Heterocyclic derivative having PGD2 receptor antagonist activity

Abstract

The present invention is related to a compound represented by formula (I), ##STR00001## wherein X.sup.1, X.sup.2, X.sup.3, X.sup.4, X.sup.5, R.sup.5, R.sup.6, R.sup.7, R.sup.8, n, p, q, ring A and ring B are as described in the specification, or a pharmaceutically acceptable salt thereof.

Claims

1. A compound of general formula (I) or a pharmaceutically acceptable salt thereof: ##STR00683## wherein ring A is a formula of: ##STR00684## wherein m and r are independently 1 or 2; and wherein each R.sup.6 is independently a halogen, cyano, substituted alkyl or unsubstituted alkyl; wherein ring B is: ##STR00685## wherein R.sup.7 is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic carbocyclyl oxy or substituted or unsubstituted non-aromatic carbocyclyl oxy; wherein —X.sup.1═ is —C(R.sup.1)═; wherein —X.sup.2═ is —C(R.sup.2)═; wherein —X.sup.3═ is —C(R.sup.3)═; wherein —X.sup.4═ is —C(R.sup.4)═; wherein —X.sup.5═ is —N═; and wherein R.sup.5 of the following formula (i) is formula: -L-R.sup.9; such that: ##STR00686## wherein R.sup.1 of formula (i-1) is a hydrogen atom or halogen; wherein R.sup.2 of formula (i-1) is a hydrogen atom, halogen, substituted alkyl or unsubstituted alkyl; wherein R.sup.3 of formula (i-1) is a hydrogen atom, halogen, substituted alkyl or unsubstituted alkyl; wherein R.sup.4 of formula (i-1) is a hydrogen atom; wherein -L- of formula (i-1) is substituted or unsubstituted methylene; and wherein R.sup.9 of formula (i-1) is carboxy; wherein n is 1 or 2; wherein q is 0; and wherein p is 0 or 1.

2. A pharmaceutical composition comprising the compound of claim 1 or the pharmaceutically acceptable salt thereof.

3. The compound or the pharmaceutically acceptable salt thereof according to claim 1, which is represented by one of the following structural formulas: ##STR00687## ##STR00688##

4. A pharmaceutical composition comprising the compound or the phaimaceutically acceptable salt thereof of claim 3.

5. The compound or the pharmaceutically acceptable salt thereof according to claim 1, which is represented by the following structural formula: ##STR00689##

6. The compound or the pharmaceutically acceptable salt thereof according to claim 1, which is represented by the following structural formula: ##STR00690##

7. The compound or the pharmaceutically acceptable salt thereof according to claim 1, which is represented by the following structural formula: ##STR00691##

8. The compound or the pharmaceutically acceptable salt thereof according to claim 1, which is represented by the following structural formula: ##STR00692##

9. The compound or the pharmaceutically acceptable salt thereof according to claim 1, which is represented by the following structural formula: ##STR00693##

10. The compound or the pharmaceutically acceptable salt thereof according to claim 1, which is represented by the following structural formula: ##STR00694##

11. The compound or the pharmaceutically acceptable salt thereof according to claim 1, which is represented by the following structural formula: ##STR00695##

12. The compound or the pharmaceutically acceptable salt thereof according to claim 1, which is represented by the following structural formula: ##STR00696##

13. The compound or the pharmaceutically acceptable salt thereof according to claim 1, which is represented by the following structural formula: ##STR00697##

14. The compound or the pharmaceutically acceptable salt thereof according to claim 1, which is represented by the following structural formula: ##STR00698##

15. A pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt thereof of claim 5.

16. A pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt thereof of claim 6.

17. A pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt thereof of claim 7.

18. A pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt thereof of claim 8.

19. A pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt thereof of claim 9.

20. A pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt thereof of claim 10.

21. A pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt thereof of claim 11.

22. A pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt thereof of claim 12.

23. A pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt thereof of claim 13.

24. A pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt thereof of claim 14.

Description

REFERENCE EXAMPLE 1

(1) ##STR00072##
Step 1

(2) Compound iii-2 was synthesized from Compound iii-1 in a similar manner as described in Journal of Medicinal Chemistry, 1992, Vol. 35, No. 12, p. 2155-2162.

(3) .sup.1H-NMR (DMSO-d.sub.6) δ: 6.97 (1H, m), 7.27 (1H, d, J=9.60 Hz), 7.75 (1H, dd, J=8.59, 5.05 Hz), 12.70 (2H, brs).

(4) Step 2

(5) Compound iii-2 was reacted with isopropyl alcohol to obtain Compound III-1 in a similar manner as described in the above document.

(6) .sup.1H-NMR (CDCl.sub.3) δ: 1.24 (6H, d, J=6.32 Hz), 3.97 (2H, s), 5.06 (1H, qq, J=6.32, 6.32 Hz), 6.94 (1H, td, J=9.00, 2.11 Hz), 7.08 (1H, dd, J=9.06, 2.11 Hz), 7.68 (1H, dd, J=8.52, 5.22 Hz), 9.92 (1H, s).

(7) The following indazole isopropyl acetate derivatives were synthesized by the method in a similar manner to the above.

(8) ##STR00073##
Compound III-2

(9) .sup.1H-NMR (CDCl3) δ: 7.73 (1H, d, J=8.1 Hz), 7.46-7.35 (2H, m), 7.17 (1H, t, J=7.4 Hz), 5.10-5.01 (1H, m), 4.00 (2H, s), 1.23 (6H, d, J=6.3 Hz).

(10) Compound III-3

(11) .sup.1H-NMR (CDCl3) δ: 7.86 (1H, d, J=8.6 Hz), 7.76 (1H, s), 7.40 (1H, d, J=8.7 Hz), 5.10-5.02 (1H, m), 4.03 (2H, s), 1.24 (6H, d, J=6.2 Hz).

(12) Compound III-4

(13) .sup.1H-NMR (CDCl.sub.3) δ: 7.62 (1H, d, J=8.54 Hz), 7.47 (1H, s), 7.08 (1H, d, J=8.85 Hz), 5.03 (1H, t, J=6.33 Hz), 3.96 (2H, s), 1.22 (6H, d, J=6.41 Hz).

(14) Compound III-5

(15) .sup.1H-NMR (CDCl.sub.3) δ: 7.60 (1H, d, J=8.2 Hz), 7.20 (1H, s), 6.99 (1H, d, J=8.2 Hz), 5.09-5.00 (1H, m), 3.96 (2H, s), 2.48 (3H, s), 1.23 (6H, d, J=6.3 Hz).

(16) Compound III-6

(17) .sup.1H-NMR (CDCl.sub.3) δ: 9.78 (1H, s), 7.56 (1H, d, J=7.9 Hz), 7.17-7.14 (2H, m), 7.08 (2H, t, J=7.5 Hz), 5.12-4.99 (1H, m), 3.99 (2H, s), 2.53 (3H, s), 1.23 (7H, d, J=6.2 Hz).

REFERENCE EXAMPLE 2

(18) ##STR00074##

(19) Compound iii-4 was synthesized from Compound iii-3 in a similar manner as described in U.S. Pat. No. 4,008,070, and was used in the next step without purification. The obtained compound was reacted with isopropylalcohol in a similar manner as described in Reference Example 1, Step 2 to give Compound III-7.

(20) .sup.1H-NMR (CDCl.sub.3) δ: 10.04 (1H, brs), 7.41-7.34 (2H, m), 7.16 (1H, td, J=8.9, 2.4 Hz), 5.11-5.02 (1H, m), 3.97 (2H, s), 1.25 (6H, d, J=6.3 Hz).

(21) The following indazole acetate derivatives were synthesized by the method in a similar manner to the above.

(22) ##STR00075##
Compound III-8

(23) .sup.1H-NMR (CDCl.sub.3) δ: 9.70 (1H, br s), 7.59 (1H, d, J=9.4 Hz), 6.84-6.80 (2H, m), 5.10-5.02 (1H, m), 3.94 (2H, s), 3.87 (3H, s), 1.23 (6H, d, J=6.3 Hz).

(24) Compound III-9

(25) .sup.1H-NMR (CDCl.sub.3) δ: 9.92 (1H, brs), 7.30-7.22 (2H, m), 6.89 (1H, d, J=6.2 Hz), 4.21 (2H, q, J=7.1 Hz), 4.14 (2H, s), 2.65 (3H, s), 1.26 (3H, t, J=7.11 Hz).

REFERENCE EXAMPLE 3

(26) ##STR00076##
Step 1

(27) In a similar manner as described in Acta Chemica Scandinavica, 1998, 52, 1214, Compound iv-1 (170 mg, 0.748 mmol) was dissolved in DMF (2 mL), and 60% sodium hydride (35.9 mg, 0.897 mmol) was added to the reaction mixture under ice-cooling. After the mixture was stirred for 30 minutes at room temperature, benzyl bromide (107 μL, 0.897 mmol) was added dropwise to the mixture at room temperature, and the resulting mixture was stirred for 24 hours. Water was added to the reaction mixture under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed by water and brine, and was dried over anhydrous magnesium sulfate. The mixture was concentrated in vacuo and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate).

(28) The obtained compound (210 mg, 0.662 mmol) was dissolved in acetonitrile (3 mL). To the reaction mixture was added a solution of sodium periodate (425 mg, 1.985 mmol) in water (3 mL) at room temperature. 10% osmium tetroxide (168 mg, 0.066 mmol) was added to the mixture, and the resulting mixture was stirred for 6 hours and standed for 2 days. The reaction mixture was diluted by water (5 mL) and ethyl acetate (5 mL), and the insoluble was removed by filtration using Celite. The filtrate was extracted with ethyl acetate. The organic layer was washed by water and brine, and dried over anhydrous magnesium sulfate. The mixture was concentrated in vacuo and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound iv-2 (117 mg, 2 steps, Yield 49%).

(29) LC/MS (Condition B) RT=2.72, [M+H].sup.+=320.

