2-aryl selenazole compound and pharmaceutical composition thereof

Abstract

A 2-aryl selenazole compound and a pharmaceutical composition are disclosed, wherein the 2-aryl selenazole compound is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. The 2-aryl selenazole compound has the activity of inhibiting xanthine oxidase. The compound or a pharmaceutically acceptable salt thereof can be applied in terms of preparing a drug used for prevention or treatment of hyperuricemia, gout, diabetic nephropathy, an inflammatory disease or a neurological disease.

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof, ##STR00061## wherein, X is selected from C.sub.1-2 alkyl or substituted C.sub.1-2 alkyl; Y is selected from —COOR.sup.a or —CONHR.sup.a; R.sup.1 is selected from halogen, —CN, C.sub.1-2 alkyl, substituted C.sub.1-2 alkyl, C.sub.1-3 alkoxy, or substituted C.sub.1-3 alkoxy; R.sup.2 is selected from H, D, halogen, C.sub.1-2 alkyl, substituted C.sub.1-2 alkyl, C.sub.1-3 alkoxy, or substituted C.sub.1-3 alkoxy; and R.sup.3 is selected from —(CH.sub.2).sub.n—O—R.sup.b, —(CH.sub.2).sub.n—S—R.sup.b, —C(O)R.sup.b, —NR.sup.cR.sup.d, —S(O)CHR.sup.cR.sup.d, —S(O).sub.2CHR.sup.cR.sup.d, —(CH.sub.2).sub.nC(O)NR.sup.cR.sup.d, aryl, substituted aryl, a heterocyclic radical, a substituted heterocyclic radical, a heteroaryl radical, or a substituted heteroaryl radical, wherein, n is 0 to 2; R.sup.a is selected from H, C.sub.1-6 alkyl or substituted C.sub.1-6 alkyl; R.sup.b is selected from H, methyl, ethyl, propyl, 2-propyl, butyl, tertiary butyl, amyl, substituted C.sub.1-8 alkyl, aryl, substituted aryl, a heterocyclic radical, a substituted heterocyclic radical, a heteroaryl radical, or a substituted heteroaryl radical; and R.sup.c and R.sup.d are respectively independently selected from H, C.sub.1-8 alkyl, or substituted C.sub.1-8 alkyl; or R.sup.c and R.sup.d are cyclized to form cycloalkyl, substituted cycloalkyl, a heteroaryl radical, or a substituted heteroaryl radical; and a substituent in groups X, Y, R.sup.1, R.sup.2, R.sup.3, R.sup.a, R.sup.b, R.sup.c or R.sup.d is selected from one or more of D, —OH, —CN, —NH.sub.2, acyl, acylamino, halogen, C.sub.1-4 alkyl, halogenated C.sub.1-4 alkyl, deuterated C.sub.1-4 alkyl, C.sub.1-2alkoxy, or C.sub.1-2 alkylamino.

2. The compound according to claim 1, wherein the compound is a compound represented by formula (II), or a pharmaceutically acceptable salt thereof ##STR00062##

3. The compound according to claim 2, wherein X is —CH.sub.3, —CH.sub.2CH.sub.3, —CH.sub.2OH, or —CF.sub.3.

4. The compound according to claim 3, wherein R.sup.a is H, C.sub.1-3 alkyl, or substituted C.sub.1-3 alkyl.

5. The compound according to claim 4, wherein R.sup.1 is selected from halogen, —CN, —CH.sub.3, —CH.sub.2CH.sub.3, —CF.sub.3, —OCHF.sub.2, or —OCF.sub.3.

6. The compound according to claim 5, wherein R.sup.2 is selected from H or D.

7. The compound according to claim 6, wherein the compound is a compound represented by formula (III), or a pharmaceutically acceptable salt thereof ##STR00063##

8. The compound according to claim 7, wherein, R.sup.3 is selected from —OR.sup.b, —SR.sup.b, —C(O)R.sup.b, —NR.sup.cR.sup.d, —S(O)CHR.sup.cR.sup.d, —S(O).sub.2CHR.sup.cR.sup.d, —C(O)NR.sup.cR.sup.d, phenyl, substituted phenyl, pyridyl, substituted pyridyl, naphthyl, substituted naphthyl, phenoxy, substituted phenoxy, thiophenyl, substituted thiophenyl, morpholinyl, substituted morpholinyl, N-ethyl morpholinyl, substituted N-ethyl morpholinyl, piperazinyl, substituted piperazinyl, 4,5,6,7-tetrahydrothieno[3,2-c]pyridyl, methylphenyl sulfonyl, or substituted methylphenyl sulfonyl; R.sup.b is methyl, ethyl, propyl, 2-propyl, butyl, tertiary butyl, amyl, substituted C.sub.1-8 alkyl, phenyl or substituted phenyl; R.sup.c or R.sup.d is independently selected from H, C.sub.1-8 alkyl, or substituted C.sub.1-8 alkyl; or R.sup.c and R.sup.d are cyclized to form cycloalkyl, substituted cycloalkyl, a heteroaryl radical, or a substituted heteroaryl radical; and the substituent is selected from one or more of D, —OH, —NH.sub.2, —CN, acyl, halogen, C.sub.1-4 alkyl, halogenated C.sub.1-4 alkyl, deuterated C.sub.1-4 alkyl, or C.sub.1-2 alkoxy.

9. The compound according to claim 8, wherein, R.sup.3 is selected from —OR.sup.b, —SR.sup.b, —C(O)R.sup.b, —NR.sup.cR.sup.d, —S(O).sub.2CHR.sup.cR.sup.d, —C(O)NR.sup.cR.sup.d, phenyl, substituted phenyl, pyridyl, substituted pyridyl, naphthyl, substituted naphthyl, quinolyl, substituted quinolyl, thiophenyl, substituted thiophenyl, phenoxy, substituted phenoxy, pyridylthio, morpholinyl, piperazinyl, substituted piperazinyl, or 4,5,6,7-tetrahydrothieno[3,2-c]pyridyl; R.sup.b is methyl, ethyl, propyl, 2-propyl, butyl, tertiary butyl, amyl, substituted C.sub.1-8 alkyl, phenyl or substituted phenyl; R.sup.c or R.sup.d is independently selected from H, C.sub.1-8 alkyl, or substituted C.sub.1-8 alkyl; or R.sup.c and R.sup.d are cyclized to form cycloalkyl, substituted cycloalkyl, a heteroaryl radical, or a substituted heteroaryl radical; and the substituent is selected from one or more of D, —OH, —CN, —NH.sub.2, —NHCH.sub.3, —F, —Cl, —Br, —CH.sub.3, —CH.sub.2CH.sub.3, —CHDCH.sub.2D, —CF.sub.3, —OCH.sub.3, or —OCH.sub.2CH.sub.3.

10. The compound according to claim 1, wherein the compound is selected from the following compounds or pharmaceutically acceptable salts thereof: 2-(3-cyano-4-ethoxyphenyl)-4 -methyl- selenazole-5-carboxylic acid, 2-(3-cyano-4-isopropoxyphenyl)-4-methyl-selenazole-5-carboxylic acid, 2-[3 -cyano-4-(3 -methyl-butoxy)phenyl]-4-methyl-selenazole-5-carboxylic acid, 2-[3-cyano-4-(cyclohexylmethoxy)phenyl]-4-methyl-selenazole-5-carboxylic acid, 2-[3 -cyano-4-(benzyloxy)phenyl]-4-methyl-selenazole-5-carboxylic acid, 2-[3 -cyano-4-(cyclopropylmethoxy)phenyl]-4-methyl-selenazole-5-carboxylic acid, 2-(2-cyano-biphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid, 2-(2-cyano-3′,4′-dimethoxybiphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid, 2-(2-cyano-3′-fluoro-4′-methoxybiphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid, 2-(2-cyano-3′,4′,5′-trimethoxybiphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid, 2-(2-cyano-4′-methoxybiphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid, 2-(2-cyano-3′-methoxybiphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid, 2-(2-cyano-3′-trifluoromethoxybiphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid, 2-(2-cyano-4′-chlorobiphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid, 2-(2-cyano-3′,4′-difluorobiphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid, 2-(2-cyano-2′,3′,4′,5′,6′-pentadeuterobiphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid, 2-(2-cyano-2′-methoxybiphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid, 2-(2-cyano-2′,4′-dimethoxybiphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid, 2-[3-cyano-4-(1-naphthyl)-phenyl]-4-methyl-selenazole-5-carboxylic acid, 2-[3-cyano-4-(4-pyridyl)-phenyl-4-yl]-4-methyl-selenazole-5-carboxylic acid, 2-(3-cyano-4-(3-pyridyl)-phenyl-4-yl]-4-methyl-selenazole-5-carboxylic acid, 2-[2-cyano-4′-(1,2-deuteroethyl)-biphenyl-4-yl]-4-methyl-selenazole-5-carboxylic acid, 2-(2-cyano-6-deuterobiphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid, 2-(3-cyano-4-isopropylthiophenyl)-4-methyl-selenazole-5-carboxylic acid, 2-(3-cyano-4-isobutylthiophenyl)-4-methyl-selenazole-5-carboxylic acid, 2-[3-cyano-4-(4-chrolophenylthio)-phenyl]-4-methyl-selenazole-5-carboxylic acid, 2-[3-cyano-4-(3-trifluoromethylphenylthio)-phenyl]-4-methyl-selenazole-5-carboxylic acid, 2-[3-cyano-4-(2-pyridylthio)-phenyl]-4-methyl-selenazole-5-carboxylic acid, 2-(3-cyano-4-benzylthio-phenyl)-4-methyl-selenazole-5-carboxylic acid, 2-(3-cyano-4-isopropyl sulfone-phenyl)-4-methyl-selenazole-5-carboxylic acid, 2-(3-cyano-4-morpholinyl-4-yl-phenyl)-4-methyl-selenazole-5-carboxylic acid, 2-[3-cyano-4-(4-methylpiperazine-1-yl)phenyl]-4-methyl-selenazole-5-carboxylic acid, 2-{3 -cyano-4-(6,7 -dihydro-4H-thieno [3 ,2-c]pyridyl)-phenyl}-4-methyl-selenazole-5-carboxylic acid, 2-(3-cyano-4-dimethylamino-phenyl)-4-methyl-selenazole-5-carboxylic acid, 2-(3-fluoro-4-isobutoxyphenyl)-4-methyl-selenazole-5-carboxylic acid, 2-(3-trifluoromethyl-4-isobutoxyphenyl)-4-methyl-selenazole-5-carboxylic acid, 2-[3 -cyano-4-(isopropylthiomethyl)-phenyl]-4-methyl-selenazole-5-carboxylic acid, 2-[3-bromo-4-(aniline formyl)-phenyl]-4-methyl-selenazole-5-carboxylic acid, 2-(2-cyano-4′-trifluoromethylbiphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid, 2-(2-cyano-3′-trifluoromethylbiphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid, 2-(2-cyano-2′-trifluoromethylbiphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid, 2-(3-cyano-4-isobutoxyphenyl)-4-hydroxymethyl-selenazole-5-carboxylic acid, 2-(3-bromo-4-isobutoxyphenyl)-4-methyl-selenazole-5-carboxylic acid, 2-(3-cyano-4-isopropylthiophenyl)-4-methyl-selenazole-5-carboxylic acid-(2-N-acetyl)ethyl ester, 2-(3-cyano-4-tertbutylthiophenyl)-4-methyl-selenazole-5-carboxylic acid, 2-(3-cyano-4-cyclohexylthiophenyl)-4-methyl-selenazole-5-carboxylic acid, or 2-(3-trifluoromethylphenyl)-4-methyl-selenazole-5-carboxylic acid.

