S1P1 agonist and application thereof

Abstract

The present invention relates to a class of tricyclic compounds and an application thereof as a sphingosine 1-phosphate type 1 (S1P1) receptor agonist. The invention specifically relates to a compound represented by formula (II), and a tautomer and pharmaceutically acceptable salt of same. ##STR00001##

Claims

1. A compound represented by formula (II), or a pharmaceutically acceptable salt of the same, ##STR00176## wherein, X is independently N or CH; m is 0, 1 or 2; n is 1 or 2; D is —C(═O)—, —C(═O)O—, —CH.sub.2—; R.sub.1 is C.sub.1-6 alkyl, C.sub.1-6 heteroalkyl or C.sub.3-6 cycloalkyl, each of which is optionally substituted by one, two or three R; each of R.sub.2 and R.sub.3 is H, halogen, OH, NH.sub.2, CN or R.sub.4-L-, or selected from the group consisting of C.sub.1-6 alkyl, C.sub.1-6 heteroalkyl, phenyl and 5-6 membered heteroaryl, each of which is optionally substituted by one, two or three R; R.sub.4 is C.sub.3-6 cycloalkyl, 3-6 membered heterocyclic alkyl, phenyl or 5-6 membered heteroaryl, each of which is optionally substituted by one, two or three R; L is —(CRR).sub.1-3—, or —O—(CRR).sub.0-3—; ring A is 5 membered heteroaryl; ring B is phenyl or 5-9 membered heteroaryl; R is H, F, Cl, Br, I, CN, OH, NH.sub.2, COOH, ##STR00177## or optionally selected from the group consisting of C.sub.1-6 alkyl and C.sub.1-6 heteroalkyl, each of which is optionally substituted by one, two or three R′; R′ is H, F, Cl, Br, I, OH, CN, NH.sub.2, COOH, Me, Et, CF.sub.3, CHF.sub.2, CH.sub.2F, NHCH.sub.3, N(CH.sub.3).sub.2; “hetero” represents a heteroatom or a heteroatom group, which is selected from the group consisting of —C(═O)N(R)—, —N(R)—, —C(═NR)—, —S(═O).sub.2N(R)—, —S(═O)N(R)—, —O—, —S—, ═O, ═S, —O—N═, —C(═O)O—, —C(═O)—, —C(═S)—, —S(═O)—, —S(═O).sub.2—, and —N(R)C(═O)N(R)—; in any one of the above cases, the number of heteroatom or heteroatom group is independently selected from one, two and three.

2. The compound of claim 1, wherein the compound is represented by formula (I), ##STR00178## wherein X is N or CH; m and n is independently selected from one or two; R.sub.1 is C.sub.1-6 alkyl or C.sub.1-6 heteroalkyl, each of which is optionally substituted by one, two or three R; each of R.sub.2 and R.sub.3 is H, halogen, OH, NH.sub.2, CN or R.sub.4-L-, or is optionally selected from the group consisting of C.sub.1-6 alkyl, C.sub.1-6 heteroalkyl, phenyl and 5-6 membered heteroaryl, each of which is optionally substituted by one, two or three R; R.sub.4 is C.sub.3-6 cycloalkyl, 3-6 membered heterocyclic alkyl, phenyl or 5-6 membered heteroaryl, each of which is optionally substituted by one, two or three R; L is —(CRR).sub.1-3— or —O—(CRR).sub.0-3—; ring A is a 5 membered heteroaryl; ring B is phenyl or a 5-9 membered heteroaryl; R is H, F, Cl, Br, I, CN, OH, NH.sub.2 or COOH, or selected from the group consisting of C.sub.1-6 alkyl and C.sub.1-6 heteroalkyl, each of which is optionally substituted by one, two or three R′; R′ is selected from the group consisting of H, F, Cl, Br, I, OH, CN, NH.sub.2, COOH, Me, Et, CF.sub.3, CHF.sub.2, CH.sub.2F, NHCH.sub.3, and N(CH.sub.3).sub.2; “hetero” represents a heteroatom or a heteroatom group, which is selected from the group consisting of —C(═O)N(R)—, —N(R)—, —C(═NR)—, —S(═O).sub.2N(R)—, —S(═O)N(R)—, —O—, —S—, ═O, ═S, —O—N═, —C(═O)O—, —C(═O)—, —C(═S)—, —S(═O)—, —S(═O).sub.2— and —N(R)C(═O)N(R)—; in any one of the above cases, the number of heteroatom or heteroatom group is independently selected from one, two or three.

3. The compound or the pharmaceutically acceptable salt of the same according to claim 2, wherein R is H, F, Cl, Br, I, CN, OH, NH.sub.2 or COOH or selected from the group consisting of C.sub.1-3 alkyl, C.sub.1-3 alkoxyl, C.sub.1-3 alkylthiol, C.sub.1-3 alkylamino, N, N′-di(C.sub.1-2 alkyl)amino, C.sub.1-3 alkyl-S(═O)— and C.sub.1-3 alkyl-S(═O).sub.2—, each of which is optionally substituted by one, two or three R′.

4. The compound or the pharmaceutically acceptable salt of the same according to claim 3, wherein R is selected from the group consisting of H, F, Cl, Br, I, CN, OH, NH.sub.2, COOH, Me, Et, CF.sub.3, ##STR00179##

5. The compound or the pharmaceutically acceptable salt of the same according to claim 2, wherein R.sub.1 is selected from the group consisting of C.sub.1-6 alkyl, C.sub.1-3 alkyl-S(═O).sub.2—C.sub.1-3 alkyl-, C.sub.1-3 alkyl-S(═O)—C.sub.1-3 alkyl-, and C.sub.1-3 alkyl-NH—C(═O).sub.2—C.sub.1-3 alkyl-, each of which is optionally substituted by one, two or three R.

6. The compound or the pharmaceutically acceptable salt of the same according to claim 5, wherein R.sub.1 is selected from the group consisting of Me, ##STR00180## each of which is substituted by one, two or three R.

7. The compound or the pharmaceutically acceptable salt of the same according to claim 6, wherein R.sub.1 is selected from the group consisting of ##STR00181##

8. The compound or the pharmaceutically acceptable salt of the same according claim 2, wherein L is —(CH.sub.2).sub.1-3— or —O—(CH.sub.2).sub.0-3—.

9. The compound or the pharmaceutically acceptable salt of the same according to claim 8, wherein L is selected from the group consisting of —CH.sub.2—, —CH.sub.2CH.sub.2—, —CH.sub.2 CH.sub.2CH.sub.2—, —O—, —O—CH.sub.2—, —O—CH.sub.2CH.sub.2— and —O—CH.sub.2CH.sub.2CH.sub.2—.

10. The compound or the pharmaceutically acceptable salt of the same according to claim 2, wherein R.sub.4 is selected from the group consisting of ##STR00182## each of which is substituted by one, two or three R.

11. The compound or the pharmaceutically acceptable salt of the same according to claim 10, wherein R.sub.4 is ##STR00183##

12. The compound or the pharmaceutically acceptable salt of the same according to claim 1, wherein R.sub.4-L- is ##STR00184##

13. The compound or the pharmaceutically acceptable salt of the same according to claim 2, wherein each of R.sub.2 and R.sub.3 is H, F, Cl, Br, I, OH, NH.sub.2, CN or R.sub.4-L-, or selected from the group consisting of C.sub.1-3 alkyl, C.sub.1-3 alkoxyl, C.sub.1-3 alkylthiol, C.sub.1-3 alkyl-S(═O)—, C.sub.1-3 alkyl-S(═O).sub.2—, phenyl, thiazolyl, isothiazolyl, oxazolyl and isoxazolyl, each of which is optionally substituted by one, two or three R.

14. The compound or the pharmaceutically acceptable salt of the same according to claim 13, wherein each of R.sub.2 and R.sub.3 is H, F, Cl, Br, I, OH, NH.sub.2, CN or R.sub.4-L-, or selected from the group consisting of Me, Et, ##STR00185## each of which is optionally substituted by one, two or three R.

15. The compound or the pharmaceutically acceptable salt of the same according to claim 14, wherein each of R.sub.2 and R.sub.3 is H, F, Cl, Br, I, OH, NH.sub.2, CN, Me, ##STR00186##

16. The compound or the pharmaceutically acceptable salt of the same according to claim 2, wherein ring A is selected from the group consisting of 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl and thienyl.

17. The compound or the pharmaceutically acceptable salt of the same according to claim 16, wherein ring A is ##STR00187##

18. The compound or the pharmaceutically acceptable salt of the same according to claim 2, wherein ring B is selected from the group consisting of phenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, imidazo[1,2-a]pyridyl, imidazo[1,2-a]pyrimidinyl, 4,5,6,7-tetrahydro[5,4-c]pyridyl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyridyl, 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridyl and 1,2,3-triazolyl.

19. The compound or the pharmaceutically acceptable salt of the same according to claim 18, wherein ring B is ##STR00188##

20. The compound or the pharmaceutically acceptable salt of the same according to claim 19, wherein the structure unit ##STR00189## ##STR00190##

21. The compound or the pharmaceutically acceptable salt of the same according to claim 2, wherein the structure unit ##STR00191##

22. The compound or the pharmaceutically acceptable salt of the same according to claim 1, wherein R is H, F, Cl, Br, I, CN, OH, NH.sub.2 COOH or ##STR00192## or selected from the group consisting of C.sub.1-3 alkyl, C.sub.1-3 alkoxyl, C.sub.1-3 alkylthiol, C.sub.1-3 alkylamino, N, N′-di(C.sub.1-2 alkyl)amino, C.sub.1-3 alkyl-S(═O)— and C.sub.1-3 alkyl-S(═O).sub.2—, each of which is optionally substituted by one, two or three R′.

23. The compound or the pharmaceutically acceptable salt of the same according to claim 22, wherein R is H, F, Cl, Br, I, CN, OH, NH.sub.2, COOH, Me, Et, CF.sub.3, ##STR00193##

24. The compound or the pharmaceutically acceptable salt of the same according to claim 1, wherein R.sub.1 is selected from the group consisting of C.sub.1-6 alkyl, C.sub.1-3 alkyl-S(═O).sub.2—C.sub.1-3 alkyl-, C.sub.1-3 alkyl-S(═O)—C.sub.1-3 alkyl-, C.sub.1-3 alkyl-NH—C(═O)—C.sub.1-3 alkyl-, and C.sub.3-6 cycloalkyl, each of which is substituted by one, two or three R.

25. The compound or the pharmaceutically acceptable salt of the same according to claim 24, wherein R.sub.1 is Me, ##STR00194## each of which is optionally substituted by one, two or three R.

26. The compound or the pharmaceutically acceptable salt of the same according to claim 25, wherein R.sub.1 is ##STR00195##

27. The compound or the pharmaceutically acceptable salt of the same according to claim 1, wherein L is —(CH.sub.2).sub.1-3— or —O—(CH.sub.2).sub.0-3—.

28. The compound or the pharmaceutically acceptable salt of the same according to claim 27, wherein L is —CH.sub.2—, —CH.sub.2CH.sub.2—, —CH.sub.2CH.sub.2CH.sub.2—, —O—, —O—CH.sub.2—, —O—CH.sub.2CH.sub.2— or —O—CH.sub.2CH.sub.2CH.sub.2—.

29. The compound or the pharmaceutically acceptable salt of the same according to claim 1, wherein R.sub.4 is ##STR00196## each of which is optionally substituted by one, two or three R.

30. The compound or the pharmaceutically acceptable salt of the same according to claim 29, wherein R.sub.4 is ##STR00197##

31. The compound or the pharmaceutically acceptable salt of the same according to claim 28, wherein R.sub.4-L- is ##STR00198##

32. The compound or the pharmaceutically acceptable salt of the same according to claim 1, wherein each of R.sub.2 and R.sub.3 is H, F, Cl, Br, I, OH, NH.sub.2, CN or R.sub.4-L-, or selected from the group consisting of C.sub.1-3 alkyl, C.sub.1-3 alkoxyl, C.sub.1-3 alkylthiol, C.sub.1-3 alkyl-S(═O)—, C.sub.1-3 alkyl-S(═O).sub.2—, phenyl, thiazolyl, isothiazolyl, oxazolyl and isoxazolyl, each of which is optionally substituted by one, two or three R.

33. The compound or the pharmaceutically acceptable salt of the same according to claim 32, wherein each of R.sub.2 and R.sub.3 is H, F, Cl, Br, I, OH, NH.sub.2, CN or R.sub.4-L-, or selected from the group consisting of Me, Et, ##STR00199## each of which is optionally substituted by one, two or three R.

34. The compound or the pharmaceutically acceptable salt of the same according to claim 33, wherein each of R.sub.2 and R.sub.3 is H, F, Cl, Br, I, OH, NH.sub.2, CN, Me, ##STR00200##

35. The compound or the pharmaceutically acceptable salt of the same according to claim 1, wherein ring A is selected from the group consisting of 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl and thienyl.

36. The compound or the pharmaceutically acceptable salt of the same according to claim 35, wherein ring A is ##STR00201##

37. The compound or the pharmaceutically acceptable salt of the same according to claim 1, wherein ring B is selected from the group consisting of phenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, imidazo[1,2-a]pyridyl, imidazo[1,2-a]pyrimidinyl, 4,5,6,7-tetrahydro[5,4-c]pyridyl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyridyl, 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridyl and 1,2,3-tri azolyl.

38. The compound or the pharmaceutically acceptable salt of the same according to claim 37, wherein ring B is ##STR00202##

39. The compound or the pharmaceutically acceptable salt of the same according to claim 38, wherein the structure unit ##STR00203## ##STR00204##

40. The compound or the pharmaceutically acceptable salt of the same according to claim 1, wherein the structure unit ##STR00205##

41. The compound or the pharmaceutically acceptable salt of the same according to claim 1, which is selected from the group consisting of ##STR00206##

42. The compound or the pharmaceutically acceptable salt of the same according to claim 41, which is selected from the group consisting of ##STR00207## ##STR00208##

43. The compound or the pharmaceutically acceptable salt of the same according to claim 1, which is selected from the group consisting of ##STR00209## ##STR00210## ##STR00211## ##STR00212## ##STR00213## ##STR00214## ##STR00215## ##STR00216## ##STR00217## ##STR00218## ##STR00219## ##STR00220## ##STR00221## ##STR00222##

44. The compound or the pharmaceutically acceptable salt of the same according to claim 43, which is selected from the group consisting of ##STR00223## ##STR00224## ##STR00225## ##STR00226## ##STR00227## ##STR00228## ##STR00229## ##STR00230## ##STR00231## ##STR00232## ##STR00233## ##STR00234## ##STR00235## ##STR00236## ##STR00237## ##STR00238## ##STR00239## ##STR00240## ##STR00241## ##STR00242## ##STR00243## ##STR00244## ##STR00245## ##STR00246## ##STR00247## ##STR00248## ##STR00249## ##STR00250##

45. A method for treating S1P1 related disease in a subject in need thereof, comprising administering a pharmaceutically effective amount of the compound represented by formula (II) or the pharmaceutically acceptable salt of the same as defined in claim 1 to the subject, the S1P1 related disease is selected from IBD, autoimmune diseases, multiple sclerosis, disseminated sclerosis, amyotrophic lateral sclerosis, bronchial asthma and stroke.

Description

EXAMPLES

(1) The invention is described in detail below by means of examples, but it is not intended to limit the invention. The present invention and the embodiments thereof are disclosed herein in detail. It is apparent to those skilled in the art that various changes and modifications can be made to the embodiments of the invention.

EMBODIMENTS

(2) The invention is described in detail below by means of examples, but it is not intended to limit the invention.

Example 1

(3) ##STR00105## ##STR00106## ##STR00107##

(4) Step 1

(5) Compound 1-1 (20.0 g, 94.8 mmol) was dissolved in anhydrous tetrahydrofuran (200 mL), and bis(trimethylsilyl)amide lithium (1M in tetrahydrofuran, 113 mL) was added dropwise at −78° C. The reaction mixture was stirred at this temperature for 30 minutes. Then, ethyl bromoacetate (17.4 g, 104 mmol) was added to the reaction mixture, and the mixture was stirred at 25° C. for 2 hours. Water (200 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (200 mL×3). The organic layers were combined and washed with saturated brine (300 mL×2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated with reduced pressure. The residue was isolated and purified by silica gel column chromatography (10:1 petroleum ether/ethyl acetate, R.sub.f=0.7) to give compound 1-2 (15.0 g, pale yellow oil); yield 53%.

(6) .sup.1H NMR: (400 MHz, CDCl.sub.3) δ 7.87 (d, J=8.0 Hz, 1H), 7.71 (d, J=8.0 Hz, 1H), 7.38 (t, J=8.0 Hz, 1H), 4.11 (q, J=6.8 Hz, 2H), 3.33-3.10 (m, 1H), 2.96-2.87 (m, 2H), 2.69-2.65 (m, 2H), 1.19 (t, J=6.8 Hz, 3H). MS-ESI: calculated value [M+H].sup.+: 297 and 299; measured value: 297 and 299.

(7) Step 2

(8) Compound 1-2 (25.0 g, 84.1 mmol) was dissolved in anhydrous ethanol (300 mL), and ammonium acetate (64.9 g, 841 mmol) was added at 25° C. The reaction was stirred at this temperature for 1 hour. Then, sodium cyanoborohydride (15.9 g, 252 mmol) was added to the reaction mixture, and the mixture was stirred at 80° C. for 12 hours. Water (300 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (400 mL×3). The organic layers were combined and washed with saturated brine (300 mL×2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated with reduced pressure. The residue was isolated and purified by silica gel column chromatography (10:1 ethyl acetate/methanol, R.sub.f=0.4) to give compound 1-3 (10.0 g, pale yellow oil); yield 47%. MS-ESI [M+H].sup.+ calculated value: 252 and 254; measured value: 252 and 254.

(9) Step 3

(10) Compound 1-3 (10.0 g, 39.7 mmol) was dissolved in N,N-dimethylformamide (80 mL), and sodium hydride (2.38 g, 59.5 mmol, 60% purity) was added in portions at 0° C. The reaction was stirred at this temperature for 30 minutes. Then, compound 1-4 (9.49 g, 39.7 mmol) was added to the reaction mixture, and the mixture was stirred at 25° C. for 2 hours. Water (200 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (200 mL×3). The organic layers were combined and washed with saturated brine (300 mL×2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated with reduced pressure. The residue was isolated and purified by silica gel column chromatography (1:1 petroleum ether/ethyl acetate, R.sub.f=0.5) to give compound 1-5 (5.0 g, colorless oil); yield 31%.

(11) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) δ 7.46-7.42 (m, 2H), 7.12 (d, J=8.0 Hz, 1H), 5.17 (d, J=7.2 Hz, 1H), 3.70-3.67 (m, 3H), 3.24-3.23 (m, 1H), 3.18-3.16 (m, 2H), 2.70-2.68 (m, 2H), 2.34-2.33 (m, 1H), 0.84 (s, 9H), 0.01 (s, 6H). MS-ESI [M+H].sup.+: calculated value: 410 and 412; measured value: 410 and 412.

(12) Step 4

(13) Compound 1-5 (5.0 g, 12.2 mmol) was dissolved in N,N-dimethylformamide (8 mL), and zinc cyanide (2.86 g, 24.4 mmol) and tetratriphenylphosphine palladium (1.41 g, 1.22 mmol) were added to the mixture. The reaction was stirred for 16 hours at 100° C. under nitrogen atmosphere. Water (30 mL) was added after the mixture was cooled to room temperature, and the mixture was extracted with ethyl acetate (50 mL×3). The organic layers were combined and washed with saturated brine (40 mL×3), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (1:1 petroleum ether/ethyl acetate, R.sub.f=0.4) to give compound 1-6 (3.1 g, colorless oil); yield 71%.

(14) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) δ 7.87 (d, J=8.0 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.74 (t, J=8.0 Hz, 1H), 5.26 (d, J=7.2 Hz, 1H), 3.82-3.70 (m, 3H), 3.51-3.49 (m, 1H), 3.30-3.27 (m, 1H), 3.01-2.81 (m, 3H), 2.45-2.41 (m, 1H), 0.93 (s, 9H), 0.00 (s, 6H). MS-ESI [M+H].sup.+: calculated value: 357; measured value: 357.

(15) Step 5

(16) Compound 1-6 (3.00 g, 8.41 mmol) was dissolved in anhydrous ethanol (8 mL), and hydroxylamine hydrochloride (1.75 g, 25.2 mmol) and triethylamine (3.40 g, 33.6 mmol) were added. The reaction was stirred at 60° C. for 12 hour under nitrogen atmosphere. Water (50 mL) was added after the mixture was cooled to room temperature, and the mixture was extracted with ethyl acetate (50 mL×3) three times. The organic layers were combined and washed with saturated brine (40 mL×2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (0:1 petroleum ether/ethyl acetate, R.sub.f=0.4) to give compound 1-7 (3.0 g, white solid); yield 92%.

(17) .sup.1H NMR: (400 MHz, CDCl.sub.3) δ 7.49 (d, J=8.0 Hz, 1H), 7.40 (d, J=8.0 Hz, 1H), 7.21 (t, J=8.0 Hz, 1H), 5.07 (d, J=7.2 Hz, 1H), 4.73 (s, 2H), 3.78-3.75 (m, 1H), 3.67-3.62 (m, 2H), 3.44-3.42 (m, 1H), 2.97-2.90 (m, 3H), 2.71-2.65 (m, 1H), 2.37-2.33 (m, 1H), 0.84 (s, 9H), 0.00 (s, 6H). MS-ESI [M+H].sup.+: calculated value: 390; measured value: 390.

(18) Step 6

(19) Compound 1-8 (695 mg, 3.39 mmol) was dissolved in N,N-dimethylformamide (10 mL), and 1-hydroxybenzotriazole (763 mg, 5.65 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.08 g, 5.65 mmol) were added. The reaction was stirred at 25° C. for 30 minutes under nitrogen atmosphere. Then, compound 1-7 (1.10 g, 2.82 mmol) was added to the reaction mixture, and the mixture was stirred at 25° C. for 1 hour, then heated to 80° C. and stirred for 12 hours. Water (30 mL) was added after the mixture was cooled to room temperature, and the mixture was extracted with ethyl acetate (30 mL×3). The organic layers were combined and washed with brine (25 mL×2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was isolated and purified by high performance liquid chromatography to give compound 1-9 (420 mg); yield 33%.

(20) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) δ 8.46-8.42 (m, 2H), 8.19 (d, J=7.2 Hz, 1H), 7.78 (d, J=7.2 Hz, 1H), 7.51-7.44 (m, 2H), 5.26 (d, J=7.2 Hz, 1H), 4.99-4.94 (m, 1H), 3.83-3.71 (m, 4H), 3.26-3.23 (m, 2H), 3.15-3.13 (m, 1H), 2.92-2.86 (m, 1H), 2.48-2.43 (m, 1H), 1.47 (d, J=6.0 Hz, 6H). MS-ESI [M+H].sup.+: calculated value: 445; measured value: 445.

(21) Step 7

(22) Compound 1-9 (200 mg, 0.450 mmol) was isolated and purified by chiral liquid chromatography to give compound 1-10 (isomer 1) and compound 1-11 (isomer 2).

(23) SFS isolation method:

(24) Chromatographic column: AD 250 mm×30 mm, 10 um;

(25) Mobile phase: A: CO.sub.2; B: 45%.-45%. Ethanol (0.1% aqueous ammonia)

(26) Flow rate: 80 mL/min

(27) Column temperature: 40° C.

(28) Compound 1-10 (56.0 mg), yield: 28%. The retention time in the high performance chiral liquid column is 5.276.

(29) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) δ 8.42-8.40 (m, 2H), 8.17 (d, J=7.6 Hz, 1H), 7.77 (d, J=7.6 Hz, 1H), 7.50-7.42 (m, 2H), 5.26 (d, J=7.2 Hz, 1H), 4.99-4.95 (m, 1H), 3.81-3.71 (m, 4H), 3.26-3.23 (m, 2H), 3.13-3.08 (m, 1H), 2.92-2.86 (m, 1H), 2.48-2.44 (m, 1H), 1.47 (d, J=6.0 Hz, 6H). MS-ESI [M+H].sup.+: calculated value: 445; measured value: 445.

