96-3.92 (m, 2H), 3.60 (s, 3H), 3.46-3.39 (m, 2H), 1.75 (d, J=12.8 Hz, 2H), 1.66-1.61 (m, 3H), 1.37-1.31 (m, 2H). MS-ESI calculated value: [M+H].sup.+ 290; measured value: 290.

Example 56

3-((4-Methoxycyclohexyl)methyl)-1-methylpyrido[4,3-d]pyrimidin-2,4-dione

(257) ##STR00136##

Step 1

3-((4-Methoxycyclohexyl)methyl)-1-methylpyrido[4,3-d]pyrimidin-2,4-dione

(258) (4-Methoxycyclohexyl)methyl methanesulfonate (37.6 mg, 0.169 mmol), 1-methylpyrido[4,3-d]pyrimidin-2,4-dione (30.0 mg, 0.169 mmol) and potassium carbonate (70.2 mg, 0.508 mmol) were dissolved in N,N-dimethylformamide (3 mL), and then potassium iodide (2.8 mg, 0.017 mmol) was added. The reaction solution was stirred at 120 C. for 3 hours. The reaction solution was filtered directly and the filtrate was concentrated under reduced pressure. The crude product obtained was purified by preparative high performance liquid chromatography to give a product 3-((4-methoxycyclohexyl)methyl)-1-methylpyrido[4,3-d]pyrimidin-2,4-dione (20.0 mg) with a yield of 37%. .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 9.14 (s, 1H), 8.69 (d, J=6.0 Hz, 1H), 7.43 (d, J=6.0 Hz, 1H), 3.95 (d, J=6.8 Hz, 2H), 3.64 (s, 3H), 3.35 (s, 3H), 3.22-3.16 (m, 1H), 2.09 (d, J=8.8 Hz, 2H), 1.85-1.77 (m, 3H), 1.18-1.12 (m, 4H). MS-ESI calculated value: [M+H].sup.+ 304, measured value: 304.

Example 57

1-Methyl-3-[(3-methylpyridin-3-yl)methyl]pyrido[3,2-d]pyrimidin-2,4-dione

(259) ##STR00137##

Step 1

Tert-butyl N-(2-chloro-3-pyridinyl) carbamate

(260) 2-Chloropyridin-3-amine (30.0 g, 233 mmol) was dissolved in methylene chloride (250 mL), and then triethylamine (47.2 g, 467 mmol) was added. Di-tert-butyl dicarbonate (102 g, 467 mmol) was added dropwise at 0 C. The reaction solution was stirred at 25 C. for 18 hours. The reaction was quenched by adding water (100 mL). The reaction solution was extracted with ethyl acetate (100 mL3). The organic phases were combined, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, the residue was separated and purified by silica gel column chromatography (15:1 petroleum ether/ethyl acetate, Rf=0.6) to give tert-butyl N-(2-chloro-3-pyridinyl) carbamate (11.0 g, white solid) with a yield of 21%. .sup.1H NMR: (400 MHz, DMSO-d.sub.6) 8.89 (s, 1H), 8.17-8.16 (m, 1H), 8.03-8.01 (m, 1H), 7.43-7.39 (m, 11-), 1.47 (s, 9H).

Step 2

Tert-butyl (2-chloropyridin-3-yl)(methyl) carbamate

(261) Tert-butyl N-(2-chloro-3-pyridinyl) carbamate (11.0 g, 48.1 mmol) was dissolved in anhydrous tetrahydrofuran (150 mL), and then sodium-hydrogen (1.39 g, 57.7 mmol) was slowly added at 0 C. under the protection of nitrogen. The reaction solution was stirred at 0 C. for half an hour. Iodomethane (10.2 g, 72.2 mmol) was slowly added and stirred at room temperature for 12 hours. The reaction was quenched by adding water (50 mL). The reaction solution was extracted with ethyl acetate (80 mL3). The organic phases were combined, washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to give tert-butyl (2-chloropyridin-3-yl)(methyl) carbamate (11.0 g, colorless oil) with a yield of 94%. .sup.1H NMR: (400 Hz, DMSO-d.sub.6) 58.33 (d, J=4.8 Hz, 1H), 7.92-7.90 (m, 1H), 7.48 (d, J=8.0 Hz, 1H), 3.06 (s, 3H), 1.45-1.14 (m, 9H). MS-ESI calculated value: [M+H].sup.+ 243; measured value: 243.

Step 3

2-Chloro-N-methylpyridin-3-amine

(262) Tert-butyl (2-chloropyridin-3-yl)(methyl) carbamate (11.0 g, 45.3 mmol) was dissolved in ethyl acetate (50 mL), and then 4M hydrochloric acid-ethyl acetate (150 mL) was added dropwise at 0 C., followed by stirring at 25 C. for 15 hours. The reaction solution was concentrated under reduced pressure, and then purified by silica gel column chromatography (10:1 petroleum ether/ethyl acetate, Rf=0.3) to give 2-chloro-N-methylpyridin-3-amine (5.50 g, colorless oil) with a yield of 85%. .sup.1H NMR: (400 Hz, DMSO-d.sub.6) 57.56 (d, J=4.8 Hz, 1H), 7.20-7.17 (m, 1H), 6.95 (d, J=8.0 Hz, 1H), 5.76-5.73 (m, 1H), 2.73 (d, J=4.8 Hz, 3H). MS-ESI calculated value: [M+H].sup.+ 143; measured value: 143.