11. A pharmaceutical composition, comprising any compound or a pharmaceutically acceptable salt thereof according to claim 1 as an active ingredient.

12. The pharmaceutical composition according to claim 11, for use in the treatment of hyperuricemia, gout, diabetic nephropathy, an inflammatory disease or a neurological disease.

13. A method for inhibiting the activity of xanthine oxidase, the method comprising administering, to an organism in need of such inhibition, an effective amount of the compound or the pharmaceutically acceptable salt of claim 1.

14. The method of claim 13, wherein the organism is a human.

15. A method of reducing uric acid generation, the method comprising administering, to an organism in need of such reduction, an effective amount of the compound or the pharmaceutically acceptable salt of claim 1.

16. The method of claim 15, wherein the organism is a human.

17. A method for the treatment of hyperuricemia, gout, diabetic nephropathy, an inflammatory disease or a neurological disease, the method comprising administering, to an organism in need of such treatment, an effective amount of the compound or the pharmaceutically acceptable salt of claim 1.

18. The method of claim 17, wherein the effective amount of the compound or the pharmaceutically acceptable salt is effective for inhibiting the activity of xanthine oxidase.

19. The method of claim 17, wherein the organism is a human.

20. A method for the treatment of hyperuricemia and gout, the method comprising administering, to an organism in need of such treatment, an effective amount of a xanthine oxidase inhibitor, wherein the xanthine oxidase inhibitor comprises the compound or the pharmaceutically acceptable salt of claim 1.

21. The method of claim 20, wherein the organism is a human.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

DETAILED DESCRIPTION

(1) The following preparation examples and embodiments are provided so that a person skilled in the art can more clearly understand and implement the present invention. They shall not be construed as a limitation on the scope of the present invention, but are merely used for illustration and representation thereof.

SYNTHESIS EMBODIMENTS

Embodiment 1

Synthesis of 2-(3-cyano-4-ethoxyphenyl)-4-methyl-selenazole-5-carboxylic acid (6)

(2) ##STR00013##

(3) Step A: Anhydrous ethanol (540 mL) was added dropwise into a mixture of selenium powder (50.0 g, 0.633 mol) and sodium borohydride (26.4 g, 0.698 mol) within 3 h to 4 h under the protection of nitrogen in an ice-water bath, then heated to room temperature, and stirred for 1 h. The mixture was then added with pyridine solution (126 mL) containing 4-cyanophenol (18.84 g, 0.158 mol), and heated until reflux occurred. After 2M hydrochloric acid solution (320 mL) was added dropwise slowly for no less than 4 h, the resulting solution was stirred overnight under reflux. A TLC analysis indicated that the reaction was completed. The solution was distilled under reduced pressure to remove most of ethanol, added with water (400 mL) for dilution, and extracted with ethyl acetate (200 mL×2). The combined organic phase was washed with 2M hydrochloric acid (100 mL), and then washed with saturated saline solution (100 mL). After the solvent was removed by means of reduced pressure distillation, the resulting product was recrystallized with petroleum ether/ethyl acetate, to obtain p-hydroxy-seleno-benzamide (1) (25.0 g), with a yield of 79.1%.

(4) Step B: The compound 1 (25.0 g, 0.125 mol) and ethyl 2-chloroacetoacetate (24.7 g, 0.150 mol) were added into anhydrous ethanol (500 mL), heated, and stirred under reflux for 3 h. A TLC analysis indicated that the reaction was completed. The reaction solution was cooled to room temperature. After suction filtration under reduced pressure, the filter cake was collected and dried, to obtain 2-(4-hydroxyphenyl)-4-methyl-selenazole-5-ethyl formate (2) (32.7 g), with a yield of 84.3%.

(5) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ 7.81 (dd, J=2.0, 6.8 Hz, 2H), 6.87 (dd, J=2.0, 6.8 Hz, 2H), 4.26 (q, J=6.8 Hz, 2H), 2.64 (s, 3H), 1.28 (t, J=6.8 Hz, 3H).

(6) Step C: The compound 2 (17.6 g, 56.7 mmol) and hexamethylene tetramine (HMTA) (9.8 g, 69.9 mmol) were added into trifluoroacetic acid (85 mL). The reaction solution was heated to 85° C. and stirred for 42 h. A TLC analysis indicated that the reaction was completed. The solution was distilled under reduced pressure to remove most of the solvent, then added with water (300 mL), stirred for 60 min and filtered. The filter cake was dissolved in ethyl acetate (200 mL), separated from residual water, and dried with anhydrous sodium sulfate. After the solvent was removed by means of reduced pressure distillation, the resulting product was separated and purified by using a silica column (200 to 300 mesh silica gel, ethyl acetate/petroleum ether=1/8 for elution), so as to obtain 2-(3-formyl-4-hydroxyphenyl)-4-methyl-selenazole-5-ethyl formate (3) (8.7 g), with a yield of 45.3%.

(7) Step D: The compound 3 (8.7 g, 25.7 mmol), hydroxylamine hydrochloride (2.6 g, 37.4 mmol) and sodium formate (2.5 g, 36.7 mmol) were added into formic acid (90 mL), and the resulting solution was heated and stirred under reflux for 42 h. A TLC analysis indicated that the reaction was completed. The reaction solution was cooled to room temperature and added with water (270 mL) to separate out abundant solids, and was then further cooled to 0-5° C., stirred for 30 min and filtered. The filter cake was washed with abundant water and vacuum-dried to obtain a light yellow solid. The solid was recrystalized with petroleum ether/ethyl acetate, to obtain 2-(3-cyano-4-hydroxyphenyl)-4-methyl-selenazole-5-ethyl formate (4) (7.0 g), with a yield of 81.2%.

(8) Step E: The compound 4 (70 mg, 0.209 mmol) was dissolved in DMF (5 mL), and added with potassium iodide (7 mg, 0.042 mmol), anhydrous potassium carbonate (34.7 mg, 0.251 mmol) and ethyl bromide (32 mg, 0.293 mmol). The resulting mixture was stirred overnight at 70° C. The mixture was cooled to room temperature, added with water for dilution, and then filtered. The filter cake was purified by using a silica column (200 to 300 mesh silica gel, ethyl acetate/petroleum ether=1/20 for elution), so as to obtain a product, 2-(3-cyano-4-ethyoxyphenyl)-4-methyl-selenazole-5-ethyl formate (5), which was directly used for the next step reaction.

(9) Step F: The compound 5 obtained from the last step reaction was dissolved in THF (4 mL) and methanol (11 mL), and added with 2M sodium hydroxide solution (3 mL). The resulting mixture was heated to 55° C. and stirred for 0.5 h. After the reaction was completed, about half of the solvent was removed by means of reduced pressure distillation. The solution was added with water (20 mL) and then with diluted hydrochloric acid so as to adjust the pH value to 5-6, filtered and dried to obtain 2-(3-cyano-4-ethyoxyphenyl)-4-methyl-selenazole-5-carboxylic acid (6).

(10) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ 8.23 (s, 1H), 8.17 (d, J=8.4 Hz, 1H), 7.32 (d, J=8.4 Hz, 1H), 4.27 (q, J=6.8 Hz, 2H), 2.67 (s, 3H), 1.39 (t, J=6.4 Hz, 3H). MS (EI, m/z): 335.1 [M−H].sup.−.

Embodiment 2

Synthesis of 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-selenazole-5-carboxylic acid (7)

(11) ##STR00014##

(12) The compound 4 was reacted with 1-bromo-2-methylpropane according to step E in Embodiment 1, then hydrolyzed according to step F in Embodiment 1, and acidized to obtain 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-selenazole-5-carboxylic acid (7).

(13) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ 8.26 (d, J=2.4 Hz, 1H), 8.18 (dd, J=2.0, 9.2 Hz, 1H), 7.34 (d, J=9.2 Hz, 1H), 4.00 (d, J=6.8 Hz, 2H), 2.63 (s, 3H), 2.14-2.04 (m, 1H), 1.02 (d, J=6.8 Hz, 6H). MS (EI, m/z): 363.2 [M−H].sup.−.

Embodiment 3

Synthesis of 2-(3-cyano-4-isopropoxyphenyl)-4-methyl-selenazole-5-carboxylic acid (8)

(14) ##STR00015##

(15) The compound 4 was reacted with isopropyl bromide according to step E in Embodiment 1, then hydrolyzed according to step F in Embodiment 1, and acidized to obtain 2-(3-cyano-4-isopropoxyphenyl)-4-methyl-selenazole-5-carboxylic acid (8).

(16) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ 8.29 (d, J=2.4 Hz, 1H), 8.20 (dd, J=2.4, 8.8 Hz, 1H), 7.38 (d, J=8.8 Hz, 1H), 4.94-4.88 (m, 1H), 2.65 (s, 3H), 1.36 (d, J=6.0 Hz, 6H). MS (EI, m/z): 349.1 [M−H].sup.−.

Embodiment 4

Synthesis of 2-[3-cyano-4-(3-methyl-butoxy)phenyl]-4-methyl-selenazole-5-carboxylic acid (9)

(17) ##STR00016##

(18) The compound 4 was reacted with 3-methyl-1-bromobutane according to step E in Embodiment 1, then hydrolyzed according to step F in Embodiment 1, and acidized to obtain 2-[3-cyano-4-(3-methyl-butoxy)phenyl]-4-methyl-selenazole-5-carboxylic acid (9).

(19) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ 13.28 (s, 1H), 8.30 (d, J=1.6 Hz, 1H), 8.22 (dd, J=1.6, 8.8 Hz, 1H), 7.38 (d, J=8.8 Hz, 1H), 4.26-4.25 (m, 2H), 2.65 (s, 3H), 1.86-1.78 (m, 1H), 1.70-1.68 (m, 2H), 0.96 (d, J=6.8 Hz, 6H). MS (EI, m/z): 377.2 [M−H].sup.−.

Embodiment 5

Synthesis of 2-[3-cyano-4-(cyclohexylmethoxy)phenyl]-4-methyl-selenazole-5-carboxylic acid (10)

(20) ##STR00017##

(21) The compound 4 was reacted with cyclohexylmethyl bromide according to step E in Embodiment 1, then hydrolyzed according to step F in Embodiment 1, and acidized to obtain 2-[3-cyano-4-(cyclohexylmethoxy)phenyl]-4-methyl-selenazole-5-carboxylic acid (10).