(30) Compound 1-11 (25.4 mg), yield: 13%. The retention time in the chiral high performance liquid column is 6.427.

(31) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) δ 8.45-8.42 (m, 2H), 8.19 (d, J=7.6 Hz, 1H), 7.77 (d, J=7.6 Hz, 1H), 7.51-7.44 (m, 2H), 5.27 (d, J=7.2 Hz, 1H), 4.99-4.94 (m, 1H), 3.83-3.71 (m, 4H), 3.26-3.23 (m, 2H), 3.15-3.13 (m, 1H), 2.92-2.88 (m, 1H), 2.48-2.44 (m, 1H), 1.47 (d, J=6.0 Hz, 6H). MS-ESI [M+H].sup.+: calculated value: 445; measured value: 445.

Example 2

(32) ##STR00108##

(33) Step 1

(34) Compound 2-1 (3.10 g, 7.55 mmol) was dissolved in dioxane (30 mL), and bis(pinacolato)diboron (2.88 g, 11.3 mmol), potassium acetate (1.48 g, 15.1 mmol) and 1,1′-bis(diphenylphosphino)ferrocene palladium chloride (553 mg, 0.755 mmol) were added. The reaction was stirred at 80° C. for 12 hours under nitrogen atmosphere. Water (30 mL) was added after the mixture was cooled to room temperature, and the mixture was extracted with ethyl acetate (30 mL×3). The organic layers were combined and washed with saturated brine (30 mL×3), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (1:1 petroleum ether/ethyl acetate, R.sub.f=0.6) to give compound 2-2 (3.00 g, colorless oil); yield 87%.

(35) .sup.1H NMR: (400 MHz, CDCl.sub.3) δ 7.68 (d, J=8.0 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.16 (t, J=8.0 Hz, 1H), 5.04 (d, J=7.2 Hz, 1H), 3.76-3.70 (m, 1H), 3.65-3.60 (m, 2H), 3.49-3.47 (m, 1H), 3.06-3.03 (m, 2H), 2.72-2.67 (m, 1H), 2.65-2.63 (m, 1H), 2.37-2.32 (m, 1H), 1.21 (s, 12H), 0.83 (s, 9H), 0.00 (s, 6H). MS-ESI [M+H].sup.+: calculated value: 458; measured value: 458.

(36) Step 2

(37) Compound 2-3 (100 mg, 0.309 mmol) was dissolved in dioxane (5 mL) and water (1 mL), and Compound 2-2 (142 mg, 0.309 mmol), potassium phosphate (131 mg, 0.619 mmol) and 1,1′-bis(diphenylphosphino)ferrocene palladium chloride (22.6 mg, 0.0309 mmol) were added. The reaction was stirred at 100° C. for 12 hours under nitrogen atmosphere. Water (30 mL) was added after the mixture was cooled to room temperature, and the mixture was extracted with ethyl acetate (30 mL×3). The organic layers were combined and washed with saturated brine (30 mL×3), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (1:1 petroleum ether/ethyl acetate, R.sub.f=0.4) to give compound 2-4 (70 mg, pale yellow oil); yield 39%.

(38) .sup.1H NMR: (400 MHz, CDCl.sub.3) δ 8.06-8.00 (m, 2H), 7.79 (s, 1H), 7.47-7.42 (m, 2H), 7.25 (d, J=7.6 Hz, 1H), 6.95 (d, J=7.6 Hz, 1H), 5.12 (d, J=7.2 Hz, 1H), 4.67-4.63 (m, 1H), 3.79-3.77 (m, 1H), 3.69-3.65 (m, 2H), 3.38-3.36 (m, 1H), 3.18-3.05 (m, 2H), 2.75-2.70 (m, 1H), 2.69-2.67 (m, 1H), 2.38-2.33 (m, 1H), 1.35 (d, J=6.0 Hz, 6H), 0.84 (s, 9H), 0.00 (s, 6H). MS-ESI [M+H].sup.+: calculated value: 574; measured value: 574.

(39) Step 3

(40) Compound 2-4 (70.0 mg, 0.122 mmol) was dissolved in dioxane (3 mL), and dioxane hydrochloride (4M, 1 mL) was added. The reaction was stirred at 25° C. for 10 minutes under nitrogen atmosphere. The reaction mixture was cooled and concentrated under reduced pressure. The residue was isolated and purified by high performance liquid chromatography to give compound 2-5 (40.0 mg); yield: 71%.

(41) .sup.1H NMR: (400 MHz, DMSO-d.sub.6) δ 8.27 (d, J=2.0 Hz, 1H), 7.21 (d, J=8.0 Hz, 1H), 8.17 (s, 1H), 7.64-7.59 (m, 2H), 7.45-7.40 (m, 2H), 5.12 (d, J=7.2 Hz, 1H), 4.94-4.88 (m, 1H), 3.58-3.53 (m, 4H), 3.24-3.22 (m, 1H), 3.01-2.97 (m, 2H), 2.69-2.68 (m, 1H), 2.32-2.31 (m, 1H), 1.36 (d, J=6.0 Hz, 6H). MS-ESI [M+H].sup.+: calculated value: 460; measured value: 460.

Example 3

(42) ##STR00109##

(43) Step 1

(44) Compound 3-1 (1.00 g, 4.87 mmol) was dissolved in phosphorus oxychloride (10 mL), and compound 3-2 (488 mg, 14.6 mmol) was added. The reaction was stirred at 85° C. for 8 hours under nitrogen atmosphere. Aqueous sodium hydroxide solution (6M, 40 mL) was added dropwise after the mixture was cooled to room temperature, and the mixture was extracted with ethyl acetate (50 mL×3). The organic layers were combined and washed with saturated brine (30 mL×3), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (0:1 petroleum ether/ethyl acetate, R.sub.f=0.4) to give compound 3-3 (450 mg, pale yellow solid); yield: 36%.

(45) .sup.1H NMR: (400 MHz, DMSO-d.sub.6) δ 8.05-8.01 (m, 2H), 7.45 (s, 2H), 7.37 (d, J=8.8 Hz, 1H), 4.90-4.84 (m, 1H), 1.34 (d, J=6.0 Hz, 6H). MS-ESI [M+H].sup.+: calculated value: 261; measured value: 261.

(46) Step 2

(47) Compound 3-3 (450 mg, 1.73 mmol) was dissolved in acetonitrile (5 mL), and cuprous bromide (298 mg, 2.08 mmol) and isoamyl nitrite (243 mg, 2.08 mmol) were added. The reaction was stirred at 25° C. for 6 hours under nitrogen atmosphere. Dilute hydrochloric acid (1 M, 20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL×3). The organic layers were combined and washed with saturated brine (10 mL×2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (3:1 petroleum ether/ethyl acetate, R.sub.f=0.5) to give compound 3-4 (170 mg, pale yellow solid); yield 30%.

(48) .sup.1H NMR: (400 MHz, DMSO-d.sub.6) δ 8.33 (s, 1H), 8.23 (d, J=8.8 Hz, 1H), 7.47 (d, J=8.8 Hz, 1H), 4.97-4.91 (m, 1H), 1.36 (d, J=6.0 Hz, 6H). MS-ESI [M+H].sup.+: calculated value: 324 and 326; measured value: 324 and 326.

(49) Step 3

(50) The reaction referred to Step 2 of Example 2, and the residue was isolated and purified by TLC (1:1 petroleum ether/ethyl acetate, R.sub.f=0.4) to give compound 3-5 (50 mg, pale yellow oil); yield: 71%. MS-ESI [M+H].sup.+: calculated value: 575; measured value: 575.

(51) Step 4

(52) The reaction referred to Step 3 of Example 2, and the residue was isolated and purified by high performance liquid chromatography to give compound 3-6 (15 mg); yield: 37%.

(53) .sup.1H NMR: (400 MHz, DMSO-d.sub.6) δ 8.37 (s, 1H), 8.28 (d, J=7.2 Hz, 1H), 7.95 (d, J=7.2 Hz, 1H), 7.77 (d, J=7.2 Hz, 1H), 7.50-7.48 (m, 2H), 5.17 (d, J=7.2 Hz, 1H), 4.96-4.90 (m, 1H), 3.69-3.62 (m, 3H), 3.52-3.51 (m, 1H), 3.23-3.21 (m, 1H), 3.06-2.98 (m, 2H), 2.72-2.68 (m, 1H), 2.33-2.28 (m, 1H), 1.37 (d, J=6.0 Hz, 6H). MS-ESI [M+H].sup.+: calculated value: 461; measured value: 461.

Example 4

(54) ##STR00110##

(55) Step 1

(56) The reaction referred to Step 2 of Example 2, and the residue was isolated and purified by TLC (3:1 petroleum ether/ethyl acetate, R.sub.f=0.4) to give compound 4-2 (70.0 mg, pale yellow oil); yield: 77%. MS-ESI [M+H].sup.+: calculated value: 558; measured value: 558.

(57) Step 2

(58) The reaction referred to Step 3 of Example 2, and the residue was isolated and purified by high performance liquid chromatography to give compound 4-3 (20.0 mg); yield: 42%.

(59) .sup.1H NMR: (400 MHz, DMSO-d.sub.6) δ 8.41 (s, 1H), 8.31 (d, J=8.8 Hz, 1H), 7.91 (d, J=8.8 Hz, 1H), 7.65 (s, 1H), 7.60 (d, J=8.8 Hz, 1H), 7.48-7.42 (m, 2H), 5.13 (d, J=7.2 Hz, 1H), 4.95-4.89 (m, 1H), 3.57-3.53 (m, 3H), 3.24-3.23 (m, 2H), 3.01-2.97 (m, 2H), 2.72-2.68 (m, 1H), 2.35-2.31 (m, 1H), 1.37 (d, J=6.0 Hz, 6H). MS-ESI [M+H].sup.+: calculated value: 444; measured value: 444.

Example 5

(60) ##STR00111##

(61) Step 1

(62) The reaction referred to Step 2 of Example 2, and the residue was isolated and purified by TLC (1:1 petroleum ether/ethyl acetate, R.sub.f=0.4) to give compound 5-2 (60.0 mg, pale yellow oil); yield: 68%. MS-ESI [M+H].sup.+: calculated value: 573; measured value: 573.

(63) Step 2

(64) The reaction referred to Step 3 of Example 2, and the residue was isolated and purified by high performance liquid chromatography to give compound 5-3 (20.0 mg); yield: 42%.

(65) .sup.1H NMR: (400 MHz, DMSO-d.sub.6) δ 8.09 (s, 1H), 7.91 (d, J=7.2 Hz, 1H), 7.60-7.59 (m, 2H), 7.54 (d, J=7.2 Hz, 1H), 7.41-7.33 (m, 3H), 5.10 (d, J=7.2 Hz, 1H), 4.88-4.82 (m, 1H), 3.57-3.50 (m, 2H), 3.24-3.22 (m, 3H), 3.01-2.97 (m, 2H), 2.69-2.66 (m, 1H), 2.32-2.28 (m, 1H), 1.35 (d, J=6.0 Hz, 6H). MS-ESI [M+H].sup.+: calculated value: 459; measured value: 459.

Example 6

(66) ##STR00112##

(67) Step 1

(68) The reaction referred to Step 2 of Example 2, and the residue was isolated and purified by TLC (1:1 petroleum ether/ethyl acetate, R.sub.f=0.4) to give compound 6-2 (70.0 mg, pale yellow oil); yield: 79%. MS-ESI [M+H].sup.+: calculated value: 575; measured value: 575.

(69) Step 2

(70) The reaction referred to Step 3 of Example 2, and the residue was isolated and purified by high performance liquid chromatography to give compound 6-3 (25.0 mg); yield: 45%.

(71) .sup.1H NMR: (400 MHz, DMSO-d.sub.6) δ 8.53 (s, 1H), 8.38 (d, J=7.6 Hz, 1H), 8.31 (d, J=7.6 Hz, 1H), 7.73 (d, J=7.6 Hz, 1H), 7.52-7.46 (m, 2H), 5.14 (d, J=7.2 Hz, 1H), 4.98-4.93 (m, 1H), 3.86-3.82 (m, 1H), 3.59-3.50 (m, 3H), 3.20-3.16 (m, 2H), 3.01-2.97 (m, 1H), 2.69-2.67 (m, 1H), 2.34-2.30 (m, 1H), 1.38 (d, J=6.0 Hz, 6H). MS-ESI [M+H].sup.+: calculated value: 461; measured value: 461.

Example 7

(72) ##STR00113##

(73) Step 1

(74) Compound 7-1 (229 mg, 0.501 mmol) was dissolved in dioxane (5 mL) and water (1 mL), and Compound 7-2 (100 mg, 0.501 mmol), potassium phosphate (213 mg, 1.00 mmol) and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (36.7 mg, 0.0501 mmol) were added. The reaction was stirred at 100° C. for 12 hours under nitrogen atmosphere. Water (30 mL) was added after the mixture was cooled to room temperature, and the mixture was extracted with ethyl acetate (30 mL×3). The organic layers were combined and washed with saturated brine (30 mL×3), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was isolated and purified by TLC (3:1 petroleum ether/ethyl acetate, R.sub.f=0.6) to give compound 7-3 (150 mg, pale yellow oil); yield: 61%.

(75) .sup.1H NMR: (400 MHz, CDCl.sub.3) δ 7.96 (d, J=8.0 Hz, 1H), 7.67 (d, J=8.0 Hz, 1H), 7.47 (t, J=8.0 Hz, 1H), 5.17 (d, J=7.2 Hz, 1H), 3.78-3.77 (m, 1H), 3.70-3.65 (m, 2H), 3.53-3.49 (m, 1H), 3.23-3.20 (m, 1H), 3.03-2.96 (m, 2H), 2.78-2.72 (m, 1H), 2.42-2.37 (m, 1H), 0.83 (s, 9H), 0.00 (s, 6H). MS-ESI [M+H].sup.+: calculated value: 494 and 496; measured value: 494 and 496.

(76) Step 2

(77) Compound 7-3 (150 mg, 0.303 mmol) was dissolved in dioxane (5 mL) and water (1 mL), and Compound 7-4 (104 mg, 0.364 mmol), potassium phosphate (129 mg, 0.607 mmol) and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (22.2 mg, 0.0303 mmol) were added. The reaction was stirred at 100° C. for 12 hours under nitrogen atmosphere. Water (30 mL) was added after the mixture was cooled to room temperature, and the mixture was extracted with ethyl acetate (30 mL×3). The organic layers were combined and washed with saturated brine (30 mL×3), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated with reduced pressure. The residue was isolated and purified by TLC (1:1 petroleum ether/ethyl acetate, R.sub.f=0.4) to give compound 2-4 (150 mg, pale yellow oil); yield: 86%. MS-ESI [M+H].sup.+: calculated value: 575; measured value: 575.

(78) Step 3

(79) Compound 7-5 (150 mg, 0.261 mmol) was dissolved in dioxane (3 mL), and dioxane hydrochloride (4M, 1 mL) was added. The reaction was stirred at 25° C. for 10 minutes under nitrogen atmosphere. The reaction mixture was cooled and concentrated under reduced pressure. The residue was isolated and purified by high performance liquid chromatography to give compound 7-6 (80.0 mg); yield: 66%.

(80) .sup.1H NMR: (400 MHz, DMSO-d.sub.6) δ 8.54-8.52 (m, 2H), 8.22 (d, J=7.6 Hz, 1H), 7.84 (d, J=7.6 Hz, 1H), 7.55-7.47 (m, 2H), 5.20 (d, J=7.2 Hz, 1H), 4.95-4.89 (m, 1H), 3.65-3.54 (m, 4H), 3.10-3.04 (m, 3H), 2.72-2.70 (m, 1H), 2.40-2.35 (m, 1H), 1.38 (d, J=6.0 Hz, 6H). MS-ESI [M+H].sup.+: calculated value: 461; measured value: 461.

Example 8

(81) ##STR00114## ##STR00115##

(82) Step 1

(83) Compound 8-1 (20.0 g, 67.3 mmol) was dissolved in tetrahydrofuran (200 mL), and 1,3 dimethoxybenzylamine (13.5 g, 80.8 mmol) and titanium tetraisopropoxide (38.3 g, 135 mmol) were added. The reaction was stirred at 60° C. for 1 hour under nitrogen atmosphere. Sodium borohydride (5.09 g, 135 mmol) and methanol (50 mL) were added to the reaction mixture after the mixture was cooled to room temperature. The mixture was then heated to 60° C. and stirred for 12 hours. Water (300 mL) was added to the reaction mixture after the mixture was cooled to room temperature, the mixture was filtered and the filtrate was extracted with ethyl acetate (500 mL×3). The organic layers were combined and washed with saturated brine (300 mL×2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated with reduced pressure. The residue was isolated and purified by silica gel column chromatography (1:1 petroleum ether/ethyl acetate, R.sub.f=0.5) to give compound 8-2 (10.0 g, pale yellow oil); yield: 37%.

(84) .sup.1H NMR: (400 MHz, CDCl.sub.3) δ 7.39-7.35 (m, 2H), 7.14 (d, J=7.6 Hz, 1H), 7.04 (d, J=7.6 Hz, 1H), 6.42-6.39 (m, 2H), 4.94 (d, J=7.2 Hz, 1H), 4.76-4.47 (m, 1H), 4.13-4.09 (m, 1H), 3.80 (s, 3H), 3.74 (s, 3H), 3.28-3.23 (m, 1H), 3.21-3.19 (m, 1H), 2.79-2.65 (m, 2H), 2.36-2.31 (m, 1H). MS-ESI: calculated value [M+H].sup.+: 402 and 404; measured value: 402 and 404.

(85) Step 2

(86) Compound 8-2 (8.00 g, 19.9 mmol) was dissolved in acetonitrile (100 mL), and zinc cyanide (4.67 g, 39.8 mmol), 2-dicyclohexylphosphine-2′,4′,7′-triisopropylbiphenyl (1.96 g, 3.98 mmol) and tris(dibenzylideneacetone) palladium (1.82 g, 1.99 mmol) were added. The reaction was stirred at 90° C. for 16 hours under nitrogen atmosphere. Water (100 mL) was added to the reaction mixture after the mixture was cooled to room temperature, and the mixture was extracted with ethyl acetate (200 mL×3). The organic layer was combined and washed with saturated brine (200 mL×2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated with reduced pressure. The residue was isolated and purified by silica gel column chromatography (1:1 petroleum ether/ethyl acetate, R.sub.f=0.3) to give compound 8-3 (5.00 g, pale yellow solid); yield: 72%.

(87) .sup.1H NMR: (400 MHz, CDCl.sub.3) δ 7.72 (d, J=8.0 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 6.49-6.41 (m, 2H), 4.88 (d, J=7.2 Hz, 1H), 4.86-4.81 (m, 1H), 4.19-4.16 (m, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 3.48-3.44 (m, 1H), 3.20-3.19 (m, 1H), 3.05-3.00 (m, 1H), 2.82-2.75 (m, 1H), 2.43-2.38 (m, 1H). MS-ESI: calculated value [M+H].sup.+: 349; measured value: 349.

(88) Step 3

(89) Compound 8-3 (5.00 g, 14.4 mmol) was dissolved in anhydrous ethanol (50 mL), and add hydroxylamine hydrochloride (2.99 g, 43.1 mmol) and triethylamine (5.81 g, 57.4 mmol) were added. The reaction was stirred at 60° C. for 12 hours under nitrogen atmosphere. Water (100 mL) was added to the reaction mixture after the mixture was cooled to room temperature, and the mixture was extracted with dichloromethane (100 mL×3). The organic layer were combined and washed with saturated brine (100 mL×2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated with reduced pressure. The residue was compound 8-4 (3.70 g, white solid); yield: 68%.

(90) .sup.1H NMR: (400 MHz, DMSO-d.sub.6) δ 9.55 (s, 1H), 7.42 (d, J=7.6 Hz, 1H), 7.35 (d, J=7.6 Hz, 1H), 7.26 (d, J=7.6 Hz, 1H), 7.02 (d, J=8.8 Hz, 1H), 6.60 (s, 1H), 6.48 (d, J=8.8 Hz, 1H), 5.73 (s, 2H), 4.73 (d, J=7.2 Hz, 1H), 4.56-4.52 (m, 1H), 4.08-4.04 (m, 1H), 3.84 (s, 3H), 3.74 (s, 3H), 3.39-3.35 (m, 1H), 3.04-3.00 (m, 1H), 2.92-2.87 (m, 1H), 2.69-2.63 (m, 1H), 2.25-2.20 (m, 1H). MS-ESI [M+H].sup.+: calculated value: 382; measured value: 382.

(91) Step 4

(92) Compound 8-5 (1.01 g, 4.91 mmol) was dissolved in N,N-dimethylformamide (10 mL), and 1-hydroxybenzotriazole (1.21 g, 8.92 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.71 g, 8.92 mmol) were added. The reaction was stirred at 25° C. for 0.5 hour under nitrogen atmosphere. Then, Compound 8-4 (1.70 g, 4.46 mmol) was added to the reaction mixture and the mixture was stirred at 25° C. for 1 hour, then heated to 80° C. and stirred for 12 hours. Water (30 mL) was added to the reaction mixture after the mixture was cooled to room temperature and the mixture was extracted with ethyl acetate (30 mL×3). The organic layers were combined and washed with saturated brine (25 mL×2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (1:1 petroleum ether/ethyl acetate, R.sub.f=0.7) to give compound 8-6 (1.2 g, white solid); yield: 49%.

(93) .sup.1H NMR: (400 MHz, DMSO-d.sub.6) δ 8.50 (d, J=2.0 Hz, 1H), 8.40 (d, J=8.8 Hz, 1H), 8.08 (d, J=7.2 Hz, 1H), 7.62-7.48 (m, 3H), 7.04 (d, J=7.2 Hz, 1H), 6.61 (d, J=2.0 Hz, 1H), 6.48 (d, J=8.8 Hz, 1H), 5.01-4.96 (m, 1H), 4.86 (d, J=7.2 Hz, 1H), 4.61-4.57 (m, 1H), 4.16-4.12 (m, 1H), 3.88 (s, 3H), 3.76 (s, 3H), 3.68-3.65 (m, 1H), 3.24-3.21 (m, 1H), 3.11-3.09 (m, 1H), 2.77-2.70 (m, 1H), 2.38-2.33 (m, 1H), 1.38 (d, J=6.0 Hz), 6H). MS-ESI [M+H].sup.+: calculated value: 551; measured value: 551.

(94) Step 5

(95) Compound 8-6 (1.20 g, 2.18 mmol) was dissolved in trifluoroacetic acid (5 mL). The reaction was stirred at 50° C. for 12 hours under nitrogen atmosphere. Saturated sodium bicarbonate aqueous solution (50 mL) was added to the mixture and the mixture was extracted with dichloromethane (50 mL×3). The organic layers were combined and washed with saturated brine (25 mL×2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated with reduced pressure. The residue was isolated and purified by silica gel column chromatography (0:1 petroleum ether/ethyl acetate, R.sub.f=0.2) to give compound 8-7 (800 mg, white solid); yield: 92%.

(96) .sup.1H NMR: (400 MHz, DMSO-d.sub.6) δ 8.51 (d, J=2.0 Hz, 1H), 8.41 (d, J=8.0 Hz, 1H), 8.32 (d, J=2.0 Hz, 1H), 8.06 (d, J=8.0 Hz, 1H), 7.57-7.50 (m, 3H), 5.02 (d, J=7.2 Hz, 1H), 5.00-4.97 (m, 1H), 3.59-3.57 (m, 2H), 3.17-3.12 (m, 1H), 2.77-2.76 (m, 1H), 2.08-2.02 (m, 1H), 1.38 (d, J=6.0 Hz, 6H). MS-ESI [M+H].sup.+: calculated value: 401; measured value: 401.