Step 4

Methyl 3-(methylamino) pyridinecarboxylate

(263) 2-Chloro-N-methylpyridin-3-amine (5.50 g, 38.6 mmol) was dissolved in methanol (100 mL). 1,1-Bis(diphenylphosphino)ferrocene palladium chloride (2.82 g, 3.86 mmol) was added into the reaction solution under the condition of 25 C. The reaction solution was allowed for reaction in a carbon monoxide atmosphere (50 psi) at 50 C. for 56 hours. The reaction solution was cooled to 25 C., concentrated under reduced pressure, separated and purified by silica gel column chromatography (5:1 petroleum ether/ethyl acetate, Rf=0.5) to give methyl 3-(methylamino) pyridinecarboxylate (6.00 g, colorless oil) with a yield of 94%. .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 7.84 (d, J=4.8 Hz, 1H), 7.45-7.42 (m, 1H), 7.29 (d, J=8.0 Hz, 1H), 3.93 (s, 3H), 2.94 (s, 3H).

(264) MS-ESI calculated value: [M+H].sup.+ 167; measured value: 167.

Step 5

3-(Methylamino)pyridin-2-carboxamide

(265) Methyl 3-(methylamino)pyridin-2-carboxylate (6.00 g, 36.1 mmol) dissolved in methanol (100 mL), and then aqueous ammonia (1.27 g, 36.1 mmol) was added. The reaction solution was stirred at 40 C. for 18 hours. Water (200 mL) was added into the reaction solution, followed by extraction with ethyl acetate (100 mL2). The organic phases were combined, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to give 3-(methylamino)pyridin-2-carboxamide (3.50 g, yellow solid) with a yield of 64%. .sup.1H NMR: (400 MHz, DMSO-d.sub.6) 58.27-8.23 (br, 1H), 7.80-7.95 (br, 1H), 7.76 (d, J=4.0 Hz, 1H), 7.37-7.32 (m, 2H), 7.11 (d, J=8.0 Hz, 1H), 2.79 (d, J=4.8 Hz, 3H).

Step 6

Ethyl N-[(2-formylamino-3-pyridinyl)-N-methyl]-carbamate

(266) 3-(Methylamino)pyridin-2-carboxamide (1.70 g, 10.9 mmol) was dissolved in ethyl chloroformate (35.3 g, 326 mmol). The reaction solution was stirred at 90 C. for 1 hour. The reaction solution was quenched with saturated aqueous sodium bicarbonate solution (20 mL), and extracted with ethyl acetate (20 mL2). The organic phases were concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (1:1 petroleum ether/ethyl acetate, Rf=0.2) to give ethyl N-[(2-formylamino-3-pyridinyl)-N-methyl]-carbamate (2.00 g, white solid) with a yield of 83%. .sup.1H NMR: (400 MHz, DMSO-d.sub.6) 8.48 (d, J=4.0 Hz, 1H), 7.90 (br, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.60-7.56 (m, 1H), 7.50 (br, 1H), 3.88 (q, J=7.2 Hz, 2H), 3.12 (s, 3H), 1.00 (t, J=7.2 Hz, 3H).

Step 7

1-Methylpyrido[3,2-d]pyrimidin-2,4-dione

(267) Ethyl N-[(2-formylamino-3-pyridinyl)-N-methyl]-carbamate (2.00 g, 8.96 mmol) and sodium hydroxide (717 mg, 17.9 mmol) were dissolved in toluene (25 mL). The reaction solution was stirred at 110 C. for 0.5 hour. The reaction solution was diluted by adding water (15 mL), followed by adjusting the pH value to pH=7 with 1N hydrochloric acid solution. The reaction solution was filtered and the filter cake was diluted with methanol (15 mL), followed by concentration under reduced pressure to give 1-methylpyrido[3,2-d]pyrimidin-2,4-dione (1.09 g, white solid) with a yield of 69%. .sup.1H NMR: (400 MHz, DMSO-d.sub.6) 11.72 (s, 1H), 8.50 (d, J=4.8 Hz, 1H), 7.89 (dd, J=8.0, 4.8 Hz, 1H), 7.74-7.71 (m, 1H), 3.41 (s, 3H).

Step 8

1-Methyl-3-[(3-methylpyridin-3-yl)methyl]pyrido[3,2-d]pyrimidin-2,4-dione

(268) 1-Methylpyrido[3,2-d]pyrimidin-2,4-dione (30.0 mg, 0.169 mmol), 3-(chloromethyl)-3-methyloxetane (26.5 mg, 0.220 mmol) and potassium carbonate (58.5 mg, 0.424 mmol) were dissolved in N,N-dimethylformamide (4 mL), and then potassium iodide (2.8 mg, 0.017 mmol) was added. The reaction solution was heated and refluxed at 120 C. for 3 hours. The reaction solution was filtered directly and the filtrate was concentrated under reduced pressure. The crude product obtained was purified by preparative high performance liquid chromatography to give a product 1-methyl-3-[(3-methylpyridin-3-yl)methyl]pyrido[3,2-d]pyrimidin-2,4-dione (12.0 mg) with a yield of 27%. .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 8.57 (d, J=4.8 Hz, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.82-7.77 (m, 1H), 4.80 (d, J=6.0 Hz, 2H), 4.31-4.25 (m, 4H), 3.64 (s, 3H), 1.40 (s, 3H). MS-ESI calculated value: [M+H].sup.+ 262; measured value: 262.