(30) Step 2

(31) Under nitrogen atmosphere, Compound iv-2 (50 mg, 0.157 mmol) was dissolved in dichloromethane (2 mL), and DAST (46 μL, 0.344 mmol) was gradually added dropwise at −78° C. The reaction mixture was allowed to warm to room temperature gradually over 6 hours with stirring and left standing overnight. To the mixture was added saturated aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed by water and brine, and dried over anhydrous magnesium sulfate. The mixture was concentrated in vacuo and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound iv-3 (36 mg, Yield 68%).

(32) Step 3

(33) Compound iv-3 (35 mg, 0.103 mmol) was dissolved in ethanol (1 mL), and Pd(OH).sub.2 (10 mg) was added to the mixture. The mixture was stirred for 4 hours under hydrogen atmosphere at atmospheric pressure. After the reaction was completed, the insoluble was removed by filtration using Celite. The filtrate was concentrated in vacuo to give Compound IV-1 (26 mg, Yield 100%).

(34) .sup.1H-NMR (CDCl.sub.3) δ: 5.94 (1H, tt, J=56.3, 4.4 Hz), 4.13-3.99 (1H, m), 3.81-3.59 (2H, m), 3.26-3.00 (2H, m), 2.36-2.19 (1H, m), 1.93-1.73 (2H, m), 1.46 (9H, s).

REFERENCE EXAMPLE 4

(35) ##STR00077##
Step 1

(36) Compound iv-2 (63 mg, 0.197 mmol) was dissolved in THF (2 mL) under nitrogen atmosphere, and sodium borohydride (8.95 mg, 0.237 mmol) was added to the solution at room temperature. The mixture was stirred for 2 hours at room temperature, and 1 mol/L aqueous hydrochloric acid was added to the resulting mixture. The mixture was extracted with ethyl acetate. The organic layer was washed by brine, and dried over anhydrous magnesium sulfate. The mixture was concentrated in vacuo and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound iv-4 (63 mg, Yield 99%).

(37) Step 2

(38) Compound iv-4 (60 mg, 0.187 mmol) was dissolved in dichloromethane (2 mL) under nitrogen atmosphere, and DAST (37 μL, 0.280 mmol) was added dropwise to the solution at −78° C. gradually. The reaction mixture was allowed to warm to room temperature gradually and stirred for 6 hours, and left standing overnight. Saturated aqueous sodium bicarbonate was added to the mixture and the resulting mixture was extracted with ethyl acetate. The organic layer was washed by water and brine, and dried over anhydrous magnesium sulfate. The mixture was concentrated in vacuo and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound iv-5 (25 mg, Yield 41%).

(39) Step 3

(40) Compound iv-5 (24 mg, 0.074 mmol) was dissolved in ethanol (1 mL), and Pd(OH).sub.2 (10 mg) was added to the solution. The mixture was stirred for 15 hours under hydrogen atmosphere at atmospheric pressure. After the reaction was completed, the insoluble was removed by filtration using Celite. The filtrate was concentrated in vacuo to give Compound IV-2 (18 mg, Yield 100%).

(41) .sup.1H-NMR (CDCl.sub.3) δ: 4.70-4.55 (1H, m), 4.55-4.40 (1H, m), 4.13-4.02 (1H, m), 3.78-3.55 (2H, m), 3.31-2.99 (2H, m), 2.26-2.11 (1H, m), 2.01-1.78 (2H, m), 1.46 (9H, s).

REFERENCE EXAMPLE 5

(42) ##STR00078##
Step 1

(43) Pyrazole (37 mg, 0.536 mmol) was dissolved in DMF (1.5 mL) under ice-cooling. To a solution was added 60% sodium hydride (21 mg, 0.536 mmol), and the mixture was stirred for 10 minutes. To the reaction mixture, the solution of Compound iv-6 (146 mg, 0.357 mmol) which was synthesized in a similar manner as described in Medicinal Chemistry letters, 2011, vol. 2, no. 2 p. 142-147, in DMF (1.5 mL) was added dropwise, and the resulting mixture was stirred for 1.5 hours at 60° C. After the reaction mixture was allowed to cool to room temperature, water was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed by water and brine, dried over magnesium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound iv-7 (136 mg, Yield 100%).

(44) .sup.1H-NMR (CDCl.sub.3) δ: 7.48 (1H, s), 7.29 (1H, s), 6.25 (1H, s), 4.64-4.33 (1H, m), 4.29 (1H, dd, J=14.27, 2.69 Hz), 4.23-4.12 (1H, br m), 3.73-3.59 (1H, br m), 3.36-3.00 (2H, m), 2.16-1.96 (1H, m), 1.95-1.80 (1H, m), 1.54-1.47 (9H, m), 0.82 (9H, s), 0.00 (−0.03) (6H, m).

(45) Step 2

(46) Compound iv-7 (136 mg, 0.356 mmol) was dissolved in THF (2.5 mL). To a solution was added 1.0 mol/L tetrabutylammonium fluoride in THF (0.535 mL, 0.535 mmol) under ice-cooling, and the mixture was stirred for 4 hours at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed by brine, and dried over sodium sulphate. The mixture was concentrated in vacuo and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound IV-3 (92 mg, Yield 97%).

(47) .sup.1H-NMR (CDCl.sub.3) δ: 7.52 (1H, d, J=1.85 Hz), 7.35 (1H, br s), 6.30 (1H, dd, J=2.18, 1.85 Hz), 4.72-4.35 (2H, m), 4.32-4.22 (1H, m), 4.06 (1H, br s), 3.61-3.30 (1H, br m), 3.11 (1H, dd, J=11.75, 4.36 Hz), 2.34-2.10 (1H, br m), 2.07-1.96 (1H, m), 1.56 (9H, s).

REFERENCE EXAMPLE 6

(48) ##STR00079##
Step 1

(49) Compound iv-6 (3.27 g, 7.98 mmol) was dissolved in THF (10 ml). To the solution was added 1 mol/L lithium triethylborohydride in THF (23.95 mL) under ice-cooling, and the mixture was stirred for 3 hours at room temperature. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed by brine, and concentrated in vacuo to give Compound iv-8 (3 g, Yield 99%).

(50) .sup.1H-NMR (CDCl.sub.3) δ: 4.34 (1H, t, J=4.88 Hz), 3.97-3.93 (1H, m), 3.43-3.39 (1H, m), 3.34-3.30 (1H, m), 2.01-1.98 (1H, m), 1.68-1.65 (1H, m), 1.46 (9H, d, J=1.37 Hz), 1.20 (3H, d, J=6.25 Hz), 0.87 (9H, d, J=1.53 Hz), 0.06 (6H, s).

(51) Step 2

(52) Compound iv-8 (2.52 g, 7.99 mmol) was dissolved in THF (13 mL). To the solution was added 1 mol/L tetra butylammonium fluoride in THF (15.97 mL, 15.97 mmol) under ice-cooling, and the mixture was stirred for 10 hours under ice-cooling. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed by water and brine, and concentrated in vacuo to give Compound IV-4 (1.6 g, Yield 99.5%).

(53) .sup.1H-NMR (CDCl.sub.3) δ: 4.42-4.39 (1H, m), 4.02-3.99 (1H, m), 3.49-3.46 (2H, m), 2.11-2.08 (1H, m), 1.76-1.73 (1H, br m), 1.57-1.53 (1H, m), 1.47 (9H, s), 1.24 (3H, t, J=5.26 Hz).

REFERENCE EXAMPLE 7

(54) ##STR00080##
Step 1

(55) Compound iv-9 (815 mg, 2.67 mmol) which was described in Heterocycles, 2000, vol. 53, No. 1, p. 173-182, was dissolved in THF (8 mL). To the solution were added 1.0 mol/L methyltriisopropoxytitanium in THF (3.21 mL, 3.21 mmol) and 3.0 mol/L ethylmagnesium bromide in diethyl ether (1.78 mL, 5.34 mmol), and the mixture was stirred for 24 hours at room temperature. To the reaction mixture were added diethyl ether (1.55 mL) and water (0.052 mL), and the resulting mixture was stirred for 4.5 hours at room temperature. After the precipitated solid was removed by filtration using Hy-flo-super cell, the filtrate was dried over sodium sulphate, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound iv-10 (218 mg, Yield 26%).

(56) .sup.1H-NMR (CDCl.sub.3) δ: 7.32-7.24 (5H, m), 4.52-4.42 (1H, m), 3.49 (1H, d, J=12.93 Hz), 3.42 (1H, d, J=12.93 Hz), 2.91 (1H, dd, J=10.83, 7.05 Hz), 2.62 (1H, dd, J=10.83, 4.11 Hz), 2.13 (1H, dd, J=13.01, 7.05 Hz), 1.90 (1H, dd, J=13.01, 4.11 Hz), 0.95-0.83 (10H, m), 0.75-0.65 (1H, m), 0.53-0.44 (1H, m), 0.40-0.31 (1H, m), 0.03-0.00 (6H, m).

(57) Step 2

(58) Compound iv-10 (218 mg, 0.686 mmol) was dissolved in THF (4 mL). To the solution was added 1.0 mol/L tetrabutylammonium fluoride in THF (1.03 mL, 1.03 mmol) under ice-cooling, and the mixture was stirred for 2 hours at room temperature and left standing overnight. The reaction mixture was concentrated, and water was added to the residue. After the mixture was extracted with ethyl acetate, the organic layer was washed by brine and dried over magnesium sulphate. The mixture was concentrated in vacuo and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound IV-5 (105 mg, Yield 76%).

(59) .sup.1H-NMR (CDCl.sub.3) δ: 7.38-7.24 (5H, m), 4.48-4.40 (1H, m), 3.50 (1H, d, J=13.09 Hz), 3.27 (1H, d, J=13.09 Hz), 2.87-2.75 (2H, m), 2.30 (1H, dd, J=13.76, 7.13 Hz), 1.97 (1H, dd, J=13.76, 2.27 Hz), 0.95-0.83 (2H, m), 0.59 (1H, dd, J=8.56, 5.71 Hz), 0.37 (1H, dd, J=8.39, 5.71 Hz).