(97) Step 6

(98) Compound 8-7 (50.0 mg, 0.125 mmol) was dissolved in N,N-dimethylformamide (3 mL), and sodium hydride (10.0 mg, 0.250 mmol, 60% purity) was added in batches at 0° C. The reaction was stirred for 30 minutes at this temperature. Then, ethyl bromoacetate (31.3 mg, 0.187 mmol) was added to the reaction mixture, and the mixture was stirred at 25° C. for 1 hour. Water (10 mL) was added to the reaction mixture and the mixture was extracted with ethyl acetate (20 mL×3). The organic layer were combined and washed with saturated brine (10 mL×2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated with reduced pressure. The residue was isolated and purified by TLC (0:1 petroleum ether/ethyl acetate, R.sub.f=0.3) to give compound 8-8 (50.0 mg, white solid); yield: 82%. MS-ESI [M+H].sup.+: calculated value: 487; measured value: 487.

(99) Step 7

(100) Compound 8-8 (50.0 mg, 0.103 mmol) was dissolved in tetrahydrofuran (4 mL) and water (1 mL), and lithium hydroxide monohydrate (8.6 mg, 0.206 mmol) was added. The reaction was stirred at 25° C. for 12 hours under nitrogen atmosphere. The mixture was cooled and concentrated under reduced pressure. The residue was isolated and purified by high performance liquid chromatography to give compound 8-9 (25.0 mg); yield: 53%.

(101) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) δ 8.48-8.43 (m, 2H), 8.20 (d, J=7.2 Hz, 1H), 7.63 (d, J=7.2 Hz, 1H), 7.51-7.45 (m, 2H), 5.20 (d, J=7.2 Hz, 1H), 4.97-4.95 (m, 1H), 4.34-4.30 (m, 1H), 3.90-3.82 (m, 2H), 3.39-3.38 (m, 1H), 3.18-3.14 (m, 1H), 2.95-2.89 (m, 1H), 2.56-2.51 (m, 1H), 1.47 (d, J=6.0 Hz, 6H). MS-ESI [M+H].sup.+: calculated value: 459; measured value: 459.

Example 9

(102) ##STR00116##

(103) Step 1

(104) Compound 9-1 (40.0 mg, 0.100 mmol) was dissolved in anhydrous N,N-dimethylformamide (3 mL), and sodium hydrogen (8.0 mg, 0.200 mmol, 60% purity) was added in batches at 0° C. The reaction was stirred at this temperature for 30 minutes. Then, methyl bromopropionate (25.0 mg, 0.150 mmol) was added to the reaction mixture, and the mixture was stirred at 25° C. for 1 hour. Water (10 mL) was added to the reaction mixture and the mixture was extracted with ethyl acetate (20 mL×3). The organic layers were combined and washed with saturated brine (10 mL×2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated with reduced pressure. The residue was isolated and purified by TLC (0:1 petroleum ether/ethyl acetate, R.sub.f=0.3) to give compound 9-2 (30.0 mg, white solid); yield: 62%. MS-ESI [M+H].sup.+: calculated value: 487; measured value: 487.

(105) Step 2

(106) Compound 9-2 (30.0 mg, 0.0617 mmol) was dissolved in methanol (3 mL) and water (1 mL), and lithium hydroxide monohydrate (5.2 mg, 0.123 mmol) was added. The reaction was stirred at 25° C. for 12 hours under nitrogen atmosphere. The mixture was cooled and concentrated under reduced pressure. The residue was isolated and purified by high performance liquid chromatography to give compound 9-3 (20.0 mg); yield: 69%.

(107) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) δ 8.48-8.43 (m, 2H), 8.21 (d, J=7.6 Hz, 1H), 7.84 (d, J=7.6 Hz, 1H), 7.52-7.45 (m, 2H), 5.20 (d, J=7.2 Hz, 1H), 4.98-4.97 (m, 1H), 3.86-3.79 (m, 2H), 3.49-3.47 (m, 1H), 3.30-3.29 (m, 1H), 3.16-3.14 (m, 1H), 2.88-2.82 (m, 1H), 2.74-2.70 (m, 1H), 2.48-2.43 (m, 2H), 1.47 (d, J=6.0 Hz, 6H). MS-ESI [M+H].sup.+: calculated value: 473; measured value: 473.

Example 10

(108) ##STR00117##

(109) Step 1

(110) The reaction referred to Step 6 of Example 8, and the residue was isolated and purified by TLC (0:1 petroleum ether/ethyl acetate, R.sub.f=0.3) to give compound 10-2 (80 mg, white solid); yield: 62%. MS-ESI [M+H].sup.+: calculated value: 515; measured value: 515.

(111) Step 2

(112) The reaction referred to Step 7 of Example 8, and the residue was isolated and purified by high performance liquid chromatography to give compound 10-3 (30.0 mg); yield: 40%.

(113) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) δ 8.48-8.43 (m, 2H), 8.21 (d, J=7.2 Hz, 1H), 7.77 (d, J=7.2 Hz, 1H), 7.52-7.45 (m, 2H), 5.17 (d, J=7.2 Hz, 1H), 4.98-4.97 (m, 1H), 3.87-3.85 (m, 1H), 3.82-3.80 (m, 1H), 3.19-3.14 (m, 3H), 2.90-2.83 (m, 1H), 2.48-2.36 (m, 3H), 1.97-1.96 (m, 1H), 1.86-1.84 (m, 1H), 1.47 (d, J=6.0 Hz, 6H). MS-ESI [M+H].sup.+: calculated value: 487; measured value: 487.

Example 11

(114) ##STR00118##

(115) Step 1

(116) The reaction referred to Step 6 of Example 8, and the residue was isolated and purified by TLC (0:1 petroleum ether/ethyl acetate, R.sub.f=0.3) to give compound 11-2 (40.0 mg, white solid); yield: 87%. MS-ESI [M+H].sup.+: calculated value: 529; measured value: 529.

(117) Step 2

(118) The reaction referred to Step 7 of Example 8, and the residue was isolated and purified by high performance liquid chromatography to give compound 11-3 (15.0 mg); yield: 40%.

(119) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) δ 8.47-8.42 (m, 2H), 8.20 (d, J=7.2 Hz, 1H), 7.71 (d, J=7.2 Hz, 1H), 7.52-7.44 (m, 2H), 5.16 (d, J=7.2 Hz, 1H), 4.98-4.97 (m, 1H), 3.86-3.79 (m, 1H), 3.63-3.62 (m, 1H), 3.13-3.09 (m, 2H), 2.88-2.84 (m, 1H), 2.49-2.44 (m, 1H), 2.37-2.35 (m, 2H), 1.64-1.59 (m, 5H), 1.47 (d, J=6.0 Hz, 6H). MS-ESI [M+H].sup.+: calculated value: 501; measured value: 501.

Example 12

(120) ##STR00119##

(121) Step 1

(122) The reaction referred to Step 6 of Example 8, and the residue was isolated and purified by high performance liquid chromatography to give compound 12-2 (20.0 mg); yield: 35%.

(123) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) δ 8.48-8.43 (m, 2H), 8.20 (d, J=7.6 Hz, 1H), 7.79 (d, J=7.6 Hz, 1H), 7.50-7.45 (m, 2H), 5.26 (d, J=7.2 Hz, 1H), 4.97-4.95 (m, 1H), 3.86-3.79 (m, 2H), 3.62-3.58 (m, 2H), 3.41 (s, 3H), 3.24-3.22 (m, 2H), 3.12-3.10 (m, 1H), 2.91-2.84 (m, 1H), 2.49-2.44 (m, 1H), 1.47 (d, J=6.0 Hz, 6H). MS-ESI [M+H].sup.+: calculated value: 459; measured value: 459.

Example 13

(124) ##STR00120##

(125) Step 1

(126) The reaction referred to Step 6 of Example 8, and the residue was isolated and purified by high performance liquid chromatography to give compound 13-2 (20.0 mg); yield: 32%.

(127) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) δ 8.43-8.40 (m, 2H), 8.19 (d, J=7.6 Hz, 1H), 7.79 (d, J=7.6 Hz, 1H), 7.52-7.43 (m, 2H), 5.24 (d, J=7.2 Hz, 1H), 4.96-4.94 (m, 1H), 4.05-4.02 (m, 1H), 3.80-3.78 (m, 1H), 3.54-3.49 (m, 2H), 3.36-3.34 (m, 2H), 3.12-3.06 (m, 4H), 2.88-2.82 (m, 1H), 2.49-2.44 (m, 1H), 1.47 (d, J=6.0 Hz, 6H). MS-ESI [M+H].sup.+: calculated value: 507; measured value: 507.

Example 14

(128) ##STR00121##

(129) Step 1

(130) The reaction referred to Step 6 of Example 8, and the residue was isolated and purified by TLC (0:1 petroleum ether/ethyl acetate, R.sub.f=0.8) to give compound 14-2 (15.0 mg, colorless oil); yield: 12%. MS-ESI [M+H].sup.+: calculated value: 515; measured value: 515.

(131) Step 2

(132) Compound 14-2 (15.0 mg, 0.0292 mmol) was dissolved in tetrahydrofuran (1 mL), and hydrochloric acid (1 M, 0.75 mL) was added to the mixture. The reaction was stirred at 60° C. for 30 minutes under nitrogen atmosphere. The mixture was cooled and concentrated under reduced pressure. The residue was isolated and purified by high performance liquid chromatography to give compound 14-3 (5.0 mg); yield: 36%.

(133) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) δ 8.48-8.43 (m, 2H), 8.20 (d, J=7.6 Hz, 1H), 7.82 (d, J=7.6 Hz, 1H), 7.52-7.45 (m, 2H), 5.35 (d, J=7.2 Hz, 1H), 4.97-4.96 (m, 1H), 3.93-3.91 (m, 1H), 3.87-3.84 (m, 1H), 3.73-3.69 (m, 1H), 3.56-3.53 (m, 2H), 3.28-3.26 (m, 2H), 3.12-3.10 (m, 1H), 2.93-2.90 (m, 1H), 2.50-2.48 (m, 1H), 1.47 (d, J=6.0 Hz, 6H). MS-ESI [M+H].sup.+: calculated value: 475; measured value: 475.

Example 15

(134) ##STR00122##

(135) Step 1

(136) The reaction referred to Step 6 of Example 8, and the residue was isolated and purified by high performance liquid chromatography to give compound 15-2 (25.0 mg); yield: 41%.

(137) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) δ 8.48-8.43 (m, 2H), 8.20 (d, J=7.6 Hz, 1H), 7.64 (d, J=7.6 Hz, 1H), 7.50-7.45 (m, 2H), 5.19 (d, J=7.2 Hz, 1H), 4.98-4.97 (m, 1H), 4.53-4.49 (m, 1H), 3.93-3.82 (m, 2H), 3.39-3.38 (m, 1H), 3.18-3.10 (m, 4H), 2.98-2.91 (m, 4H), 2.55-2.50 (m, 1H), 1.47 (d, J=6.0 Hz, 6H). MS-ESI [M+H].sup.+: calculated value: 486; measured value: 486.

Example 16

(138) ##STR00123##

(139) Step 1

(140) 4-(Difluoromethoxy)benzoic acid (29.0 mg, 154 umol) was dissolved in anhydrous N,N-dimethylformamide (0.2 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (44.3 mg, 0.231 mmol), 1-hydroxybenzotriazole (41.6 mg, 0.308 mmol) were added at 20° C. under nitrogen atmosphere. The reaction was stirred at 20° C. for 1 hour. Then, Compound 16-1 (60.0 mg, 0.154 mmol) was added in N,N-dimethylformamide (0.3 mL) to the reaction mixture, and the mixture was stirred at 20° C. for 1 hour, then heated to 85° C. and stirred for 10 hours. The mixture was quenched with saturated sodium chloride aqueous solution (20 mL) and extracted with ethyl acetate (50 mL×3). The organic layer was washed with saturated brine (20 mL×3), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated with reduced pressure, then isolated and purified by high performance liquid chromatography to give compound 16-2 (50.0 mg); yield: 76%.

(141) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) δ 8.26 (d, J=8.8 Hz, 2H), 8.18 (d, J=7.6 Hz, 1H), 7.76 (d, J=7.6 Hz, 1H), 7.47 (t, J=7.6 Hz, 1H), 7.37 (d, J=8.8 Hz, 2H), 7.04 (t, J=73.2 Hz, 1H), 5.24 (d, J=7.2 Hz, 1H), 3.79-3.69 (m, 4H), 3.31-3.12 (m, 3H), 2.91-2.84 (m, 1H), 2.46-2.42 (m, 1H).

(142) MS-ESI [M+H].sup.+: calculated value: 428; measured value: 428.

Example 17

(143) ##STR00124##

(144) Step 1

(145) The reaction referred to Step 1 of Example 16, and the residue was isolated and purified by high performance liquid chromatography to give compound 17-2 (55.0 mg); yield: 70%.

(146) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) δ 8.58 (s, 1H), 8.52 (d, J=8.0 Hz, 1H), 8.22 (d, J=8.0 Hz, 1H), 8.06 (d, J=8.0 Hz, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.80 (t, J=8.0 Hz, 1H), 7.52 (t, J=8.0 Hz, 1H), 5.27 (d, J=7.2 Hz), 1H), 3.79-3.72 (m, 4H), 3.34-3.12 (m, 3H), 2.91-2.86 (m, 1H), 2.49-2.45 (m, 1H). MS-ESI [M+H].sup.+: calculated value: 387; measured value: 387.

Example 18

(147) ##STR00125##

(148) Step 1

(149) 4-Methoxybenzoic acid (19.5 mg, 0.128 mmol) was dissolved in anhydrous N,N-dimethylformamide (2.00 mL), and 1-hydroxybenzotriazole (34.6 mg, 0.256 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbonyldiimide hydrochloride (36.9 mg, 0.192 mmol) were added. The reaction was stirred at 25° C. for 1 hour. Then, Compound 18-1 (50.0 mg, 0.128 mmol) was added to the reaction mixture, and the mixture was stirred at 25° C. for 1 hour, then stirred at 90° C. for 12 hours under nitrogen atmosphere. The mixture was quenched with saturated sodium chloride aqueous solution (20 mL) and extracted with ethyl acetate (50 mL×3). The organic layer was washed with saturated brine (20 mL×3), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was isolated and purified by high performance liquid chromatography to give compound 18-2 (3.0 mg); yield: 6%.

(150) .sup.1H NMR: (400 MHz, DMSO-d.sub.6) δ 8.22-8.04 (m, 3H), 7.78 (d, J=7.6 Hz, 1H), 7.50 (t, J=7.6 Hz, 1H), 7.20 (d, J=8.4 Hz, 2H), 5.15 (d, J=7.2 Hz, 1H), 3.89 (s, 3H), 3.74-3.46 (m, 3H), 3.22-3.20 (m, 2H), 3.06-2.92 (m), 2H), 2.75-2.63 (m, 1H), 2.31-2.28 (m, 1H). MS-ESI [M+H].sup.+: calculated value: 392; measured value: 392.

Example 19

(151) ##STR00126##

(152) The reaction referred to Step 1 of Example 16, and the residue was isolated and purified by high performance liquid chromatography to give compound 19-2 (14.0 mg); yield: 25%.

(153) .sup.1H NMR: (400 MHz, DMSO-d.sub.6) δ 8.34 (d, J=8.4 Hz, 2H), 8.11 (d, J=7.2 Hz, 1H), 7.81 (d, J=7.2 Hz, 1H), 7.68 (d, J=8.4 Hz, 2H), 7.52 (t, J=7.2 Hz, 1H), 5.17 (d, J=7.2 Hz, 1H), 4.87 (t, J=5.2 Hz, 1H), 3.76-3.46 (m, 4H), 3.26-3.17 (m, 1H), 3.06-2.95 (m, 2H), 2.74-2.67 (m, 1H), 2.34-2.28 (m, 1H). MS-ESI [M+H].sup.+: calculated value: 446; measured value: 446.

Example 20

(154) ##STR00127##

(155) Step 1

(156) Compound 20-1 (1.00 g, 6.57 mmol) was dissolved in N,N-dimethylformamide (10 mL), and isopropyl bromide (1.62 g, 13.1 mmol) and potassium carbonate (2.27 g, 16.4 mmol) were add. The reaction was stirred at 65° C. for 3 hours under nitrogen atmosphere. Water (30 mL) was added to the reaction mixture after the mixture was cooled to 25° C. and the mixture was extracted with ethyl acetate (50 mL×3). The combined organic layer was washed with saturated brine (40 mL×4), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subject to silica gel column chromatography (10:1 petroleum ether/ethyl acetate, R.sub.f=0.5) to give compound 20-2 (1.10 g, colorless oil); yield: 86%.

(157) .sup.1H NMR: (400 MHz, CDCl.sub.3) δ 7.61 (d, J=7.6 Hz, 1H), 7.50 (s, 1H), 7.33 (t, J=7.6 Hz, 1H), 7.07 (d, J=7.6 Hz, 1H), 4.65-4.60 (m, 1H), 3.92 (s, 3H), 1.36 (d, J=6.0 Hz, 6H).

(158) Step 2

(159) Compound 20-2 (1.10 g, 5.66 mmol) was dissolved in tetrahydrofuran (10 mL), and aqueous lithium hydroxide (712 mg, 16.9 mmol) solution (2 mL) was added. The reaction was stirred at 50° C. for 4 hours. The solution was acidified with 1 M hydrochloric acid to pH=4 after the mixture was cooled to 25° C.; and the mixture was extracted with ethyl acetate (40 mL×2). The combined organic layer was washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 20-3 (880 mg, yellow solid); yield: 86%.

(160) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) δ 7.61 (d, J=7.6 Hz, 1H), 7.50 (s, 1H), 7.33 (t, J=7.6 Hz, 1H), 7.07 (d, J=7.6 Hz, 1H), 4.65-4.60 (m, 1H), 1.36 (d, J=6.0 Hz, 6H).

(161) Step 3

(162) Compound 20-3 (23.1 mg, 0.128 mmol) was dissolved in N,N-dimethylformamide (2 mL), and 1-hydroxybenzotriazole (34.6 mg, 0.256 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (36.9 mg, 0.192 mmol) were added. The reaction was stirred at 25° C. for 1 hour. Then, Compound 20-4 (50.0 mg, 0.128 mmol) was added, and the mixture was stirred at 25° C. for 1 hour, then heated to 80° C. and stirred for 10 hours under nitrogen atmosphere. The mixture was quenched with saturated aqueous sodium chloride solution (20 mL) and extracted with ethyl acetate (50 mL×3). The organic layer was washed with saturated brine (20 mL×3), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was isolated and purified by high performance liquid chromatography to give compound 20-5 (10.0 mg); yield: 18%.

(163) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) δ 8.18 (d, J=7.6 Hz, 1H), 7.78-7.68 (m, 3H), 7.54-7.45 (m, 2H), 7.22 (d, J=7.6 Hz, 1H), 5.25 (d, J=7.2 Hz, 1H), 4.79-4.66 (m, 1H), 3.97-3.62 (m, 5H), 3.27-3.18 (m, 1H), 3.13-3.07 (m, 1H), 2.91-2.85 (m, 1H), 2.46-2.43 (m, 1H), 1.39 (d, J=6.0 Hz, 6H). MS-ESI [M+H].sup.+: calculated value: 420; measured value: 420.

Example 21

(164) ##STR00128##

(165) Step 1

(166) Compound 21-1 (2.00 g, 11.5 mmol) was dissolved in N-methylpyrrolidone (40 mL), and cyclopropyl bromide (2.80 g, 23.1 mmol) and cesium carbonate (9.42 g, 28.9 mmol) were added. The reaction was stirred at 130° C. for 16 hours under nitrogen atmosphere. Water (30 mL) was added to the reaction mixture after the mixture was cooled to 25° C.; and the mixture was extracted with ethyl acetate (50 mL×3). The combined organic layer was washed with saturated brine (40 mL×4), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subject to silica gel column chromatography (petroleum ether, R.sub.f=0.5) to give compound 21-2 (1.20 g, colorless oil); yield: 48%.

(167) .sup.1H NMR: (400 MHz, CDCl.sub.3) δ 7.38 (d, J=9.2 Hz, 2H), 6.93 (d, J=9.2 Hz, 2H), 3.77-3.61 (m, 1H), 0.83-0.70 (m, 4H).

(168) Step 2

(169) Compound 21-2 (1.20 g, 5.63 mmol) was dissolved in methanol (30 mL), and triethylamine (2.85 g, 28.1 mmol) and 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (205 mg, 281 umol) were added. The reaction was stirred at 70° C. for 12 hours under carbon monoxide atmosphere (50 psi). The reaction mixture was filtered with diatomite after cooled to 25° C. and then concentrated under reduced pressure. The residue was subject to silica gel column chromatography (10:1 petroleum ether/ethyl acetate, R.sub.f=0.5) to give compound 21-3 (20 mg, colorless oil); yield: 2%.

(170) .sup.1H NMR: (400 MHz, CDCl.sub.3) δ 7.99 (d, J=9.2 Hz, 2H), 7.07 (d, J=9.2 Hz, 2H), 3.89 (s, 3H), 3.81-3.77 (m, 1H), 0.86-0.75 (m, 4H).

(171) Step 3

(172) Compound 21-3 (20.0 mg, 0.104 mmol) was dissolved in tetrahydrofuran (1 mL), and aqueous lithium hydroxide (13.1 mg, 0.312 mmol) solution (1 mL) was added. The reaction was stirred at 50° C. for 4 hours. The solution was acidified with 1 M hydrochloric acid to pH=4 after cooled to 25° C. and then the mixture was extracted with ethyl acetate (40 mL×2). The combined organic layer was washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 21-4 (14.0 mg, white solid); yield: 75%.

(173) .sup.1H NMR: (400 MHz, Methanol-d.sub.4) δ 7.86 (d, J=9.2 Hz, 2H), 7.00 (d, J=9.2 Hz, 2H), 3.77-3.72 (m, 1H), 0.78-0.68 (m, 2H), 0.64-0.53 (m, 2H).

(174) Step 4

(175) Compound 21-4 (13.7 mg, 0.0770 mmol) was dissolved in N,N-dimethylformamide (2 mL), and 1-hydroxybenzotriazole (20.8 mg, 0.154 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbonyldiimide hydrochloride (22.1 mg, 0.115 mmol) were added. The reaction was stirred at 25° C. for 1 hour. Then, Compound 21-5 (30.0 mg, 0.770 mmol) was added, and the mixture was stirred at 25° C. for 1 hour, then 80° C. for 10 hours under nitrogen atmosphere. The mixture was quenched with saturated aqueous sodium chloride solution (20 mL) and extracted with ethyl acetate (50 mL×3). The organic layer was washed with saturated brine (20 mL×3), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography to give compound 21-6 (1.0 mg); yield: 3%.

(176) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) δ 8.25-8.13 (m, 3H), 7.77 (d, J=7.6 Hz, 1H), 7.49 (t, J=7.6 Hz, 1H), 7.29 (d, J=9.2 Hz, 2H), 5.26 (d, J=7.2 Hz, 1H), 3.95-3.93 (m, 1H), 3.85-3.70 (m, 4H), 3.30-3.19 (m, 2H), 3.13-3.11 (m, 1H), 2.90-2.88 (m, 1H), 2.48-2.43 (m, 1H), 0.93-0.85 (m, 2H), 0.81-0.74 (m, 2H). MS-ESI [M+H].sup.+: calculated value: 418; measured value: 418.

Example 22

(177) ##STR00129##

(178) The reaction referred to Step 1 of Example 16, and the residue was isolated and purified by high performance liquid chromatography to give compound 22-4 (6.0 mg); yield: 11%.

(179) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) δ 8.20 (d, J=8.0 Hz, 1H), 8.20 (d, J=8.0 Hz, 1H), 7.77 (d, J=8.0 Hz, 1H), 7.61 (t, J=8.0 Hz, 1H), 7.50 (t, J=8.0 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H), 7.14 (t, J=8.0 Hz, 1H), 5.27 (d), J=7.2 Hz, 1H), 4.85-4.79 (m, 2H), 3.90-3.70 (m, 4H), 3.27-3.11 (m, 2H), 2.92-2.86 (m, 1H), 2.48-2.43 (m, 1H), 1.44 (d, J=6.0 Hz, 6H). MS-ESI [M+H].sup.+: calculated value: 420; measured value: 420.