Example 58

3-[(3-Ethyloxetan-3-yl)methyl]-1-methylpyrido[3,2-d]pyrimidin-2,4-dione

(269) ##STR00138##

Step 1

3-[(3-Ethyloxetan-3-yl)methyl]-1-methylpyrido[3,2-d]pyrimidin-2,4-dione

(270) 1-Methylpyrido[3,2-d]pyrimidin-2,4-dione (30.0 mg, 169 mmol), (3-ethyloxetan-3-yl)methyl methanesulfonate (42.8 mg, 220 mmol) and potassium carbonate (70.2 mg, 508 mmol) were dissolved in N,N-dimethylformamide (4 mL), and then potassium iodide (2.80 mg, 0.017 mmol) was added. The reaction solution was heated and refluxed at 120 C. for 3 hours. The reaction solution was filtered directly and the filtrate was concentrated under reduced pressure. The crude product obtained was purified by preparative high performance liquid chromatography to give a product 3-[(3-ethyloxetan-3-yl)methyl]-1-methylpyrido[3,2-d]pyrimidin-2,4-dione (16.0 mg) with a yield of 34%. .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 8.57 (d, J=4.4 Hz, 1H), 8.00 (d, J=4.4 Hz, 1H), 7.83-7.79 (m, 1H), 4.69 (d, J=6.8 Hz, 2H), 4.33 (d, J=6.8 Hz, 2H), 4.25 (s, 2H), 3.65 (s, 3H), 1.86-1.80 (m, 2H), 1.09 (t, J=7.4 Hz, 3H). MS-ESI calculated value: [M+H].sup.+ 276; measured value: 276.

Example 59

1-Methyl-3-((tetrahydrofuran-3-yl)methyl)pyrido[3,2-d]pyrimidin-2,4-dione

(271) ##STR00139##

Step 1

1-Methyl-3-((tetrahydrofuran-3-yl)methyl)pyrido[3,2-d]pyrimidin-2,4-dione

(272) (Tetrahydrofuran-3-yl)methyl methanesulfonate (30.5 mg, 0.169 mmol), 1-methylpyrido[3,2-d]pyrimidin-2,4-dione (25.0 mg, 0.141 mmol), potassium iodide (2.3 mg, 0.014 mmol) and potassium carbonate (39.0 mg, 0.282 mmol) were dissolved in N,N-dimethylformamide (3 mL). The reaction solution was heated to 120 C. and stirred for 3 hours, and then cooled to room temperature, followed by filtration. The filtrate was concentrated under reduced pressure, and the residue was then purified by preparative high performance liquid chromatography to give 1-methyl-3-((tetrahydrofuran-3-yl)methyl)pyrido[3,2-d]pyrimidin-2,4-dione (20.0 mg) with a yield of 54%. .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 8.56 (d, J=4.4 Hz, 1H), 7.98 (d, J=8.0 Hz, 1H), 7.81-7.77 (m, 1H), 4.21-4.14 (m, 2H), 3.96-3.90 (m, 1H), 3.81-3.78 (m, 2H), 3.67-3.63 (m, 4H), 2.82-2.79 (m, 1H), 2.06-2.03 (m, 1H), 1.83-1.79 (m, 1H). MS-ESI calculated value: [M+H].sup.+ 262; measured value: 262.

Example 60

1-Methyl-3-((tetrahydropyran-4-yl)methyl)pyrido[3,2-d]pyrimidin-2,4-dione

(273) ##STR00140##

Step 1

1-Methyl-3-((tetrahydropyran-4-yl)methyl)pyrido[3,2-d]pyrimidin-2,4-dione

(274) (Tetrahydropyran-4-yl)methyl methanesulfonate (39.5 mg, 0.203 mmol), 1-methylpyrido[3,2-d]pyrimidin-2,4-dione (30.0 mg, 0.169 mmol), potassium iodide (2.8 mg, 0.017 mmol) and potassium carbonate (46.8 mg, 0.339 mmol) were dissolved in N,N-dimethylformamide (3 mL). The reaction solution was heated to 120 C. and stirred for 3 hours, and then cooled to room temperature, followed by filtration. The filtrate was concentrated under reduced pressure, and the residue was then purified by preparative high performance liquid chromatography to give 1-methyl-3-((tetrahydropyran-4-yl)methyl)pyrido[3,2-d]pyrimidin-2,4-dione (20.0 mg) with a yield of 43%. .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 8.56 (d, J=3.6 Hz, 1H), 7.98 (d, J=8.0 Hz, 1H), 7.81-7.77 (m, 1H), 4.06-4.04 (m, 2H), 3.96-3.93 (m, 2H), 3.63 (s, 3H), 3.38-3.33 (m, 2H), 2.17-2.14 (m, 1H), 1.64-1.61 (m, 2H), 1.49-1.44 (m, 2H). MS-ESI calculated value: [M+H].sup.+ 276; measured value: 276.

Example 61

1-Methyl-3-(2-(tetrahydropyran-4-yl)ethyl)pyrido[3,2-d]pyrimidin-2,4-dione

(275) ##STR00141##

Step 1

1-Methyl-3-(2-(tetrahydropyran-4-yl)ethyl)pyrido[3,2-d]pyrimidin-2,4-dione

(276) 2-(Tetrahydropyran-4-yl)ethyl methanesulfonate (35.3 mg, 0.169 mmol), 1-methylpyrido[3,2-d]pyrimidin-2,4-dione (25.0 mg, 0.141 mmol), potassium iodide (2.3 mg, 0.014 mmol) and potassium carbonate (39.0 mg, 0.282 mmol) were dissolved in N,N-dimethylformamide (3 mL). The reaction solution was heated to 120 C. and stirred for 3 hours, and then cooled to room temperature, followed by filtration. The filtrate was concentrated under reduced pressure, and the residue was then purified by preparative high performance liquid chromatography to give 1-methyl-3-(2-(tetrahydropyran-4-yl)ethyl)pyrido[3,2-d]pyrimidin-2,4-dione (20.0 mg) with a yield of 49%. .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 8.55 (d, J=4.0 Hz, 1H), 7.99 (d, J=8.0 Hz, 1H), 7.78 (d, J=8.0, 4.0 Hz, 1H), 4.19-4.15 (m, 2H), 3.95-3.93 (m, 2H), 3.63 (s, 3H), 3.47-3.40 (m, 2H), 1.79-1.76 (m, 2H), 1.68-1.64 (m, 3H), 1.37-1.33 (m, 2H). MS-ESI calculated value: [M+H].sup.+ 290; measured value: 290.