REFERENCE EXAMPLE 8

(60) ##STR00081##
Step 1

(61) Compound iv-11 (181 mg, 0.485 mmol) which was synthesized by the method in a similar manner as described in US2008/9497, was dissolved in THF (2 mL) and methanol (1 mL). To the solution was added 2 mol/L aqueous sodium hydroxide (0.97 mL, 1.94 mmol), and the mixture was stirred for 2.5 hours at room temperature. After the mixture was left standing overnight, to the mixture were added water and 10% aqueous citric acid. The resulting mixture was extracted with ethyl acetate. The organic layer was washed by brine, and dried over magnesium sulphate. The mixture was concentrated in vacuo, and the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to give Compound iv-12 (101 mg, Yield 85%).

(62) .sup.1H-NMR (CDCl.sub.3) δ: 4.40-4.26 (1H, m), 3.90-3.58 (1H, m), 3.47 (1H, dd, J=11.92, 3.86 Hz), 2.83-2.39 (1H, m), 2.15-1.90 (1H, m), 1.60 (3H, d, J=19.81 Hz), 1.51-1.43 (9H, m).

(63) Step 2

(64) Compound iv-12 (99 mg, 0.405 mmol) was dissolved in THF (2 mL). To the solution were added triethylamine (0.084 mL, 0.608 mmol) and benzyl bromide (0.072 mL, 0.608 mmol), and the mixture was stirred for 26.5 hours at room temperature. The reaction mixture was filtered and filtrate was concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound IV-6 (93 mg, Yield 68%).

(65) .sup.1H-NMR (CDCl.sub.3) δ: 7.39-7.33 (5H, m), 5.31-5.12 (2H, m), 4.28-4.16 (1H, br m), 3.88-3.39 (3H, m), 2.33-2.20 (1H, m), 2.15-2.00 (1H, m), 1.63-1.53 (3H, m), 1.46-1.35 (9H, m).

REFERENCE EXAMPLE 9

(66) ##STR00082##

(67) Compound iv-13 (2.83 g, 8.31 mmol) which is described in Tetrahedron, 2005, vol. 61, 2005, 3725-3731, was dissolved in 2-propanol (42 mL). To the solution was added Pd-Carbon (2.8 g), and the mixture was stirred for 47 hours under hydrogen atmosphere at atmospheric pressure. The reaction mixture was diluted with ethyl acetate and filtered using Celite The filtrate was concentrated in vacuo and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound IV-7 (145.1 mg, Yield 5.8%) and Compound IV-8 (163.2 mg, Yield 6.5%).

(68) Compound IV-7

(69) .sup.1H-NMR (CDCl.sub.3) δ: 3.90-3.19 (5H, m), 2.33-2.24 (1H, m), 1.50-1.43 (18H, m), 1.13-1.08 (3H, m).

(70) Compound IV-8

(71) .sup.1H-NMR (CDCl.sub.3) δ: 4.23-4.17 (1H, br m), 4.03-3.49 (4H, m), 2.29-2.19 (1H, m), 1.50-1.46 (18H, m), 1.21-1.17 (3H, m).

(72) Compound IV-9 and Compound IV-10 were synthesized by the method in a similar manner to the above.

(73) ##STR00083##
Compound IV-9

(74) .sup.1H-NMR (CDCl.sub.3) δ: 3.90-3.20 (5H, m), 2.34-2.25 (1H, m), 1.50-1.44 (18H, m), 1.14-1.08 (3H, m).

(75) Compound IV-10

(76) .sup.1H-1-NMR (CDCl.sub.3) δ: 4.20 (1H, br s), 3.84-3.76 (1H, m), 3.67-3.49 (2H, m), 2.29-2.20 (1H, br m), 1.51-1.46 (18H, m), 1.22-1.17 (3H, m).

REFERENCE EXAMPLE 10

(77) ##STR00084##

(78) To a solution of Compound iv-14 (1.0 g, 5.17 mmol) in methanol (20 mL) were added 10% Pd-Carbon (wet 50%) (0.22 g) and Boc.sub.2O (1.32 mL), and the mixture was stirred under hydrogen atmosphere. The reaction mixture was filtered using Celite, and the filtrate was concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (methanol-chloroform) to give Compound iv-15 (0.42 g, Yield 40%).

(79) To the mixture of Compound iv-15 (300 mg, 1.48 mmol) in dichloromethane (3 mL) and THF (6 mL) was added pyridine (0.239 mL, 2.95 mmol) and the mixture was added dropwise methanesulfonyl chloride (0.121 mL, 1.55 mmol) under ice-cooling. To the reaction mixture was added triethylamine (0.409 mL, 2.95 mmol), and the resulting mixture was stirred. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed by aqueous citric acid, aqueous sodium bicarbonate, and brine, dried over anhydrous magnesium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography to give Compound iv-16 (148 mg, Yield 30%).

(80) To a solution of Compound iv-16 (90 mg, 0.32 mmol) in dichloromethane (1 mL), was added DAST (0.127 mL) under ice-cooling, and the mixture was stirred at room temperature. After aqueous sodium bicarbonate was added to the reaction mixture under ice-cooling, the resulting mixture was extracted with ethyl acetate. The organic layer was washed by aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate-chloroform) to give crude product of Compound IV-11 (47 mg).

REFERENCE EXAMPLE 11

(81) ##STR00085##
Step 1

(82) Compound vii-1 (1.0 g, 7.35 mmol) was dissolved in acetonitrile (25 mL). To the solution was added concentrated hydrochloric acid (10 mL) at room temperature. The reaction mixture was allowed to cool to 0° C., and a solution of sodium nitrite (608 mg, 8.82 mmol) in water (1 mL) was added to the mixture. The reaction mixture was stirred for 1.5 hours at 0° C. To the reaction mixture was added acetic acid (12 mL), and the resulting mixture was stirred for 10 minutes at 0° C. In addition, sodium hydrogensulfate (7.64 g, 73.5 mmol) was added to the mixture and the resulting mixture was stirred for 5 minutes. Copper (II) chloride (988 mg, 7.35 mmol) and copper (I) chloride (72.7 mg, 0.735 mmol) were added to the mixture at the same timing. The resulting solution was allowed to warm to room temperature gradually from 0° C. and stirred for 3.5 hours. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed by water and brine, and dried over anhydrous magnesium sulfate. The mixture was concentrated in vacuo, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound VII-1 (965 mg, Yield 60%).

(83) .sup.1H-NMR (CDCl.sub.3) δ: 8.26 (1H, dd, J=9.0, 4.9 Hz), 7.69 (1H, dd, J=7.5, 2.6 Hz), 7.54 (1H, ddd, J=9.4, 6.8, 2.2 Hz).

(84) LC/MS (Condition B) RT=1.80, [M+H].sup.+=220.

(85) The following sulfonyl chloride derivatives were synthesized in a similar manner described in the above.

(86) ##STR00086##
Compound VII-2

(87) .sup.1H-NMR (CDCl3) δ: 7.84 (1H, t, J=8.7 Hz), 6.77-6.71 (2H, m), 4.68-4.59 (1H, m), 1.40 (6H, d, J=6.1 Hz).

(88) Compound VII-3

(89) .sup.1H-NMR (CDCl3) δ: 6.59-6.53 (2H, m), 4.11 (2H, q, J=6.9 Hz), 1.47 (3H, t, J=7.0 Hz).

REFERENCE EXAMPLE 12

(90) ##STR00087##
Step 1

(91) To a solution of Compound vii-2 (2.0 g, 11.49 mmol) in DMF (20 mL) was added sodium hydride (0.644 g, 16.09 mmol) at room temperature, and the mixture was stirred for 30 minutes. Iodoethane (1.858 mL, 22.99 mmol) was added to the mixture and the resulting mixture was stirred for additional 3.5 hours at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed by water and brine, dried over anhydrous magnesium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound vii-3 (2.32 g, Yield 100%).

(92) .sup.1H-NMR (CDCl.sub.3) δ: 8.03 (1H, d, J=2.75 Hz), 7.35 (1H, d, J=8.69 Hz), 7.07 (1H, dd, J=8.62, 2.97 Hz), 4.05 (2H, q, J=6.91 Hz), 1.43 (3H, t, J=6.94 Hz).

(93) Step 2

(94) To a solution of Compound vii-3 (1.5 g, 7.42 mmol) in toluene (15 mL) were added α-toluene thiol (0.966 ml, 8.17 mmol), DIPEA (2.85 mL, 16.33 mmol), Pd.sub.2(dba).sub.3 (0.272 g, 0.297 mmol) and Xantphos (0.344 g, 0.594 mmol) under nitrogen atmosphere, and the mixture was stirred for 6.5 hours at 85° C. The reaction mixture was allowed to cool to room temperature, and diluted with ethyl acetate. The insoluble was removed by filtration by using Celite. The filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound vii-4 (1.82 g, Yield 100%).

(95) .sup.1H-NMR (CDCl.sub.3) δ: 8.18 (1H, s), 7.36-7.02 (7H, m), 4.36 (2H, s), 4.04 (2H, q, J=6.91 Hz), 1.42 (3H, t, J=7.02 Hz).

(96) Step 3

(97) To the mixture of Compound vii-4 (1.82 g, 7.42 mmol), acetic acid (12 mL), and purified water (4 mL), under nitrogen atmosphere was added N-chlorosuccinimide (3.73 g, 27.9 mmol) at room temperature, and the mixture was stirred for 3 hours. After the reaction mixture was concentrated in vacuo, water was added to the resulting mixture. The mixture was extracted with ethyl acetate. The organic layer was washed by brine, dried over anhydrous magnesium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound VII-4 (1.34 g, Yield 80%).

(98) .sup.1H-1-NMR (CDCl.sub.3) δ: 8.40 (1H, d, J=1.8 Hz), 8.04 (1H, d, J=8.7 Hz), 7.33 (1H, t, J=5.7 Hz), 4.21 (2H, ddd, J=14.0, 6.9, 1.1 Hz), 1.51 (3H, td, J=7.0, 1.2 Hz).

(99) The following compound was synthesized by the method in a similar manner to the above.