Example 23

(180) ##STR00130##

(181) The reaction referred to Step 1 of Example 16, and the residue was isolated and purified by high performance liquid chromatography to give compound 23-2 (30.0 mg); yield: 45%.

(182) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) δ 8.18-8.13 (m, 3H), 7.75 (d, J=7.6 Hz, 1H), 7.48 (t, J=7.6 Hz, 1H), 7.12 (d, J=9.2 Hz, 2H), 5.25 (d, J=7.2 Hz, 1H), 3.96-3.94 (m, 2H), 3.77-3.69 (m, 4H), 3.34-3.12 (m, 3H), 2.90-2.84 (m, 1H), 2.47-2.42 (m, 1H), 1.31-1.30 (m, 1H), 0.68-0.63 (m, 2H), 0.41-0.38 (m, 2H). MS-ESI [M+H].sup.+: calculated value: 432; measured value: 432.

Example 24

(183) ##STR00131##

(184) Step 1

(185) Compound 24-1 (2.00 g, 16.4 mmol) was dissolved in acetone (40 mL), and potassium carbonate (5.66 g, 41.0 mmol) and chloromethyl methyl ether (1.58 g, 19.7 mmol) were added at 0° C. under nitrogen atmosphere. The reaction was stirred at 20° C. for 12 hours. The mixture was added with saturated aqueous sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (70 mL×3). The organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (5:1 petroleum ether/ethyl acetate, R.sub.f=0.6) to give compound 24-2 (1.50 g, white solid), yield: 55%.

(186) .sup.1H NMR: (400 MHz, CDCl.sub.3) δ 9.91 (s, 1H), 7.85 (d, J=8.8 Hz, 2H), 7.16 (d, J=8.8 Hz, 2H), 5.27 (s, 2H), 3.50 (s, 3H).

(187) Step 2

(188) Compound 24-2 (1.00 g, 6.02 mmol) and sulfamic acid (701 mg, 7.22 mmol) were dissolved in tetrahydrofuran (10 mL) and water (5 mL), and sodium chlorite (599 mg, 6.62 mmol) was added in portions at 0° C. under nitrogen atmosphere. The reaction was stirred at 20° C. for 12 hours. Water (30 mL) was added and the mixture was concentrated to 40 mL under reduced pressure, followed by filtrating off solid. The residue was washed with water (20 mL×3) and dried in vacuum to give compound 24-3 (800 mg, yellow solid); yield: 73%.

(189) .sup.1H NMR: (400 MHz, DMSO-d.sub.6) δ 12.7 (brs, 1H), 7.89 (d, J=8.8 Hz, 2H), 7.12 (d, J=8.8 Hz, 2H), 5.24 (s, 2H), 3.46 (s, 3H).

(190) Step 3

(191) The reaction referred to Step 1 of Example 16, and the residue was isolated and purified by high performance liquid chromatography to give compound 22-4 (40.0 mg); yield: 60%.

(192) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) δ 8.19-8.16 (m, 3H), 7.76 (d, J=7.6 Hz, 1H), 7.48 (t, J=7.6 Hz, 1H), 7.26-7.24 (d, J=8.0 Hz, 2H), 5.31 (s, 2H), 5.25 (d, J=7.2 Hz, 1H), 3.77-3.69 (m, 4H), 3.49 (s, 3H), 3.30-3.12 (m), 3H), 2.91-2.84 (m, 1H), 2.47-2.46 (m, 1H). MS-ESI [M+H].sup.+: calculated value: 422; measured value: 422.

Example 25

(193) ##STR00132##

(194) Step 1

(195) Compound 25-1 (800 mg, 3.46 mmol) was dissolved in N,N-dimethylformamide (10 mL), and potassium carbonate (957 mg, 6.93 mmol) and bromoisopropane (639 mg, 5.19 mmol) were added. The reaction was stirred at 80° C. for 12 hours under nitrogen atmosphere. Water (30 mL) was added to the reaction mixture after the mixture was cooled to room temperature and the mixture was extracted with ethyl acetate (30 mL×3). The organic layer was combined and washed with saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10:1 petroleum ether/ethyl acetate, R.sub.f=0.8) to give compound 25-2 (600 mg, colorless oil); yield: 63%.

(196) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) δ 8.15 (s, 1H), 7.96 (d, J=8.8 Hz, 1H), 7.11 (d, J=8.8 Hz, 1H), 4.81-4.75 (m, 1H), 3.89 (s, 3H), 1.39 (d, J=6.0 Hz, 6H). MS-ESI [M+H].sup.+: calculated value: 273 and 275; measured value: 273 and 275.

(197) Step 2

(198) Compound 25-2 (600 mg, 2.20 mmol) was dissolved in tetrahydrofuran (5 mL) and water (1 mL), and lithium hydroxide monohydrate (185 mg, 4.40 mmol) was added. The reaction was stirred at 25° C. for 12 hours under nitrogen atmosphere. The filtrate was concentrated under reduced pressure. Then, diluted hydrochloric acid (1 M, 10 mL) was added into the resultant, the mixture was filtered and the filtrate was concentrated with reduced pressure to give compound 25-3 (500 mg, white solid); yield: 88%.

(199) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) δ 8.16 (s, 1H), 7.98 (d, J=8.8 Hz, 1H), 7.11 (d, J=8.8 Hz, 1H), 4.81-4.75 (m, 1H), 1.39 (d, J=6.0 Hz, 6H). MS-ESI [M+H].sup.+: calculated value: 259 and 261; measured value: 259 and 261.

(200) Step 3

(201) Compound 25-3 (79.8 mg, 0.308 mmol) was dissolved in N,N-dimethylformamide (3 mL), and 1-hydroxybenzotriazole (69.4 mg, 0.513 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (98.4 mg, 0.513 mmol) were added. The reaction was stirred at 25° C. for 0.5 hour under nitrogen atmosphere. Then, Compound 25-4 (100 mg, 0.257 mmol) was added to the reaction mixture, and the mixture was stirred at 25° C. for 1 hour, then heated to 80° C. and stirred for 12 hours. Water (30 mL) was added to the reaction mixture after the mixture was cooled to room temperature and the mixture was extracted with ethyl acetate (30 mL×3). The organic layers were combined and washed with saturated brine (25 mL×2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was isolated and purified by high performance liquid chromatography to give compound 25-5 (50.0 mg); yield: 39%.

(202) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) δ 8.40 (s, 1H), 8.21-8.17 (m, 2H), 7.78 (d, J=7.2 Hz, 1H), 7.50 (d, J=7.2 Hz, 1H), 7.29 (d, J=8.8 Hz, 1H), 5.27 (d, J=7.2 Hz, 1H), 4.97-4.95 (m, 1H), 3.84-3.82 (m, 1H), 3.79-3.61 (m, 3H), 3.36-3.35 (m, 1H), 3.24-3.22 (m, 1H), 3.16-3.15 (m, 1H), 2.90-2.86 (m, 1H), 2.49-2.45 (m, 1H), 1.44 (d, J=6.0 Hz, 6H). MS-ESI [M+H].sup.+: calculated value: 498 and 500; measured value: 498 and 500.

Example 26

(203) ##STR00133##

(204) Step 1

(205) The reaction referred to Step 1 of Example 25, and the residue was isolated and purified by silica gel column chromatography (10:1 petroleum ether/ethyl acetate, R.sub.f=0.8) to give compound 26-2 (1.20 g, colorless oil); yield: 98%. MS-ESI [M+H].sup.+: calculated value: 229; measured value: 229.

(206) .sup.1H NMR: (400 MHz, Methanol-d.sub.4) δ 7.98 (s, 1H), 7.90 (d, J=8.8 Hz, 1H), 7.14 (d, J=8.8 Hz, 1H), 4.81-4.74 (m, 1H), 3.88 (s, 3H), 1.39 (d, J=6.0 Hz, 6H).

(207) Step 2

(208) The reaction referred to Step 2 of Example 25, the residue was compound 26-3 (1.00 g, white solid); yield: 89%. MS-ESI [M+H].sup.+: calculated value: 215; measured value: 215.

(209) .sup.1H NMR: (400 MHz, Methanol-d.sub.4) δ 7.99 (s, 1H), 7.93 (d, J=8.8 Hz, 1H), 7.15 (d, J=8.8 Hz, 1H), 4.83-4.76 (m, 1H), 1.39 (d, J=6.0 Hz, 6H).

(210) Step 3

(211) The reaction referred to Step 3 of Example 25, and the residue was isolated and purified by high performance liquid chromatography to give compound 26-4 (30.0 mg); yield: 25%.

(212) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) δ 8.22-8.20 (m, 2H), 8.16 (d, J=8.8 Hz, 1H), 7.77 (d, J=7.6 Hz, 1H), 7.50 (d, J=7.6 Hz, 1H), 7.32 (d, J=8.8 Hz, 1H), 5.27 (d, J=7.2 Hz, 1H), 4.86-4.84 (m, 1H), 3.81-3.71 (m, 4H), 3.36-3.35 (m, 1H), 3.24-3.22 (m, 1H), 3.16-3.15 (m, 1H), 2.92-2.86 (m, 1H), 2.49-2.45 (m, 1H), 1.44 (d, J=6.0 Hz, 6H). MS-ESI [M+H].sup.+: calculated value: 454; measured value: 454.

Example 27

(213) ##STR00134## ##STR00135##

(214) Step 1

(215) Compound 27-1 (3.00 g, 15.1 mmol), 2-bromopropane (3.70 g, 30.3 mmol), potassium carbonate (6.30 g, 45.4 mmol) were dissolved in N,N-dimethylformamide (10 mL). The mixture was heated to 80° C. and stirred for 15 hours. The mixture was filtered after cooled to the room temperature, the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane (30 mL) and washed with water (20 mL). The aqueous layer was extracted with dichloromethane (30 mL×3), the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (4:1 petroleum ether/ethyl acetate, R.sub.f=0.6) to give compound 27-2 (3.40 g, white solid); yield: 93%.

(216) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.57 (d, J=2.4 Hz, 1H), 7.52 (d, J=2.4, 9.2 Hz, 1H), 6.78 (d, J=9.2 Hz, 1H), 4.58-4.52 (m, 1H), 1.33 (d, J=6.4 Hz, 6H).

(217) Step 2

(218) Compound 27-2 (2.00 g, 8.30 mmol) was dissolved in anhydrous toluene (20 mL), and diisobutylaluminum hydride (1 M in toluene, 9.16 mL) was added at −78° C. The reaction was stirred at this temperature for 2 hours. The mixture was quenched with saturated aqueous ammonia chloride solution (10 mL). Sodium potassium tartrate solution (10 mL) was added and the mixture was stirred for 12 hours. The aqueous layer was extracted with ethyl acetate (30 mL×3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (20:1-10:1 petroleum ether/ethyl acetate, R.sub.f=0.3) to give compound 27-3 (1.60 g, colorless oil); yield: 79%.

(219) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 10.39 (s, 1H), 7.92 (d, J=2.8 Hz, 1H), 7.62-7.57 (d, J=2.8, 8.8 Hz, 1H), 6.89 (d, J=8.8 Hz, 1H), 4.68-4.62 (m, 1H), 1.40 (d, J=6.0 Hz, 6H).

(220) Step 3

(221) Compound 27-3 (1.30 g, 5.30 mmol) was dissolved in anhydrous dichloromethane (30 mL), and diethylamine sulfur trifluoride (5.10 g, 32.1 mmol) was added dropwise. The reaction was stirred at 20° C. for 15 hours. The mixture was quenched with water (20 mL) and stirred for 5 minutes. The aqueous layer was extracted with dichloromethane (20 mL×3). The organic layer was combined and dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (1:0 petroleum ether/ethyl acetate, R.sub.f=0.6) to give compound 27-4 (1.00 g, colorless oil); yield: 70%.

(222) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.59 (d, J=2.8 Hz, 1H), 7.41 (d, J=2.8, 9.2 Hz, 1H), 6.81 (t, J=55.2 Hz, 1H), 6.74 (d, J=9.2 Hz, 1H), 4.54-4.44 (m, 1H), 1.27 (d, J=6.0 Hz, 6H).

(223) Step 4

(224) Compound 27-4 (1.00 g, 3.70 mmol), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (275 mg, 0.370 mmol) were dissolved in N,N-dimethylformamide (6 mL), methanol (6 mL), triethylamine (6 mL). The solution was charged with argon three times and heated to 80° C., stirred at this temperature for 15 hours under carbon monoxide atmosphere (50 psi). The solution was cooled to the room temperature and concentrated under reduced pressure. The residue was dissolved in dichloromethane (20 mL) and washed with water (10 mL). The aqueous layer was extracted with dichloromethane (20 mL×3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (1:0-0:1 petroleum ether/ethyl acetate, R.sub.f=0.1) to give compound 27-5 (120 mg, colorless oil); yield: 13%.

(225) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.27 (s, 1H), 8.12 (d, J=8.8 Hz, 1H), 6.98 (d, J=8.8 Hz, 1H), 6.94 (t, J=55.2 Hz, 1H), 4.77-4.67 (m, 1H), 1.41 (d, J=6.0 Hz, 6H).

(226) Step 5

(227) Compound 27-5 (100 mg, 0.410 mmol) was dissolved in methanol (2 mL) and water (2 mL), and potassium hydroxide (46.0 mg, 0.820 mmol) was added. The reaction was stirred at 20° C. for 15 hours. The solution was concentrated with reduced pressure to remove methanol. The aqueous layer was acidified with diluted hydrochloric acid to pH=7, extracted with dichloromethane (10 mL×3). The organic layer were combined and dried over anhydrous sodium sulfate, filtered, concentrated. The residue was purified by silica gel column chromatography (3:1 petroleum ether/ethyl acetate, R.sub.f=0.1) to give compound 27-6 (90 mg, white solid); yield: 95%.

(228) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.26 (s, 1H), 8.10 (d, J=8.8 Hz, 1H), 6.91 (d, J=8.8 Hz, 1H), 6.86 (t, J=55.2 Hz, 1H), 4.69-4.62 (m, 1H), 1.33 (d, J=6.0 Hz, 6H).

(229) Step 6

(230) Compound 27-6 (90.0 mg, 0.391 mmol), 1-hydroxybenzotriazole (106 mg, 0.782 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (150 mg, 0.782 mmol) were dissolved in anhydrous N,N-dimethylformamide (4 mL). The solution was charged with nitrogen three times. After the mixture was stirred for 1 hour at 20° C., a solution of Compound 27-7 (152 mg, 0.391 mmol) in anhydrous N, N-dimethylformamide (2 mL) was added. After stirred for another 1 hour, the mixture was heated to 90° C. stirred for another 13 hours. The solution was concentrated under reduced pressure. The residue was dissolved in dichloromethane (20 mL) and washed with water (10 mL). The aqueous layer was extracted with dichloromethane (20 mL×3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by high performance liquid chromatography to give compound 27-8 (27.0 mg); yield: 15%.

(231) .sup.1H NMR (400 MHz, Methonal-d.sub.4) δ 8.38-8.30 (m, 2H), 8.20 (d, J=8.0 Hz, 1H), 7.77 (d, J=7.6 Hz, 1H), 7.50 (t, J=7.6 Hz, 1H), 7.36 (d, J=8.0 Hz, 1H), 7.04 (t, J=55.2 Hz, 1H), 5.27 (d, J=7.2 Hz, 1H), 4.89-4.93 (m, 2H), 3.83 (d, J=9.2, 18.0 Hz, 1H), 3.67-3.77 (m, 3H), 3.14-3.16 (m, 1H), 3.12 (dd, J=6.8, 18.0 Hz, 1H), 2.89 (dd, J=9.2, 17.6 Hz, 1H), 2.46 (dd, J=2.0, 17.0 Hz, 1H), 1.44 (d, J=6.0 Hz, 6H). MS-ESI [M+H].sup.+: calculated value: 470; measured value: 470.

Example 28

(232) ##STR00136##

(233) Step 1

(234) Compound 28-1 (500 mg, 3.01 mmol) was dissolved in tetrahydrofuran (13 mL), and cesium carbonate (2.94 g, 9.03 mmol) and potassium iodide (50.0 mg, 0.301 mmol) and 2-chloro-N,N-dimethylethylamine hydrochloride (650 mg, 4.51 mmol) were added at 20° C. under nitrogen atmosphere. The reaction was stirred at 80° C. for 12 hours. The mixture was added with saturated aqueous sodium chloride solution (50 mL) and extracted with ethyl acetate (70 mL×3). The organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (1:1 petroleum ether/ethyl acetate, R.sub.f=0.3) to give compound 28-2 (538 mg, white solid) yield: 73%.

(235) .sup.1H NMR: (400 MHz, CDCl.sub.3) δ 8.00 (d, J=8.8 Hz, 2H), 6.94 (d, J=8.8 Hz, 2H), 4.35 (q, J=6.8 Hz, 2H), 4.13 (t, J=5.6 Hz, 2H), 2.76 (t, J=5.6 Hz, 2H), 1.66 (s, 6H), 1.35 (t, J=6.8 Hz, 3H).

(236) Step 2

(237) Compound 28-2 (538 mg, 2.27 mmol) and lithium hydroxide monohydrate (143 mg, 3.40 mmol were dissolved in methanol (11 mL) and water (3.5 mL), and the mixture was stirred at 40° C. for 12 hours under nitrogen atmosphere. The mixture was added with 1M hydrochloric acid (3.7 mL), concentrated to gain solid. Then, a mixture of 30 mL/30 mL chloroform and methanol was added. The mixture was stirred for 0.5 hour and filtered. The filtrate was concentrated by a rotary evaporator and dried in vacuum to obtain compound 28-3 (500 mg, pale yellow solid), yield: 84%.

(238) .sup.1H NMR: (400 MHz, DMSO-d.sub.6) δ 10.78 (brs, 1H), 7.91 (d, J=8.8 Hz, 2H), 7.08 (d, J=8.8 Hz, 2H), 4.44 (t, J=4.8 Hz, 2H), 3.51 (t, J=4.8 Hz, 2H), 2.82 (s, 6H). MS-ESI [M+H].sup.+: calculated value: 210; measured value: 210.

(239) Step 3

(240) The reaction referred to Step 3 of Example 25, and the residue was isolated and purified by high performance liquid chromatography to give compound 26-4 (5.0 mg); yield: 7%.

(241) .sup.1H NMR: (400 MHz, CDCl.sub.3) δ 8.22-8.18 (m, 3H), 7.57 (d, J=7.6 Hz, 1H), 7.43 (t, J=7.6 Hz, 1H), 7.10 (d, J=7.6 Hz, 2H), 5.10 (d, J=7.2 Hz, 1H), 4.68-4.64 (m, 2H), 3.86-3.69 (m, 4H), 3.55-3.51 (m, 2H), 3.44-3.30 (m, 2H), 3.24-3.18 (m, 2H), 2.98 (s, 6H), 2.91-2.84 (m, 1H), 2.55-2.51 (m, 1H). MS-ESI [M+H].sup.+: calculated value: 449; measured value: 449.

Example 29

(242) ##STR00137##

(243) Step 1

(244) Compound 29-2 (21.7 mg, 0.154 mmol) was dissolved in N,N-dimethylformamide (2 mL), and 1-hydroxybenzotriazole (34.7 mg, 0.257 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (49.2 mg, 0.257 mmol) were added. The reaction was stirred at 25° C. for 0.5 hour under nitrogen atmosphere. Then Compound 29-1 (50.0 mg, 0.128 mmol) was added to the reaction mixture, and the mixture was stirred at 25° C. for 1 hour, heated to 80° C. and stirred for 12 hours. Water (10 mL) was added to the reaction mixture after the mixture was cooled to room temperature and the mixture was extracted with ethyl acetate (10 mL×3). The organic layers were combined and washed with saturated brine (10 mL×2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography to give compound 29-3 (30.0 mg); yield: 61%.

(245) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) δ 8.18 (d, J=7.6 Hz, 1H), 7.79 (d, J=7.6 Hz, 1H), 7.50 (t, J=7.6 Hz, 1H), 5.28 (d, J=7.2 Hz, 1H), 3.82-3.71 (m, 4H), 3.24-3.20 (m, 2H), 3.14-3.10 (m, 1H), 2.93-2.87 (m, 1H), 2.61 (s, 6H), 2.48-2.44 (m, 1H). MS-ESI [M+H].sup.+: calculated value: 381; measured value: 381.

Example 30

(246) ##STR00138##

(247) Step 1

(248) The reaction referred to Step 1 of Example 29, and the residue was isolated and purified by high performance liquid chromatography to give compound 30-2 (30.0 mg); yield: 57%.

(249) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) δ 8.19 (d, J=7.6 Hz, 1H), 7.82 (d, J=7.6 Hz, 1H), 7.52 (t, J=7.6 Hz, 1H), 5.28 (d, J=7.2 Hz, 1H), 3.82-3.72 (m, 4H), 3.60-3.56 (m, 2H), 3.32-3.28 (m, 2H), 3.17-3.15 (m, 1H), 2.93-2.87 (m, 1H), 2.48-2.43 (m, 1H), 2.04-1.99 (m, 2H), 1.14-1.10 (m, 3H). MS-ESI [M+H].sup.+: calculated value: 412; measured value: 412.

Example 31

(250) ##STR00139##

(251) Step 1

(252) The reaction referred to Step 1 of Example 29, and the residue was isolated and purified by high performance liquid chromatography to give compound 31-2 (30.0 mg); yield: 56%.

(253) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) δ 8.66 (d, J=7.2 Hz, 1H), 8.20 (d, J=7.2 Hz, 1H), 7.91-7.79 (m, 3H), 7.52-7.48 (m, 2H), 5.28 (d, J=7.2 Hz, 1H), 3.85-3.73 (m, 4H), 3.35-3.34 (m, 1H), 3.25-3.22 (m, 1H), 3.16-3.13 (m, 1H), 2.95-2.88 (m, 1H), 2.46-2.44 (m, 1H). MS-ESI [M+H].sup.+: calculated value: 420; measured value: 420.

Example 32

(254) ##STR00140##

(255) Step 1

(256) The reaction referred to Step 1 of Example 29, and the residue was isolated and purified by high performance liquid chromatography to give compound 32-2 (20.0 mg); yield: 35%.

(257) .sup.1H NMR: (400 MHz, DMSO-d.sub.6) δ 8.94 (s, 1H), 8.14-8.08 (m, 3H), 7.82 (d, J=7.6 Hz, 1H), 7.60-7.57 (m, 3H), 7.54 (d, J=7.6 Hz, 1H), 5.18 (d, J=7.2 Hz, 1H), 4.88-4.87 (m, 1H), 3.72-3.67 (m, 1H), 3.58-3.55 (m, 3H), 3.27-3.25 (m, 1H), 3.06-3.00 (m, 2H), 2.72-2.70 (m, 1H), 2.34-2.30 (m, 1H). MS-ESI [M+H].sup.+: calculated value: 445; measured value: 445.

Example 33

(258) ##STR00141##

(259) Step 1

(260) The reaction referred to Step 1 of Example 29, and the residue was isolated and purified by high performance liquid chromatography to give compound 33-2 (30.0 mg); yield: 53%.

(261) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) δ 8.18 (d, =7.6 Hz, 1H), 7.81 (d, J=7.6 Hz, 1H), 7.50 (t, J=7.6 Hz, 1H), 5.28 (d, J=7.2 Hz, 1H), 4.67-4.65 (m, 1H), 3.83-3.80 (m, 1H), 3.78-3.72 (m, 5H), 3.40-3.38 (m, 4H), 3.25-3.15 (m, 5H), 2.93-2.89 (m, 1H), 2.48-2.44 (m, 1H). MS-ESI [M+H].sup.+: calculated value: 438; measured value: 438.