(22) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ 8.18 (d, J=2.4 Hz, 1H), 8.12 (dd, J=2.0, 8.8 Hz, 1H), 7.32 (d, J=8.8 Hz, 1H), 4.01 (d, J=6.0 Hz, 2H), 2.64 (s, 3H), 1.91-1.65 (m, 5H), 1.29-1.07 (m, 6H). MS (EI, m/z): 403.2 [M−H].sup.−.

Embodiment 6

Synthesis of 2-[3-cyano-4-(benzyloxy)phenyl]-4-methyl-selenazole-5-carboxylic acid (11)

(23) ##STR00018##

(24) The compound 4 was reacted with benzyl bromide according to step E in Embodiment 1, then hydrolyzed according to step F in Embodiment 1, and acidized to obtain 2-[3-cyano-4-(benzyloxy)phenyl]-4-methyl-selenazole-5-carboxylic acid (11).

(25) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ 8.34 (d, J=2.4 Hz, 1H), 8.24 (dd, J=2.4, 8.8 Hz, 1H), 7.52-7.38 (m, 6H), 5.38 (s, 2H), 2.65 (s, 3H). MS (EI, m/z): 397.2 [M−H].sup.−.

Embodiment 7

Synthesis of 2-[3-cyano-4-(cyclopropylmethoxy)phenyl]-4-methyl-selenazole-5-carboxylic acid (12)

(26) ##STR00019##

(27) The compound 4 (100 mg, 0.298 mmol) was dissolved in THF (5 mL), added with cyclopropyl methanol (35 mg, 0.485 mmol) and triphenylphosphine (130 mg, 0.496 mmol), and then added dropwise with diethyl diazodicarboxylate (85 mg, 0.488 mmol). The resulting mixture was stirred overnight at room temperature. The solvent was removed by means of reduced pressure distillation, and the resulting product was purified by using a silica column (200 to 300 mesh silica gel, ethyl acetate/petroleum ether=1/20 for elution). The product was then hydrolyzed according to step F in Embodiment 1, and acidized to obtain 2-[3-cyano-4-(cyclopropylmethoxy)phenyl]-4-methyl-selenazole-5-carboxylic acid (12).

(28) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ 8.30 (t, J=1.2 Hz, 1H), 8.22-8.19 (m, 1H), 7.33 (d, J=8.8 Hz, 1H), 4.09 (d, J=7.2 Hz, 2H), 2.65 (s, 3H), 1.30-1.28 (m, 1H), 0.65-0.61 (m, 2H), 0.42-0.40 (m, 2H). MS (EI, m/z): 361.2 [M−H].sup.−.

Embodiment 8

Synthesis of 2-(2-cyano-biphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid (14)

(29) ##STR00020##

(30) Step A: The compound 4 (7.0 mg, 20.9 mmol) was suspended in anhydrous dichloromethane (100 mL), and then added with DMAP (262 mg, 2.14 mmol) and pyridine (7.0 mL). The resulting mixture was stirred until becoming clear, then cooled by means of an ice-salt bath, and added with trifluoromethanesulfonic anhydride (10.8 mL), and then stirred for 1 h in the ice-salt bath. A TLC analysis indicated that the reaction was completed. The solution was distilled under reduced pressure to remove dichloromethane, then added with a proper amount of water and extracted with ethyl acetate (70 mL×3). The combined organic phase was respectively washed with diluted hydrochloric acid (50 mL) and saturated saline solution (50 mL), and dried with anhydrous sodium sulfate. The solvent was removed by means of reduced pressure distillation, so as to obtain 2-(3-cyano-4-trifluoromethanesulfonyl-phenyl)-4-methyl-selenazole-5-ethyl formate (13) (9.7 g), with a yield of 99%.

(31) Step B(1): A mixture of the compound 13 (110 mg, 0.235 mmol), phenylboronic acid (52.7 mg, 0.422 mmol) and anhydrous potassium carbonate (20 mg, 0.017 mmol) was added with methylbenzene (10 mL) and tetrakis(triphenylphosphine)platinum (20 mg, 0.017 mmol). The resulting mixture was heated to 110° C. under the protection of nitrogen, and stirred overnight. The reaction solution was cooled to room temperature, and filtered with a diatomite pad. The filtrate was purified by using a silica column (200 to 300 mesh silica, ethyl acetate/petroleum ether=1/15 for elution), to obtain 2-(2-cyano-biphenyl-4-yl)-4-methyl-selenazole-5-ethyl formate.

(32) .sup.1H NMR (CDCl.sub.3, 400 MHz) δ 8.50 (d, J=1.6 Hz, 1H), 8.33 (dd, J=1.6, 8.0 Hz, 1H), 7.64-7.61 (m, 3H), 7.57-7.51 (m, 3H), 4.37 (q, J=6.4 Hz, 2H), 2.82 (s, 3H), 1.42 (t, J=6.4 Hz, 3H).

(33) Step B(2): The ester obtained in step B(1) was hydrolyzed according to step F in Embodiment 1, and acidized to obtain 2-(2-cyano-biphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid (14).

(34) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ 8.50 (d, J=1.6 Hz, 1H), 8.33 (dd, J=1.6, 8.4 Hz, 1H), 7.77-7.54 (m, 6H), 2.70 (s, 3H). MS (EI, m/z): 367.1 [M−H].sup.−.

Embodiment 9

Synthesis of 2-(2-cyano-3′,4′-dimethoxybiphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid (15)

(35) ##STR00021##

(36) The compound 13 was reacted with 3,4-dimethoxyphenylboronic acid according to step B(1) in Embodiment 8, and was then hydrolyzed according to step F in Embodiment 1, and acidized to obtain 2-(2-cyano-3′,4′-dimethoxybiphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid (15).

(37) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ 8.46 (d, J=2.0 Hz, 1H), 8.30 (dd, J=2.0, 8.4 Hz, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.27-7.22 (m, 2H), 7.14 (d, J=8.4 Hz, 1H), 3.85 (s, 6H), 2.70 (s, 3H). MS (EI, m/z): 427.2 [M−H].sup.−.

Embodiment 10

Synthesis of 2-(2-cyano-3′-fluoro-4′-methoxybiphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid (16)

(38) ##STR00022##

(39) The compound 13 was reacted with 3-fluoro-4-methoxyphenylboronic acid according to step B(1) in Embodiment 8, then hydrolyzed according to step F in Embodiment 1, and acidized to obtain 2-(2-cyano-3′-fluoro-4′-methoxybiphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid (16).

(40) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ 8.47 (d, J=2.0 Hz, 1H), 8.31 (dd, J=2.0, 8.4 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.60 (dd, J=2.4, 12.0 Hz, 1H), 7.49-7.47 (m, 1H), 7.37 (t, J=8.8 Hz, 1H), 3.94 (s, 3H), 2.69 (s, 3H). MS (EI, m/z): 415.2 [M−H].sup.−.

Embodiment 11

Synthesis of 2-(2-cyano-3′,4′,5′-trimethoxybiphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid (17)

(41) ##STR00023##

(42) The compound 13 was reacted with 3,4,5-trimethoxyphenylboronic acid according to step B(1) in Embodiment 8, then hydrolyzed according to step F in Embodiment 1, and acidized to obtain 2-(2-cyano-3′,4′,5′-trimethoxybiphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid (17).

(43) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ 8.46 (d, J=1.6 Hz, 1H), 8.29 (dd, J=1.6, 8.4 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 6.97 (s, 2H), 3.86 (s, 6H), 3.76 (s, 3H), 2.69 (s, 3H). MS (EI, m/z): 457.2 [M−H].sup.−.

Embodiment 12

Synthesis of 2-(2-cyano-4′-methoxybiphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid (18)

(44) ##STR00024##

(45) The compound 13 was reacted with 4-methoxyphenylboronic acid according to step B(1) in Embodiment 8, then hydrolyzed according to step F in Embodiment 1, and acidized to obtain 2-(2-cyano-4′-methoxybiphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid (18).

(46) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ 8.45 (d, J=2.0 Hz, 1H), 8.28 (dd, J=2.0, 8.0 Hz, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.62 (dd, J=2.0, 6.8 Hz, 2H), 7.13 (dd, J=2.0, 6.8 Hz, 2H), 3.85 (s, 3H), 2.69 (s, 3H). MS (EI, m/z): 397.2 [M−H].sup.−.

Embodiment 13

Synthesis of 2-(2-cyano-3′-methoxybiphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid (19)

(47) ##STR00025##

(48) The compound 13 was reacted with 3-methoxyphenylboronic acid according to step B(1) in Embodiment 8, then hydrolyzed according to step F in Embodiment 1, and acidized to obtain 2-(2-cyano-3′-methoxybiphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid (19).

(49) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ 8.50 (d, J=2.0 Hz, 1H), 8.32 (dd, J=2.0, 8.0 Hz, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.48 (t, J=8.0, 1H), 7.22-7.12 (m, 2H), 7.10-7.09 (m, 1H), 3.85 (s, 3H), 2.70 (s, 1H). MS (EI, m/z): 397.2 [M−H].sup.−.

Embodiment 14

Synthesis of 2-(2-cyano-3′-trifluoromethoxybiphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid (20)

(50) ##STR00026##

(51) The compound 13 was reacted with 3-trifluoromethoxyphenylboronic acid according to step B(1) in Embodiment 8, then hydrolyzed according to step F in Embodiment 1, and acidized to obtain 2-(2-cyano-3′-trifluoromethoxybiphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid (20).

(52) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ 8.52 (s, 1H), 8.34 (dd, J=2.0, 8.0 Hz, 1H), 7.81-7.69 (m, 4H), 7.55 (d, J=2.4 Hz, 1H), 2.69 (s, 3H). MS (EI, m/z): 451.2 [M−H].sup.−.

Embodiment 15

Synthesis of 2-(2-cyano-4′-chlorobiphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid (21)

(53) ##STR00027##

(54) The compound 13 was reacted with 4-chlorophenylboronic acid according to step B(1) in Embodiment 8, then hydrolyzed according to step F in Embodiment 1, and acidized to obtain 2-(2-cyano-4′-chlorobiphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid (21).

(55) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ 8.51 (d, J=2.0 Hz, 1H), 8.33 (dd, J=2.0, 8.0 Hz, 1H), 7.76 (d, J=8.0, 1H), 7.71-7.64 (m, 4H), 2.69 (s, 3H). MS (EI, m/z): 401.1 [M−H].sup.−.

Embodiment 16

Synthesis of 2-(2-cyano-3′,4′-difluorobiphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid (22)

(56) ##STR00028##

(57) The compound 13 was reacted with 3.4-difluorophenylboronic acid according to step B(1) in Embodiment 8, then hydrolyzed according to step F in Embodiment 1, and acidized to obtain 2-(2-cyano-3′,4′-difluorobiphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid (22).