(100) ##STR00088##
Compound VII-5

(101) LC/MS (Condition B) RT=2.10, [M+H].sup.+=236.

REFERENCE EXAMPLE 13

(102) ##STR00089##

(103) To a solution of 2-ethoxythiazole (2.0 g, 15.5 mmol) in THF (40 mL) was added dropwise 1.02 mol/L sec-butyl lithium in hexane (16.7 mL, 17.0 mmol) at −78° C. under nitrogen atmosphere, and the mixture was stirred for 1 hour at the same temperature. To the reaction mixture was added sulfur dioxide (9.92 g, 155 mmol), and the resulting mixture was stirred for 3 hours at room temperature. N-chlorosuccinimide (2.07 g, 15.5 mmol) was added to the mixture, and the resulting mixture was stirred for additional 1 hour at room temperature. To the reaction mixture was added 2 mol/L aqueous hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was by purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound VII-6 (2.27 g, Yield 65%).

REFERENCE EXAMPLE 14

(104) ##STR00090##
Step 1

(105) To a solution of 4-hydroxycyclohexanone (2.0 g, 17.5 mmol) in ethanol (8 ml) were added triethyl orthoformate (8.78 ml, 52.6 mmol) and p-toluenesulfonic acid monohydrate (3.3 mg, 0.018 mmol), and the mixture was stirred overnight at room temperature. To the reaction mixture was added saturated aqueous sodium bicarbonate, and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound vii-7 (2.93 g, Yield 89%).

(106) .sup.1H-NMR (CDCl.sub.3) δ: 1.15-1.21 (m, 6H), 1.49-1.60 (m, 4H), 1.76-1.81 (m, 2H), 1.93-2.00 (m, 2H), 3.43-3.50 (m, 4H), 3.77 (brs, 1H).

(107) Step 2

(108) To a solution of Compound vii-7 (2.93 g, 15.6 mmol) in dichloromethane (6 ml) were added triethylamine (6.48 ml, 46.7 mmol) and DMAP (0.571 g, 4.67 mmol) under ice-cooling. Then, a solution of TsCl (4.46 g, 23.4 mmol) in dichloromethane (9 ml) was added dropwise to the mixture, and the resulting mixture was stirred for 19 hours at room temperature. The mixture was concentrated in vacuo and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound vii-8 (4.67 g, Yield 87%).

(109) .sup.1H-NMR (CDCl.sub.3) δ: 1.11-1.18 (m, 6H), 1.58-1.89 (m, 8H), 2.45 (s, 3H), 3.37-3.45 (m, 4H), 4.60-4.65 (m, 1H), 7.33 (d, J=8.0 Hz, 2H), 7.79 (d, J=8.0 Hz, 2H).

(110) Step 3

(111) To the mixture of Compound vii-8 (1.04 g, 3.03 mmol) and triethylsilane (0.58 ml, 3.64 mmol) was added dropwise a solution of trimethylsilyl triflate (5.48 μl, 0.030 mmol) in dichloromethane (0.3 ml) under ice-cooling, and the mixture was stirred for 30 minutes. Then, the reaction mixture was stirred for 3 hours at room temperature. To the mixture was added aqueous sodium bicarbonate, and the resulting mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound vii-9 (0.88 g, Yield 98%) as a mixture of diastereomers (60:40).

(112) .sup.1H-NMR (CDCl.sub.3) δ: 4.14-1.92 (m, 11H), 2.45 (s, 3H), 3.29-3.33 (m, 1H), 3.44 (t, J=6.8 Hz, 2H), 4.50-4.54 (m, 1H, minor isomer), 4.60-4.63 (m, 1H, major isomer), 7.33 (d, J=8.0 Hz, 2H, major isomer), 7.34 (d, J=8.0 Hz, 2H, minor isomer), 7.79 (d, J=8.0 Hz, 2H).

(113) Step 4

(114) To a solution of Compound vii-9 (0.88 g, 2.98 mmol) in DMF (3 ml) was added potassium thiolacetate (0.85 g, 7.44 mmol), and the mixture was stirred for 1 hour at 80° C. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed by water and brine, dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound vii-10 (85.4 mg, Yield 14%) and Compound vii-11 (136 mg, Yield 23%).

(115) Compound vii-10

(116) .sup.1H-NMR (CDCl.sub.3) δ: 1.19 (t, J=6.8 Hz, 3H), 1.34-1.46 (m, 4H), 2.02-2.08 (m, 4H), 2.30 (s, 3H), 3.21-3.26 (m, 1H), 3.37-3.46 (m, 1H), 3.50 (q, J=6.8 Hz, 2H).

(117) Compound vii-11

(118) .sup.1H-NMR (CDCl.sub.3) δ: 1.19 (t, J=6.8 Hz, 3H), 1.66-1.88 (m, 8H), 2.30 (s, 3H), 3.40-3.52 (m, 1H), 3.47 (q, J=6.8 Hz, 2H), 3.59-3.63 (m, 1H).

(119) Step 5

(120) To a solution of Compound vii-10 (85.4 mg, 0.42 mmol) in acetonitrile (0.25 ml) were added 2 mol/L aqueous hydrochloric acid (0.05 ml) and N-chlorosuccinimide (225 mg, 1.69 mmol) under ice-cooling, and the mixture was stirred for 1 hour. To the reaction mixture was added water, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound VII-7 (87.1 mg, Yield 91%).

(121) .sup.1H-NMR (CDCl.sub.3) δ: 1.21 (t, J=6.8 Hz, 3H), 1.31-1.41 (m, 2H), 1.78-1.88 (m, 2H), 2.26-2.29 (m, 2H), 2.46-2.50 (m, 2H), 3.26-3.33 (m, 1H), 3.54 (q, J=6.8 Hz, 2H).

(122) Compound VII-8 was synthesized by the method in a similar manner to the above.

REFERENCE EXAMPLE 15

(123) ##STR00091##
Step 1

(124) To a solution of 4-bromophenol (7.00 g, 40.5 mmol) in DMF (140 ml) was added sodium hydride (60 wt %) (1.94 g, 48.6 mmol), and the mixture was stirred for 30 minutes at room temperature. To the reaction mixture was added (chloromethyl)methyl sulfide (4.01 ml, 48.6 mmol), and the mixture was stirred for 2.5 hours at 50° C. To the reaction mixture was added saturated aqueous ammonium chloride, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed by water, dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound vii-13 (8.84 g, Yield 94%).

(125) .sup.1H-NMR (CDCl.sub.3) δ: 2.24 (s, 3H), 5.12 (s, 2H), 6.82-6.86 (m, 2H), 7.38-7.42 (m, 2H).

(126) Step 2

(127) To a solution of Compound vii-13 (1.00 g, 4.29 mmol) in dichloromethane (6 ml) was added sulfuryl chloride (0.35 ml, 4.29 mmol), and the mixture was stirred for 10 minutes at room temperature. The resulting mixture was concentrated in vacuo. To a solution of the resulting residue in dichloromethane (6 ml) was added dropwise 1.0 mol/L tetrabutylammonium fluoride in THF (8.58 mL, 8.58 mmol) under ice-cooling, and the mixture was stirred for 3 hours at room temperature. The reaction mixture was concentrated in vacuo, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound vii-14 (0.63 g, Yield 71%).

(128) .sup.1H-NMR (CDCl.sub.3) δ: 5.68 (d, J.sub.HF=54.5 Hz, 2H), 6.97 (d, J=8.8 Hz, 2H), 7.44 (d, J=8.8 Hz, 2H).

(129) Step 3

(130) Compound VII-9 was synthesized by the method described in the general procedures c) in the specification.

(131) .sup.1H-NMR (CDCl.sub.3) δ: 5.81 (d, J.sub.HF=53.2 Hz, 2H), 7.24-7.29 (m, 2H), 8.03-8.06 (m, 2H).

REFERENCE EXAMPLE 16

(132) ##STR00092##
Steps 1 to 2

(133) To a solution of Compound xi-1 (75 mg, 0.392 mmol), which was synthesized in a similar manner as described in EP0443498, in dichloromethane, were added dropwise triethylamine (0.109 mL, 0.784 mmol) and methanesulfonyl chloride (46 μL, 0.588 mmol) under nitrogen atmosphere under ice-cooling. After the reaction mixture was stirred for 30 minutes at room temperature, saturated aqueous sodium bicarbonate was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed by brine, and dried over anhydrous magnesium sulfate. The mixture was concentrated in vacuo to give Compound xi-2. Compound xi-2 was used in the next step without purification.

(134) To a solution of the obtained compound xi-2 in DMA (2 mL) was added cesium acetate (226 mg, 1.176 mmol) under nitrogen atmosphere. The mixture was heated at 100° C., and stirred for 7.5 hours. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed by brine, and dried over anhydrous magnesium sulfate. The mixture was concentrated in vacuo, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound xi-3 (50 mg, Yield 55%).

(135) .sup.1H-NMR (CDCl.sub.3) δ: 7.32-7.20 (5H, m), 4.74-4.70 (1H, m), 3.59 (2H, dd, J=35.0, 12.9 Hz), 3.04 (1H, t, J=8.2 Hz), 2.76 (2H, dd, J=10.7, 2.1 Hz), 2.65 (2H, dd, J=11.1, 6.3 Hz), 2.33-2.20 (1H, m), 2.04 (3H, s), 1.95 (1H, t, J=8.5 Hz), 1.11 (3H, d, J=7.2 Hz).

(136) LC/MS (Condition B) RT=1.83, [M+H].sup.+=300.

(137) Step 3

(138) To a solution of Compound xi-3 (50 mg, 0.214 mmol) in ethanol (2 mL) was added Pd(OH).sub.2 (10 mg), and the mixture was stirred for 7 hours under hydrogen atmosphere at atmospheric pressure. After the reaction was completed, the insoluble was removed by filtration using Celite. The filtrate was concentrated in vacuo to give Compound xi-4.