Example 62

3-((4-Methoxycyclohexyl)methyl)-1-methylpyrido[3,2-d]pyrimidin-2,4-dione

(277) ##STR00142##

Step 1

3-((4-Methoxycyclohexyl)methyl)-1-methylpyrido[3,2-d]pyrimidin-2,4-dione

(278) (4-Methoxycyclohexyl)methyl methanesulfonate (37.7 mg, 0.169 mmol), 1-methylpyrido[3,2-d]pyrimidin-2,4-dione (25.0 mg, 0.141 mmol), potassium iodide (2.3 mg, 0.014 mmol) and potassium carbonate (39.0 mg, 0.282 mmol) were dissolved in N,N-dimethylformamide (3 mL). The reaction solution was heated to 120 C. and stirred for 3 hours. Then the reaction solution was cooled to room temperature, and filtered. The filtrate was concentrated under reduced pressure, and the residue was then purified by preparative high performance liquid chromatography to give 3-((4-methoxycyclohexyl)methyl)-1-methylpyrido[3,2-d]pyrimidin-2,4-dione (20.0 mg) with a yield of 47%. .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 8.55 (d, J=4.0 Hz, 1H), 7.97 (d, J=8.4 Hz, 1H), 7.80-7.77 (m, 1H), 3.99-3.97 (m, 2H), 3.62 (s, 3H), 3.33 (s, 3H), 3.18-3.15 (m, 1H), 2.09-2.06 (m, 2H), 1.86-1.76 (m, 3H), 1.19-1.10 (m, 4H). MS-ESI calculated value: [M+H].sup.+ 304; measured value: 304.

Example 63

1-Methyl-3-((3-methyloxetan-3-yl)methyl)pteridin-2,4-dione

(279) ##STR00143##

Step 1

6-Amino-1-methylpyrimidin-2,4-dione

(280) At 25 C., metallic sodium (7.80 g, 340 mmol) was added into anhydrous ethanol (180 mL) in batches while stirring, followed by heating to 80 C. and refluxing for 0.5 hour. Methylurea (12.6 g, 170 mmol) was then added in batches, and refluxing was continued for 0.5 hour. Ethyl cyanoacetate (19.0 g, 170 mmol) was added into the reaction solution dropwise, and a large amount of precipitate was produced. Refluxing was continued for 3 hours, and then ethanol was recovered under reduced pressure. The residue was dissolved in water (50 mL), and the pH value was adjusted to pH=7 with diluted hydrochloric acid (1N), followed by filtration to give 6-amino-1-methylpyrimidin-2,4-dione (7.60 g, white solid) with a yield of 32%. .sup.1H NMR: (400 MHz, DMSO-d.sub.6) 10.39 (s, 1H), 6.79 (s, 2H), 4.54 (s, 1H), 3.14 (s, 3H). MS-ESI calculated value: [M+H].sup.+ 142; measured value: 142.

Step 2 5,6-Diamino-1-methylpyrimidin-2,4-dione

(281) 6-Amino-1-methylpyrimidin-2,4-dione (10.0 g, 70.1 mmol) was dissolved in water (100 mL), and then hydrochloric acid (7 mL, 84.0 mmol, 12N) was added dropwise at 0 C. while stirring. Sodium nitrite (5.80 g, 84.2 mmol) was dissolved in water (50 mL), which was added dropwise into the reactants, then a purple precipitate appeared. The reaction solution was stirred 25 C. for 2 hours, the then was filtered. The filtrate was washed with cold water to give a purple solid. The solid was dissolved in water (100 mL), and then sodium hypodisulfite (18.7 g, 118 mmol) was added in batches while stirring. The reaction solution was heated to 60 C. and stirred for 0.5 hour, and then was cooled to 25 C. and stirred for 16 hours. The reaction solution was filtered and the filtrate was washed with water (50 mL), ethanol (50 mL) and propanone (50 mL), respectively, followed by drying to give a product 5,6-diamino-1-methylpyrimidin-2,4-dione (8.60 g, pale yellow solid), with a yield of 93%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.49 (s, 1H), 6.15 (s, 2H), 3.25 (s, 3H), 2.95 (s, 2H). MS-ESI calculated value: [M+H].sup.+ 157; measured value: 157.

Step 3

1-Methylpteridin-2,4-dione

(282) 5,6-Diamino-1-methylpyrimidin-2,4-dione (4.00 g, 25.6 mmol) was dissolved in water (150 mL), and then glyoxal (5.58 g, 38.4 mmol, 40% aqueous solution) was added at one time at 25 C. The reaction solution was heated to 60 C. and stirred for 16 hours, and then filtered. The solid obtained was washed with water (50 mL) to give a product 1-methylpteridin-2,4-dione (3.60 g, yellow solid) with a yield of 79%.

Step 4

1-Methyl-3-((3-methyloxetan-3-yl)methyl)pteridin-2,4-dione

(283) 1-Methylpteridin-2,4-dione (299 mg, 1.68 mmol) was dissolved in N,N-dimethylformamide (8 mL), and then 3-(chloromethyl)-3-methyl-oxetane (222 mg, 1.85 mmol), potassium iodide (334 mg, 2.02 mmol) and potassium carbonate (464 mg, 3.36 mmol) were added at 25 C. The reaction solution was heated to 120 C. and stirred for 17 hours. The reaction solution was cooled to room temperature and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography to give 1-methyl-3-((3-methyloxetan-3-yl)methyl)pteridin-2,4-dione (40.0 mg) with a yield of 9%. .sup.1H NMR: (400 MHz, CDCl.sub.3) 8.68 (d, J=4.0 Hz, 1H), 8.62 (d, J=4.0 Hz, 1H), 4.78 (d, J=8.0 Hz, 2H), 4.32-4.29 (m, 4H), 3.73 (s, 3H), 1.42 (s, 3H). Calculated value: [M+H].sup.+ 263; measured value: 263.