(58) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ 8.45 (s, 1H), 8.28 (dd, J=2.0, 8.0 Hz, 1H), 7.84-7.74 (m, 2H), 7.69-7.62 (m, 1H), 7.55-7.51 (m, 1H), 2.68 (s, 3H). MS (EI, m/z): 403.1 [M−H].sup.−.

Embodiment 17

Synthesis of 2-(2-cyano-2′,3′,4′,5′,6′-pentadeuterobiphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid (23)

(59) ##STR00029##

(60) The compound 13 was reacted with 2,3,4,5,6-pentadeuterophenylboronic acid according to step B(1) in Embodiment 8, then hydrolyzed according to step F in Embodiment 1, and acidized to obtain 2-(2-cyano-2′,3′,4′,5′,6′-pentadeuterobiphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid (23).

(61) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ 8.50 (d, J=1.6 Hz, 1H), 8.33 (dd, J=1.6, 8.4 Hz, 1H), 7.76 (d, J=8.4 Hz, 1H), 2.69 (s, 3H). MS (EI, m/z): 372.2 [M−H].sup.−.

Embodiment 18

Synthesis of 2-(2-cyano-2′-methoxybiphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid (24)

(62) ##STR00030##

(63) The compound 13 was reacted with 2-methoxyphenylboronic acid according to step B(1) in Embodiment 8, where potassium carbonate was replaced with cesium carbonate. The product was then hydrolyzed according to step F in Embodiment 1, and acidized to obtain 2-(2-cyano-2′-methoxybiphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid (24).

(64) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ 8.44 (d, J=2.0 Hz, 1H), 8.30 (dd, J=2.0, 8.4 Hz, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.53-7.48 (m, 1H), 7.34 (dd, J=2.0, 7.2 Hz, 1H), 7.21 (d, J=8.0 Hz, 1H), 7.13-7.09 (m, 1H), 3.80 (s, 3H), 2.69 (s, 3H). MS (EI, m/z): 397.1 [M−H].sup.−.

Embodiment 19

Synthesis of 2-(2-cyano-2′,4′-dimethoxybiphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid (25)

(65) ##STR00031##

(66) The compound 13 was reacted with 2.4-dimethoxyphenylboronic acid according to step B(1) in Embodiment 8, where potassium carbonate was replaced with cesium carbonate. The product was then hydrolyzed according to step F in Embodiment 1, and acidized to obtain 2-(2-cyano-2′,4′-dimethoxybiphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid (25).

(67) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ 8.40 (d, J=1.6 Hz, 1H), 8.26 (dd, J=1.6, 8.0 Hz, 1H), 7.59 (d, J=8.4 Hz, 1H), 7.27 (d, J=8.4 Hz, 1H), 6.75-6.68 (m, 2H), 3.85 (s, 3H), 3.80 (s, 3H), 2.69 (s, 3H). MS (EI, m/z): 427.2 [M−H].sup.−.

Embodiment 20

Synthesis of 2-[3-cyano-4-(1-naphthyl)-phenyl]-4-methyl-selenazole-5-carboxylic acid (26)

(68) ##STR00032##

(69) The compound 13 was reacted with 1-naphthaleneboronic acid according to step B(1) in Embodiment 8, then hydrolyzed according to step F in Embodiment 1, and acidized to obtain 2-[3-cyano-4-(1-naphthyl)-phenyl]-4-methyl-selenazole-5-carboxylic acid (26).

(70) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ 8.60 (d, J=2.0 Hz, 1H), 8.40 (dd, J=2.0, 8.0 Hz, 1H), 8.13-8.07 (m, 2H), 7.76-7.54 (m, 6H), 2.72 (s, 3H). MS (EI, m/z): 417.3 [M−H].sup.−.

Embodiment 21

Synthesis of 2-[3-cyano-4-(4-pyridyl)-phenyl-4-yl]-4-methyl-selenazole-5-carboxylic acid (27)

(71) ##STR00033##

(72) A mixture of the compound 13 (110 mg, 0.235 mmol), 4-pyridineboronic acid (86.8 mg, 0.706 mmol), lithium bromide (102 mg, 1.17 mmol) and sodium carbonate (40 mg, 0.377 mmol) was added with 1,4-dioxane (8 mL) and water (2 mL), and then added with tetrakis(triphenylphosphine)platinum (20 mg, 0.017 mmol). The reaction solution was heated under the protection of nitrogen until reflux occurred, and stirred overnight. After being cooled to room temperature, the solution was filtered with a diatomite pad, and the filtrate was purified by using a silica column (200 to 300 mesh silica gel, ethyl acetate/petroleum ether=1/15 for elution). The resulting product was then hydrolyzed according to step F in Embodiment 1, and acidized to obtain 2-[3-cyano-4-(4-pyridyl)-phenyl-4-yl]-4-methyl-selenazole-5-carboxylic acid (27).

(73) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ 8.81 (s, 2H), 8.58 (d, J=2.0 Hz, 1H), 8.40 (dd, J=2.0, 8.0 Hz, 1H), 7.84 (d, J=8.0 Hz, 1H), 7.71 (d, J=5.6 Hz, 2H), 2.70 (s, 3H). MS (EI, m/z): 368.1 [M−H].sup.−.

Embodiment 22

Synthesis of 2-[3-cyano-4-(3-pyridyl)-phenyl-4-yl]-4-methyl-selenazole-5-carboxylic acid (28)

(74) ##STR00034##

(75) The compound 13 was reacted with 1-naphthaleneboronic acid according to the operation procedure in Embodiment 21, then hydrolyzed according to step F in Embodiment 1, and acidized to obtain 2-[3-cyano-4-(3-pyridyl)-phenyl-4-yl]-4-methyl-selenazole-5-carboxylic acid (28).

(76) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ 8.74 (s, 1H), 8.73 (d, J=5.2 Hz, 1H), 8.55 (d, J=1.6 Hz, 1H), 8.36 (dd, J=2.0, 8.0 Hz, 1H), 8.14-8.11 (m, 1H, 7.83 (d, J=8.0 Hz, 1H), 7.61 (dd, J=4.8, 8.0 Hz, 1H), 2.70 (s, 3H). MS (EI, m/z): 368.1 [M−H].sup.−.

Embodiment 23

Synthesis of 2-[2-cyano-4′-(1.2′-deuteroethyl)-biphenyl-4-yl]-4-methyl-selenazole-5-carboxylic acid (30)

(77) ##STR00035##

(78) Step A: A mixture of the compound 13 (110 mg, 0.235 mmol), 4-vinylphenylboronic acid (39 mg, 0.264 mmol) and anhydrous potassium carbonate (53 mg, 0.384 mmol) was added with methylbenzene (10 mL) and tetrakis(triphenylphosphine)platinum (20 mg, 0.017 mmol). The reaction solution was heated to 110° C. under the protection of nitrogen, and stirred overnight. The solution was cooled to room temperature, and filtered with a diatomite pad. The filtrate was purified by using a silica column (200 to 300 mesh silica gel, ethyl acetate/petroleum ether=1/20 for elution), to obtain 2-(2-cyano-4′-vinyl-biphenyl-4-yl)-4-methyl-selenazole-5-ethyl formate (29).

(79) Step B: the compound 29 was dissolved in THF (10 mL) and heavy water (1 mL), and added with 5% palladium carbon (20 mg). The mixture was deuterated in deuterium gas under normal pressure for 24 h. After being filtered with diatomite, the filtrate was distilled under reduced pressure so as to remove the solvent. The product was then hydrolyzed according to step F in Embodiment 1, and acidized to obtain 2-[2-cyano-4′-(1.2′-deuteroethyl)-biphenyl-4-yl]-4-methyl-selenazole-5-carboxylic acid (30).

(80) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ 8.48 (d, J=2.0 Hz, 1H), 8.31 (dd, J=2.0, 8.4 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.58 (d, J=8.4 Hz, 2H), 7.41 (d, J=8.4 Hz, 2H), 2.70-2.68 (m, 4H), 1.23 (t, J=4.0 Hz, 2H). MS (EI, m/z): 397.2 [M−H].sup.−.

Embodiment 24

Synthesis of 2-(2-cyano-6-deuterobiphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid (35)

(81) ##STR00036##

(82) Step A: A mixture of the compound 4 (250 mg, 0.745 mmol), methanol (8 mL) and triethylamine (1 mL) was added with NBS (160 mg, 0.898 mmol) in batches in an ice-water bath, and then the resulting mixture was stirred for reaction over 1 h. The solvent was removed by reduced pressure distillation, and the resulting product was dissolved in ethyl acetate (25 mL), filtered to remove insoluble substances, washed with water until the pH value was adjusted to 2-3, and then filtered. The collected solid was directly used for the next step reaction.

(83) Step B: The product obtained in the last step reaction was dissolved in DMF (3 mL), and added with anhydrous potassium carbonate (240 mg, 1.739 mmol) and benzyl bromide (159 mg, 0.930 mmol). The resulting mixture was heated to 60° C. for reaction over about 20 min, and then added with DMF (5 mL) for reaction at constant temperature over 2 h. After being cooled to room temperature, the solution was diluted with water (45 mL), and filtered. The filter cake was dried and then directly used for the next step reaction.

(84) Step C: The product obtained from the last step reaction was dissolved in DMF (10 mL) and heavy water (1 mL), and added with 5% palladium carbon (30 mg). The resulting mixture was deuterated in deuterium gas under normal pressure for 24 h, and filtered with a diatomite pad. The filtrate was distilled under reduced pressure to remove the solvent, so as to obtain 2-(3-cyano-4-hydroxyl-5-deutero-phenyl)-4-methyl-selenazole-5-ethyl formate (33) (102 mg), with a total yield of 40.6% in the three steps of reactions.

(85) Step D: The compound 33 (102 mg, 0.302 mmol) was dissolved in dichloromethane (10 mL), added with DMAP (4 mg, 0.033 mmol) and pyridine (0.1 mL), and then added with trifluoromethanesulfonic anhydride (257 mg, 0.910 mmol) in an ice-water bath. The reaction solution was stirred for 1 h in the ice-water bath. Most of dichloromethane was removed by means of reduced pressure distillation. The solution was then added with water (10 mL) and extracted with ethyl acetate (10 mL×3). The combined organic phase was washed with 2M diluted hydrochloric acid (10 mL), and dried with anhydrous sodium sulfate. After the solvent was removed by means of reduced pressure distillation, the product was purified by using a silica column (200 to 300 mesh silica gel, ethyl acetate/petroleum ether=1/20 for elution), to obtain 2-(3-cyano-4-trifluoromethanesulfonyl-5-deuterophenyl)-4-methyl-selenazole-5-ethyl formate (34) (70 mg), with a yield of 49.5%.