(139) Steps 4 to 5

(140) To a solution of the obtained Compound xi-4 (4 mg, 0.028 mmol) in dichloromethane (1 mL) were added triethylamine (7.7 μL, 0.056 mmol) and 4-isopropoxybenzenesulfonyl chloride (7.2 mg, 0.031 mmol) under nitrogen atmosphere under ice-cooling. The mixture was stirred for 1 hour at room temperature. After the reaction was completed, the mixture was concentrated in vacuo. The resulting residue was dissolved in methanol (1 mL). To the mixture was added 2 mol/L aqueous sodium hydroxide (70 μL, 0.140 mmol) at room temperature. The reaction mixture was stirred for 30 minutes at room temperature, and 2 mol/L aqueous hydrochloric acid (70 μL, 0.140 mmol) and water were added to the mixture. The resulting mixture was extracted with ethyl acetate. The organic layer was washed by brine, and dried over anhydrous magnesium sulfate. The mixture was concentrated in vacuo, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound XI-1 (8.4 mg, Yield 100%).

(141) LC/MS (Condition B) RT=1.83, [M+H].sup.+=300.

(142) Compound XI-2 which is an enantiomer of Compound XI-1, and Compound XI-3 which is a racemic compound of Compound XI-1 were synthesized in a similar manner as described in the above.

(143) ##STR00093##
Compound XI-2

(144) LC/MS (Condition B) RT=1.83, [M+H].sup.+=300.

(145) Compound XI-3

(146) LC/MS (Condition B) RT=1.83, [M+H].sup.+=300.

REFERENCE EXAMPLE 17

(147) ##STR00094##
Step 1

(148) Compound XI-2 (415 mg, 1.386 mmol) was treated in a similar manner as described in Steps 1-2 of Reference Example 8 to give Compound xi-6 (435 mg, Yield 92%).

(149) LC/MS (Condition B) RT=2.21, [M+H].sup.+=342.

(150) Step 2

(151) To a solution of Compound xi-6 (430 mg, 1.259 mmol) in methanol (10 mL) was added 2 mol/L aqueous sodium hydroxide (1.259 mL, 2.52 mmol) at room temperature, and the mixture was stirred for 3.5 hours. After the reaction was completed, 2 mol/L aqueous hydrochloric acid (1.259 mL) and water were added to the mixture. The resulting mixture was extracted with ethyl acetate. The organic layer was washed by water and brine, and dried over anhydrous magnesium sulfate. The mixture was concentrated in vacuo, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound XI-4 (403 mg, Yield 100%).

(152) .sup.1H-NMR (CDCl.sub.3) δ: 7.74 (2H, d, J=8.7 Hz), 6.94 (2H, d, J=8.8 Hz), 4.66-4.58 (1H, m), 4.12 (1H, t, J=3.4 Hz), 3.50-3.44 (2H, m), 3.32 (1H, d, J=11.3 Hz), 2.93 (1H, t, J=9.9 Hz), 2.21-2.03 (1H, m), 1.37 (6H, d, J=5.9 Hz), 0.99 (3H, d, J=6.9 Hz).

(153) LC/MS (Condition B) RT=1.86, [M+H].sup.+=300.

(154) Compound XI-5 which is an enantiomer of Compound XI-4, and Compound XI-6 which is a racemic compound of Compound XI-4 were synthesized in a similar manner as described in the above.

(155) ##STR00095##
Compound XI-5

(156) LC/MS (Condition B) RT=1.86, [M+H].sup.+=300.

(157) Compound XI-6

(158) LC/MS (Condition B) RT=1.86, [M+H].sup.+=300.

REFERENCE EXAMPLE 18

(159) ##STR00096##
Step 1

(160) To a solution of Compound xi-7 (1.03 g, 3.96 mmol), which is described in Organic and Biomolecular Chemistry, 2003, vol. 1, no. 19 p. 3277-3292, in ethyl acetate (10 mL), was added 4 mol/L hydrochloric acid in ethyl acetate (9.91 mL, 39.6 mmol). The mixture was stirred for 1.5 hours at room temperature. To the reaction mixture was added 4 mol/L hydrochloric acid in ethyl acetate (1.98 mL, 7.93 mmol), and the resulting mixture was stirred for additional 2 hours. The reaction mixture was concentrated in vacuo, and the resulting residue was dissolved in dichloromethane (10 mL). To the mixture was added triethylamine (1.37 mL, 9.91 mmol), and the resulting mixture was stirred for 5 minutes. To the mixture was added 4-isopropoxybenzenesulfonyl chloride (1.02 g, 4.36 mmol) and the resulting mixture was stirred for 30 minutes at room temperature. After the reaction mixture was left standing overnight, water and 2 mol/L aqueous hydrochloric acid (1.2 mL) were added to the mixture. The resulting mixture was extracted with ethyl acetate. The organic layer was washed by saturated aqueous sodium bicarbonate and brine, dried over magnesium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound xi-8 (1.25 g, Yield 88%).

(161) .sup.1H-NMR (CDCl.sub.3) δ: 7.86 (2H, d, J=8.90 Hz), 6.99 (2H, d, J=8.90 Hz), 4.73-4.59 (1H, m), 4.53-4.41 (2H, m), 4.30-4.19 (2H, m), 3.63 (1H, dd, J=11.41, 4.03 Hz), 3.46-3.39 (1H, m), 2.33-2.22 (1H, m), 2.20-2.10 (1H, m), 1.41 (6H, d, J=6.04 Hz), 1.33 (3H, t, J=7.16 Hz).

(162) Step 2

(163) Compound xi-8 (500 mg, 1.399 mmol) was dissolved in DMF (10 mL). To the solution was added sodium hydride (67 mg, 1.679 mmol) under ice-cooling. The mixture was stirred for 15 minutes. To the reaction mixture was added benzyl bromide (0.249 mL, 2.098 mmol), and the resulting mixture was allowed to warm to room temperature and stirred for 8 hours. After the mixture was left standing overnight, water was added to the mixture under ice-cooling, and then, the resulting mixture was extracted with ethyl acetate. The organic layer was washed by water and brine, dried over sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound xi-9 (211 mg, Yield 34%).

(164) .sup.1H-NMR (CDCl.sub.3) δ: 7.78 (2H, d, J=8.39 Hz), 7.30-7.23 (3H, m), 7.11-7.04 (2H, m), 6.88 (2H, d, J=8.39 Hz), 4.59-4.50 (1H, m), 4.31-4.17 (5H, m), 4.16-4.10 (1H, m), 3.63 (1H, dd, J=11.29, 4.27 Hz), 3.50 (1H, d, J=11.29 Hz), 2.35-2.23 (1H, m), 2.15-2.03 (1H, m), 1.36-1.23 (9H, m).

(165) Step 3

(166) Compound xi-9 (200 mg, 0.448 mmol) was dissolved in THF (4 mL). To the solution was added lithium borohydride (24 mg, 1.12 mmol) under ice-cooling, and the mixture was stirred for 8.5 hours at room temperature. To the reaction mixture was added lithium borohydride (24 mg, 1.12 mmol), and the resulting mixture was stirred for additional 1.5 hours. After the mixture was left standing overnight, iced-water was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed by 10% aqueous citric acid, saturated aqueous sodium bicarbonate and brine, dried over magnesium sulphate, and concentrated in vacuo. The resulting mixture was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound xi-10 (180 mg, Yield 99%).

(167) .sup.1H-NMR (CDCl.sub.3) δ: 7.80 (2H, d, J=8.90 Hz), 7.34-7.29 (3H, m), 7.10-7.08 (2H, m), 6.90 (2H, d, J=8.90 Hz), 4.63-4.49 (1H, m), 4.27 (2H, s), 4.08-4.01 (1H, br m), 3.97-3.88 (1H, m), 3.80-3.54 (4H, m), 3.04-2.97 (1H, m), 2.07-1.90 (2H, m), 1.40-1.35 (6H, m).

(168) Step 4

(169) Compound xi-10 (121 mg, 0.299 mmol) was dissolved in dichloromethane (2.5 mL). To the solution was added Dess-Martin Periodinane (190 mg, 0.449 mmol) under ice-cooling, and the mixture was stirred for 9 hours at room temperature. The mixture was left standing overnight, 6% aqueous sodium thiosulfate and water were added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed by saturated aqueous sodium bicarbonate and brine, dried over sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound xi-11 (103 mg, Yield 85%).

(170) .sup.1H-NMR (CDCl.sub.3) δ: 9.68 (1H, d, J=3.66 Hz), 7.74 (2H, d, J=8.69 Hz), 7.29-7.23 (3H, m), 7.02-6.96 (2H, m), 6.91 (2H, d, J=8.69 Hz), 4.60-4.51 (1H, m), 4.23 (2H, d, J=2.29 Hz), 4.10-4.04 (1H, br m), 4.00-3.92 (1H, m), 3.68 (1H, dd, J=11.59, 4.27 Hz), 3.48-3.41 (1H, m), 2.20-2.10 (1H, m), 2.09-1.98 (1H, m), 1.37-1.32 (6H, m).

(171) Step 5

(172) Compound xi-11 (102 mg, 0.253 mmol) was dissolved in dichloromethane (2 mL). To the solution was added DAST (0.074 mL, 0.557 mmol), and the mixture was allowed to warm to room temperature gradually and stirred for 1.5 hours. To the mixture was added saturated aqueous sodium bicarbonate, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed by brine, dried over sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound xi-12 (86 mg, Yield 82%).

(173) .sup.1H-NMR (CDCl.sub.3) δ: 7.74 (2H, d, J=8.85 Hz), 7.32-7.24 (3H, m), 7.12-7.07 (2H, m), 6.87 (2H, d, J=8.85 Hz), 6.24 (1H, ddd, J=58.56, 56.58, 1.53 Hz), 4.58-4.49 (1H, m), 4.25 (2H, s), 4.16-4.08 (1H, m), 4.00-3.84 (1H, m), 3.56 (1H, dd, J=11.29, 4.42 Hz), 3.41-3.33 (1H, m), 2.34-2.24 (1H, m), 1.98-1.86 (1H, m), 1.34 (6H, d, J=6.25 Hz).