Example 34

(262) ##STR00142##

(263) Step 1

(264) The reaction referred to Step 1 of Example 29, and the residue was isolated and purified by high performance liquid chromatography to give compound 34-2 (25.0 mg); yield: 47%.

(265) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) δ 8.54 (s, 1H), 8.16 (d, J=7.6 Hz, 1H), 7.79 (d, J=7.6 Hz, 1H), 7.50 (t, J=7.6 Hz, 1H), 5.26 (d, J=7.2 Hz, 1H), 3.82-3.71 (m, 4H), 3.46-3.45 (m, 1H), 3.24-3.22 (m, 2H), 3.14-3.11 (m, 1H), 2.92-2.85 (m, 1H), 2.48-2.43 (m, 1H), 1.49 (d, J=6.0 Hz, 6H). MS-ESI [M+H].sup.+: calculated value: 411; measured value: 411.

Example 35

(266) ##STR00143## ##STR00144##

(267) Step 1

(268) The reaction referred to Step 1 of Example 29, and the residue was isolated and purified by high performance liquid chromatography to obtain compound 35-2 and compound 35-3.

(269) Compound 35-2 (25.0 mg); yield: 48%.

(270) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) δ 9.33 (d, J=7.2 Hz, 1H), 9.17 (d, J=7.2 Hz, 1H), 9.12 (s, 1H), 8.26 (d, J=7.6 Hz, 1H), 7.84 (d, J=7.6 Hz, 1H), 7.72 (t, J=7.2 Hz, 1H), 7.55 (t, J=8.0 Hz, 1H), 5.30 (d, J=7.2 Hz), 1H), 3.86-3.73 (m, 4H), 3.37-3.36 (m, 1H), 3.24-3.14 (m, 2H), 2.95-2.89 (m, 1H), 2.49-2.45 (m, 1H). MS-ESI [M+H].sup.+: calculated value: 403; measured value: 403.

(271) Compound 35-3 (20.0 mg); yield: 38%.

(272) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) δ 10.20 (d, J=7.2 Hz, 1H), 9.36 (s, 1H), 9.30 (d, J=7.2 Hz, 1H), 8.37 (d, J=7.6 Hz, 1H), 7.99 (d, J=7.6 Hz, 1H), 7.86 (t, J=8.0 Hz, 1H), 7.56 (t, J=8.0 Hz, 1H), 5.31 (d, J=7.2 Hz), 1H), 3.88-3.84 (m, 1H), 3.77-3.73 (m, 3H), 3.38-3.37 (m, 1H), 3.27-3.21 (m, 2H), 2.95-2.89 (m, 1H), 2.51-2.47 (m, 1H). MS-ESI [M+H].sup.+: calculated value: 403; measured value: 403.

Example 36

(273) ##STR00145##

(274) Step 1

(275) The reaction referred to Step 1 of Example 29, and the residue was isolated and purified by high performance liquid chromatography to give compound 36-2 (20.0 mg); yield: 38%.

(276) .sup.1H NMR: (400 MHz, DMSO-d.sub.6) δ 8.11 (s, 1H), 8.05 (d, J=7.6 Hz, 1H), 7.77 (d, J=7.6 Hz, 1H), 7.50 (t, J=7.6 Hz, 1H), 5.15 (d, J=7.2 Hz, 1H), 4.85 (s, 1H), 4.08-4.07 (m, 2H), 3.65-3.50 (m, 4H), 3.22-3.21 (m, 1H), 3.01-2.96 (m, 2H), 3.84-3.82 (m, 2H), 2.69-2.67 (m, 1H), 2.31-2.27 (m, 1H), 1.93-1.90 (m, 4H). MS-ESI [M+H].sup.+: calculated value: 406; measured value: 406.

Example 37

(277) ##STR00146##

(278) Step 1

(279) The reaction referred to Step 1 of Example 29, and the residue was isolated and purified by high performance liquid chromatography to give compound 37-2 (30.0 mg); yield: 54%.

(280) .sup.1H NMR: (400 MHz, DMSO-d.sub.6) δ 8.20-8.19 (m, 2H), 8.10 (d, J=7.6 Hz, 1H), 7.95 (s, 1H), 7.83 (d, J=7.6 Hz, 1H), 7.55 (t, J=7.6 Hz, 1H), 5.17 (d, J=7.2 Hz, 1H), 3.72-3.58 (m, 4H), 3.26-3.24 (m, 1H), 3.06-3.00 (m, 2H), 2.70-2.68 (m, 1H), 2.34-2.30 (m, 1H). MS-ESI [M+H].sup.+: calculated value: 436; measured value: 436.

Example 38

(281) ##STR00147##

(282) Step 1

(283) The reaction referred to Step 1 of Example 29, and the residue was isolated and purified by high performance liquid chromatography to give compound 38-2 (20.0 mg); yield: 35%.

(284) .sup.1H NMR: (400 MHz, DMSO-d.sub.6) δ 9.32 (s, 1H), 8.08 (d, J=7.6 Hz, 1H), 7.80 (d, J=7.6 Hz, 1H), 7.52 (t, J=7.6 Hz, 1H), 7.42-7.38 (m, 5H), 5.78 (s, 2H), 5.16 (d, J=7.2 Hz, 1H), 3.67-3.51 (m, 3H), 3.20-3.18 (m, 2H), 3.02-2.97 (m, 2H), 2.69-2.67 (m, 1H), 2.32-2.31 (m, 1H). MS-ESI [M+H].sup.+: calculated value: 443; measured value: 443.

Example 39

(285) ##STR00148##

(286) Step 1

(287) Compound 39-1 (300 mg, 1.81 mmol) was dissolved in tetrahydrofuran (5 mL), and cesium carbonate (1.77 g, 5.43 mmol) and potassium iodide (30.1 mg, 0.181 mmol) and 2-bromopropane (668 mg, 5.43 mmol) were added at 20° C. under nitrogen atmosphere. The reaction was stirred at 80° C. for 12 hours. Then, the mixture was added with saturated aqueous sodium chloride solution (50 mL), and extracted with ethyl acetate (70 mL×3). The organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated with reduced pressure. The residue was purified by silica gel column chromatography (1:1 petroleum ether/ethyl acetate, R.sub.f=0.5) to give compound 39-2 (166 mg, white solid); yield: 44%.

(288) .sup.1H NMR: (400 MHz, CDCl.sub.3) δ 7.98 (d, J=8.8 Hz, 2H), 6.89 (d, J=8.8 Hz, 2H), 4.67-4.61 (m, 1H), 4.38-4.32 (q, J=7.2 Hz, 2H), 1.40-1.36 (m, 9H).

(289) Step 2

(290) Compound 39-2 (166 mg, 0.797 mmol), lithium hydroxide monohydrate (50.2 mg, 1.20 mmol) were dissolved in methanol (3 mL) and water (1 mL). The mixture was stirred at 40° C. for 12 hours under nitrogen atmosphere. The mixture was added with 1M hydrochloric acid (1.2 mL). The mixture was concentrated under reduced pressure to gain solid. Then, a mixture of 20 mL/20 mL chloroform and methanol was added. The mixture was stirred for 0.5 hour and filtered. The filtrate was concentrated by a rotary evaporator and dried in vacuum to obtain compound 39-3 (144 mg, pale yellow solid) yield: 70%.

(291) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) δ 7.95 (d, J=8.8 Hz, 2H), 6.95 (d, J=8.8 Hz, 2H), 4.74-4.66 (m, 1H), 1.35-1.29 (d, J=6.0 Hz, 6H).

(292) Step 3

(293) The reaction referred to Step 1 of Example 29, and the residue was isolated and purified by high performance liquid chromatography to give compound 39-3 (10.0 mg); yield: 15%.

(294) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) δ 8.19-8.14 (m, 3H), 7.77 (d, J=7.6 Hz, 1H), 7.48 (t, J=7.6 Hz, 1H), 7.11 (d, J=8.0 Hz, 2H), 5.25 (d, J=7.2 Hz, 1H), 4.81-4.76 (m, 2H), 3.82-3.69 (m, 4H), 3.22-3.09 (m, 2H), 2.91-2.84 (m, 1H), 2.47-2.42 (m, 1H), 1.38-1.37 (m, 6H). MS-ESI [M+H].sup.+: calculated value: 420; measured value: 420.

Example 40

(295) ##STR00149##

(296) Step 1

(297) Compound 40-1 (10.0 g, 54.9 mmol), 2-bromopropane (6.75 g, 54.9 mmol), potassium carbonate (7.59 g, 54.9 mmol) were dissolved in N,N-dimethylformamide (200 mL) at 0° C. and the mixture was stirred for 2 hours, then heated to 20° C. and further stirred for 13 hours. The solution was filtered and the filtrated was concentrated under reduced pressure. The residue was dissolved in dichloromethane (50 mL) and washed with water (30 mL). The aqueous layer was extracted with dichloromethane (50 mL×3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (10:1-3:1 petroleum ether/ethyl acetate, R.sub.f=0.7) to give compound 40-2 (5.20 g, colorless oil); yield: 42%.

(298) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.59-7.63 (m, 2H), 6.88 (d, J=8.0 Hz, 1H), 5.74 (s, 1H), 4.75-4.66 (m, 1H), 4.36 (q), J=7.2 Hz, 2H), 1.42 (d, J=6.0 Hz, 6H), 1.39 (t, J=7.2 Hz, 3H).

(299) Step 2

(300) Compound 40-2 (300 mg, 1.34 mmol) was dissolved in anhydrous N,N-dimethylformamide (3 mL). Sodium hydride (107 mg, 2.68 mmol, purity: 60%) was added slowly at 20° C. and the mixture was stirred for 30 minutes. Difluoromonochloromethane (gas) was introduced into the reaction solution slowly and the mixture was stirred for 30 minutes. The mixture was quenched with water (5 mL) and diluted with dichloromethane (10 mL). The aqueous layer was extracted with dichloromethane (10 mL×3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (10:1-5:1 petroleum ether/ethyl acetate, R.sub.f=0.5) to give compound 40-3 (180 mg, colorless oil); yield: 49%.

(301) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.91 (dd, J=2.0, 8.8 Hz, 1H), 7.85 (d, J=2.0 Hz, 1H), 7.00 (d, J=8.8 Hz, 1H), 6.58 (t, J=74.8 Hz, 1H), 4.73-4.64 (m, 1H), 4.37 (q, J=7.2 Hz, 2H), 1.42 (d, J=6.0 Hz, 6H), 1.40 (t, J=7.2) Hz, 3H).

(302) Step 3

(303) Compound 40-3 (180 mg, 0.656 mmol) was dissolved in tetrahydrofuran (2 mL) and water (2 mL), and lithium hydroxide (31.4 mg, 1.31 mmol) was added to the mixture. The reaction was stirred at 20° C. for 15 hours. The solution was concentrated under reduced pressure to remove tetrahydrofuran. The aqueous layer was acidified with diluted hydrochloric acid to pH=7, then extracted with dichloromethane (10 mL×3). The organic layers were combined and dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by TLC (10:1 dichloromethane/methanol, R.sub.f=0.05) to give compound 40-4 (160 mg, white solid); yield: 99%.

(304) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.89 (dd, J=2.0, 8.4 Hz, 1H), 7.83 (d, J=2.0 Hz, 1H), 6.94 (d, J=8.4 Hz, 1H), 6.50 (t, J=74.8 Hz, 1H), 4.69-4.56 (m, 1H), 1.34 (d, J=6.0 Hz, 6H).

(305) Step 4

(306) The reaction referred to Step 1 of Example 29, and the residue was isolated and purified by high performance liquid chromatography to give compound 40-5 (18.0 mg); yield: 18%.

(307) .sup.1H NMR (400 MHz, Methonal-d.sub.4) δ 8.21 (d, J=7.6 Hz, 1H), 8.11 (dd, J=2.0, 8.8 Hz, 1H), 7.98 (d, J=2.0 Hz, 1H), 7.78 (d, J=7.6 Hz, 1H), 7.50 (t, J=7.6 Hz, 1H), 7.37 (d, J=8.8 Hz, 1H), 6.86 (t, J=74.8 Hz, 1H), 5.27 (d, J=7.6 Hz, 1H), 4.62 (s, 2H), 3.86-3.79 (m, 1H), 3.78-3.71 (m, 3H), 3.29-3.21 (m, 1H), 3.16-3.09 (m, 1H), 2.93-2.85 (m, 1H), 2.46 (d, J=15.6 Hz, 1H), 1.44 (d, J=6.0 Hz, 6H). MS-ESI [M+H].sup.+: calculated value: 486; measured value: 486.

Example 41

(308) ##STR00150##

(309) Step 1

(310) Compound 41-1 (200 mg, 0.892 mmol), Compound 41-2 (192 mg, 1.78 mmol), cesium carbonate (581 mg, 1.78 mmol) and potassium iodide (13.4 mg, 0.0892 mmol) were dissolved in tetrahydrofuran (4 mL). The mixture was heated to 70° C. and stirred for 15 hours. The mixture was filtered and the filtrate was concentrated with reduced pressure. The residue was dissolved in dichloromethane (10 mL) and washed with water (10 mL). The aqueous layer was extracted with dichloromethane (10 mL×3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (10:1-0:1 petroleum ether/ethyl acetate, R.sub.f=0.05) to give compound 41-3 (170 mg, white solid); yield: 65%.

(311) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.67 (dd, J=2.0, 8.8 Hz, 1H), 7.59 (d, J=2.0 Hz, 1H), 6.91 (d, J=8.8 Hz, 1H), 4.58-4.69 (m, 1H), 4.36 (q, J=7.2 Hz, 2H), 4.16 (t, J=6.0 Hz, 2H), 2.81 (t, J=6.0 Hz, 2H), 2.38 (s, 6H), 1.36-1.43 (m, 9H). MS-ESI [M+H].sup.+: calculated value: 296; measured value: 296.

(312) Step 2

(313) Compound 41-3 (170 mg, 0.576 mmol) was dissolved in tetrahydrofuran (2 mL) and water (2 mL), and lithium hydroxide (48.3 mg, 1.15 mmol) was added. The reaction was stirred at 20° C. for 15 hours. The solution was concentrated under reduced pressure to remove tetrahydrofuran. The aqueous layer was acidified with diluted hydrochloric acid to pH=7, extracted with dichloromethane (10 mL×3). The organic layers were combined and dried with anhydrous sodium sulfate, filtered and concentrated. The residue was purified by TLC (10:1 dichloromethane/methanol, R.sub.f=0.03) to give compound 41-4 (120 mg, white solid); yield: 62%.

(314) .sup.1H NMR (400 MHz, Methonal-d.sub.4) δ 7.69 (dd, J=2.0, 8.8 Hz, 1H), 7.64 (d, J=2.0 Hz, 1H), 7.04 (d, J=8.8 Hz, 1H), 4.68-4.78 (m, 1H), 4.36 (d, J=4.8 Hz, 2H), 3.53 (d, J=4.8 Hz, 2H), 3.00 (s, 6H), 1.38 (d, J=6.0 Hz, 6H). MS-ESI [M+H].sup.+: calculated value: 268; measured value: 268.

(315) Step 3

(316) The reaction referred to Step 1 of Example 29, and the residue was isolated and purified by high performance liquid chromatography to give compound 41-5 (1.5 mg); yield: 1%.

(317) .sup.1H NMR (400 MHz, Methonal-d.sub.4) δ 8.19 (d, J=7.6 Hz, 1H), 7.97 (dd, J=2.0, 8.4 Hz, 1H), 7.90 (d, J=2.0 Hz, 1H), 7.79 (d, J=7.6 Hz, 1H), 7.51 (t, J=7.6 Hz, 1H), 7.30 (d, J=8.4 Hz, 1H), 5.28 (d, J=7.2 Hz, 1H), 4.47-4.52 (m, 2H), 3.79-3.85 (m, 1H), 3.66-3.77 (m, 5H), 3.21-3.27 (m, 1H), 3.11-3.15 (m, 1H), 3.11 (s, 6H), 2.85-2.93 (m, 1H), 2.48-2.42 (m, 1H), 1.96 (s, 2H), 1.44 (d, J=6.0 Hz, 6H). MS-ESI [M+H].sup.+: calculated value: 507; measured value: 507.

Example 42

(318) ##STR00151##

(319) Step 1

(320) Compound 42-1 (500 mg, 2.08 mmol) was dissolved in a mixture of methanol (9 mL), N,N-dimethylformamide (3 mL) and triethylamine (3 mL) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (152 mg, 0.208 mmol) was added. The reaction solution was stirred at 80° C. for 12 hours under carbon monoxide atmosphere (50 psi). Water (30 mL) was added to the reaction mixture after the mixture was cooled to the room temperature, and the mixture was extracted with ethyl acetate (30 mL×3). The organic layers were combined and washed with saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10:1 petroleum ether/ethyl acetate, R.sub.f=0.5) to give compound 42-2 (400 mg, white solid); yield: 88%. MS-ESI [M+H].sup.+: calculated value: 220; measured value: 220.

(321) .sup.1H NMR: (400 MHz, Methanol-d.sub.4) δ 8.10 (dJ=7.2 Hz, 1H), 7.38 (s, 1H), 7.27 (d, J=7.2 Hz, 1H), 4.82-4.76 (m, 1H), 3.95 (s, 3H), 1.38 (d, J=6.0 Hz, 6H).

(322) Step 2

(323) The reaction referred to Step 2 of Example 25, the residue was compound 42-3 (350 mg, white solid); yield: 94%.

(324) .sup.1H NMR: (400 MHz, Methanol-d.sub.4) δ 8.10 (d, J=7.2 Hz, 1H), 7.37 (s, 1H), 7.27 (d, J=7.2 Hz, 1H), 4.82-4.76 (m, 1H), 1.38 (d, J=6.0 Hz, 6H). MS-ESI [M+H].sup.+: calculated value: 206; measured value: 206.

(325) Step 3

(326) The reaction referred to Step 3 of Example 25, and the residue was isolated and purified by high performance liquid chromatography to give compound 42-4 (30.0 mg); yield: 26%.

(327) .sup.1H NMR: (400 MHz, DMSO-d.sub.6) δ 8.29 (d, J=7.2 Hz, 1H), 8.09 (d, J=7.6 Hz, 1H), 7.81 (d, J=7.6 Hz, 1H), 7.71 (d, J=7.2 Hz, 1H), 7.55-7.49 (m, 2H), 5.17 (d, J=7.2 Hz, 1H), 4.92-4.86 (m, 2H), 3.71-3.70 (m, 1H), 3.59-3.52 (m, 3H), 3.24-3.22 (m, 1H), 3.06-3.01 (m, 2H), 2.71-2.68 (m, 1H), 2.31-2.29 (m, 1H), 1.34 (d, J=6.0 Hz, 6H). MS-ESI [M+H].sup.+: calculated value: 445; measured value: 445.

Example 43

(328) ##STR00152##

(329) Step 1

(330) Compound 43-1 (800 mg, 2.93 mmol) was dissolved in dimethyl sulfoxide (10 mL), and sodium methylsulfinate (897 mg, 8.79 mmol), cuprous iodide (112 mg, 0.586 mmol), L-valine (135 mg, 1.17 mmol) and sodium hydroxide (46.9 mg, 1.17 mmol) were added. The reaction solution was stirred at 100° C. for 18 hours under nitrogen atmosphere. Water (30 mL) was added to the reaction mixture after the mixture was cooled to the room temperature, and the mixture was extracted with ethyl acetate (30 mL×3). The organic layers were combined and washed with saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated with reduced pressure. The residue was purified by silica gel column chromatography (3:1 petroleum ether/ethyl acetate, R.sub.f=0.2) to give compound 43-2 (80.0 mg, white solid); yield: 10%.

(331) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) δ 8.54 (s, 1H), 8.30 (d, J=8.8 Hz, 1H), 7.37 (d, J=8.8 Hz, 1H), 5.03-4.99 (m, 1H), 3.93 (s, 3H), 3.28 (s, 3H), 1.47 (d, J=6.0 Hz, 6H). MS-ESI [M+H].sup.+: calculated value: 273; measured value: 273.

(332) Step 2

(333) The reaction referred to Step 2 of Example 39, the residue was compound 43-3 (70.0 mg, white solid); yield: 92%.

(334) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) δ 8.55 (s, 1H), 8.30 (d, J=8.8 Hz, 1H), 7.36 (d, J=8.8 Hz, 1H), 5.01-4.98 (m, 1H), 3.28 (s, 3H), 1.47 (d, J=6.0 Hz, 6H). MS-ESI [M+H].sup.+: calculated value: 259; measured value: 259.

(335) Step 3

(336) The reaction referred to Step 1 of Example 29, and the residue was isolated and purified by high performance liquid chromatography to give compound 43-4 (25.0 mg); yield: 33%.

(337) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) δ 8.71 (s, 1H), 8.48 (d, J=7.6 Hz, 1H), 8.21 (d, J=7.6 Hz, 1H), 7.78 (d, J=7.6 Hz, 1H), 7.54-7.48 (m, 2H), 5.27 (d, J=7.2 Hz, 1H), 5.09-5.03 (m, 1H), 3.82-3.79 (m, 1H), 3.76-3.72 (m, 3H), 3.34 (s, 3H), 3.24-3.22 (m, 2H), 3.15-3.11 (m, 1H), 2.93-2.87 (m, 1H), 2.49-2.45 (m, 1H), 1.51 (d, J=6.0 Hz, 6H). MS-ESI [M+H].sup.+: calculated value: 498; measured value: 498.

Example 44

(338) ##STR00153## ##STR00154##

(339) Step 1

(340) Sodium (122 mg, 5.33 mmol) was dissolved in methanol (8 mL), and Compound 44-1 (1.00 g, 4.85 mmol) was added. The reaction solution was stirred at 65° C. with 1 hour under nitrogen atmosphere. Saturated aqueous ammonium chloride solution (10 mL) was added to the reaction mixture after the mixture was cooled to 25° C., and the mixture was extracted with ethyl acetate (30 mL×2). The organic layers were combined and washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subject to silica gel column chromatography (petroleum ether, R.sub.f=0.6) to give compound 44-2 (620 mg, white solid); yield: 63%.

(341) .sup.1H NMR: (400 MHz, CDCl.sub.3) δ 7.45 (s, 1H), 7.23 (s, 1H), 3.98 (s, 3H), 3.95 (s, 3H).

(342) Step 2

(343) Compound 44-2 (420 mg, 2.08 mmol) was dissolved in toluene (15 mL), and cyclopentylboronic acid (308 mg, 2.70 mmol), tricyclohexylphosphine (233 mg, 0.832 mmol), potassium phosphate (1.32 g, 6.24 mmol), palladium acetate (93.4 mg, 0.416 mmol) and water (2 mL) were added. The reaction solution was stirred at 100° C. for 12 hours under nitrogen atmosphere. Ethyl acetate (50 mL) was added to the reaction mixture after the mixture was cooled to 25° C. and the mixture was washed with water (20 mL×2) and saturated brine (20 mL×2), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subject to silica gel chromatography (100:1 petroleum ether/acetone, R.sub.f=0.3) to give compound 50-3 (50 mg, colorless oil); yield: 10%.

(344) .sup.1H NMR: (400 MHz, CDCl.sub.3) δ 7.28 (s, 1H), 7.09 (s, 1H), 3.95 (s, 3H), 3.92 (s, 3H), 3.21-3.10 (m, 1H), 2.10-1.97 (m, 2H), 1.89-1.67 (m, 6H).

(345) Step 3

(346) Compound 44-3 (50.0 mg, 0.212 mmol) was dissolved in methanol (3 mL), and lithium hydroxide (35.6 mg, 0.85 mmol) and water (0.5 mL) were added. The reaction solution was stirred at 40° C. for 2 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (30 mL). The solution was acidified with 1 M hydrochloric acid to pH=3. The organic layer was washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, concentrated to give Compound 44-4 (46 mg, white solid).

(347) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) δ 7.28 (s, 1H), 7.04 (s, 1H), 3.92 (s, 3H), 3.21-3.09 (m, 1H), 2.08-1.97 (m, 2H), 1.89-1.64 (m, 6H).