(86) Step E: A mixture of the compound 34 (70 mg, 0.149 mmol), phenylboronic acid (33.5 mg, 0.275 mmol) and anhydrous potassium carbonate (33.7 mg, 0.244 mmol) was added with methylbenzene (10 mL) and tetrakis(triphenylphosphine)platinum (20 mg, 0.017 mmol). The reaction solution was heated to 110° C. under the protection of nitrogen, and stirred overnight. After being cooled to room temperature, the reaction solution was filtered with a diatomite pad, and the filtrate was purified by using a silica column (200 to 300 mesh silica gel, ethyl acetate/petroleum ether=1/20 for elution). The resulting product was then hydrolyzed according to step F in Embodiment 1, and acidized to obtain 2-[2-cyano-6-deuterobiphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid (35).

(87) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ 8.50 (s, 1H), 8.33 (s, 1H), 7.69-7.56 (m, 5H), 2.69 (s, 3H). MS (EI, m/z): 368.2 [M−H].sup.−.

Embodiment 25

Synthesis of 2-(3-cyano-4-isopropylthiophenyl)-4-methyl-selenazole-5-carboxylic acid (37)

(88) ##STR00037##

(89) Step A: Under the protection of nitrogen, a three-mouth flask A was successively added with 1,4-dioxane (4 mL), isopropyl mercaptan (27 mg, 0.355 mmol), and diisopropylethylamine (61 mg, 0.472 mmol). The mixed solution was stirred for 40 min at room temperature. Another three-mouth flask B was added with 1,4-dioxane (6 mL), the compound 13 (110 mg, 0.235 mmol), Pd.sub.2(dba).sub.3 (11 mg, 0.012 mmol) and 4,5-diphenylphosphine-9,9-dimethylxanthene (13.7 mg, 0.0236 mmol). The mixed solution in the three-mouth flask B was stirred for 20 min under the protection of nitrogen, and then transferred to the aforementioned three-mouth flask A by using a syringe. The resulting mixture was stirred under reflux overnight. After being cooled to room temperature, the reaction solution was added with ethyl acetate (40 mL), washed with water (10 mL×2), and dried with anhydrous sodium sulfate. The solution was purified by using a silica column (200 to 300 mesh silica gel, ethyl acetate/petroleum ether=1/20 for elution), to obtain 2-(3-cyano-4-isopropylthiophenyl)-4-methyl-selenazole-5-ethyl formate (36).

(90) .sup.1H NMR (CDCl.sub.3, 400 MHz) δ 8.17 (d, J=2.0 Hz, 1H), 8.03 (dd, J=2.0, 8.4 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 4.36 (q, J=7.2 Hz, 2H), 3.71-3.63 (m, 1H), 2.79 (s, 3H), 1.43-1.39 (m, 9H).

(91) Step B: The compound 36 was hydrolyzed according to step F in Embodiment 1, and acidized to obtain 2-(3-cyano-4-isopropylthiophenyl)-4-methyl-selenazole-5-carboxylic acid (37).

(92) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ 8.36 (d, J=1.6 Hz, 1H), 8.19 (dd, J=1.6, 8.4 Hz, 1H), 7.71 (d, J=8.4 Hz, 1H), 3.88-3.81 (m, 1H), 2.67 (s, 3H), 1.35 (d, J=6.4 Hz, 6H). MS (EI, m/z): 365.1 [M−H].sup.−.

Embodiment 26

Synthesis of 2-(3-cyano-4-isobutylthiophenyl)-4-methyl-selenazole-5-carboxylic acid (38)

(93) ##STR00038##

(94) The compound 13 was reacted with isobutyl mercaptan according to step A in Embodiment 25, then hydrolyzed according to step F in Embodiment 1, and acidized to obtain 2-(3-cyano-4-isobutylthiophenyl)-4-methyl-selenazole-5-carboxylic acid (38).

(95) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ 8.33 (d, J=2.0 Hz, 1H), 8.16 (dd, J=2.0, 8.4 Hz, 1H), 7.64 (d, J=8.4 Hz, 1H), 3.09 (d, J=6.4 Hz, 2H), 2.67 (s, 3H), 1.94-1.86 (m, 1H), 1.04 (d, J=6.8 Hz, 6H). MS (EI, m/z): 379.2 [M−H].sup.−.

Embodiment 27

Synthesis of 2-[3-cyano-4-(4-chrolophenylthio)-phenyl]-4-methyl-selenazole-5-carboxylic acid (39)

(96) ##STR00039##

(97) The compound 13 was reacted with 4-chlorothiophenol according to step A in Embodiment 25, then hydrolyzed according to step F in Embodiment 1, and acidized to obtain 2-[3-cyano-4-(4-chrolophenylthio)-phenyl]-4-methyl-selenazole-5-carboxylic acid (39).

(98) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ 8.44 (d, J=2.0 Hz, 1H), 8.15 (dd, J=2.0, 8.4 Hz, 1H), 7.85-7.84 (m, 4H), 7.24 (d, J=8.4 Hz, 1H), 2.65 (s, 3H). MS (EI, m/z): 433.1 [M−H].sup.−.

Embodiment 28

Synthesis of 2-[3-cyano-4-(3-trifluoromethylphenylthio)-phenyl]-4-methyl-selenazole-5-carboxylic acid (40)

(99) ##STR00040##

(100) The compound 13 was reacted with 3-trifluoromethylthiophenol according to step A in Embodiment 25, then hydrolyzed according to step F in Embodiment 1, and acidized to obtain 2-[3-cyano-4-(3-trifluoromethylphenylthio)-phenyl]-4-methyl-selenazole-5-carboxylic acid (40).

(101) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ 8.49 (d, J=2.0 Hz, 1H), 8.20 (dd, J=2.0, 8.4 Hz, 1H), 7.91 (s, 1H), 7.86-7.71 (m, 3H), 7.36 (d, J=8.4 Hz, 1H), 2.66 (s, 3H). MS (EI, m/z): 467.1 [M−H].sup.−.

Embodiment 29

Synthesis of 2-[3-cyano-4-(2-pyridylthio)-phenyl]-4-methyl-selenazole-5-carboxylic acid (41)

(102) ##STR00041##

(103) The compound 13 was reacted with 2-mercaptopyridine according to step A in Embodiment 25, then hydrolyzed according to step F in Embodiment 1, and acidized to obtain 2-[3-cyano-4-(2-pyridylthio)-phenyl]-4-methyl-selenazole-5-carboxylic acid (41). .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ 8.54 (s, 1H), 8.45-8.43 (m, 1H), 8.29 (dd, J=2.0, 8.0 Hz, 1H), 7.85-7.77 (m, 2H), 7.39 (d, J=8.0 Hz, 1H), 7.31-7.27 (m, 1H), 2.69 (s, 3H). MS (EI, m/z): 400.3 [M−H].sup.−.

Embodiment 30

Synthesis of 2-(3-cyano-4-benzylthio-phenyl)-4-methyl-selenazole-5-carboxylic acid (42)

(104) ##STR00042##

(105) The compound 13 was reacted with 2-mercaptomethyl benzene according to step A in Embodiment 25, then hydrolyzed according to step F in Embodiment 1, and acidized to obtain 2-(3-cyano-4-benzylthio-phenyl)-4-methyl-selenazole-5-carboxylic acid (42). .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ 8.35 (d, J=2.0 Hz, 1H), 8.16 (dd, J=2.0, 8.4 Hz, 1H), 7.73 (d, J=8.4 Hz, 1H), 7.47-7.29 (m, 5H), 4.51 (s, 2H), 2.65 (s, 3H). MS (EI, m/z): 413.3 [M−H].sup.−.

Embodiment 31

Synthesis of 2-(3-cyano-4-isopropyl sulfone-phenyl)-4-methyl-selenazole-5-carboxylic acid (43)

(106) ##STR00043##

(107) The compound 36 (80 mg, 0.203 mmol) was dissolved in acetic acid (5 mL), and the resulting solution was added with hydrogen peroxide (1.5 mL), and then stirred overnight at room temperature. The reaction solution was added with water (20 mL) for dilution and filtered. The filter cake was then collected. The obtained product was hydrolyzed according to step F in Embodiment 1, and acidized to obtain 2-(3-cyano-4-isopropyl sulfone-phenyl)-4-methyl-selenazole-5-carboxylic acid (43).

(108) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ 13.56 (s, 1H), 8.71 (d, J=2.0 Hz, 1H), 8.52 (dd, J=2.0, 8.4 Hz, 1H), 8.17 (d, J=8.4 Hz, 1H), 3.65 (t, J=6.8 Hz, 1H), 2.71 (s, 3H), 1.26 (d, J=6.8 Hz, 6H). MS (EI, m/z): 397.1 [M−H].sup.−.

Embodiment 32

Synthesis of 2-(3-cyano-4-morpholinyl-4-yl-phenyl)-4-methyl-selenazole-5-carboxylic acid (44)

(109) ##STR00044##

(110) The compound 13 (100 mg, 0.214 mmol) was added into morpholine (3 mL). The resulting reaction solution was heated to 80° C., stirred for 15 min, then cooled to room temperature, and added with water (20 mL) for dilution. After filtration, the filter cake was collected. The obtained product was hydrolyzed according to step F in Embodiment 1, and acidized to obtain 2-(3-cyano-4-morpholinyl-4-yl-phenyl)-4-methyl-selenazole-5-carboxylic acid (44).

(111) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ 8.24 (d, J=2.0 Hz, 1H), 8.13 (dd, J=2.0, 8.8 Hz, 1H), 7.22 (d, J=8.8 Hz, 1H), 3.78 (d, J=4.0 Hz, 4H), 3.31 (d, J=4.0 Hz, 4H), 2.64 (s, 3H). MS (EI, m/z): 367.2 [M−H].sup.−.

Embodiment 33

Synthesis of 2-[3-cyano-4-(4-methylpiperazin-1-yl)phenyl]-4-methyl-selenazole-5-carboxylic acid (45)

(112) ##STR00045##

(113) The compound 13 was reacted with methylpiperidine according to the experimental procedure in Embodiment 32, then hydrolyzed according to step F in Embodiment 1, and acidized to obtain 2-[3-cyano-4-(4-methylpiperazin-1-yl)phenyl]-4-methyl-selenazole-5-carboxylic acid (45).

(114) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ 8.30 (d, J=2.0 Hz, 1H), 8.16 (dd, J=2.0, 8.8 Hz, 1H), 7.32 (d, J=8.8 Hz, 1H), 3.65-3.14 (m, 8H), 2.81 (s, 3H), 2.64 (s, 3H). MS (EI, m/z): 389.1 [M−H].sup.−.

Embodiment 34

Synthesis of 2-{3-cyano-4-(6,7-dihydro-4H-thieno[3,2-c]pyridyl)-phenyl}-4-methyl-selenazole-5-carboxylic acid (46)

(115) ##STR00046##

(116) 4,5,6,7-4H-thieno[3,2-c]pyridine hydrochloride (173 mg, 0.984 mmol) was dissolved in DMF (5 mL). The resulting solution was added with the compound 13 (100 mg, 0.214 mmol) and diisopropylethylamine (138 mg, 1.067 mmol), then heated to 90° C. and stirred for 40 min. After being cooled to room temperature, the solution was poured into water (30 mL), and then extracted with ethyl acetate (15 mL×3). The organic phase was washed with water (10 mL×2), and the solvent was removed by means of reduced pressure distillation. The product was purified by using a silica column (200 to 300 mesh silica, ethyl acetate/petroleum ether=1/15 for elution). The obtained product was hydrolyzed according to step F in Embodiment 1, and acidized to obtain 2-{3-cyano-4-(6,7-dihydro-4H-thieno[3,2-c]pyridyl)-phenyl}-4-methyl-selenazole-5-carboxylic acid (46).