(174) Step 6

(175) Compound xi-12 (86 mg, 0.208 mmol) was dissolved in ethanol (1.5 mL) and ethyl acetate (0.5 mL). To the solution was added Pd(OH).sub.2 (18 mg), and the mixture was stirred for 3.5 hours under hydrogen atmosphere at room temperature. The reaction mixture was diluted with ethyl acetate, and filtrated by using Hyflo-super cell. The filtrate was concentrated in vacuo, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound XI-7 (68 mg, Yield 98%).

(176) .sup.1H-NMR (CDCl.sub.3) δ: 7.82 (2H, d, J=8.90 Hz), 7.01 (2H, d, J=8.90 Hz), 6.23 (1H, ddd, J=58.50, 54.81, 1.59 Hz), 4.73-4.63 (1H, m), 4.53-4.44 (1H, m), 4.21-3.99 (1H, m), 3.56 (1H, dd, J=11.50, 4.28 Hz), 3.35-3.26 (1H, m), 2.39-2.28 (1H, m), 1.96-1.85 (1H, m), 1.42 (6H, d, J=6.04 Hz).

REFERENCE EXAMPLE 19

(177) ##STR00097##
Step 1

(178) Compound xi-13 (1.02 g, 10.09 mmol) was dissolved in DMF (10 mL). To the solution was added 60% sodium hydride (888 mg, 22.19 mmol) under ice-cooling, and the mixture was stirred for 10 minutes. Benzyl bromide (2.88 mL, 24.21 mmol) was added to the mixture, and the resulting mixture was allowed to warm to room temperature and stirred for 30 minutes. After the mixture was left standing overnight, water was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed by water and brine, dried over magnesium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound xi-14 (1.79 g, Yield 63%).

(179) .sup.1H-NMR (CDCl.sub.3) δ: 7.41-7.24 (10H, m), 4.57-4.45 (4H, m), 4.29-4.22 (1H, m), 3.51 (1H, dd, J=10.74, 6.38 Hz), 3.36 (1H, dd, J=10.74, 3.36 Hz), 2.75 (1H, dd, J=17.29, 6.38 Hz), 2.64 (1H, dd, J=17.29, 3.36 Hz).

(180) Step 2

(181) Compound xi-14 (164 mg, 0.584 mmol) was dissolved in THF (1.75 mL). To the solution were added 1.0 mol/L methyltriisopropoxytitanium in THF (0.70 mL, 0.700 mmol) and 0.90 mol/L ethylmagnesium bromide in THF (1.56 mL, 1.401 mmol), and the resulting mixture was stirred for 24 hours at room temperature. After the mixture was allowed to stand for 3 days, diethyl ether (1.75 mL) and water (0.058 mL) were added to the mixture, and the resulting mixture was stirred for 1 hour at room temperature. The precipitated solid was removed by filtration using Hyflo-super cell. To the filtrate was added water, and the mixture was extracted by diethyl ether. The organic layer was washed by brine, dried over sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound xi-15 (49 mg, Yield 29%).

(182) .sup.1H-NMR (CDCl.sub.3) δ: 7.34-7.24 (10H, m), 4.46 (2H, s), 4.28-4.19 (1H, m), 3.50 (1H, d, J=12.96 Hz), 3.39 (1H, d, J=12.96 Hz), 2.93 (1H, dd, J=11.29, 6.71 Hz), 2.83 (1H, dd, J=11.29, 3.58 Hz), 2.17 (1H, dd, J=13.27, 6.71 Hz), 2.06 (1H, dd, J=13.27, 3.58 Hz), 0.96-0.86 (1H, m), 0.82-0.72 (1H, m), 0.58-0.49 (1H, m), 0.42-0.33 (1H, m).

(183) Step 3

(184) After Compound xi-15 (48 mg, 0.163 mmol) was dissolved in ethanol (2 mL), Pd(OH).sub.2 (9 mg) was added to the solution under hydrogen atmosphere, and the resulting mixture was stirred for 21 hours at room temperature. The reaction mixture was diluted with ethyl acetate, filtered by using Hyflo-super cell, and concentrated in vacuo. The obtained compound was dissolved in dichloromethane (1.5 mL). To the solution were added triethylamine (0.045 mL, 0.326 mmol) and 4-isopropoxybenzenesulfonyl chloride (42.0 mg, 0.179 mmol), and the resulting mixture was stirred for 50 minutes at room temperature. The mixture was left standing overnight, and the reaction residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound xi-16 (31 mg, Yield 47%).

(185) LC/MS (Condition B) RT=2.75, [M+H].sup.+=404.

(186) Step 4

(187) After Compound xi-16 (30 mg, 0.074 mmol) was dissolved in ethanol (1.5 mL), Pd(OH).sub.2 (9.0 mg) was added to the mixture, and the resulting mixture was stirred for 15 hours under hydrogen atmosphere at room temperature. Further, Pd(OH).sub.2 (9.0 mg) was added to the mixture, and the resulting mixture was stirred for 4.5 hours under hydrogen atmosphere at room temperature. The reaction mixture was diluted with ethyl acetate, and the mixture was filtered by using Hyflo-super cell and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound XI-8 (17 mg, Yield 73%).

(188) .sup.1H-NMR (CDCl.sub.3) δ: 7.74 (2H, d, J=8.85 Hz), 6.94 (2H, d, J=8.85 Hz), 4.68-4.58 (1H, m), 4.15-4.04 (1H, m), 3.60-3.50 (1H, m), 3.44 (1H, dd, J=11.74, 5.19 Hz), 3.31 (1H, dd, J=11.74, 5.19 Hz), 2.11-1.89 (2H, m), 1.78-1.62 (3H, m), 1.38 (6H, d, J=6.10 Hz), 0.94 (3H, t, J=7.47 Hz).

REFERENCE EXAMPLE 20

(189) ##STR00098##
Step 1

(190) Compound xi-8 (1.00 g, 2.80 mmol) was dissolved in DMF (15 mL). To the solution were added imidazole (381 mg, 5.60 mmol) and tert-butyldimethylsilyl chloride (464 mg, 3.08 mmol), and the mixture was stirred for 9 hours at room temperature. After the mixture was left standing overnight, water was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed by water and brine, dried over magnesium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound xi-17 (1.22 g, Yield 93%).

(191) .sup.1H-NMR (CDCl.sub.3) δ: 7.78 (2H, d, J=8.73 Hz), 6.92 (2H, d, J=8.73 Hz), 4.66-4.53 (1H, m), 4.42-4.35 (1H, br m), 4.30-4.18 (3H, m), 3.65 (1H, dd, J=10.58, 4.70 Hz), 3.17 (1H, dd, J=10.58, 2.35 Hz), 2.10-2.05 (2H, m), 1.39-1.23 (9H, m), 0.74 (9H, s), −0.05 (3H, s), −0.06 (3H, s).

(192) Step 2

(193) Compound xi-17 (1.20 g, 2.55 mmol) was dissolved in THF (12 mL) and ethanol (6 mL). To the solution was added 2 mol/L aqueous sodium hydroxide (2.55 mL, 5.10 mmol), and the mixture was stirred for 2.5 hours at room temperature. The mixture was neutralized by adding 2 mol/L aqueous hydrochloric acid (5.1 mL) and water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed by brine, dried over magnesium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (chloroform-methanol) to give Compound xi-18 (1.02 g, Yield 90%).

(194) .sup.1H-NMR (CDCl.sub.3) δ: 7.78 (2H, d, J=8.90 Hz), 6.94 (2H, d, J=8.90 Hz), 4.66-4.56 (1H, m), 4.40-4.33 (1H, br m), 4.28-4.19 (1H, m), 3.67 (1H, dd, J=10.58, 4.45 Hz), 3.17 (1H, dd, J=10.58, 2.85 Hz), 2.30-1.99 (2H, m), 1.37 (6H, d, J=6.04 Hz), 0.74 (9H, s), −0.06 (6H, s).

(195) Step 3

(196) Compound xi-18 (150 mg, 0.338 mmol) was dissolved in THF (1.5 mL). To the solution were added HOBt (68.5 mg, 0.507 mmol) and EDC (52.5 mg, 0.338 mmol), and the mixture was stirred for 30 minutes at room temperature. To the reaction mixture was added 28% aqueous ammonia (0.470 mL, 3.38 mmol), and the mixture was stirred for 23.5 hours at room temperature. Additionally, 28% aqueous ammonia (0.470 mL, 3.38 mmol) was added to the mixture, and the resulting mixture was stirred for additional 10 hours at room temperature. After the mixture was left standing overnight, water was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed by water and brine, dried over magnesium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound xi-19 (75.6 mg, Yield 51%).

(197) .sup.1H-NMR (CDCl.sub.3) δ: 7.76 (2H, d, J=8.79 Hz), 6.96 (2H, d, J=8.79 Hz), 6.77 (1H, br s), 5.40 (1H, br s), 4.70-4.57 (1H, m), 4.34-4.25 (1H, m), 4.13-4.05 (1H, m), 3.69 (1H, dd, J=10.71, 4.67 Hz), 3.15 (1H, dd, J=10.71, 4.53 Hz), 2.27-2.16 (1H, m), 1.95-1.84 (1H, m), 1.40-1.35 (6H, m), 0.75 (9H, s), −0.05 (3H, s), −0.08 (3H, s).

(198) Step 4

(199) Compound xi-19 (75 mg, 0.170 mmol) was dissolved in dimethylformamide dimethyl acetal (0.75 mL), and the solution was heated at 100° C. for 2 hours. After the mixture was allowed to cool to room temperature, toluene was added to the mixture, and the resulting mixture was concentrated. The resulting residue was dissolved in acetic acid (1 ml). To the solution was added hydrazine monohydrate (0.017 mL, 0.341 mmol) under ice-cooling, and the mixture was heated at 90° C. and stirred for 1 hour. The mixture was allowed to cool to room temperature, and then, concentrated in vacuo. To the resulting residue were added ethyl acetate and saturated aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed by water and brine, dried over magnesium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound xi-20 (70 mg, Yield 88%).