(348) Step 4

(349) The reaction referred to Step 1 of Example 16, and the residue was isolated and purified by high performance liquid chromatography to give compound 44-5 (36.0 mg); yield: 38%.

(350) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) δ 8.13 (d, J=7.2 Hz, 1H), 7.74 (d, J=7.2 Hz, 1H), 7.49-7.43 (m, 2H), 7.19 (s, 1H), 5.23 (d, J=7.2 Hz, 1H), 3.97 (s, 3H), 3.78-3.70 (m, 4H), 3.31-3.16 (m, 3H), 3.09-3.03 (m, 1H), 2.91-2.84 (m, 1H), 2.47-2.42 (m, 1H), 2.12-2.04 (m, 2H), 1.91-1.73 (m, 6H). MS-ESI [M+H].sup.+: calculated value: 461; measured value: 461.

Example 45

(351) ##STR00155## ##STR00156##

(352) Step 1

(353) Compound 45-1 (2.00 g, 94.8 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and bis(trimethylsilyl)amide lithium (1M in tetrahydrofuran, 11.4 mL) was added dropwise at −78° C. The reaction was stirred at this temperature for 30 minutes. Then, ethyl bromopropionate (1.89 g, 10.4 mmol) was added to the reaction mixture, and the mixture was stirred at 25° C. for 2 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL×3). The organic layers were combined and washed with saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated with reduced pressure. The residue was purified by silica gel column chromatography (10:1 petroleum ether/ethyl acetate, R.sub.f=0.7) to give compound 45-2 (300 mg, pale yellow oil); yield: 10%.

(354) 1H NMR: (400 MHz, Methonal-d.sub.4) δ 7.87 (d, J=8.0 Hz, 1H), 7.71 (d, J=8.0 Hz, 1H), 7.38 (t, J=8.0 Hz, 1H), 4.15 (q, J=7.2 Hz, 2H), 3.38-3.36 (m, 1H), 2.83-2.75 (m, 2H), 2.57-2.53 (m, 2H), 2.21-2.18 (m, 1H), 1.84-1.82 (m, 1H), 1.28 (t, J=7.2 Hz, 3H). MS-ESI [M+H].sup.+: calculated value: 311 and 313; measured value: 311 and 313.

(355) Step 2

(356) Compound 45-2 (300 mg, 0.964 mmol) was dissolved in tetrahydrofuran (3 mL), and Compound 45-3 (186 mg, 1.06 mmol) and titanium tetraisopropoxide (548 mg, 1.93 mmol) were added. The reaction was stirred at 60° C. for 1 hour under nitrogen atmosphere. Then, sodium borohydride (72.9 mg, 1.93 mmol) and methanol (10 mL were added to the reaction mixture which was cooled to room temperature. The mixture was then heated to 60° C. and stirred for 12 hours. Water (30 mL) was added to the reaction mixture after the mixture was cooled to room temperature, followed by filtering. The filtrate was extracted with ethyl acetate (20 mL×3). The organic layers were combined and washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (3:1 petroleum ether/ethyl acetate, R.sub.f=0.5) to give compound 45-4 (150 mg, pale yellow oil); yield: 37%.

(357) .sup.1H NMR: (400 MHz, CDCl.sub.3) δ 7.34 (d, J=8.0 Hz, 1H), 7.25 (d, J=8.0 Hz, 1H), 7.04 (t, J=8.0 Hz, 1H), 5.13 (d), J=7.2 Hz, 1H), 4.23-4.19 (m, 1H), 3.90-3.88 (m, 1H), 3.70-3.67 (m, 1H), 3.29-3.27 (m, 1H), 3.02-2.98 (m, 1H), 2.74-2.69 (m, 1H), 2.40-2.19 (m, 3H), 1.76-1.75 (m, 1H), 1.63-1.61 (m, 1H), 0.79 (s, 9H), 0.00 (s, 6H). MS-ESI [M+H].sup.+: calculated value: 424 and 426; measured value: 424 and 426.

(358) Step 3

(359) Compound 45-4 (150 mg, 0.353 mmol) was dissolved in acetonitrile (5 mL), and zinc cyanide (83.0 mg, 0.707 mmol), 2-dicyclohexylphosphine-2′,4′,7′-triisopropylbiphenyl (34.9 mg, 0.0707 mmol) and tris(dibenzylideneacetone) dipalladium(0) (32.4 mg, 0.0353 mmol) were added. The reaction was stirred at 90° C. for 16 hours under nitrogen atmosphere. Water (10 mL) was added to the reaction mixture after the mixture was cooled to room temperature. The mixture was extracted with ethyl acetate (20 mL×3). The organic layers were combined and washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by TLC (1:1 petroleum ether/ethyl acetate, R.sub.f=0.3) to give compound 45-5 (100 mg, pale yellow oil); yield: 76%.

(360) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) δ 7.65 (d, J=8.0 Hz, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.33 (t, J=8.0 Hz, 1H), 5.14 (d, J=7.2 Hz, 1H), 4.12-4.08 (m, 1H), 3.87-3.85 (m, 1H), 3.70-3.69 (m, 1H), 3.39-3.37 (m, 1H), 3.16-3.14 (m, 1H), 2.90-2.89 (m, 1H), 2.46-2.44 (m, 1H), 2.25-2.24 (m, 1H), 2.15-2.14 (m, 1H), 1.80-1.78 (m, 1H), 1.60-1.58 (m, 1H), 0.82 (s, 9H), 0.00 (s, 6H). MS-ESI [M+H].sup.+: calculated value: 371; measured value: 371.

(361) Step 4

(362) Compound 45-5 (100 mg, 0.270 mmol) was dissolved in anhydrous ethanol (3 mL), and hydroxylamine hydrochloride (56.3 mg, 0.810 mmol) and triethylamine (109 mg, 1.08 mmol) were added. The reaction was stirred at 60° C. for 12 hours under nitrogen atmosphere. Water (10 mL) was added to the reaction mixture after the mixture was cooled to room temperature. The mixture was extracted with ethyl acetate (10 mL×3). The organic layers were combined and washed with saturated brine (10 mL×2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by gel column chromatography (0:1 petroleum ether/ethyl acetate, R.sub.f=0.4) to give compound 45-6 (60.0 mg, pale yellow oil); yield: 55%.

(363) .sup.1H NMR: (400 MHz, CDCl.sub.3) δ 7.37-7.35 (m, 2H), 7.22-7.20 (t, J=8.0 Hz, 1H), 5.07 (d, J=7.2 Hz, 1H), 4.74 (s, 2H), 4.24-4.20 (m, 1H), 3.92-3.91 (m, 1H), 3.70-3.68 (m, 1H), 3.30-3.28 (m, 1H), 3.13-3.11 (m, 1H), 2.95-2.91 (m, 1H), 2.76-2.74 (m, 1H), 2.27-2.19 (m, 2H), 1.72-1.70 (m, 1H), 1.59-1.56 (m, 1H), 0.83 (s, 9H), 0.00 (s, 6H). MS-ESI [M+H].sup.+: calculated value: 404; measured value: 404.

(364) Step 5

(365) Compound 45-7 (33.6 mg, 0.164 mmol) was dissolved in N,N-dimethylformamide (5 mL), and 1-hydroxybenzotriazole (40.2 mg, 0.297 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (57.0 mg, 0.297 mmol) were added. The reaction was stirred at 25° C. for 0.5 hour under nitrogen atmosphere. Then, Compound 45-6 (60.0 mg, 0.149 mmol) was added into the reaction mixture and the mixture was stirred at 25° C. for 1 hour, then heated to 80° C. and further stirred for 12 hours. Water (30 mL) was added to the reaction mixture after the mixture was cooled to room temperature. The mixture was extracted with ethyl acetate (30 mL×3). The organic layers were combined and washed with brine (25 mL×2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography to give compound 45-8 (25.0 mg); yield: 36%.

(366) .sup.1H NMR: (400 MHz, DMSO-d.sub.6) δ 8.52 (s, 1H), 8.41 (d, J=7.6 Hz, 1H), 8.04 (d, J=7.6 Hz, 1H), 7.67 (d, J=7.6 Hz, 1H), 7.56 (d, J=7.6 Hz, 1H), 7.48 (t, J=7.6 Hz, 1H), 5.12 (d, J=7.2 Hz, 1H), 4.99-4.96 (m, 1H), 4.83-4.82 (m, 1H), 4.04-4.00 (m, 1H), 3.63-3.60 (m, 1H), 3.51-3.49 (m, 2H), 3.20-3.19 (m, 1H), 2.94-2.93 (m, 1H), 2.23-2.21 (m, 1H), 2.15-2.12 (m, 1H), 1.82-1.81 (m, 1H), 1.60-1.58 (m, 1H), 1.38 (d, J=6.0 Hz, 6H). MS-ESI [M+H].sup.+: calculated value: 459; measured value: 459.

Example 46

(367) ##STR00157## ##STR00158##

(368) Step 1

(369) Aluminum trichloride (57.0 g, 427 mmol) was heated to 80° C. and Compound 46-1 (25.0 g, 171 mmol) was slowly added dropwise, the mixture was stirred for 5 minutes. Bromine (32.0 g, 205 mmol) was added dropwise to the reaction mixture, and the mixture was continued stirred for 5 minutes. After the mixture was cooled to room temperature, a mixture of ice (200 g) and concentrated hydrochloric acid (12M, 50 mL) was poured into the mixture, the resultant was stirred for 20 minutes. The reaction solution was diluted with ethyl acetate (200 mL) and the aqueous layer was extracted with ethyl acetate (200 mL×3). The organic layers were combined and dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (1:0 petroleum ether/ethyl acetate, R.sub.f=0.5) to give compound 46-2 (12.0 g, pale yellow oil); yield: 31%.

(370) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.04 (dd, J=1.2, 8.0 Hz, 1H), 7.76 (dd, J=1.2, 8.0 Hz, 1H), 7.21. (t, J=8.0 Hz, 1H), 3.04 (t, J=6.0 Hz, 2H), 2.68 (t, J=6.0 Hz, 2H), 2.18-2.23 (m, 2H).

(371) Step 2

(372) Compound 46-2 (10.0 g, 44.4 mmol) was dissolved in anhydrous tetrahydrofuran (150 mL), and bis(trimethylsilyl)amide lithium (1M in tetrahydrofuran, 44.4 mL) was added dropwise at −78° C., the mixture was stirred for 30 minutes. Ethyl bromoacetate (7.42 g, 44.4 mmol) was added to the reaction mixture and continued stirred at −78° C. for 2 hours. The mixture was quenched with saturated aqueous ammonia chloride solution (50 mL). The aqueous layer was extracted with ethyl acetate (100 mL×3). The organic layers were combined and dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (20:1-10:1 petroleum ether/ethyl acetate, R.sub.f=0.3) to give compound 46-3 (6.00 g, pale yellow oil); yield: 31%.

(373) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.93 (dd, J=1.2, 8.0 Hz, 1H), 7.67 (dd, J=1.2, 8.0 Hz, 1H), 7.13 (t, J=8.0 Hz, 1H), 4.12 (t, J=7.2 Hz, 2H), 3.10-3.18 (m, 1H), 2.94-3.03 (m, 1H), 2.89-2.93 (m, 1H), 2.77-2.86 (m, 1H), 2.33-2.41 (m, 1H), 2.20-2.26 (m, 1H), 1.86-1.91 (m, 1H), 1.22 (t, J=7.2 Hz, 3H). MS-ESI [M+H].sup.+: calculated value: 311 and 313; measured value: 311 and 313.

(374) Step 3

(375) Compound 46-3 (6.00 g, 19.3 mmol), compound 46-4 (6.76 g, 38.6 mmol), and tetraisopropoxytitanium (10.9 g, 38.6 mmol) were dissolved in anhydrous tetrahydrofuran (50 mL). The solution was charged with nitrogen three times, heated to 70° C. and stirred for 15 hours. Then, sodium borohydride (1.46 g, 38.6 mmol) was added to the reaction mixture in portions after the mixture was cooled to 25° C. and the resultant was stirred for 2 hours, then heated to 70° C. again and continued stirred for 13 hours. The reaction mixture was cooled to room temperature and poured into water (30 mL), stirred for 5 minutes to precipitate white solid. The mixture was filtered and the filter cake was washed with ethyl acetate (20 mL×3). The filtrate was combined and partitioned, the aqueous layer was extracted with ethyl acetate (50 mL×3). The organic layers were combined and dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (10:1-3:1 petroleum ether/ethyl acetate, R.sub.f=0.3) to give compound 46-5 (700 mg, pale yellow oil); yield: 4%.

(376) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.50 (d, J=8.0 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.06 (t, J=8.0 Hz, 1H), 4.82 (d, J=6.4 Hz, 1H), 3.82-3.72 (m, 1H), 3.52-3.44 (m, 2H), 3.03-2.96 (m, 1H), 2.78-2.72 (m, 2H), 2.71-2.60 (m, 2H), 2.22 (d, J=14.4 Hz, 1H), 1.76-1.66 (m, 2H), 0.85 (s, 9H), 0.01 (d, J=4.8 Hz, 6H). MS-ESI [M+H].sup.+: calculated value: 424 and 426; measured value: 424 and 426.

(377) Step 4

(378) Compound 46-5 (700 mg, 0.792 mmol), zinc cyanide (279 mg, 2.37 mmol), tris(dibenzylideneacetone) dipalladium (36.2 mg, 39.5 umol), 2-dicyclohexylphosphon-2′,4′,6′-triisopropylbiphenyl (37.7 mg, 79.1 umol) were dissolved in acetonitrile (10 mL). The solution was charged with nitrogen three times and heated to 90° C., stirred for 15 hours. After the reaction mixture was cooled to room temperature, the mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane (20 mL), washed with water (10 mL) and the aqueous layer was extracted with dichloromethane (20 mL×3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (10:1-3:1 petroleum ether/ethyl acetate, R.sub.f=0.2) to give compound 46-6 (210 mg, pale yellow oil); yield: 63%.

(379) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.75 (d, J=8.0 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.28 (t, J=8.0 Hz, 1H), 4.87 (d, J=6.8 Hz, 1H), 3.84-3.73 (m, 1H), 3.54-3.47 (m, 2H), 2.94-2.83 (m, 3H), 2.78-2.67 (m, 2H), 2.29-2.18 (m, 1H), 1.75 (q, J=6.0 Hz, 2H), 0.84 (s, 9H), 0.01 (d, J=4.0 Hz, 6H). MS-ESI [M+H].sup.+: calculated value: 371; measured value: 371.

(380) Step 5

(381) Compound 46-6 (210 mg, 0.493 mmol) was dissolved in ethanol (10 mL), and hydroxylamine hydrochloride (103 mg, 1.48 mmol), triethylamine (199 mg, 1.97 mmol) were added in turn. The mixture was heated to 75° C. and stirred for 20 hours. After the reaction mixture was cooled to room temperature, the mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane (20 mL), washed with water (10 mL) and the aqueous layer was extracted with dichloromethane (20 mL×3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by TLC (1:1 petroleum ether/ethyl acetate, R.sub.f=0.1) to give compound 46-7 (130 mg, white solid); yield: 57%.

(382) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.52 (d, J=8.0 Hz, 1H), 7.40 (d, J=8.0 Hz, 1H), 7.26 (t, J=8.0 Hz, 1H), 4.97-4.90 (m, 1H), 4.82 (brs, 2H), 3.85-3.77 (m, 1H), 3.56-3.40 (m, 2H), 2.96-2.88 (m, 2H), 2.80-2.74 (m, 3H), 2.35-2.26 (m, 1H), 1.74-1.69 (m, 2H), 0.91 (s, 9H), 0.06 (d, J=4.0 Hz, 6H). MS-ESI [M+H].sup.+: calculated value: 404; measured value: 404.

(383) Step 6

(384) 3-Cyano-4-isopropoxybenzoic acid (66.1 mg, 0.322 mmol), 1-hydroxybenzotriazole (87.1 mg, 0.644 mmol), 1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide hydrochloride (123 mg, 0.644 mmol) were dissolved in anhydrous N,N-dimethylformamide (2 mL). The solution was charged with nitrogen three times. After the mixture was stirred at 20° C. for 30 minutes, a solution of Compound 46-7 (130 mg, 0.322 mmol) in anhydrous N,N-dimethylformamide (2 mL) was added. After further stirred for 30 minutes, the mixture was heated to 90° C. and continued stirred for 14 hours. The mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane (20 mL), washed with water (10 mL) and the aqueous layer was extracted with dichloromethane (20 mL×3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by high performance liquid chromatography to give compound 46-8 (19.0 mg); yield: 13%.

(385) .sup.1H NMR (400 MHz, Methonal-d.sub.4) δ 8.46-8.36 (m, 2H), 7.99 (d, J=7.6 Hz, 1H), 7.68 (d, J=7.6 Hz, 1H), 7.51-7.41 (m), 2H), 5.07 (d, J=7.2 Hz, 1H), 4.99-4.93 (m, 1H), 3.62-3.51 (m, 1H), 3.54-3.40 (m, 1H), 3.42-3.38 (m, 1H), 3.27-3.22 (m, 1H), 3.04-2.83 (m, 4H), 2.23-2.29 (m, 1H), 1.85-1.70 (m, 2H), 1.47 (d, J=6.0 Hz, 6H). MS-ESI [M+H].sup.+: calculated value: 459; measured value: 459.

Example 47

(386) ##STR00159##

(387) Step 1

(388) Compound 47-1 (i.e., Compound 1-11) (80.0 mg, 0.180 mmol) and pyridine sulfur trioxide hydrochloride were dissolved in anhydrous N,N-dimethylformamide (5.0 mL). The reaction was stirred at 50° C. for 16 hours. The reaction mixture was concentrated under reduced pressure directly. The residue was purified by TLC (silica, methylene chloride:methanol=8:1) to give Compound 47-2.

(389) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.52 (s, 1H), 8.40 (d, J=8.0 Hz, 1H), 8.09 (d, J=7.6 Hz, 1H), 7.89 (d, J=7.6 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.49 (t, J=7.6 Hz, 1H), 5.21 (d, J=7.2 Hz, 1H), 5.00-4.95 (m, 1H), 3.93-3.83 (m, 2H), 3.71-3.64 (m, 2H), 3.27-3.11 (m, 3H), 3.04-2.98 (m, 1H), 2.75-2.64 (m, 1H), 2.33-2.28 (m, 1H), 1.38 (d, J=6.0 Hz, 6H).

(390) MS-ESI [M+H].sup.+: calculated value: 525; measured value: 525.

Example 48

(391) ##STR00160## ##STR00161##

(392) Step 1

(393) Compound 48-1 (500 mg, 3.42 mmol) and isopropanol (247 mg, 4.11 mmol) were dissolved in anhydrous N,N-dimethylformamide (5.0 mL), and potassium hydroxide (384 mg, 6.84 mmol) was added. The reaction was stirred at 25° C. for 2 hours. Then, the reaction solution was poured into water (8 mL) and extracted with ethyl acetate (8 mL×3). The organic layer was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate and concentrated to give the crude. The residue was purified by silica gel column chromatography (silica, petroleum ether:ethyl acetate=100:1 to 0:100) to give Compound 48-2.

(394) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.86 (d, J=2.0 Hz, 1H), 7.79 (dd, J=2.0, 8.8 Hz, 1H), 7.05 (d, J=8.8 Hz, 1H), 4.79-4.73 (m, 1H), 1.46 (s, 3H), 1.45 (s, 3H).

(395) Step 2

(396) Compound 48-2 (100 mg, 0.537 mmol) was dissolved in ethanol (5.0 mL), and hydroxylamine hydrochloride (56.0 mg, 0.806 mmol) and sodium bicarbonate (67.7 mg, 0.806 mmol) were added. The reaction was stirred at 60° C. for 3 hours. Then, the mixture was concentrated and the residue was poured into water (10 mL), extracted with ethyl acetate (15 mL×3). The organic layer was dried over anhydrous sodium sulfate, filtrated and purified by silica gel column chromatography (silica, petroleum ether:ethyl acetate=100:1 to 0:100) to give Compound 48-3.

(397) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.82 (d, J=2.0 Hz, 1H), 7.79 (dd, J=2.0, 8.8 Hz, 1H), 6.99 (d, J=8.8 Hz, 1H), 4.82 (Brs, 2H), 4.71-4.69 (m, 1H), 1.44 (d, J=6.0 Hz, 6H).

(398) MS-ESI [M+H].sup.+: calculated value: 220; measured value: 220.

(399) Step 3

(400) Compound 48-4 (2 g, 7.93 mmol) was dissolved in methanol (15.0 mL) and anhydrous N,N-dimethylformamide (5.0 mL), and triethylamine (5 mL) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (580 g, 0.793 mmol) were added. The reaction was stirred at 80° C. for 12 hours under carbon monoxide atmosphere (15 psi). Then, the reaction solution was poured into water (30 mL) and the mixture was extracted with ethyl acetate (20 mL×3). The organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate and concentrated to give the crude. The crude was purified by silica gel column chromatography (silica gel, petroleum ether:ethyl acetate=8:1 to 0:1, ethyl acetate:methanol=1:1 to 10:1) to give Compound 48-5.

(401) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.90 (d, J=8.0 Hz, 1H), 7.40 (d, J=8.0 Hz, 1H), 7.25 (t, J=8.0 Hz, 1H), 6.72 (s, 1H), 4.98 (d, J=7.6 Hz, 1H), 3.83 (s, 3H), 3.68-3.63 (m, 1H), 3.31-3.22 (m, 1H), 3.19-1.35 (m, 1H), 2.69-2.64 (m, 1H), 2.19-2.15 (m, 1H).

(402) MS-ESI [M+H].sup.+: calculated value: 232; measured value: 232.

(403) Step 4

(404) Compound 48-5 (300 mg, 1.30 mmol) was dissolved in tetrahydrofuran (8.0 mL) and water (2.0 mL), and lithium hydroxide (218 mg, 5.19 mmol) was added. The reaction was stirred at 25° C. for 16 hours. Then, the mixture was concentrated and acidified with 2 M hydrochloric acid to pH=2 to precipitate pale yellow solid, filtered to give Compound 48-6.

(405) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.87 (s, 1H), 8.25 (s, 1H), 7.84 (d, J=6.8 Hz, 1H), 7.54 (d, J=7.6 Hz, 1H), 7.38-7.34 (m, 1H), 4.93 (d, J=8.0 Hz, 1H), 3.54-3.47 (m, 1H), 3.24-3.18 (m, 1H), 3.07 (dd, J=4, 18.4 Hz, 1H), 2.56-2.52 (m, 1H), 1.99 (dd, J=5.6, 22.8 Hz, 1H).

(406) MS-ESI [M+H].sup.+: calculated value: 218; measured value: 218.

(407) Step 5

(408) Compound 48-3 (50 mg, 0.228 mmol) was dissolved in N,N-dimethylformamide (3.00 mL), and 1-hydroxybenzotriazole (9.2 mg, 0.0684 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (52.5 mg, 0.274 mmol) and 48-6 (49.5 mg, 0.228 mmol) were added. The reaction was stirred at 20° C. for 2 hours, then heated to 80° C. and continued stirred for 12 hours. Then, water (30 mL) was added and the mixture was extracted with ethyl acetate (8 mL×3). The organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate and concentrated to give crude. The crude was purified by silica gel column chromatography (silica gel, dichloromethane:methanol=10:1) to give Compound 48-7.

(409) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.39 (d, J=2.0 Hz, 1H), 8.31 (dd, J=2.0, 8.8 Hz, 1H), 8.19 (d, J=7.6 Hz, 1H), 7.55 (d, J=7.6 Hz, 1H), 7.46 (t, J=7.6 Hz, 1H), 7.10 (d, J=8.8 Hz, 1H), 6.25 (s, 1H), 5.14 (d, J=7.6 Hz, 1H), 4.81-4.75 (m, 1H), 3.88-3.82 (m, 1H), 3.49-3.39 (m, 2H), 2.90-2.79 (m, 1H), 2.37-3.31 (m, 1H), 1.48 (d, J=6.0 Hz, 6H).