(117) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ 8.25 (d, J=2.4 Hz, 1H), 8.11 (d, J=2.4, 8.8 Hz, 1H), 7.39 (d, J=5.2 Hz, 1H), 7.26 (d, J=5.2 Hz, 1H), 6.93 (d, J=5.2 Hz, 1H), 4.45 (s, 2H), 3.78 (t, J=5.2 Hz, 2H), 3.03 (t, J=5.2 Hz, 2H), 2.64 (s, 3H). MS (EI, m/z): 428.2 [M−H].sup.−.

Embodiment 35

Synthesis of 2-(3-cyano-4-dimethylamino-phenyl)-4-methyl-selenazole-5-carboxylic acid (47)

(118) ##STR00047##

(119) The compound 13 (150 mg, 0.321 mmol) was dissolved in DMF (4.5 mL), and then added with 30% dimethylamine aqueous solution (1.5 mL). The reaction solution was stirred for 2 h at room temperature, then added with water (20 mL) for dilution, and extracted with ethyl acetate (10 mL×3). The organic phase was washed with water (10 mL×2), and distilled under reduced pressure to remove the solvent. The product was purified by using a silica column (200 to 300 mesh silica gel, ethyl acetate/petroleum ether=1/15 for elution). The obtained product was hydrolyzed according to step F in Embodiment 1, and acidized to obtain 2-(3-cyano-4-dimethylamino-phenyl)-4-methyl-selenazole-5-carboxylic acid (47).

(120) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ 8.10 (d, J=2.4 Hz, 1H), 7.98 (dd, J=2.4, 9.2 Hz, 1H), 7.03 (d, J=9.2 Hz, 1H), 3.15 (s, 6H), 2.63 (s, 3H). MS (EI, m/z): 334.2 [M−H].sup.−.

Embodiment 36

Synthesis of 2-(3-chloro-4-isobutoxyphenyl)-4-methyl-selenazole-5-carboxylic acid (51)

(121) ##STR00048##

(122) Step A: At 0-10° C., anhydrous ethanol (36 mL) was slowly added into a mixture of selenium powder (3.3 g, 41.8 mmol) and sodium borohydride (1.73 g, 45.8 mmol), then heated to room temperature and stirred for 30 min, and then added with pyridine solution (8.3 mL) containing 3-chloro-4-hydroxybenzonitrile (1.6 g, 10.4 mmol). The reaction solution was heated until reflux occurred, then slowly added dropwise with 2M hydrochloric acid (21 mL), and stirred under reflux for 1 h. A TLC analysis indicated that the reaction was completed. The reaction solution was cooled to room temperature, added with water (100 mL) for dilution and extracted with ethyl acetate (30 mL×3). The combined organic phase was respectively washed with 2M hydrochloric acid (15 mL×2) and saturated saline solution (20 mL). The solvent was removed by means of reduced pressure distillation, so as to obtain 3-chloro-4-hydroxy selenobenzamide (49) (2.4 g), with a yield of 98.1%.

(123) Step B: The compound 49 (2.4 g, 10.2 mmol) was dissolved in ethanol (25 mL), and added with ethyl 2-chloroacetoacetate (2.04 g, 12.4 mmol). The mixed solution was heated until reflux occurred, and stirred for 2 h. A TLC analysis indicated that the reaction was completed. The reaction solution was cooled to room temperature, and was dried after suction filtration to obtain 2-(3-chloro-4-hydroxyphenyl)-4-methyl-selenazole-5-ethyl formate (50) (3.1 g), with a yield of 88.1%.

(124) Step C: The compound 50 (80 mg, 0.232 mmol) was dissolved in DMF (5 mL), and then added with potassium iodide (8.0 mg, 0.048 mmol), anhydrous potassium carbonate (42.6 mg, 0.309 mmol), and 1-bromo-2-methylpropane (49.4 mg, 0.361 mmol). The resulting mixture was heated to 70° C. and stirred overnight. After being cooled to room temperature, the mixture was added with water (20 mL) for dilution and filtered. The filter cake was purified by using a silica column (200 to 300 mesh silica gel, ethyl acetate/petroleum ether=1/15 for elution). The obtained product was hydrolyzed according to step F in Embodiment 1, and acidized to obtain 2-(3-chloro-4-isobutoxyphenyl)-4-methyl-selenazole-5-carboxylic acid (51).

(125) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ 13.24 (s, 1H), 7.99 (s, 1H), 7.88 (d, J=8.8 Hz, 1H), 7.24 (d, J=8.8 Hz, 1H), 3.93 (d, J=6.4 Hz, 2H), 2.64 (s, 3H), 2.12-2.05 (m, 1H), 1.02 (d, J=6.8 Hz, 6H). MS (EI, m/z): 372.1 [M−H].sup.−.

Embodiment 37

Synthesis of 2-(3-trifluoromethyl-4-isobutoxyphenyl)-4-methyl-selenazole-5-carboxylic acid (55)

(126) ##STR00049##

(127) A compound 3-trifluoromethyl-4-hydroxybenzonitrile was used to prepare selenoamide according to step A in Embodiment 32, then cyclized according to step B in Embodiment 32 and reacted with 1-bromo-2-methylpropane according to step C in Embodiment 32, and finally hydrolyzed according to step F in Embodiment 1 and acidized to obtain 2-(3-trifluoromethyl-4-isobutoxyphenyl)-4-methyl-selenazole-5-carboxylic acid (55).

(128) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ 8.18 (dd, J=2.4, 8.8 Hz, 1H), 8.13 (d, J=2.4 Hz, 1H), 7.36 (d, J=9.2 Hz, 1H), 3.99 (d, J=6.0 Hz, 2H), 2.65 (s, 3H), 2.10-2.03 (m, 1H), 1.01 (d, J=6.8 Hz, 6H). MS (EI, m/z): 406.3 [M−H].sup.−.

Embodiment 38

Synthesis of 2-[3-cyano-4-(isopropylthiomethyl)-phenyl]-4-methyl-selenazole-5-carboxylic acid (62)

(129) ##STR00050##

(130) Step A: Concentrated sulfuric acid (20 mL) was added into water (20 mL) to prepare sulfuric acid solution, and the resulting solution was then added with 4-methylbenzonitrile (5.86 g, 50.0 mmol) and NBS (8.9 g, 50.0 mmol). The resulting mixture was stirred overnight at room temperature while being protected from light. After filtration, the filter cake was dissolved in ethyl acetate (150 mL), respectively washed with water (30 mL×2), sodium bicarbonate aqueous solution (30 mL) and saturated saline solution (20 mL), and dried with anhydrous sodium sulfate. The solvent was removed by means of reduced pressure distillation, so as to obtain 3-bromo-4-methylbenzonitrile (57) (6.78 g), with a yield of 69.2%.

(131) .sup.1H NMR (CDCl.sub.3, 400 MHz) δ 7.84 (d, J=1.6 Hz, 1H), 7.52 (dd, J=1.6, 8.0 Hz, 1H), 7.35 (d, J=8.0 Hz, 1H).

(132) Step B: The compound 57 (804 mg, 4.04 mmol) was dissolved in carbon tetrachloride (8 mL), and then added with NBS (730 mg, 4.10 mmol) and benzoyl peroxide (7 mg, 0.0289 mmol). The resulting mixture was heated under the protection of nitrogen until reflux occurred, and was stirred overnight. The mixture was cooled to room temperature, filtered to remove insoluble substances and distilled under reduced pressure to remove the solvent, then dissolved in ethyl acetate (30 mL) and respectively washed with water (10 mL) and saturated saline solution (10 mL). After the solvent was removed by means of reduced pressure distillation, the resulting product was purified by using a silica column (200 to 300 mesh silica gel, ethyl acetate/petroleum ether=1/35 for elution) to obtain 3-bromo-4-cyanobenzyl bromide (58) (583 mg), with a yield of 52.5%.

(133) Step C: The compound 58 (275 mg, 1.0 mmol) was dissolved in DMF (5 mL), cooled to 0-10° C., and added with cesium carbonate (652 mg, 2.0 mmol) and isopropyl mercaptan (114 mg, 1.5 mmol), heated to room temperature and stirred for 2 h. A TLC analysis indicated that the reaction was completed. The reaction solution was added with water (30 mL), and extracted with ethyl acetate (15 mL×3). The combined organic phase was then washed with water (10 mL×2) and dried with anhydrous sodium sulfate. The solvent was removed by means of reduced pressure distillation, so as to obtain an oily substance, 3-bromo-4-isopropyl cyanobenzyl sulfide (59) (278 mg), with a yield of 100%.

(134) Step D: At 0-10° C., anhydrous ethanol (10 mL) was slowly added into selenium powder (340 mg, 4.306 mmol) and sodium borohydride (178 mg, 4.709 mmol), then heated to room temperature and stirred for 30 min. The resulting mixture was then added with pyridine solution (1.5 mL) containing the compound 59 (270 m, 1.0 mmol), heated until reflux occurred, and slowly added dropwise with 2M hydrochloric acid solution (10 mL). After addition, the solution was stirred under reflux for 1 h. A TLC analysis indicated that the reaction was completed. The solution was cooled to room temperature, added with water (30 mL) for dilution, and extracted with ethyl acetate (15 mL×3). The combined organic phase was respectively washed with 2M hydrochloric acid (15 mL) and saturated saline solution (15 mL). The solvent was removed by means of reduced pressure distillation, so as to obtain a product, 3-bromo-4-isopropylthiomethyl selenobenzamide (60), which was directly used for the next step reaction.

(135) Step E: The compound 60 was dissolved in ethanol (10 mL), added with ethyl 2-chloroacetoacetate (248 mg, 1.506 mmol), then heated until reflux occurred and stirred for 2 h. After ethanol was removed by means of reduced pressure distillation, the resulting product was purified by using a silica column (200 to 300 mesh silica gel, ethyl acetate/petroleum ether=1/20 for elution), to obtain 2-[3-bromo-4-(isopropylthiomethyl)phenyl]-4-methyl-selenazole-5-ethyl formate (61) (118 mg), with a yield of 25.6%.

(136) Step F: The compound 61 (115 mg, 0.249 mmol) was dissolved in N-methylpyrrolidone (6 mL), added with cuprous cyanide (40 mg, 0.446 mmol), then heated under the protection of nitrogen until reflux occurred, and stirred for 6 h. After the solvent was removed by means of reduced pressure distillation, the resulting product was purified by using a silica column (200 to 300 mesh silica gel, ethyl acetate/petroleum ether=1/15 for elution), to obtain 2-[3-cyano-4-(isopropylthiomethyl)phenyl]-4-methyl-selenazole-5-ethyl formate.