(200) .sup.1H-NMR (CDCl.sub.3) δ: 7.94 (1H, s), 7.75 (2H, d, J=9.06 Hz), 6.95 (2H, d, J=9.06 Hz), 4.90-4.83 (1H, m), 4.67-4.57 (1H, m), 4.43-4.35 (1H, m), 3.69 (1H, dd, J=10.58, 4.53 Hz), 3.24 (1H, dd, J=10.58, 4.36 Hz), 2.62-2.51 (1H, m), 2.18-2.08 (1H, m), 1.40-1.36 (6H, m), 0.78 (9H, s), −0.02 (3H, s), −0.05 (3H, s).

(201) Step 5

(202) Compound xi-20 (69 mg, 0.147 mmol) was dissolved in THF (1.5 mL). To the solution were added diisopropylethylamine (0.051 mL, 0.294 mmol) and trityl chloride (82 mg, 0.294 mmol), and the mixture was stirred for 1 hour 45 minutes at room temperature. The mixture was left standing overnight, and then, stirred for additional 10 hours. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed by brine, dried over magnesium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound xi-21 (42 mg, Yield 41%).

(203) .sup.1H-NMR (CDCl.sub.3) δ: 7.88 (1H, s), 7.69 (2H, d, J=8.85 Hz), 7.38-7.31 (10H, m), 7.21-7.16 (5H, m), 6.80 (2H, d, J=8.85 Hz), 4.76-4.70 (1H, m), 4.58-4.50 (1H, m), 4.46-4.43 (1H, br m), 3.87 (1H, dd, J=10.83, 4.88 Hz), 3.30-3.24 (1H, m), 2.41-2.30 (1H, m), 2.11-1.99 (1H, m), 1.37-1.32 (6H, m), 0.73 (9H, s), −0.06 (3H, s), −0.06 (3H, s).

(204) Step 6

(205) Compound xi-21 (42 mg, 0.059 mmol) was dissolved in THF (1 mL). To the solution was added 1.0 mol/L tetrabutylammonium fluoride in THF (0.088 mL, 0.088 mmol), and the mixture was stirred for 1.5 hours at room temperature. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed by brine, dried over magnesium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound XI-9 (35 m, Yield 100%).

(206) .sup.1H-NMR (CDCl.sub.3) δ: 7.84 (1H, s), 7.69 (2H, d, J=8.85 Hz), 7.37-7.31 (9H, m), 7.20-7.11 (6H, m), 6.78 (2H, d, J=8.85 Hz), 4.92-4.85 (1H, m), 4.59-4.50 (2H, m), 3.84 (1H, dd, J=11.59, 4.27 Hz), 3.49-3.42 (1H, m), 2.47-2.37 (1H, m), 2.25-2.16 (1H, m), 1.34 (6H, d, J=5.95 Hz).

REFERENCE EXAMPLE 21

(207) ##STR00099##
Step 1

(208) Compound xi-22 (250 mg, 0.964 mmol) was dissolved in 2 mol/L hydrochloric acid in dioxane (2 mL), and the solution was stirred for 10 hours at room temperature. The mixture was concentrated in vacuo to give Compound xi-23 (190 mg, Yield 99%).

(209) .sup.1H-NMR (DMSO-d.sub.6) δ: 9.14 (2H, s), 5.21 (1H, d, J=4.12 Hz), 4.18 (1H, d, J=7.69 Hz), 3.44-3.41 (1H, m), 2.93 (1H, d, J=8.79 Hz), 2.22 (1H, t, J=14.83 Hz), 1.89 (1H, d, J=14.01 Hz), 1.63-1.49 (2H, m).

(210) Step 2

(211) Compound xi-23 (190 mg, 0.971 mmol) was dissolved in dichloromethane (2 mL). To the solution were added 4-isopropoxybenzenesulfonyl chloride (274 mg, 1.165 mmol), and triethylamine (0.404 mL, 2.91 mmol), and the mixture was stirred for 1 hour at room temperature. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed by brine and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound xi-24 (364 mg, Yield 99%).

(212) .sup.1H-NMR (CDCl.sub.3) δ: 7.73 (2H, d, J=8.79 Hz), 6.92 (2H, d, J=8.79 Hz), 4.70 (1H, d, J=6.59 Hz), 4.66-4.58 (1H, m), 4.12 (2H, d, J=7.14 Hz), 3.58 (3H, s), 3.53 (1H, dd, J=12.22, 7.28 Hz), 2.39 (1H, d, J=14.01 Hz), 1.98 (1H, dd, J=12.91, 5.49 Hz), 1.73-1.70 (2H, m), 1.65-1.62 (1H, m), 1.36 (6H, d, J=6.04 Hz).

(213) Step 3

(214) Compound xi-24 (274 mg, 0.767 mmol) was dissolved in pyridine (2 mL). To the solution was added p-tosyl chloride (219 mg, 1.15 mmol), and the mixture was stirred for 5 hours at room temperature. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed by 10% aqueous citric acid and brine, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound xi-25 (148 mg, Yield 37.8%).

(215) LC/MS (Condition B) RT=2.45, [M+H].sup.+=512.

(216) Step 4

(217) Compound xi-25 (187 mg, 0.366 mmol) was dissolved in THF (1 mL). To the solution was added lithium borohydride (20 mg, 0.914 mmol), and the resulting mixture was stirred for 20 hours at room temperature. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed by 10% aqueous citric acid and brine, and concentrated in vacuo to give Compound XI-10 (2.7 g, Yield 99%).

(218) .sup.1H-NMR (CDCl.sub.3) δ: 7.78-7.73 (5H, m), 7.33 (2H, d, J=8.08 Hz), 6.90 (2H, d, J=9.00 Hz), 4.76 (1H, s), 4.60 (1H, dd, J=12.12, 6.02 Hz), 3.98 (1H, s), 3.84 (1H, t, J=12.20 Hz), 3.67-3.59 (2H, m), 3.31 (1H, t, J=11.51 Hz), 2.45 (3H, d, J=4.58 Hz), 2.07 (1H, d, J=7.93 Hz), 1.94 (1H, d, J=16.93 Hz), 1.69 (2H, dd, J=25.16, 9.61 Hz), 1.36 (6H, d, J=6.10 Hz).

REFERENCE EXAMPLE 22

(219) ##STR00100##
Step 1

(220) Compound xi-26 (103 mg, 0.275 mmol) which was synthesized in a similar manner as described in US2008/9497, was dissolved in ethyl acetate (1 mL). To the solution was added 4 mol/L hydrochloric acid in ethyl acetate (1.0 mL, 4.00 mmol), and the mixture was stirred for 25 minutes at room temperature. After the mixture was left standing overnight, and the reaction mixture was concentrated in vacuo to give Compound xi-27. Compound xi-27 was used in the next step without purification.

(221) Step 2

(222) Compound xi-27 was dissolved in dichloromethane (2 mL). To the solution were added triethylamine (0.095 mL, 0.688 mmol) and p-isopropoxybenzenesulfonyl chloride (71 mg, 0.303 mmol), and the mixture was stirred for 2.5 hours at room temperature. The reaction mixture was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound xi-28 (66 mg, 2 steps, Yield 67%).

(223) .sup.1H-NMR (CDCl.sub.3) δ: 7.85-7.79 (2H, m), 6.99-6.93 (2H, m), 4.71-4.61 (1H, m), 4.61-4.52 (1H, m), 3.85-3.78 (4H, m), 3.39 (1H, ddd, J=10.03, 3.23, 1.18 Hz), 2.52 (1H, dd, J=13.60, 5.88 Hz), 2.03 (1H, ddd, J=13.60, 4.36, 1.18 Hz), 1.82 (3H, s), 1.76 (1H, d, J=4.36 Hz), 1.41 (6H, d, J=6.04 Hz).

(224) Step 3

(225) Compound xi-28 (64 mg, 0.178 mmol) was dissolved in THF (1 mL) and methanol (0.5 mL). To the solution was added 2 mol/L aqueous sodium hydroxide (0.355 mL, 0.711 mmol), and the mixture was stirred for 1.5 hours at room temperature. After the mixture was left standing overnight, water and 2 mol/L aqueous hydrochloric acid (0.71 mL) were added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed by brine, dried over magnesium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (chloroform-methanol) to give Compound xi-29 (58 mg, Yield 94%).

(226) .sup.1H-NMR (CDCl.sub.3) δ: 7.85 (2H, d, J=8.90 Hz), 6.97 (2H, d, J=8.90 Hz), 4.72-4.55 (2H, m), 3.82 (1H, dd, J=10.41, 5.71 Hz), 3.37 (1H, dd, J=10.41, 3.36 Hz), 2.67 (1H, dd, J=13.60, 5.88 Hz), 2.10-2.01 (1H, m), 1.84 (3H, s), 1.41 (6H, d, J=6.04 Hz).

(227) Step 4

(228) Compound xi-29 (193 mg, 0.561 mmol) was dissolved in THF (3 mL). To the solution were added triethylamine (0.117 mL, 0.841 mmol) and benzyl bromide (0.100 mL, 0.841 mmol), and the mixture was stirred for 6.5 hours at room temperature. After the mixture was left standing overnight, the reaction mixture was filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound XI-11 (204 mg, Yield 84%).

(229) .sup.1H-NMR (CDCl.sub.3) δ: 7.79-7.73 (2H, m), 7.42-7.31 (5H, m), 6.91-6.85 (2H, m), 5.24 (1H, d, J=12.42 Hz), 5.11 (1H, d, J=12.42 Hz), 4.65-4.55 (1H, m), 4.52-4.43 (1H, m), 3.75 (1H, dd, J=10.07, 5.54 Hz), 3.33 (1H, ddd, J=10.07, 3.69, 1.18 Hz), 2.46 (1H, dd, J=13.43, 5.54 Hz), 1.97 (1H, ddd, J=13.43, 4.03, 1.18 Hz), 1.81 (3H, s), 1.36 (6H, d, J=6.04 Hz).