Example 64

3-((3-Ethyloxetan-3-yl)methyl)-1-methylpteridin-2,4-dione

(284) ##STR00144##

Step 1

3-((3-Ethyloxetan-3-yl)methyl)-1-methylpteridin-2,4-dione

(285) 1-Methylpteridin-2,4-dione (100 mg, 0.560 mmol) was dissolved in N,N-dimethylformamide (4 mL), and then (3-ethyloxetan-3-yl)methyl methanesulfonate (119 mg, 0.620 mmol), potassium iodide (19.0 mg, 0.110 mmol) and potassium carbonate (155 mg, 1.12 mmol) were added at 25 C. The reaction solution was heated to 120 C. and stirred for 16 hours. The reaction solution was cooled to room temperature and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography to give a product 3-((3-ethyloxetan-3-yl)methyl)-1-methylpteridin-2,4-dione (18.0 mg) with a yield of 12%.

(286) .sup.1H NMR: (400 MHz, CDCl.sub.3) 8.68 (d, J=2.0 Hz, 1H), 8.62 (d, J=2.0 Hz, 1H), 4.66 (d, J=6.4 Hz, 2H), 4.35 (d, J=6.8 Hz, 2H), 4.26 (s, 2H), 3.73 (s, 3H), 1.86-1.80 (m, 2H), 1.09 (t, J=7.2 Hz, 3H).

(287) MS-ESI calculated value: [M+H].sup.+ 277; measured value: 277.

Example 65

1-Methyl-3-((tetrahydrofuran-3-yl)methyl)pteridin-2,4-dione

(288) ##STR00145##

Step 1

1-Methyl-3-((tetrahydrofuran-3-yl)methyl)pteridin-2,4-dione

(289) 1-Methylpteridin-2,4-dione (60.0 mg, 0.337 mmol) was dissolved in N,N-dimethylformamide (4 mL), and then (tetrahydrofuran-3-yl)methyl methanesulfonate (61.0 mg, 0.337 mmol), potassium iodide (11.0 mg, 0.0670 mmol) and potassium carbonate (93.0 mg, 0.674 mmol) were added at 25 C. The reaction solution was heated to 120 C. and stirred for 16 hours. The reaction solution was cooled to room temperature and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography to give a product 1-methyl-3-((tetrahydrofuran-3-yl)methyl)pteridin-2,4-dione (6.0 mg) with a yield of 7%. .sup.1H NMR: (400 MHz, CDCl.sub.3) 8.66 (d, J=2.4 Hz, 1H), 8.61 (d, J=2.4 Hz, 1H), 4.31-4.25 (m, 1H), 4.18-4.12 (m, 1H), 3.98-3.94 (m, 1H), 3.87-3.78 (m, 2H), 3.73 (s, 3H), 3.67-3.63 (m, 1H), 2.84-2.78 (m, 1H), 2.04-1.98 (m, 1H), 1.83-1.75 (m, 1H). MS-ESI calculated value: [M+H].sup.+ 263; measured value: 263.

Example 66

1-Methyl-3-((tetrahydropyran-4-yl)methyl)pteridin-2,4-dione

(290) ##STR00146##

Step 1

1-Methyl-3-((tetrahydropyran-4-yl)methyl)pteridin-2,4-dione

(291) 1-Methylpteridin-2,4-dione (100 mg, 0.560 mmol) was dissolved in N,N-dimethylformamide (4 mL), and then (tetrahydropyran-4-yl)methyl methanesulfonate (119 mg, 0.622 mmol), potassium iodide (19.0 mg, 0.112 mmol) and potassium carbonate (155 mg, 1.12 mmol) were added at 25 C. The reaction solution was heated to 120 C. and stirred for 16 hours. The reaction solution was cooled to room temperature and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography to give a product 1-methyl-3-((tetrahydropyran-4-yl)methyl)pteridin-2,4-dione (14.0 mg) with a yield of 9%.

(292) .sup.1H NMR: (400 MHz, CDCl.sub.3) 8.65 (d, J=2.0 Hz, 1H), 8.60 (d, J=2.0 Hz, 1H), 4.08 (d, J=7.2 Hz, 2H), 3.98-3.95 (m, 2H), 3.72 (s, 3H), 3.37-3.31 (m, 2H), 2.19-2.09 (m, 1H), 1.61-1.49 (m, 4H).

(293) MS-ESI calculated value: [M+H].sup.+ 277; measured value: 277.

Example 67

1-Methyl-3-(2-(tetrahydropyran-4-yl)ethyl)pteridin-2,4-dione

(294) ##STR00147##

Step 1

1-Methyl-3-(2-(tetrahydropyran-4-yl)ethyl)pteridin-2,4-dione

(295) 2-(Tetrahydropyran-4-yl)ethyl methanesulfonate (117 mg, 0.561 mmol), 1-methylpteridin-2,4-dione (100 mg, 0.561 mmol) and potassium carbonate (233 mg, 1.68 mmol) were dissolved in N,N-dimethylformamide (5 mL), and then potassium iodide (9.3 mg, 0.0561 mmol) was added. The reaction solution was stirred at 120 C. for 3 hours. The reaction solution was cooled to room temperature and then filtered. The filtrate was concentrated under reduced pressure. The crude product obtained was purified by preparative high performance liquid chromatography to give a product 1-methyl-3-(2-(tetrahydropyran-4-yl)ethyl)pteridin-2,4-dione (12.0 mg) with a yield of 7.4%. .sup.1H NMR: (400 MHz, CDCl.sub.3) 8.65 (d, J=2.4 Hz, 1H), 8.60 (d, J=2.4 Hz, 1H), 4.18 (t, J=7.2 Hz, 2H), 3.98-3.95 (m, 2H), 3.72 (s, 3H), 3.42-3.37 (m, 2H), 1.73 (d, J=12.8 Hz, 2H), 1.67 (t, J=7.2 Hz, 2H), 1.58 (s, 1H), 1.43-1.33 (m, 2H). MS-ESI calculated value: [M+H].sup.+ 291; measured value: 291.