(137) .sup.1H NMR (CDCl.sub.3, 400 MHz) δ 8.16 (d, J=1.6 Hz, 1H), 7.83 (dd, J=1.6, 8.0 Hz, 1H), 7.50 (d, J=8.0 Hz, 1H), 4.36 (q, J=6.8 Hz, 2H), 3.90 (s, 2H), 2.95-2.89 (m, 1H), 2.81 (s, 3H), 1.40 (t, J=2.8 Hz, 3H), 1.30 (d, J=10.0 Hz, 6H).

(138) The ester was hydrolyzed according to step F in Embodiment 1, and acidized to obtain 2-[3-cyano-4-(isopropylthiomethoxy)phenyl]-4-methyl-selenazole-5-carboxylic acid (62).

(139) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ 8.38 (d, J=2.0 Hz, 1H), 8.22 (dd, J=2.0, 8.4 Hz, 1H), 7.70 (d, J=8.4 Hz, 1H), 3.98 (s, 2H), 2.90-2.83 (m, 1H), 2.67 (s, 3H), 1.23 (d, J=6.8 Hz, 6H). MS (EI, m/z): 379.1 [M−H].sup.−.

Embodiment 39

Synthesis of 2-[3-bromo-4-(aniline formyl)-phenyl]-4-methyl-selenazole-5-carboxylic acid (67)

(140) ##STR00051##

(141) Step A: The compound 58 (2.6 g, 9.46 mmol) was dissolved in 1,4-dioxane (20 mL) and water (20 mL), then added with calcium carbonate (4.3 g, 43 mmol), heated until reflux occurred and stirred overnight. The solution was cooled to room temperature, added with water (40 mL) and extracted with ethyl acetate (30 mL×3). The combined organic phase was filtered with a short silicone pad. The solvent was removed by means of reduced pressure distillation, so as to obtain 3-bromo-4-hydroxymethyl benzonitrile (63) (1.8 g), with a yield of 89.7%.

(142) Step B: At 0-10° C., anhydrous ethanol (27 mL) was slowly added dropwise into a mixture of selenium powder (2.7 g, 34.2 mmol) and sodium borohydride (1.57 g, 41.5 mmol), then heated to room temperature and stirred for 30 min, and then added with pyridine solution (7.2 mL) containing 3-bromo-4-isopropylthiomethyl benzonitrile (63) (1.8 g, 8.49 mmol). The reaction solution was heated until reflux occurred, slowly added dropwise with 2M hydrochloric acid solution (18 mL) and then stirred under reflux for 1 h. A TLC analysis indicated that the reaction was completed. The solution was cooled to room temperature, added with a proper amount of water and then extracted with ethyl acetate (30 mL×3). The organic phase was respectively washed with 2M hydrochloric acid (20 mL) and saturated saline solution (20 mL), and dried with anhydrous sodium sulfate. The solvent was removed by means of reduced pressure distillation, so as to obtain pink 3-bromo-4-hydroxymethyl selenobenzamide (64) (1.98 g), with a yield of 79.6%.

(143) Step C: The compound 64 (293 mg, 1.0 mmol) was dissolved in ethanol (10 mL), added with ethyl 2-chloroacetoacetate (197 mg, 1.20 mmol), and then heated under reflux for 1.5 h. A TLC analysis indicated that the reaction was completed. The solution was cooled to room temperature, added with a proper amount of water, and filtered to obtain a compound 2-(3-bromo-4-hydroxymethylphenyl)-4-methyl-selenazole-5-ethyl formate (65) (340 mg), with a yield of 84.3%.

(144) Step D: The compound 65 (200 mg, 0.496 mmol) was dissolved in acetone (5 mL), and then added with potassium permanganate (158 mg, 1.0 mmol). After being stirred at room temperature for 2 h, the resulting mixture was quenched with sodium hydrogen sulfite aqueous solution, added with a proper amount of water, and filtered to remove insoluble substances. The filtrate was extracted with ethyl acetate (20 mL×2), and the water phase was added with 2M hydrochloric acid to adjust the pH value to 3-4. After filtration, 2-(3-bromo-4-carboxylphenyl)-4-methyl-selenazole-5-ethyl formate (66) (168 mg) was obtained, with a yield of 81.2%.

(145) Step E: The compound 66 (147 mg, 0.352 mmol) was dissolved in dichloromethane (10 mL), and then added with thionyl chloride (168 mg, 1.41 mmol). The resulting solution was heated until reflux occurred, then stirred for 3 h, and distilled under reduced pressure to remove the solvent. The product was then added with dichloromethane (10 mL), and added with triethylamine (107 mg, 1.059 mmol) and aniline (33 mg, 0.354 mmol) while being cooled in an ice-water bath. After the ice-water bath was removed, the solution was stirred at room temperature for 1 h. The reaction solution was washed with a proper amount of water and dried with anhydrous sodium sulfate. The solvent was removed by means of reduced pressure distillation, and the product was purified by using a silica column (200 to 300 mesh silica gel, ethyl acetate/petroleum ether=1/15 for elution). The obtained product was hydrolyzed according to step F in Embodiment 1, and acidized to obtain 2-[3-bromo-4-(aniline formyl)-phenyl]-4-methyl-selenazole-5-carboxylic acid (67).

(146) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ 10.62 (s, 1H), 8.26 (d, J=1.6 Hz, 1H), 8.07 (dd, J=1.6, 8.0 Hz, 1H), 7.73-7.67 (m, 3H), 7.37 (t, J=8.0 Hz, 2H), 7.14 (d, J=8.0 Hz, 1H), 2.69 (s, 3H). MS (EI, m/z): 435.1 [M+H].sup.+.

Embodiment 40

Synthesis of 2-(2-cyano-4′-trifluoromethylbiphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid (68)

(147) ##STR00052##

(148) The compound 13 was reacted with 4-trifluoromethoxyphenylboronic acid according to step B(1) in Embodiment 8, then hydrolyzed according to step F in Embodiment 1, and acidized to obtain 2-(2-cyano-4′-trifluoromethylbiphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid (68).

(149) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ 8.55 (d, J=2.0 Hz, 1H), 8.38 (dd, J=2.0, 8.0 Hz, 1H), 7.95 (d, J=8.0 Hz, 2H), 7.89 (d, J=8.4 Hz, 2H), 7.82 (d, J=8.4 Hz, 1H), 2.66 (s, 3H). MS (EI, m/z): 434.8 [M−H].sup.−.

Embodiment 41

Synthesis of 2-(2-cyano-3′-trifluoromethylbiphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid (69)

(150) ##STR00053##

(151) For the experimental operation, refer to step B in Embodiment 8, where potassium carbonate was replaced with cesium carbonate in the reaction (1).

(152) The compound 13 was reacted with 3-trifluoromethoxyphenylboronic acid according to step B(1) in Embodiment 8, where potassium carbonate was replaced with cesium carbonate. The product was then hydrolyzed according to step F in Embodiment 1, and acidized to obtain 2-(2-cyano-3′-trifluoromethylbiphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid (69).

(153) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ 8.55 (d, J=2.0 Hz, 1H), 8.37 (dd, J=2.0, 8.4 Hz, 1H), 8.03-7.81 (m, 5H), 2.70 (s, 3H). MS (EI, m/z): 434.8 [M−H].sup.−.

Embodiment 42

Synthesis of 2-(2-cyano-3′-trifluoromethylbiphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid (70)

(154) ##STR00054##

(155) The compound 13 was reacted with 2-trifluoromethoxyphenylboronic acid according to step B(1) in Embodiment 8, then hydrolyzed according to step F in Embodiment 1, and acidized to obtain 2-(2-cyano-3′-trifluoromethylbiphenyl-4-yl)-4-methyl-selenazole-5-carboxylic acid (70).

(156) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ 8.34 (dd, J=1.6, 8.0 Hz, 1H), 8.32 (d, J=2.0 Hz, 1H), 7.95 (d, J=8.0 Hz, 1H), 7.86-7.56 (m, 4H), 2.70 (s, 3H). MS (EI, m/z): 434.8 [M−H].sup.−.

Embodiment 43

Synthesis of 2-(3-cyano-4-isobutoxyphenyl)-4-hydroxymethyl-selenazole-5-carboxylic acid (74)

(157) ##STR00055##

(158) Step A: The compound 4 (1.0 g, 2.983 mmol) was dissolved in DMF (10 mL), and added with anhydrous potassium carbonate (1.2 g, 8.70 mmol) and 1-bromo-2-methylpropane (0.82 g, 5.985 mmol), and the resulting mixture was stirred overnight at 80° C. The mixture was cooled to room temperature, added with water for dilution, and then filtered. The filter cake was purified by using a silica column (200 to 300 mesh silica gel, ethyl acetate/petroleum ether=1/20 for elution), to obtain 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-selenazole-5-ethyl formate (71) (1.10 g), with a yield of 94.2%.

(159) Step B: The compound 71 (1.1 g, 2.811 mmol) was dissolved in carbon tetrachloride (25 mL), and then added with NBS (0.55 g, 3.090 mmol) and benzoyl peroxide (0.40 g, 1.65 mmol). The resulting mixture was heated under the protection of nitrogen until reflux occurred, and then stirred overnight. After the solvent was removed by means of reduced pressure distillation, the product was purified by using a silica column (200 to 300 mesh silica gel, ethyl acetate/petroleum ether=1/5 for elution), to obtain 2-(3-cyano-4-isobutoxyphenyl)-4-bromomethyl-selenazole-5-ethyl formate (72) (0.91 g), with a yield of 68.8%.

(160) Step C: The compound 72 (0.90 g, 1.914 mmol) was dissolved in 1,4-dioxane (15 mL) and water (15 mL), then added with calcium carbonate (0.80 g, 8.0 mmol), heated until reflux occurred and stirred overnight under reflux. The solution was cooled to room temperature, added with water (30 mL) and extracted with ethyl acetate (30 mL×3). The organic solvent was removed by means of reduced pressure distillation, and the product was purified by using a silica column (200 to 300 mesh silica gel, ethyl acetate/petroleum ether=1/5 for elution), so as to obtain 2-(3-cyano-4-isobutoxyphenyl)-4-hydroxymethyl-selenazole-5-ethyl formate (73) (0.20 g), with a yield of 25.7%.

(161) Step D: The compound 73 was hydrolyzed according to step F in Embodiment 1, and acidized to obtain 2-(3-chloro-4-isobutoxyphenyl)-4-hydroxymethyl-selenazole-5-carboxylic acid (74).

(162) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ 8.36 (d, J=2.0 Hz, 1H), 8.25 (dd, J=2.0, 8.8 Hz, 1H), 7.37 (d, J=8.8 Hz, 1H), 4.81 (s, 2H), 4.02 (d, J=6.4 Hz, 2H), 2.15-2.05 (m, 1H), 1.02 (d, J=6.4 Hz, 6H). MS (EI, m/z): 379.0 [M−H].sup.−.