(410) MS-ESI [M+H].sup.+: calculated value: 401; measured value: 401

(411) Step 6

(412) Compound 48-7 (56 mg, 0.140 mmol) was dissolved in anhydrous N,N-dimethylformamide (5.0 mL), and sodium hydride (11.2 mg, 0.280 mmol, 60% purity) was added in portions at 0° C. The reaction was stirred at this temperature for 0.5 hour. Then, Compound 48-8 (66.9 mg, 0.280 mmol) was added to the reaction solution and stirred at 20° C. for 12 hours. Methanol hydrochloride (2.0 mL, 4 M) was added to reaction solution and the mixture was stirred for 0.5 hour, then concentrated under reduced pressure. The residue was purified by high performance liquid chromatography to obtain Compound 2-9.

(413) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.33 (s, 2H), 8.29 (d, J=9.2 Hz, 1H), 8.14 (d, J=7.6 Hz, 1H), 7.89 (d, J=7.6 Hz), 1H), 7.54 (t, J=7.6 Hz, 1H), 7.50 (d, J=9.2 Hz, 1H), 5.17 (d, J=7.6 Hz, 1H), 4.95-4.90 (m, 2H), 3.82-3.75 (m, 1H), 3.63-3.56 (m, 3H), 3.27-3.23 (m, 1H), 3.16-3.10 (m, 1H), 3.03-2.96 (m, 1H), 2.74-2.67 (m, 1H), 2.36-2.32 (m, 1H), 1.36 (d, J=6.0 Hz, 6H).

(414) MS-ESI [M+H].sup.+: calculated value: 445; measured value: 445.

Example 49

(415) ##STR00162## ##STR00163##

(416) Step 1

(417) Compound 49-1 (5.00 g, 16.8 mmol) was dissolved in anhydrous ethanol (300 mL), and ammonium acetate (13.0 g, 168 mmol) was added at 25° C. The reaction was stirred at this temperature for 1 hour. Then, sodium cyanoborohydride (3.17 g, 50.5 mmol) was added to the mixture, the resultant was stirred at 80° C. for 12 hours. Water (300 mL) was added to the reaction mixture and the mixture was extracted with ethyl acetate (400 mL×3). The organic layers were combined and washed with saturated brine (200 mL×2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10:1 ethyl acetate/methanol, R.sub.f=0.4) to give Compound 49-2.

(418) MS-ESI [M+H].sup.+: calculated value: 252 and 254; measured value: 252 and 254.

(419) Step 2

(420) Compound 49-2 (3.50 g, 5.55 mmol) was dissolved in anhydrous dichloromethane (40 mL), and di-tert-butyl dicarbonate (3.64 g, 16.7 mmol) and triethylamine (1.69 g, 16.7 mmol) were added. The reaction was stirred at 25° C. for 12 hours. Then, water (20 mL) was added to the reaction mixture and the resultant was extracted with dichloromethane (30 mL×3). The organic layers were combined and washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5:1 petroleum ether/ethyl acetate, R.sub.f=0.6) to obtain Compound 49-3. .sup.1H NMR: (400 MHz, CDCl.sub.3) δ 7.69-7.67 (m, 0.5H), 7.53-7.51 (m, 0.5H), 7.40-7.37 (m, 1H), 7.11-7.06 (m, 1H), 5.39-5.37 (m, 0.5H), 5.31-5.29 (m, 0.5H), 3.53-3.40 (m, 1H), 3.36-3.33 (m, 1H), 3.11-3.05 (m, 1H), 2.81-2.77 (m, 1H), 2.14-2.09 (m, 1H), 1.57 (s, 9H).

(421) MS-ESI [M+H].sup.+: calculated value: 352 and 354; measured value: 352 and 354.

(422) Step 3

(423) Compound 49-3 (600 mg, 1.70 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), and a solution of borane in dimethyl sulfide (0.850 mL, 8.50 mmol, 10 M) was slowly added dropwise at 0° C. The reaction was stirred at 70° C. for 12 hours. Then, methanol (50 mL) was slowly added to the reaction mixture and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10:1 petroleum ether/ethyl acetate, R.sub.f=0.6) to give Compound 49-4. MS-ESI [M+H].sup.+: calculated value: 338 and 340; measured value: 338 and 340.

(424) Step 4

(425) Compound 49-4 (100 mg, 0.296 mmol) was dissolved in acetonitrile (5 mL), and zinc cyanide (69.4 mg, 0.591 mmol), 2-dicyclohexylphosphine-2′,4′,7′-triisopropylbiphenyl (14.1 mg, 0.0296 mmol) and tris(dibenzylideneacetone)dipalladium(0) (13.5 mg, 0.0148 mmol) were added. The reaction was stirred at 90° C. for 16 hours under nitrogen atmosphere. Then, water (20 mL) was added to the reaction mixture after the mixture was cooled to room temperature, and the mixture was extracted with ethyl acetate (20 mL×3). The organic layers were combined and washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by TLC (10:1 petroleum ether/ethyl acetate, R.sub.f=0.5) to obtain Compound 49-5.

(426) .sup.1H NMR: (400 MHz, CDCl.sub.3) δ 8.00-7.98 (m, 0.5H), 7.81-7.79 (m, 0.5H), 7.54-7.51 (m, 1H), 7.33-7.29 (m, 1H), 5.35-5.33 (m, 0.5H), 5.30-5.26 (m, 0.5H), 3.54-3.42 (m, 1H), 3.38-3.24 (m, 4H), 3.00-2.95 (m, 1H), 2.18-2.13 (m, 1H), 1.58 (s, 9H).

(427) MS-ESI [M+H].sup.+: calculated value: 285; measured value: 285.

(428) Step 5

(429) Compound 49-5 (70.0 mg, 0.246 mmol) was dissolved in anhydrous ethanol (3 mL), and hydroxylamine hydrochloride (51.3 mg, 0.739 mmol) and triethylamine (99.6 mg, 0.985 mmol) were added. The reaction was stirred at 70° C. for 12 hours under nitrogen atmosphere. Then, water (20 mL) was added to the reaction mixture after the mixture was cooled to room temperature, and the mixture was extracted with ethyl acetate (10 mL×3). The organic layers were combined and washed with saturated brine (10 mL×2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by TLC (3:1 petroleum ether/ethyl acetate, R.sub.f=0.2) to obtain Compound 49-6.

(430) .sup.1H NMR: (400 MHz, CDCl.sub.3) δ 7.50-7.48 (m, 1H), 7.41-7.39 (m, 1H), 7.23-7.19 (m, 1H), 5.08-5.06 (m, 1H), 4.73 (s), 2H), 3.78-3.76 (m, 1H), 3.67-3.62 (m, 2H), 3.44-3.42 (m, 1H), 2.97-2.90 (m, 3H), 2.71-2.65 (m, 1H), 2.37-2.33 (m, 1H), 0.84 (s, 9H), 0.02-0.00 (m, 6H).

(431) MS-ESI [M+H].sup.+: calculated value: 318; measured value: 318.

(432) Step 6

(433) Compound 49-7 (49.8 mg, 0.243 mmol) was dissolved in N,N-dimethylformamide (3 mL), and 1-hydroxybenzotriazole (59.6 mg, 0.441 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (84.6 mg, 0.441 mmol) were added. The reaction was stirred at 25° C. for 1 hour under nitrogen atmosphere. Then, Compound 49-6 (70.0 mg, 0.221 mmol) was added to the reaction mixture and the mixture was stirred at 25° C. for 1 hour, then heated to 80° C. and continued stirred for 12 hours. Water (20 mL) was added to the reaction mixture after the mixture was cooled to room temperature, and the mixture was extracted with ethyl acetate (20 mL×3). The organic layers were combined and washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by TLC (3:1 petroleum ether/ethyl acetate, R.sub.f=0.7) to give Compound 49-8.

(434) .sup.1H NMR: (400 MHz, CDCl.sub.3) δ 8.42 (s, 1H), 8.33 (d, J=9.2 Hz, 1H), 8.12-8.08 (m, 1H), 7.93-7.92 (m, 0.5H), 7.77-7.76 (m, 0.5H), 7.40-7.38 (m, 1H), 7.12 (d, J=9.2 Hz, 1H), 5.40-5.38 (m, 0.5H), 5.32-5.30 (m, 0.5H), 4.82-4.76 (m, 1H), 3.57-3.42 (m, 3H), 3.36-3.17 (m, 2H), 2.16-2.12 (m, 1H), 1.67-1.59 (m, 10H), 1.47 (d, J=6.0 Hz, 6H).

(435) MS-ESI [M+H].sup.+: calculated value: 487; measured value: 487.

(436) Step 7

(437) Compound 49-8 (55.0 mg, 0.113 mmol) was dissolved in dioxane (3 mL), and hydrochloric acid dioxane (4M, 1 mL) was added. The reaction was stirred at 25° C. for 1 hour under nitrogen atmosphere. Then, saturated aqueous sodium bicarbonate solution (30 mL) was added to the reaction mixture and the mixture was extracted with ethyl acetate (20 mL×3). The organic layers were combined and washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, filtered and concentrate the filtrate was concentrated under reduced pressure to obtain Compound 49-9.

(438) MS-ESI [M+H].sup.+: calculated value: 387; measured value: 387.

(439) Step 8

(440) Compound 49-9 (20.0 mg, 0.0518 mmol) was dissolved in acetonitrile (3 mL), and Compound 49-10 (12.4 mg, 0.0518 mmol), potassium carbonate (21.5 mg, 0.155 mmol) and sodium iodide (23.3 mg, 0.155 mmol) were added. The reaction was stirred at 90° C. for 48 hours under nitrogen atmosphere. Then, water (10 mL) was added to the reaction mixture after the mixture was cooled to room temperature, and the mixture was extracted with ethyl acetate (10 mL×3). The organic layers were combined and washed with saturated brine (10 mL×2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by TLC (3:1 petroleum ether/ethyl acetate, R.sub.f=0.4) to obtain Compound 49-11.

(441) MS-ESI [M+H].sup.+: calculated value: 545; measured value: 545.

(442) Step 9

(443) Compound 49-11 (20.0 mg, 0.0367 mmol) was dissolved in dioxane (3 mL), and dioxane hydrochloride (4M, 1 mL) was added. The reaction was stirred at 25° C. for 10 minutes under nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography to obtain Compound 49-12.

(444) .sup.1H NMR: (400 MHz, CD.sub.3OD) δ 8.47-8.43 (m, 2H), 8.32 (d, J=7.6 Hz, 1H), 7.91 (d, J=7.6 Hz, 1H), 7.64-7.60 (m, 1H), 7.46 (d, J=8.8 Hz, 1H), 5.34-5.32 (m, 1H), 4.99-4.96 (m, 1H), 4.04-4.03 (m, 2H), 3.80-3.77 (m, 2H), 3.68-3.62 (m, 1H), 3.56-3.36 (m, 4H), 2.63-2.60 (m, 1H), 1.96-1.91 (m, 1H), 1.47 (d, J=6.0 Hz, 6H).

(445) MS-ESI [M+H].sup.+: calculated value: 431; measured value: 431.

Example 50

(446) ##STR00164## ##STR00165##

(447) Step 1

(448) Compound 50-1 (2.00 g, 9.48 mmol) was dissolved in ethanol (20.0 mL), and sodium borohydride (466 mg, 12.3 mmol) was added. The reaction was stirred at 20° C. for 12 hours, then concentrated under reduced pressure. The residue was dissolved in dichloromethane (40 mL). Then, 1M hydrochloric acid (20 mL) was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate (20 mL×2). The organic layers were combined and washed with saturated brine (30 mL×2), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give Compound 50-2.

(449) 1H NMR: (400 MHz, CDCl.sub.3) δ 7.43 (d, J=7.6 Hz, 1H), 7.36 (d, J=7.6 Hz, 1H), 7.13 (t, J=7.6 Hz, 1H), 5.35-5.27 (m, 1H), 3.11-3.04 (m, 1H), 2.91-2.76 (m, 1H), 2.60-2.44 (m, 1H), 2.02-1.91 (m, 1H), 1.87 (s, 1H).

(450) Step 2

(451) Compound 50-2 (11.7 g, 54.9 mmol) was dissolved in toluene (80 mL), and p-toluenesulfonic acid (1.04 g, 5.49 mmol) was added. The reaction was stirred at 80° C. for 2 hours under nitrogen atmosphere. The reaction mixture was washed with saturated sodium bicarbonate (40 mL×2) and brine (40 mL×2), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subject to silica gel chromatography (petroleum ether, R.sub.f=0.7) to obtain Compound 50-3.

(452) .sup.1H NMR: (400 MHz, CDCl.sub.3) δ 7.36-7.34 (m, 2H), 7.17 (t, J=7.6 Hz, 1H), 6.96-6.89 (m, 1H), 6.66-6.60 (m, 1H), 3.41 (s, 2H).

(453) Step 3

(454) Compound 50-3 (3.90 g, 19.9 mmol) was dissolved in dichloromethane (150 mL), and sodium bicarbonate (5.04 g, 59.9 mmol) and m-chloroperoxybenzoic acid (5.68 g, 27.9 mmol) were added at 0° C. The mixture was slowly heated to 10° C. and stirred at this temperature for 12 hours under nitrogen atmosphere. Then, saturated sodium thiosulfate solution (40 mL) was added and the mixture was washed with saturated brine (50 mL×2), dried over anhydrous sodium sulfate and concentrated to give Compound 50-4.

(455) .sup.1H NMR: (400 MHz, CDCl.sub.3) δ 7.46-7.42 (m, 2H), 7.11 (t, J=7.6 Hz, 1H), 4.33 (d, J=1.2 Hz, 1H), 4.16 (t, J=3.2 Hz, 1H), 3.25 (d, J=18.6 Hz, 1H), 2.94 (dd, J=3.2, 18.6 Hz, 1H).

(456) Step 4

(457) Compound 50-4 (3.80 g, 18.0 mmol) was dissolved in ethanol (150 mL), and 2-benzylethanolamine (4.08 g, 27.0 mmol) and water (5 mL) were added. The reaction was stirred at 60° C. for 2 hours. Then, ethyl acetate (150 mL) was added and the mixture was washed with water (40 mL×2) and saturated brine (40 mL×2), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subject to silica gel chromatography (10:1 dichloromethane/methanol, R.sub.f=0.7) to obtain Compound 50-5.

(458) .sup.1H NMR: (400 MHz, CDCl.sub.3) δ 7.33-7.22 (m, 6H), 7.16 (d, J=7.6 Hz, 1H), 7.01 (t, J=7.6 Hz, 1H), 4.48 (s, 2H), 4.29-4.26 (m, 1H), 4.06 (d, J=5.6 Hz, 1H), 3.57 (t, J=5.2 Hz, 2H), 3.28-3.22 (m, 1H), 3.05-2.89 (m, 2H), 2.72-2.70 (m, 1H).

(459) Step 5

(460) Compound 50-5 (1.00 g, 2.76 mmol) was dissolved in dichloromethane (20 mL), and triethylamine (418 mg, 4.14 mmol) and di-tert-butyl dicarbonate (783 mg, 3.59 mmol) were added. The reaction was stirred at 25° C. for 3 hours. Then, the mixture was washed with water (15 mL×2) and saturated brine (15 mL×2), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subject to silica gel chromatography (3:1 petroleum ether/ethyl acetate, R.sub.f=0.2) to obtain Compound 50-6.

(461) .sup.1H NMR: (400 MHz, CDCl.sub.3) δ 7.41-7.27 (m, 6H), 7.08-7.06 (m, 1H), 6.98-6.95 (m, 1H), 4.94-4.66 (m, 1H), 4.65-4.47 (m, 2H), 3.87-3.22 (m, 6H), 2.78-2.74 (m, 1H), 1.46 (s, 3H), 1.35-1.08 (m, 6H).

(462) MS-ESI [M+H].sup.+: calculated value: 484 and 486; measured value: 484 and 486.

(463) Step 6

(464) Compound 50-6 (680 mg, 1.47 mmol) was dissolved in tetrahydrofuran (8 mL), and 4-nitrobenzoic acid (294 mg, 1.76 mmol) and triphenylphosphine (963 mg, 3.68 mmol) were added. Then, a solution of diisopropyl azodicarboxylate (743 mg, 3.68 mmol) in tetrahydrofuran (2 mL) was added at 0° C. The reaction was stirred at 20° C. for 24 hours under nitrogen atmosphere. Then, saturated brine (20 mL) was added to the reaction mixture and the mixture was extracted with ethyl acetate (40 mL×2). The organic layers were combined and washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subject to silica gel chromatography (3:1 petroleum ether/ethyl acetate, R.sub.f=0.3) to obtain Compound 50-7.

(465) .sup.1H NMR: (400 MHz, CDCl3) δ7.52-7.48 (m, 2H), 7.41-7.29 (m, 5H), 7.15 (t, J=7.6 Hz, 1H), 5.47-5.45 (m, 1H), 5.36-5.24 (m, 1H), 4.68-4.53 (m, 2H), 3.85-3.73 (m, 3H), 3.51-3.22 (m, 3H).

(466) MS-ESI [M+H].sup.+: calculated value: 388 and 390; measured value: 388 and 390.

(467) Step 7

(468) Compound 50-7 (650 mg, 1.67 mmol) was dissolved in acetonitrile (10 mL), and zinc cyanide (588 mg, 5.01 mmol), tris(dibenzylideneacetone)dipalladium (305 mg, 0.334 mmol) and 2-dicyclohexylphosphorin-2′,4′,6′-triisopropylbiphenyl (318 mg, 0.668 mmol) were added. The reaction was stirred at 90° C. for 12 hours under nitrogen atmosphere. Then, ethyl acetate (30 mL) was added to the reaction mixture and the mixture was washed with water (20 mL×2) and saturated brine (20 mL×2), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subject to silica gel chromatography (1:1 petroleum ether/ethyl acetate, R.sub.f=0.3) to obtain Compound 50-8.

(469) .sup.1H NMR: (400 MHz, CDCl.sub.3) δ 7.81 (d, J=7.6 Hz, 1H), 7.65 (d, J=7.6 Hz, 1H), 7.42-7.30 (m, 6H), 5.46 (d, J=7.6 Hz, 1H), 5.39-5.29 (m, 1H), 4.68-4.52 (m, 2H), 3.88-3.75 (m, 3H), 3.68-3.58 (m, 1H), 3.55-3.47 (m, 1H), 3.44-3.34 (m, 1H).

(470) MS-ESI [M+H].sup.+: calculated value: 335; measured value: 335.

(471) Step 8

(472) Compound 50-8 (270 mg, 807 umol) was dissolved in ethanol (6 mL), and hydroxylamine hydrochloride (168 mg, 2.42 mmol) and triethylamine (245 mg, 2.42 mmol) were added. The reaction was stirred at 60° C. for 12 hours under nitrogen atmosphere. The mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate (30 mL). The mixture was washed with water (15 mL×2) and saturated brine (15 mL×2), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain Compound 50-9.

(473) MS-ESI [M+H].sup.+: calculated value: 368; measured value: 368.

(474) Step 9

(475) 3-Cyano-4-isopropylbenzoic acid (150 mg, 0.734 mmol) was dissolved in N,N-dimethylformamide (3 mL), and 1-hydroxybenzotriazole (198 mg, 1.47 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (211 mg, 1.10 mmol) were added. The reaction was stirred at 20° C. for 1 hour. Compound 50-9 (270 mg, 0.734 mmol) in N,N-dimethylformamide (1 mL) was added and the mixture was stirred at 20° C. for 1 hour. Then, the reaction was stirred at 90° C. for 10 hours under nitrogen atmosphere. The reaction mixture was cooled and concentrated under reduced pressure. The residue was subject to silica gel chromatography (1:1 petroleum ether/ethyl acetate, R.sub.f=0.4) to obtain Compound 50-10.

(476) .sup.1H NMR: (400 MHz, CDCl.sub.3) δ 8.43 (d, J=2.0 Hz, 1H), 8.34 (dd, J=2.0, 9.2 Hz, 1H), 8.22 (d, J=7.6 Hz, 1H), 7.71 (d, J=7.6 Hz, 1H), 7.46-7.44 (m, 1H), 7.39-7.29 (m, 5H), 7.13 (d, J=9.2 Hz, 1H), 5.49-5.43 (m, 1H), 5.41-5.32 (m, 1H), 4.82-4.78 (m, 1H), 4.68-4.54 (m, 2H), 3.88-3.70 (m, 5H), 3.48-3.40 (m, 1H), 1.48 (d, J)=6.0 Hz, 6H).

(477) MS-ESI [M+H].sup.+: calculated value: 537; measured value: 537.

(478) Step 10

(479) Compound 50-10 (180 mg, 0.335 mmol) was dissolved in trifluoroacetic acid (5 mL), and the mixture was stirred at 70° C. for 4 hours. The mixture was concentrated under reduced pressure and the residue was dissolved in methanol (4 mL). Potassium carbonate (40 mg) was added and the mixture was stirred at 25° C. for 1 hour. Then, dichloromethane (50 mL) was added to the reaction mixture and the mixture was washed with water (20 mL×2) and saturated brine (20 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by high performance liquid chromatography to obtain Compound 50-11.

(480) .sup.1H NMR: (400 MHz, DMSO) δ 8.51 (s, 1H), 8.41 (d, J=9.2 Hz, 1H), 8.14 (d, J=7.6 Hz, 1H), 7.82 (d, J=7.6 Hz, 1H), 7.55 (d, J=8.0 Hz, 2H), 5.43 (s, 2H), 4.99 (s, 2H), 3.81-3.50 (m, 5H), 1.38 (d, J=5.4 Hz, 6H).

(481) MS-ESI [M+H].sup.+: calculated value: 447; measured value: 447.

Example 51

(482) ##STR00166## ##STR00167##

(483) Step 1

(484) Compound 51-1 (1.2 g, 5.52 mmol) was dissolved in N,N-dimethylformamide (20.0 mL), and 1-hydroxybenzotriazole (1.49 g, 11.05 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (2.12 g, 11.05 mmol), triethylamine (1.12 g, 11.05 mmol) and 51-2 (730.1 mg, 5.52 mmol) were added. The reaction was stirred at 25° C. for 16 hours. Then, water (25 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL×3). The combined organic layer was dried over anhydrous sodium sulfate and concentrated to give crude. The crude was purified by silica gel column chromatography (silica, methylene chloride:methanol=100 to 10:1) to obtain Compound 51-3.

(485) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.87 (brs, 1H), 7.61 (d, J=7.6 Hz, 1H), 7.32 (d, J=7.6 Hz, 1H), 7.22 (t, J=7.6 Hz, 1H), 7.12 (brs, 1H), 6.73 (brs, 1H), 4.98 (d, J=7.6 Hz, 1H), 3.59-3.55 (m, 1H), 3.31-3.27 (m, 1H), 3.14-3.10 (m, 1H), 2.77-2.73 (m, 1H), 2.14-2.10 (m, 1H), 1.53 (s, 9H).

(486) MS-ESI [M+H].sup.+: calculated value: 354; measured value: 354.

(487) Step 2

(488) Compound 51-3 (1.45 g, 4.38 mmol) was dissolved in methanol (2 mL), and methanol hydrochloride (4M, 10 mL) was added. The reaction was stirred at 25° C. for 4 hours. The reaction mixture was concentrated directly to obtain Compound 51-4.

(489) MS-ESI [M+H].sup.+: calculated value: 254; measured value: 254.

(490) Step 3

(491) Compound 51-4 (0.6 g, 2.59 mmol) was dissolved in dichloromethane (5 mL), and diisopropylethylamine (503 mg, 3.89 mmol) and 51-5 (609 mg, 2.72 mmol) were added. The reaction was stirred at 25° C. for 16 hours. Then, water (10 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (15 mL×3), dried over anhydrous sodium sulfate and concentrated to give the crude. The crude was washed with ethyl acetate (10 mL), followed by filtering to obtain Compound 51-6. MS-ESI [M+H].sup.+: calculated value: 419; measured value: 419.