Example 68

3-((4-Methoxycyclohexyl)methyl)-1-methylpteridin-2,4-dione

(296) ##STR00148##

Step 1

3-((4-Methoxycyclohexyl)methyl)-1-methylpteridin-2,4-dione

(297) (4-Methoxycyclohexyl)methyl methanesulfonate (162 mg, 0.729 mmol), 1-methylpteridin-2,4-dione (100 mg, 0.561 mmol) and potassium carbonate (233 mg, 1.68 mmol) were dissolved in N,N-dimethylformamide (5 mL), and then potassium iodide (9.3 mg, 0.056 mmol) was added. The reaction solution was stirred at 120 C. for 3 hours. The reaction solution was cooled to room temperature and then filtered. The filtrate was concentrated under reduced pressure. The crude product obtained was purified by preparative high performance liquid chromatography to give a product 3-((4-methoxycyclohexyl)methyl)-1-methylpteridin-2,4-dione (19.0 mg) with a yield of 11%. .sup.1H NMR: (400 MHz, CDCl.sub.3) 8.64 (d, J=2.0 Hz, 1H), 8.59 (d, J=2.0 Hz, 1H), 4.03 (d, J=7.2 Hz, 2H), 3.72 (s, 3H), 3.34 (s, 3H), 3.15-3.09 (m, 1H), 2.08-2.06 (m, 2H), 1.90-1.84 (m, 1H), 1.77 (d, J=10.0 Hz, 2H), 1.20-1.13 (m, 4H). MS-ESI calculated value: [M+H].sup.+ 305; measured value: 305.

Example 69

1-Methyl-3-((3-methylpyridin-3-yl)methyl)pyrimido[4,5-d]pyrimidin-2,4-dione

(298) ##STR00149##

Step 1

1-Methylpyrimido[4,5-d]pyrimidin-2,4-dione

(299) 6-Amino-1-methylpyrimidin-2,4-dione (3.50 g, 24.8 mmol) was added into formamide (5.00 g, 111 mmol). The reaction solution was heated to 180 C. and stirred for 3 hours, and then cooled to room temperature, followed by filtration. Water (10 mL) was added into the filtrate and stirred, and the solution was then filtered to give 1-methylpyrimido[4,5-d]pyrimidin-2,4-dione (1.60 g, pale yellow solid), with a yield of 36%. .sup.1H NMR: (400 MHz, DMSO-d.sub.6) 9.16 (s, 1H), 9.08 (s, 1H), 3.43 (s, 3H).

Step 2

1-Methyl-3-((3-methylpyridin-3-yl)methyl)pyrimido[4,5-d]pyrimidin-2,4-dione

(300) 1-Methylpyrimido[4,5-d]pyrimidin-2,4-dione (300 mg, 1.68 mmol) was dissolved in N,N-dimethylformamide (8 mL), and then 3-(chloromethyl)-3-methyloxetane (403 mg, 1.85 mmol), potassium carbonate (465 mg, 3.37 mmol) and potassium iodide (335 mg, 2.02 mmol) were added at 25 C. The reaction solution was heated to 120 C. and stirred for 16 hours. The reaction solution was cooled to room temperature and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography to give 1-methyl-3-((3-methylpyridin-3-yl)methyl)pyrimido[4,5-d]pyrimidin-2,4-dione (135 mg) with a yield of 31%. .sup.1H NMR: (400 MHz, CDCl.sub.3) 9.29 (s, 1H), 9.16 (s, 1H), 4.73 (d, J=6.4 Hz, 2H), 4.29 (d, J=6.4 Hz, 2H), 4.22 (s, 2H), 3.69 (s, 3H), 1.39 (s, 3H). MS-ESI calculated value: [M+H].sup.+ 263; measured value: 263.

Example 70

3-((3-Ethyloxetan-3-yl)methyl)-1-methylpyrimido[4,5-d]pyrimidin-2,4-dione

(301) ##STR00150##

Step 1

3-((3-Ethyloxetan-3-yl)methyl)-1-methylpyrimido[4,5-d]pyrimidin-2,4-dione

(302) 1-Methylpyrimido[4,5-d]pyrimidin-2,4-dione (60 mg, 0.337 mmol) was dissolved in N,N-dimethylformamide (4 mL), and then (3-ethyloxetan-3-yl)methyl methanesulfonate (71.0 mg, 0.370 mmol), potassium iodide (11.0 mg, 0.0674 mmol) and potassium carbonate (93.0 mg, 0.673 mmol) were added at 25 C. The reaction solution was heated to 120 C. and stirred for 16 hours. The reaction solution was cooled to room temperature and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography to give a product 3-((3-ethyloxetan-3-yl)methyl)-1-methylpyrimido[4,5-d]pyrimidin-2,4-dione (43.0 mg) with a yield of 46%. .sup.1H NMR: (400 MHz, CDCl.sub.3) 9.31 (s, 1H), 9.17 (s, 1H), 4.61 (d, J=6.4 Hz, 2H), 4.34 (d, J=6.4 Hz, 2H), 4.18 (s, 2H), 3.71 (s, 3H), 1.81 (q, J=7.2 Hz, 2H), 1.08 (t, J=7.2 Hz, 3H).