Embodiment 44

Synthesis of 2-(3-bromo-4-isobutoxyphenyl)-4-methyl-selenazole-5-carboxylic acid (78)

(163) ##STR00056##

(164) A compound 3-bromo-4-hydroxybenzonitrile was used to prepare selenoamide according to step A in Embodiment 36, then cyclized according to step B in Embodiment 32 and reacted with 1-bromo-2-methylpropane according to step C in Embodiment 32, and finally hydrolyzed according to step F in Embodiment 1 and acidized to obtain 2-(3-bromo-4-isobutoxyphenyl)-4-methyl-selenazole-5-carboxylic acid (78). .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ 8.13 (d, J=2.0 Hz, 1H), 7.91 (dd, J=2.4, 8.8 Hz, 1H), 7.19 (d, J=8.8 Hz, 1H), 3.92 (d, J=6.4 Hz, 2H), 2.64 (s, 3H), 2.11-2.03 (m, 1H), 1.02 (q, J=6.8 Hz, 6H). MS (EI, m/z): 416.0 [M−H].sup.−.

Embodiment 45

Synthesis of 2-(3-cyano-4-isopropylthiophenyl)-4-methyl-selenazole-5-carboxylic acid-(2-N-acetyl)ethyl ester (79)

(165) ##STR00057##

(166) A mixture of the compound 37 (120 mg, 0.328 mmol), N-(2-hydroxyethyl)acetamide (50.8 mg, 0.493 mmol), N-methylmorpholine (99.7 mg, 0.985 mmol), HOBT (66.6 mg, 0.493 mmol) and DMF (5 mL) was added with EDCI in an ice-water bath, and then stirred overnight at room temperature. The reaction solution was added with water (20 mL), and extracted with ethyl acetate (15 mL×3). The combined organic phase was then washed with water (15 mL) once more. After the solvent was removed by means of reduced pressure distillation, the product was purified by using a silica column (200 to 300 mesh silica gel, ethyl acetate for elution), to obtain 2-(3-cyano-4-isopropylthiophenyl)-4-methyl-selenazole-5-carboxylic acid-(2-N-acetyl)ethyl ester (79).

(167) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ 8.39 (d, J=2.0 Hz, 1H), 8.22-8.19 (m, 1H), 8.07-8.04 (m, 1H), 7.72 (dd, J=4.0, 8.4 Hz, 1H), 4.24 (t, J=5.2 Hz, 2H), 3.89-3.82 (m, 1H), 3.41-3.29 (m, 2H), 2.68 (s, 3H), 1.87 (s, 3H), 1.37-1.36 (m, 6H). MS (EI, m/z): 449.9 [M−H].sup.−.

(168) The compound 79 may be a prodrug of the compound 37.

Embodiment 46

Synthesis of 2-(3-cyano-4-tertbutylthiophenyl)-4-methyl-selenazole-5-carboxylic acid (81)

(169) ##STR00058##

(170) The compound was reacted with tert-butyl mercaptan according to step A in Embodiment 25, then hydrolyzed according to step F in Embodiment 1, and acidized to obtain 2-(3-cyano-4-tertbutylthiophenyl)-4-methyl-selenazole-5-carboxylic acid (81).

(171) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ 8.47 (d, J=2.0 Hz, 1H), 8.26 (dd, J=2.0, 8.4 Hz, 1H), 7.86 (d, J=8.4 Hz, 1H), 2.68 (s, 3H), 1.36 (s, 9H). MS (EI, m/z): 381.4 [M+H].sup.+.

Embodiment 47

Synthesis of 2-(3-cyano-4-cyclohexylthiophenyl)-4-methyl-selenazole-5-carboxylic acid (83)

(172) ##STR00059##

(173) The compound was reacted with cyclopentyl mercaptan according to step A in Embodiment 25, then hydrolyzed according to step F in Embodiment 1, and acidized to obtain 2-(3-cyano-4-cyclohexylthiophenyl)-4-methyl-selenazole-5-carboxylic acid (83).

(174) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ 8.34 (d, J=2.0 Hz, 1H), 8.18 (dd, J=2.0, 8.4 Hz, 1H), 7.69 (d, J=2.0 Hz, 1H), 4.01-3.96 (m, 1H), 2.66 (s, 3H), 2.22-2.17 (m, 2H), 1.76-1.74 (m, 2H), 1.67-1.64 (m, 4H). MS (EI, m/z): 393.1 [M+H].sup.+.

Embodiment 48

Synthesis of 2-(3-trifluoromethylphenyl)-4-methyl-selenazole-5-carboxylic acid (86)

(175) ##STR00060##

(176) Step A: Anhydrous ethanol (30 mL) was added dropwise into a mixture of selenium powder (1.84 g, 23.3 mmol) and sodium borohydride (0.97 g, 25.6 mmol) under the protection of nitrogen in an ice-water bath, then heated to room temperature, and stirred for 30 min. The resulting mixture was then added with pyridine solution (6 mL) containing 3-(trifluoromethyl)benzonitrile (1.0 g, 5.84 mmol), heated until reflux occurred, and slowly added dropwise with 2M hydrochloric acid solution (4 mL) and then stirred under reflux for 1 h. A TLC analysis indicated that the reaction was completed. Most of ethanol was removed by means of reduced pressure distillation. The resulting product was added with water (30 mL) for dilution, and extracted with ethyl acetate (20 mL×3). The combined organic phase was washed with 2M hydrochloric acid (10 mL) and then with saturated saline solution (15 mL). The solvent was removed by means of reduced pressure distillation, so as to obtain a compound 3-trifluoromethyl selenobenzamide (84) (1.6 g), which was directly used for the next step reaction without being purified.

(177) Step B: the compound 84 (1.0 g, NMT 3.65 mmol) and ethyl 2-chloroacetoacetate (653 mg, 3.97 mmol) were added into anhydrous ethanol (10 mL), heated, and stirred under reflux for 2 h. A TLC analysis indicated that the reaction was completed. The reaction solution was cooled to room temperature. After suction filtration under reduced pressure, the filter cake was collected and dried, to obtain 2-(3-trifluoromethylphenyl)-4-methyl-selenazole-5-ethyl formate (85) (930 mg), with a total yield of 70.3% in the two steps of reactions.

(178) Step C: The compound 85 was hydrolyzed according to step F in Embodiment 1, and acidized to obtain 2-(3-trifluoromethylphenyl)-4-methyl-selenazole-5-carboxylic acid (86).

(179) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ 8.26-8.23 (m, 2H), 7.92 (d, J=8.0 Hz, 1H), 7.77-7.73 (m, 1H), 2.68 (s, 3H).

Embodiment 49

(180) Test for Inhibition of the Activity of Xanthine Oxidase

(181) I. Principle

(182) The inhibition of the activity of xanthine oxidase (XO) is tested through a coupled enzymatic reaction of xanthine oxidase, horseradish peroxidase (HRP) and a substrate thereof. First, xanthine oxidase oxidizes hypoxanthine to produce xanthine and hydrogen peroxide, and further oxidizes xanthine to produce uric acid and hydrogen peroxide. Then, hydrogen peroxide reacts with 10-acetyl-3,7-dihydroxyphenoxazine (Ampliflu Red) under catalytic action of horseradish peroxidase so as to produce resorufin, a compound with strong fluorescence. The fluorescence intensity of resorufin is determined by using a fluorescence microplate, which is in direct proportion to the activity of xanthine oxidase.

(183) II. Test Compound and Preparation of Reaction Solutions

(184) A certain amount of a test compound and a control compound, febuxostat (by Beijing Lianben Pharm-chemicals Tech. Co., Ltd.) were dissolved in DMSO (by Sinopharm Chemical Reagent Co., Ltd.). A 2.5-fold serial dilution of the test compound was diluted with DMSO in a 96-well polypropylene reaction plate (by Greiner Bio One), so as to obtain a 200-fold dilution. The solution was further diluted in ultrapure water to obtain a 3-fold serial dilution.

(185) Reaction solution A: 6 mU/mL xanthine oxidase (sourced from milk, by Sigma) was prepared in 0.1 M Tris-HCl (pH 7.5) buffer solution.

(186) Reaction solution B: A mixed solution of 0.6 U/mL horseradish peroxidase (by Shanghai Yuanye Biological Technology Co., Ltd.), 0.15 mM Ampliflu Red (by Sigma), and 0.3 mM hypoxanthine (by Sigma) was prepared in 0.1 M Tris-HCl (pH 7.5) buffer solution. The solution was placed away from light at 4° C., and used immediately after preparation.

(187) III. Determination Method

(188) 9 μL reaction solution A and 9 μL 3-fold serial dilution of the test compound were mixed in a 96-well test plate (by Greiner Bio One), placed on a flat plate type oscillator, and mixed at 30° C. for 30 min at 100 rpm. 9 μL reaction solution B was then added. A enzymatic reaction was carried out for 30 min at 30° C. The fluorescence intensity at 530 nm exciting light and 590 nm emitted light was determined by using a fluorescence microplate (Perkin Elmer Vitor X4). The fluorescence intensity without xanthine oxidase for comparison is 0%, and the fluorescence intensity without the test compound for comparison is 100%, according to which 50% inhibition concentration (IC.sub.50) of the test compound and control compound febuxostat was calculated.

(189) For the test results, refer to Table 1. It can be shown from Table 1 that, the compound of the present invention exhibited an excellent effect of xanthine oxidase inhibition in a pharmacological test in vitro.

(190) TABLE-US-00001 TABLE 1 Xanthine Oxidase Inhibition Activity (IC.sub.50) of Compounds Compound No. IC.sub.50 (nM) Compound 6 2.29 Compound 7 2.05 Compound 8 2.40 Compound 9 3.28 Compound 10 12.43 Compound 11 2.85 Compound 12 2.97 Compound 14 1.70 Compound 15 3.25 Compound 16 2.99 Compound 17 3.79 Compound 18 2.70 Compound 19 4.61 Compound 20 3.92 Compound 21 2.61 Compound 22 3.24 Compound 23 2.37 Compound 24 1.67 Compound 25 3.47 Compound 26 2.78 Compound 27 2.53 Compound 28 2.67 Compound 30 4.84 Compound 35 2.63 Compound 37 1.32 Compound 38 2.56 Compound 39 3.58 Compound 40 12.06 Compound 41 5.19 Compound 42 3.07 Compound 43 13.89 Compound 44 2.30 Compound 45 9.13 Compound 46 4.11 Compound 47 2.52 Compound 51 10.25 Compound 55 3.06 Compound 62 8.56 Compound 67 >100 Compound 68 2.84 Compound 69 6.01 Compound 70 31.07 Compound 74 10.08 Compound 81 2.29 Compound 83 2.43 Compound 86 25.45 Febuxostat 2.78