(492) Step 4

(493) Compound 51-6 (100 mg, 0.240 mmol) was dissolved in acetonitrile (2 mL), and diisopropylethylamine (77.2 mg, 0.597 mmol) and p-toluenesulfonyl chloride (54.7 mg, 0.287 mmol) were added. The reaction was stirred at 60° C. for 16 hours. The reaction mixture was concentrated directly to give crude and the crude was washed with ethyl acetate (8 mL), followed by filtering to obtain Compound 51-7.

(494) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.48 (s, 1H), 8.37-8.32 (m, 2H), 8.12 (d, J=7.2 Hz, 1H), 7.59 (d, J=7.2 Hz, 1H), 7.55-7.50 (m, 2H), 5.03 (d, J=7.6 Hz, 1H), 4.99-4.93 (m, 1H), 3.67-3.64 (m, 1H), 3.26-3.22 (m, 1H), 2.62-2.55 (m, 2H), 2.11-2.05 (m, 1H), 1.39 (d, J=6.0 Hz, 6H).

(495) MS-ESI [M+H].sup.+: calculated value: 401; measured value: 401.

(496) Step 5

(497) Compound 51-7 (70.0 mg, 0.175 mmol) was dissolved in N,N-dimethylformamide (5.0 mL), and sodium hydride (14.0 mg, 0.350 mmol, 60% purity) was added in portions at 0° C. The reaction was stirred at this temperature for 0.5 hour. Then, Compound 51-8 (83.6 mg, 0.350 mmol) was added to the reaction mixture and the mixture was stirred at 20° C. for 12 hours. Then, methanol hydrochloride (2.0 mL, 4 M) was added to the reaction mixture and the mixture was stirred for 0.5 hour. The mixture was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (hydrochloride system) to obtain Compound 51-9.

(498) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.48 (d, J=2.2 Hz, 1H), 8.35 (dd, J=2.0, 8.8 Hz, 1H), 8.15 (d, J=7.6 Hz, 1H), 7.82 (d, J=7.6 Hz, 1H), 7.54-7.50 (m, 2H), 5.17 (d, J=7.6 Hz, 1H), 4.98-4.92 (m, 1H), 4.88-4.84 (m, 1H), 3.77-3.73 (m, 1H), 3.63-3.49 (m, 3H), 3.28-3.21 (m, 1H), 3.15-3.08 (m, 1H), 3.03-2.97 (m, 1H), 2.74-2.70 (m, 1H), 2.36-2.31 (m, 1H), 1.38 (d, J=6.0 Hz, 6H).

(499) MS-ESI [M+H].sup.+: calculated value: 445; measured value: 445.

Example 52

(500) ##STR00168##

(501) Step 1

(502) Compound 52-1 (100 mg, 0.259 mmol) was dissolved in acetonitrile (6 mL), and methyl bromoacetate (39.6 mg, 0.259 mmol), potassium carbonate (107 mg, 0.776 mmol) and sodium iodide (116 mg, 0.776 mmol) were added. The mixture was stirred at 90° C. for 16 hours. Then, water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL×3). The organic layer was dried over anhydrous sodium sulfate and concentrated to give the crude. The crude was purified by TLC (silica, petroleum ether:ethyl acetate=1:1) to obtain Compound 52-2.

(503) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.43 (d, J=2.0 Hz, 1H), 8.34 (dd, J=2.0, 8.8 Hz, 1H), 8.11 (d, J=7.6 Hz, 1H), 7.54 (d, J=7.6 Hz, 1H), 7.39 (t, J=7.6 Hz 1H), 7.13 (d, J=8.8 Hz, 1H), 4.83-4.77 (m, 1H), 4.44 (d, J=7.6 Hz), 1H), 3.78 (s, 3H), 3.74-3.71 (m, 1H), 3.67-3.62 (m, 1H), 3.58-3.51 (m, 1H), 3.28-3.23 (m, 2H), 3.10-3.05 (m, 1H), 2.89-2.83 (m, 1H), 2.28-2.20 (m, 1H), 1.78-1.70 (m, 1H), 1.49 (d, J=6.0 Hz, 6H).

(504) MS-ESI [M+H].sup.+: calculated value: 459; measured value: 459.

(505) Step 2

(506) Compound 52-2 (100 mg, 0.218 mmol) was dissolved in tetrahydrofuran (8 mL) and water (2 mL), and lithium hydroxide (36.6 mg, 0.872 mmol) was added. The mixture was stirred at 25° C. for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (hydrochloride system) to obtain Compound 52-3.

(507) .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 8.46 (s, 2H), 8.43 (d, J=8.8 Hz, 1H), 8.32 (d, J=7.6 Hz, 1H), 8.05 (d, J=7.6) Hz, 1H), 7.61 (t, J=7.6 Hz, 1H), 7.46 (d, J=8.8 Hz, 1H), 5.38 (d, J=7.6 Hz, 1H), 5.00-4.97 (m, 1H), 4.41-4.37 (m, 1H), 4.14-4.10 (m, 1H), 3.82-3.75 (m, 1H), 3.63-3.57 (m, 1H), 3.51-3.50 (m, 2H), 3.40-3.39 (m, 1H), 2.62-2.53 (m, 1H), 2.13-2.09 (m, 1H), 1.48 (d, J=6.0 Hz, 6H).

(508) MS-ESI [M+H].sup.+: calculated value: 445; measured value: 445.

Example 53

(509) ##STR00169##

(510) Step 1

(511) Compound 53-1 (30.0 g, 0.078 mmol) was dissolved in ethylene glycol dimethyl ether (5 mL), and Compound 53-2 (10.0 mg, 0.078 mmol) and tetraisopropyl titanate (44.1 mg, 0.155 mmol) were added at 50° C. The reaction was stirred for 1 hour. Then, sodium triacetoxyborohydride (32.9 mg, 0.155 mmol) was added and the mixture was stirred at 80° C. for 12 hours. Then, water (5 mL) was added and the mixture was extracted with ethyl acetate (8 mL×3). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain crude Compound 53-3.

(512) MS-ESI [M+H].sup.+: calculated value: 491; measured value: 499.

(513) Step 2

(514) Compound 53-3 (38.0 mg, 0.076 mmol) was dissolved in tetrahydrofuran (4 mL) and water (1 mL), and lithium hydroxide (12.8 mg, 0.305 mmol) was added. The mixture was stirred at 60° C. for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (hydrochloride system) to obtain Compound 53-4.

(515) .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 8.48-8.43 (m, 2H), 8.29 (d, J=8.8 Hz, 1H), 7.78 (d, J=7.6 Hz, 1H), 7.61 (t, J=7.6 Hz, 1H), 7.46 (d, J=8.8 Hz, 1H), 5.12 (d, J=7.6 Hz, 1H), 5.01-4.98 (m, 1H), 3.94-3.87 (m, 1H), 3.74-3.67 (m, 1H), 3.54-3.51 (m, 1H), 3.42-3.35 (m, 2H), 3.29-3.27 (m, 1H), 2.93-2.82 (m, 2H), 2.69-2.67 (m, 1H), 2.56-2.47 (m, 2H), 2.42-2.35 (m, 1H), 1.99-1.91 (m, 1H), 1.48 (d, J=6.0 Hz, 6H).

(516) MS-ESI [M+H].sup.+: calculated value: 485; measured value: 485.

Example 54

(517) ##STR00170## ##STR00171##

(518) Step 1

(519) Compound 54-1 (300 m g, 1.32 mmol) was dissolved in tetrahydrofuran (5 mL), and N,N-dicyclohexylmethylamine (387 mg, 1.98 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (264.57 mg, 1.59 mmol) were added. The reaction was stirred at 25° C. for 16 hours. Then, water (10 mL) was added and the mixture was extracted with ethyl acetate (10 mL×3). The organic layer was dried over anhydrous sodium sulfate and concentrated to give the crude. The crude was purified by silica gel column chromatography (silica, petroleum ether:ethyl acetate=5:1) to obtain Compound 54-2.

(520) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.46 (s, 2H), 3.68 (d, J=8.0 Hz, 2H), 0.93 (d, J=8.0 Hz, 2H), 0.01 (s, 9H).

(521) Step 2

(522) Compound 54-3 (50 mg, 0.109 mmol) was dissolved in N,N-dimethylformamide (5.0 mL), and Compound 54-2 (46.8 mg, 0.131 mmol), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (8.0 mg, 0.011 mmol) and cesium carbonate (107 mg, 0.328 mmol) were added. The solution was charged with nitrogen three times. The mixture was stirred at 100° C. for 16 hours. Then, the reaction mixture was poured into water (8 mL) and extracted with ethyl acetate (5 mL×3). The organic layer was washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate and concentrated to give the crude. The residue was purified by TLC (silica, petroleum ether:ethyl acetate=1:1) to obtain Compound 54-4.

(523) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.71 (d, J=7.6 Hz, 2H), 7.40 (t, J=7.6 Hz, 1H), 5.37 (s, 2H), 5.23 (d, J=7.2 Hz, 1H), 3.91-3.76 (m, 4H), 3.58-3.50 (m, 2H), 3.19-3.14 (m, 2H), 2.98-2.92 (m, 1H), 2.80-2.73 (m, 1H), 2.42-2.37 (m, 1H), 1.00-0.95 (m, 2H), 0.94 (s, 9H), 0.11 (s, 3H), 0.10 (s, 3H), 0.03-0.01 (s, 9H).

(524) MS-ESI [M+H].sup.+: calculated value: 607 and 609; measured value: 607 and 609

(525) Step 3

(526) Compound 54-4 (30.0 mg, 0.049 mmol) was dissolved in N,N-dimethylformamide (1.0 mL), and Compound 54-5 (17.0 mg, 0.059 mmol), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (3.6 mg, 0.005 mmol) and cesium carbonate (48.3 mg, 0.148 mmol) were added. The solution was charged with nitrogen three times. The mixture was stirred at 100° C. for 16 hours. Then, the reaction mixture was added into water (8 mL) and extracted with ethyl acetate (5 mL×3). The organic layer was washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate and concentrated to obtain 54-6.

(527) MS-ESI [M+H].sup.+: calculated value: 574; measured value: 574.

(528) Step 4

(529) Compound 54-6 (0.028 g, 0.049 mmol) was dissolved in dioxane (2 mL), and hydrochloric acid/dioxane (2 mL, 4 M) was added. The mixture was stirred at 60° C. for 10 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (hydrochloride system) to obtain Compound 54-7.

(530) .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ 8.33-8.24 (m, 2H), 7.93 (d, J=8.0 Hz, 1H), 7.75 (d, J=7.6 Hz, 1H), 7.48 (t, J=7.6 Hz, 1H), 7.39 (d, J=8.0 Hz, 1H), 5.24 (d, J=7.2 Hz, 1H), 4.94-4.90 (m, 1H), 3.84-3.65 (m, 4H), 3.25-3.11 (m, 3H), 2.89-2.83 (m, 1H), 2.46-2.42 (m, 1H), 1.44 (d, J=6.0 Hz, 6H).

(531) MS-ESI [M+H].sup.+: calculated value: 444; measured value: 444.

Example 55

(532) ##STR00172## ##STR00173##

(533) Step 1

(534) Compound 55-1 (200 mg, 0.743 mmol) was dissolved in anhydrous toluene (3 mL), and Compound 55-2 (153 mg, 1.49 mmol) and p-toluenesulfonic acid monohydrate (28.3 mg, 0.149 mmol) were added. The mixture was stirred at 130° C. for 12 hours while water was separated by a water separator. Water (10 mL) was added after the mixture was cooled to room temperature and the mixture was extracted with ethyl acetate (10 mL×3). The organic layers were combined and washed with saturated brine (10 mL×2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by TLC (3:1 petroleum ether/ethyl acetate, R.sub.f=0.5) to obtain Compound 55-3. MS-ESI [M+H].sup.+: calculated value: 336 and 338; measured value: 336 and 338.

(535) Step 2

(536) The reaction was referred to Step 4 of Example 1. The residue was purified by TLC (3:1 petroleum ether/ethyl acetate, R.sub.f=0.5) to obtain Compound 55-4.

(537) .sup.1H NMR: (400 MHz, CDCl.sub.3) δ 7.68 (d, J=7.6 Hz, 1H), 7.59 (d, J=7.6 Hz, 1H), 7.43 (t, J=7.6 Hz, 1H), 4.21-4.17 (m, 1H), 4.12-4.08 (m, 1H), 3.84-3.82 (m, 1H), 3.48-3.42 (m, 1H), 3.03-2.94 (m, 2H), 2.90-2.87 (m, 1H), 2.41-2.35 (m, 1H), 1.95-1.93 (m, 1H), 1.09 (d, J=6.4 Hz, 3H), 1.04 (d, J=6.4 Hz, 3H).

(538) MS-ESI [M+H].sup.+: calculated value: 283; measured value: 283.

(539) Step 3

(540) The reaction referred to Step 5 of Example 1. The residue was purified by TLC (0:1 petroleum ether/ethyl acetate, R.sub.f=0.2) to obtain Compound 55-5. MS-ESI [M+H].sup.+: calculated value: 316; measured value: 316.

(541) Step 4

(542) The reaction referred to Step 6 of Example 1. The residue was purified by TLC (1:1 petroleum ether/ethyl acetate, R.sub.f=0.5) to obtain Compound 55-7.

(543) .sup.1H NMR: (400 MHz, CDCl.sub.3) δ 8.37 (s, 1H), 8.26 (d, J=8.8 Hz, 1H), 8.20 (d, J=7.6 Hz, 1H), 7.49-7.42 (m, 2H), 7.06 (d, J=7.6 Hz, 1H), 4.76-4.72 (m, 1H), 4.18-4.15 (m, 1H), 4.08-4.04 (m, 1H), 3.78-3.77 (m, 1H), 3.53-3.51 (m, 1H), 3.28-3.24 (m, 1H), 3.01-2.97 (m, 1H), 2.86-2.80 (m, 1H), 2.39-2.32 (m, 1H), 1.96-1.93 (m, 1H), 1.48 (d, J=6.0 Hz, 6H), 1.05 (d, J=6.4 Hz, 3H), 0.98 (d, J=6.4 Hz, 3H).

(544) MS-ESI [M+H].sup.+: calculated value: 485; measured value: 485.

(545) Step 5

(546) Compound 55-7 (40.0 mg, 0.0823 mmol) was dissolved in anhydrous dichloromethane (2 mL), and triethylsilylhydrogen (24.0 mg, 0.206 mmol) was added. Then, titanium tetrachloride (39.2 mg, 0.206 mmol) was slowly added dropwise at −78° C. The mixture was stirred at 25° C. for 12 hours under nitrogen atmosphere. Then, saturated aqueous ammonium chloride solution (10 mL) was added into the reaction mixture and the mixture was extracted with dichloromethane (10 mL×3). The organic layers were combined and washed with saturated brine (10 mL×2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography to obtain Compound 55-8.

(547) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) δ 8.49-8.44 (m, 2H), 8.19 (d, J=7.6 Hz, 1H), 7.80 (d, J=7.6 Hz, 1H), 7.48-7.45 (m, 2H), 5.23 (d, J=7.2 Hz, 1H), 4.95-4.93 (m, 1H), 4.58-4.56 (m, 1H), 4.05-4.03 (m, 1H), 3.81-3.76 (m, 2H), 3.61-3.59 (m, 1H), 3.21-3.15 (m, 1H), 2.90-2.83 (m, 1H), 2.53-2.49 (m, 1H), 2.00-1.96 (m, 1H), 1.48 (d, J=6.0 Hz, 6H), 0.99 (d, J=6.4 Hz, 3H), 0.69 (d, J=6.4 Hz, 3H).

(548) MS-ESI [M+H].sup.+: calculated value: 487; measured value: 487.

Example 56

(549) ##STR00174## ##STR00175##

(550) Step 1

(551) The reaction referred to Step 1 of Example 55. The residue was purified by TLC (3:1 petroleum ether/ethyl acetate, R.sub.f=0.5) to obtain Compound 56-3. MS-ESI [M+H].sup.+: calculated value: 308 and 309; measured value: 308 and 309.

(552) Step 2

(553) The reaction referred to Step 4 of Example 1. The residue was purified by TLC (3:1 petroleum ether/ethyl acetate, R.sub.f=0.5) to obtain Compound 56-4.

(554) .sup.1H NMR: (400 MHz, CDCl.sub.3) δ 7.68-7.59 (m, 2H), 7.39 (t, J=15.6 Hz, 1H), 4.32-4.29 (m, 1H), 4.20-4.16 (m, 1H), 4.00-3.97 (m, 1H), 3.42-3.35 (m, 1H), 2.96-2.80 (m, 3H), 2.33-2.26 (m, 1H), 1.44 (d, J=6.4 Hz, 3H).

(555) [M+H].sup.+: calculated value: 255; measured value: 255.

(556) Step 3

(557) The reaction referred to Step 5 of Example 1. The residue was purified by TLC (0:1 petroleum ether/ethyl acetate, R.sub.f=0.2) to obtain Compound 56-5. [M+H].sup.+: calculated value: 288; measured value: 288.

(558) Step 4

(559) The reaction referred to Step 6 of Example 1. The residue was purified by TLC (1:1 petroleum ether/ethyl acetate, R.sub.f=0.5) to obtain Compound 56-7.

(560) .sup.1H NMR: (400 MHz, CDCl.sub.3) δ 8.35 (s, 1H), 8.28-8.19 (d, J=8.8 Hz, 1H), 7.58-7.54 (d, J=8.8 Hz, 1H), 7.44 (t, J=8.8 Hz, 1H), 7.06 (d, J=8.8 Hz, 1H), 6.91 (d, J=8.8 Hz, 1H), 4.74-4.73 (m, 1H), 4.64-4.61 (m, 1H), 4.30-4.28 (m, 1H), 4.23-4.19 (m, 1H), 4.06-4.04 (m, 1H), 3.53-3.51 (m, 1H), 3.26-3.22 (m, 1H), 2.83-2.79 (m, 1H), 2.38-2.31 (m, 1H), 1.48 (d, J=6.4 Hz, 3H), 1.47 (d, J=6.0 Hz, 6H).

(561) [M+H].sup.+: calculated value: 457; measured value: 457.

(562) Step 5

(563) The reaction referred to Step 5 of Example 55. The residue was purified by high performance liquid chromatography to obtain Compound 56-8.

(564) .sup.1H NMR: (400 MHz, Methonal-d.sub.4) δ 8.48-8.43 (m, 2H), 8.19 (d, J=7.6 Hz, 1H), 7.76 (d, J=7.6 Hz, 1H), 7.50-7.45 (m, 2H), 5.20 (d, J=7.2 Hz, 1H), 5.00-4.95 (m, 1H), 3.97-3.95 (m, 1H), 3.77-3.71 (m, 3H), 3.27-3.25 (m, 1H), 3.23-3.21 (m, 1H), 2.84-2.77 (m, 1H), 2.45-2.40 (m, 1H), 1.47 (d, J=6.0 Hz, 6H), 1.27 (d, J=6.4 Hz), 3H).

(565) [M+H].sup.+: calculated value: 459; measured value: 459.

Experimental Example 1

(566) Test Method:

(567) 1. Cell Processing

(568) i) Thaw the PathHunter cell strain according to the standard procedures.

(569) ii) Seed the cell in the 20 μL 384-microwell plate and incubate at 37° C. for an appropriate period.

(570) 2. Agonist

(571) i) For agonist testing, cells were incubated with the sample to be test to initiate a reaction;

(572) ii) The stock solution to be tested has been diluted 5 folds to be a buffer solution;

(573) iii) Inject the 5-fold diluted solution (5 μL) into the cells and incubate at 37° C. for 90-180 minutes. The solvent concentration was 1%.

(574) 3. Signal Detection

(575) i) Add 12.5 μL or 15 μL PathHunter detection reagent (50 vol. %) in one portion. Then, incubate at room temperature for 1 hour and generate the detection signal;

(576) ii) Use PerkinElmer Evision™ instrument to read the microwell plate to proceed with chemiluminescent signal detection.

(577) 4. Data Analysis

(578) i) Use CBIS data analysis system for the compound activity analysis.

(579) ii) Calculation formula:
%.Math.activity=100%.Math.×(Average RLU of samples to be tested−Average RLU of solvents)/(Average maximum control ligand−Average RLU of solvents)

(580) The experimental results were shown as Table 1.

(581) TABLE-US-00001 TABLE 1 Testing results of S1P1 receptor agonistic activity Sample to be tested S1P1 receptor (Compound prepared in each example) agonistic activity Example 1 Mixture/Isomer 1/Isomer 2 +++/+++/+++ Example 2 +++ Example 3 +++ Example 4 +++ Example 5 +++ Example 6 +++ Example 7 +++ Example 8 +++ Example 9 +++ Example 10 +++ Example 11 +++ Example 12 +++ Example 13 +++ Example 14 +++ Example 15 ++ Example 16 + Example 17 + Example 18 + Example 19 + Example 20 + Example 21 + Example 22 + Example 23 + Example 24 + Example 25 +++ Example 26 +++ Example 27 +++ Example 28 + Example 29 + Example 30 + Example 31 + Example 32 + Example 33 + Example 34 + Example 35 Compound 35-2/Compound 35-3 +/+ Example 36 + Example 37 + Example 38 + Example 39 ++ Example 40 +++ Example 41 + Example 42 + Example 43 ++ Example 44 ++ Example 45 +++ Example 46 +++ Example 47 +++ Example 48 +++ Example 49 ++ Example 50 +++ Example 51 +++ Example 52 +++ Example 53 +++ Example 54 ++ Example 55 ++ Example 56 +++ Note: 100 nM < “+”; 10 nM ≤ “++” < 100 nM; “+++” < 10 nM

(582) Conclusion: The compounds of the present invention have significant and unexpected S1P1 receptor agonistic activity.

Experimental Example 2: Evaluation of Compound Pharmacokinetic

(583) Aim of the experiments: To test pharmacokinetics of the compounds in SD rats.

(584) Experimental Materials:

(585) Sprague Dawley rats (male, 200-300 g, 7-9 weeks old, Shanghai Slack)

(586) Experimental Procedure:

(587) The rodent pharmacokinetic characteristics of the compounds after intravenous injection and oral administration were tested by the standard protocol. In the experiments, the transparent solution was prepared with the compounds to be test. The rats were administered single intravenous injection and oral administration. The solvent for intravenous injection and oral administration was aqueous hydroxypropyl β-cyclodextrin solution or normal saline solution with a certain concentration. Collect the blood samples within 24 hours and centrifuge at 3000 G for 15 minutes. Separate the supernatant to obtain the plasma samples. A volume of acetonitrile solution containing internal standard was added 4 times as the sample to precipitate the protein. The supernatant was obtained after centrifuge. An equal volume of water was added and then centrifuge again to collect the supernatant. The LC-MS/MS method was used to quantitatively analyze the blood drug concentration and the pharmacokinetic parameters such as peak concentration, peak time, clearance rate, half-life period, area under the curve of the drug concentration, and fraction of bioavailability, etc. were calculated.

(588) Experimental Results:

(589) TABLE-US-00002 TABLE 2 Testing results of pharmacokinetics Sample to Half- be tested life Drug (Compound Clearance period: concentration Fraction of prepared in rate T.sub.1/2 integral: AUC bioavailability: each example) (mL/min/kg) (h) (nM .Math. hr) F (%) Ozanimod 46.3 5.24 1123 41.6 (3 mpk) Example 1 44.3 1.48 1114 42.8 Isomer 1 (3 mpk) Example 1 11.5 3.46 6825 85.8 Isomer 2 (3 mpk) Example 14 7.22 3.27 5763 59 (2 mpk) Example 26 7.5 26.7 4353 88.2 (2 mpk) Example 27 8.86 21.2 4779 92.6 (2 mpk) Example 40 14.1 10.7 444 82.3 (2 mpk) Example 50 6.59 4.82 8518 72.4 (2 mpk) Example 56 14.6 1.63 3322 66.7 (2 mpk)

(590) Conclusion: The compounds of the present invention can significantly increase the single or partial parameters of rat pharmacokinetics compared with Ozanimod.