(303) MS-ESI calculated value: [M+H].sup.+ 277; measured value: 277.

Example 71

1-Methyl-3-((tetrahydrofuran-3-yl)methyl)pyrimido[4,5-d]pyrimidin-2,4-dione

(304) ##STR00151##

Step 1

1-Methyl-3-((tetrahydrofuran-3-yl)methyl)pyrimido[4,5-d]pyrimidin-2,4-dione

(305) 1-Methylpyrimido[4,5-d]pyrimidin-2,4-dione (50.0 mg, 0.281 mmol) was dissolved in N,N-dimethylformamide (4 mL), and then (tetrahydrofuran-3-yl)methyl methanesulfonate (56.0 mg, 0.308 mmol), potassium iodide (9.0 mg, 0.056 mmol) and potassium carbonate (78.0 mg, 0.561 mmol) were added at 25 C. The reaction solution was heated to 120 C. and stirred for 16 hours. The reaction solution was cooled to room temperature and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography to give a product 1-methyl-3-((tetrahydrofuran-3-yl)methyl)pyrimido[4,5-d]pyrimidin-2,4-dione (45.0 mg) with a yield of 61%. .sup.1H NMR: (400 MHz, CDCl.sub.3) 9.30 (s, 1H), 9.15 (s, 1H), 4.23-4.14 (m, 1H), 4.11-4.03 (m, 1H), 3.99-3.92 (m, 1H), 3.85-3.75 (m, 2H), 3.69 (s, 3H), 3.64-3.59 (m, 1H), 2.82-2.70 (m, 1H), 2.06-1.96 (m, 1H), 1.80-1.64 (m, 1H). MS-ESI calculated value: [M+H].sup.+ 263; measured value: 263.

Example 72

1-Methyl-3-((tetrahydropyran-4-yl)methyl)pyrimido[4,5-d]pyrimidin-2,4-dione

(306) ##STR00152##

Step 1

1-Methyl-3-((tetrahydropyran-4-yl)methyl)pyrimido[4,5-d]pyrimidin-2,4-dione

(307) 1-Methylpteridin-2,4-dione (60.0 mg, 0.337 mmol) was dissolved in N,N-dimethylformamide (4 mL), and then (tetrahydropyran-4-yl)methyl methanesulfonate (72.0 mg, 0.370 mmol), potassium iodide (11.0 mg, 0.674 mmol) and potassium carbonate (93.0 mg, 0.674 mmol) were added at 25 C. The reaction solution was heated to 120 C. and stirred for 16 hours. The reaction solution was cooled to room temperature and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography to give a product 1-methyl-3-((tetrahydropyran-4-yl)methyl)pyrimido[4,5-d]pyrimidin-2,4-dione (43.0 mg) with a yield of 46%. .sup.1H NMR: (400 MHz, CDCl.sub.3) 9.30 (s, 1H), 9.15 (s, 1H), 4.02-3.94 (m, 4H), 3.69 (s, 3H), 3.38-3.30 (m, 2H), 2.15-2.03 (m, 1H), 1.67-1.58 (m, 2H), 1.54-1.44 (m, 2H).

(308) MS-ESI calculated value: [M+H].sup.+ 277; measured value: 277.

Example 73

1-Methyl-3-(2-(tetrahydropyran-4-yl)ethyl)pyrimido[4,5-d]pyrimidin-2,4-dione

(309) ##STR00153##

Step 1

1-Methyl-3-(2-(tetrahydropyran-4-yl)ethyl)pyrimido[4,5-d]pyrimidin-2,4-dione

(310) 2-(Tetrahydropyran-4-yl)ethyl methanesulfonate (117 mg, 0.561 mmol), 1-methylpyrimido[4,5-d]pyrimidin-2,4-dione (100.0 mg, 0.561 mmol) and potassium carbonate (233 mg, 1.68 mmol) were dissolved in N,N-dimethylformamide (5 mL), and then potassium iodide (4.7 mg, 0.028 mmol) was added. The reaction solution was stirred at 120 C. for 3 hours. The reaction solution was cooled to room temperature and then filtered. The filtrate was concentrated under reduced pressure. The crude product obtained was purified by preparative high performance liquid chromatography to give a product 1-methyl-3-(2-(tetrahydropyran-4-yl)ethyl)pyrimido[4,5-d]pyrimidin-2,4-dione (49.0 mg) with a yield of 30%. .sup.1H NMR: (400 MHz, CDCl.sub.3) 9.32 (s, 1H), 9.17 (s, 1H), 4.13 (t, J=7.2 Hz, 2H), 4.01-3.97 (m, 2H), 3.71 (s, 3H), 3.41 (t, J=10.8 Hz, 2H), 1.75-1.69 (m, 2H), 1.67-1.63 (m, 2H), 1.60 (s, 1H), 1.42-1.36 (m, 2H). MS-ESI calculated value: [M+H].sup.+ 291; measured value: 291.

Example 74

3-((4-Methoxycyclohexyl)methyl)-1-methylpyrimido[4,5-d]pyrimidin-2,4-dione

(311) ##STR00154##

Step 1

3-((4-Methoxycyclohexyl)methyl)-1-methylpyrimido[4,5-d]pyrimidin-2,4-dione

(312) (4-Methoxycyclohexyl)methyl methanesulfonate (81.1 mg, 0.364 mmol), 1-methylpyrimido[4,5-d]pyrimidin-2,4-dione (50.0 mg, 0.280 mmol) and potassium carbonate (38.7 mg, 0.280 mmol) were dissolved in N,N-dimethylformamide (5 mL), and then potassium iodide (46.5 mg, 0.280 mmol) was added. The reaction solution was stirred at 120 C. for 3 hours. The reaction solution was cooled to room temperature and then filtered. The filtrate was concentrated under reduced pressure. The crude product obtained was purified by preparative high performance liquid chromatography to give a product 3-((4-methoxycyclohexyl)methyl)-1-methylpyrimido[4,5-d]pyrimidin-2,4-dione (53.0 mg) with a yield of 62%. .sup.1H NMR: (400 MHz, Methonal-d.sub.4) 9.20 (s, 1H), 9.13 (s, 1H), 3.93 (d, J=7.2 Hz, 2H), 3.67 (s, 3H), 3.35 (s, 3H), 3.22-3.16 (m, 1H), 2.10-2.07 (m, 2H), 1.84-1.78 (m, 3H), 1.21-1.08 (m, 4H). MS-ESI calculated value: [M+H].sup.+ 305; measured value: 305.

Experimental Example 1 In Vitro Evaluation of PDE2 Phosphodiesterase Inhibitory Activity

(313) Experiment Objective: Determining the concentration of AMP/GMP produced in the reaction system by way of detecting the AlexaFluor 633 fluorescent dye substituted on AMP/GMP antibody by fluorescence polarization assay, and thereby to calculate the IC.sub.50 value of PDE2 phosphodiesterase inhibition by the test compound.
Experimental Materials:
Detecting buffer solution: 10 mM Tris-HCl, pH 7.5, 5 mM MgCl.sub.2, 0.01% Brij 35, 1 mM DTT, and 1% DMSO.
Enzyme: Recombinant full-length human PDE2A protein with an N-terminal GST-tag expressed in insect Sf9 cells by baculovirus
Substrate: 1 M cGMP
Detection System:
Transcreener AMP.sup.2/GMP.sup.2 antibody, AMP2/GMP2 AlexaFluor 633 fluorescent dye
Experimental Operation:

(314) The enzyme solution was prepared by using the freshly prepared buffer solution, and then was added into the reaction wells. The DMSO solution of the test compound was added via Echo550, a nanoliter-scale contactless acoustic liquid transferring system, and then pre-incubated at room temperature for 10 minutes. The substrate (1 LM cGMP) was added to initiate the reaction at room temperature for one hour. The detection system (Transcreener AMP.sup.2/GMP.sup.2 antibody, AMP2/GMP2 AlexaFluor 633 fluorescent dye) was then added, and the reaction was conducted at room temperature for 90 minutes. Fluorescence polarization was then detected by using Ex/Em 620/688.

(315) The intensity of fluorescence polarization was converted to nM concentration by the AMP/GMP standard curve, and then calculate the relative enzyme activity inhibition relative to the DMSO blank. The IC.sub.50 values and curves were calculated by using the Prism software package (GraphPad Software, San Diego Calif., USA)

(316) Experimental Results:

(317) TABLE-US-00002 TABLE 1 Results of PDE2 phosphodiesterase inhibitory activity assay Test Compounds PDE2 phosphodiesterase (compounds obtained in each example) inhibitory activity Example 1 Example 2 Example 3 + Example 4 + Example 5 + Example 6 Example 7 Example 8 Example 9 Example 10 Example 11 Isomer 1 + Example 11 Isomer 2 Example 12 Isomer 1 + Example 12 Isomer 2 + Example 13 Example 14 + Example 15 + Example 16 + Example 18 + Example 19 Example 20 + Example 21 + Example 22 Example 23 + Example 25 Example 26 + Example 33 + Example 39 Notes: 10 M <+ 50 M; 1 M <++ 10 M; +++ 1 M; N/A
Conclusion: The compounds of the present invention have significant and even unexpected PDE2A protease inhibitory activity.

Experimental Example 2: In Vitro Evaluation of the Compound's Impact on Induction of TNF- in Rat Blood by LPS

(318) Experiment Objective: Determining the impact of the compounds on induction of TNF- in rat blood by LPS in vitro, and evaluating the effect of the compounds on inhibiting induction of TNF- in rat blood by LPS.

(319) Experimental Materials:

(320) Sprague Dawley rats (male, 210-260 g, 8-10 weeks old, Shanghai SLAC)

(321) Rat TNF-alpha Quantikine ELISA Kit (R&D, # SRTA00)

(322) Experimental Operation:

(323) The test compound solutions were prepared at a concentration of 1 mM. 40 l of each of the solutions was added into a 48-well cell culture plate (at the final concentration of 100 M). After the rat was anesthetized with isoflurane, the blood was collected from the heart (heparin for anticoagulation). The blood was added into the 48-well plate containing the test compound, in the amount of 320 L per well. The 48-well plate was placed into a cell incubator, and then taken out after 30 minutes of incubation. Then, 40 L of LPS solution (100 g/ml) was added and mixed. The 48-well plate was placed into the incubator for further incubation. After 5 hours, the 48-well plate was taken out and the blood sample was transferred to a 1.5 mL centrifuge tube, followed by centrifugation in a centrifuge (4,500 rpm, 4 C., 5 minutes). The supernatant was separated and the plasma was obtained. The plasma was subpackaged in portions, quickly frozen, and stored in a 80 C. refrigerator. In the next day, the TNF- level of the plasma samples was determined by using the R&D ELISA kit in accordance with the instructions.

(324) Experimental Results:

(325) TABLE-US-00003 TABLE 2 Results of TNF inhibitory activity assay Test Compounds (compounds obtained in each example) Rate of TNF inhibition Example 3 + Example 17 Notes: 80% >+ 60%; ++ 80%; N/A
Conclusion: The compounds of the present invention have significant and even unexpected TNF inhibitory activity.