REFERENCE EXAMPLE 23

(230) ##STR00101##
Step 1

(231) To a solution of Compound xi-30 (4.98 g, 20.3 mmol) in DMF (150 ml) was added sodium hydride (60 wt %) (0.974 g, 24.3 mmol) under ice-cooling, and the mixture was stirred for 10 minutes. Then, benzyl bromide (2.65 ml, 22.3 mmol) was added to the reaction, and the resulting mixture was stirred for 1 hour at room temperature. To the reaction mixture was added saturated aqueous ammonium chloride, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed by water, dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound xi-31 (6.81 g, Yield 78%).

(232) Step 2

(233) To a solution of DIPEA (6.87 ml, 48.9 mmol) in THF (50 ml) was added 1.65 mol/L n-butyllithium in hexane (28.7 mL, 47.3 mmol) at −78° C., and the mixture was stirred for 30 minutes at 0° C. The reaction mixture was allowed to cool to −78° C., and a solution of Compound xi-31 (5.29 g, 15.8 mmol) in THF (50 ml) was added dropwise over 1.5 hours. After the mixture was allowed to warm to −40° C., the resulting mixture was allowed to cool to −78° C. Then, methyl chloroformate (3.64 ml, 47.3 mmol) was added dropwise to the mixture over 30 minutes and the resulting mixture was stirred for 3.5 hours. To the reaction mixture was added saturated aqueous ammonium chloride, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed by 10% aqueous citric acid and saturated aqueous sodium chloride, dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound xi-32 (6.21 g, Yield 96%).

(234) LC/MS (Condition B) RT=2.15, [M+H].sup.+=294.

(235) Step 3

(236) To a solution of lithium aluminium hydride (2.19 g, 57.7 mmol) in THF (30 ml) was added dropwise a solution of Compound xi-32 (5.68 g, 14.4 mmol) in THF (30 ml) over 40 minutes under ice-cooling. The reaction mixture was stirred for 1.5 hours at room temperature. Then, the mixture was diluted with water (8.8 ml) under ice-cooling, and 2 mol/L aqueous sodium hydroxide (2.2 ml) was added to the resulting mixture. The resulting mixture was stirred for 3 hours at room temperature. To the reaction suspension was added anhydrous magnesium sulphate, and mixture was filtered. The filtrate was concentrated in vacuo and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound xi-33 (0.87 g, Yield 18%).

(237) LC/MS (Condition B) RT=1.77, [M+H].sup.+=338.

(238) Step 4

(239) Compound xi-33 (0.87 g, 2.6 mmol) was cooled, and 4 mol/L hydrochloric acid in 1,4-dioxane (5 ml) was added. The reaction mixture was stirred for 3.5 hours at room temperature. The resulting mixture was concentrated in vacuo, and the resulting residue was dissolved in dichloromethane (5 ml) To the mixture were added triethylamine (1.08 ml, 7.8 mmol) and 4-ethoxybenzenesulphonyl chloride (0.69 g, 3.1 mmol) under ice-cooling, and the resulting mixture was stirred for 1 hour at room temperature. The mixture was concentrated in vacuo and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound xi-34 (0.62 g, Yield 57%).

(240) LC/MS (Condition B) RT=1.93, [M+H].sup.+=422.

(241) Step 5

(242) To a solution of Compound xi-34 (0.59 g, 1.4 mmol) in THF (6 ml) were added 1.65 mol/L n-butyllithium in hexane (0.84 mL, 1.4 mmol) and a solution of TsCl (0.27 g, 1.4 mmol) in THF (6 ml) under ice-cooling, and the mixture was stirred for 1.5 hours at 0° C. To the reaction mixture was added 1.65 mol/L n-butyllithium in hexane (0.84 mL, 1.4 mmol), the resulting mixture was stirred for 30 minutes at 0° C. and for 1 hour at 60° C. To the reaction mixture was added saturated aqueous ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound xi-35 (253 mg, Yield 45%).

(243) .sup.1H-NMR (CDCl.sub.3)δ:1.43 (t, J=7.0 Hz, 3H), 2.26 (dd, J=13.6, 4.3 Hz, 1H), 2.75 (d, J=13.3 Hz, 1H), 3.48 (dd, J=10.7, 4.1 Hz, 1H), 3.59 (d, J=11.0 Hz, 1H), 4.03-4.08 (m, 3H), 4.41 (s, 2H), 4.46 (m, 2H), 5.22 (d, J=6.3 Hz, 1H), 5.56 (d, J=6.0 Hz, 1H), 6.90 (d, J=9.0 Hz, 2H), 7.17 (d, J=6.5 Hz, 2H), 7.28-7.34 (m, 3H), 7.79 (d, J=8.8 Hz, 2H).

(244) LC/MS (Condition B) RT=2.16, [M+H].sup.+=404.

(245) Step 6

(246) To a solution of Compound xi-35 (253 mg, 0.63 mmol) in ethanol (2 ml) was added 10 wt % Pd(OH).sub.2 (44 mg), and mixture was stirred for 8.5 hours under hydrogen atmosphere. The mixture was filtered off, and the filtrate was concentrated in vacuo. The resulting residue was dissolved in dichloromethane (2 ml). To the mixture was added a mixture of triethylamine (0.22 mL, 1.58 mmol), trimethylamine hydrochloride (15 mg, 0.16 mmol), TsCl (165 mg, 0.87 mmol) and dichloromethane (2 ml) under ice-cooling, and the resulting mixture was stirred for 20 hours at room temperature. The reaction mixture was concentrated in vacuo, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound XI-12 (197 mg, Yield 80%).

(247) LC/MS (Condition B) RT=2.11, [M+H].sup.+=468.

REFERENCE EXAMPLE 24

(248) ##STR00102## ##STR00103##
Step 1

(249) To a solution of Compound xi-36 (10.2 g, 100 mmol) in dichloromethane (100 ml) were added MsCl (12.5 ml, 160 mmol) and a mixture of triethylamine (21.8 ml, 150 mmol) and dichloromethane (30 ml) under ice-cooling, and the mixture was stirred for 1.5 hours at 0° C. To the reaction mixture was added water, and the resulting mixture was extracted with dichloromethane. The organic layer was washed by water, dried over anhydrous magnesium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate).

(250) To a solution of the obtained Compound in acetonitrile (170 ml) were added benzylamine (12.1 ml, 111 mmol) and DIPEA (14.3 ml, 111 mmol) under ice-cooling, and the mixture was stirred for 16 hours at room temperature. The mixture was concentrated in vacuo and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound xi-37 (11.2 g, Yield 64%).

(251) .sup.1H-NMR (CDCl.sub.3)δ:2.39 (dd, J=17.4, 4.6 Hz, 1H), 2.39 (dd, J=17.4, 4.6), 3.66-3.71 (m, 1H), 3.78 (d, J=13.6 Hz, 1H), 3.82 (d, J=13.6 Hz, 1H), 4.10-4.15 (m, 1H), 4.37 (dd, J=8.8, 6.0 Hz, 1H), 7.24-7.37 (m, 5H).

(252) Step 2

(253) To a solution of Compound xi-37 (2.16 g, 1.3 mmol) in acetonitrile (20 ml) were added DIPEA (7.90 ml, 45.2 mmol) and methyl bromoacetate (4.18 ml, 45.2 mmol) under ice-cooling, and the mixture was stirred for 24 hours at room temperature. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed by water, dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound xi-38 (2.34 g, Yield 79%).

(254) .sup.1H-NMR (CDCl.sub.3)δ:2.61 (dd, J=17.5, 7.5 Hz, 1H), 2.61 (dd, J=17.4, 7.9 Hz, 1H), 3.33 (s, 2H), 3.69 (s, 3H), 3.77 (d, J=13.8 Hz, 1H), 3.85 (d, J=13.8 Hz, 1H), 3.99-4.06 (m, 1H), 4.23 (dd, J=9.2, 6.6 Hz, 1H), 4.45 (dd, J=8.2, 8.2 Hz, 1H), 7.28-7.36 (m, 5H).

(255) LC/MS (Condition RT=1.60, [M+H].sup.+=264.

(256) Step 3

(257) To a solution of Compound xi-38 (10.9 g, 41 mmol) in toluene (110 ml) was added 1.0 mol/L potassium tert-butoxide in THF (49.5 mL, 50 mmol) under ice-cooling, and the mixture was stirred for 20 minutes at 0° C. The reaction mixture was added to 2 mol/L aqueous hydrochloric acid (25 ml, 50 mmol), and neutralized. To the mixture was added saturated aqueous sodium bicarbonate, and the resulting mixture was made alkaline. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound xi-39 (6.06 g, Yield 64%).

(258) .sup.1H-NMR (DMSO-d6)δ:2.98 (d, J=16.6 Hz, 1H), 3.09 (d, J=16.8 Hz, 1H), 3.59 (d, J=13.3 Hz, 1H), 3.83 (d, J=6.3 Hz, 1H), 3.89-3.91 (m, 1H), 4.11 (d, J=13.3 Hz, 1H), 4.31 (dd, J=9.8, 3.3 Hz, 1H), 4.41 (d, J=10.0 Hz, 1H), 7.28-7.36 (m, 5H).

(259) LC/MS (Condition B) RT=1.48, [M+H].sup.+=232.

(260) Step 4

(261) To a solution of Compound xi-39 (50 mg, 0.22 mmol) in methanol (1 ml) was added sodium borohydride (8.2 mg, 0.22 mmol) at −78° C., and the mixture was stirred for 5.5 hours. To the reaction mixture were added 2 mol/L aqueous hydrochloric acid (0.11 ml, 0.22 mmol) and water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound xi-40 (31 mg, Yield 62%).

(262) .sup.1H-NMR (CDCl.sub.3)δ:2.55 (dd, J=10.3, 4.5 Hz, 1H), 2.83 (d, J=4.0 Hz, 1H), 3.11 (d, J=10.3 Hz, 1H), 3.34 (dd, J=7.8, 7.8 Hz, 1H), 3.43 (dd, J=7.0, 7.0 Hz, 1H), 3.65 (d, J=12.8 Hz, 1H), 3.76 (d, J=13.1 Hz, 1H), 4.09 (d, J=9.8 Hz, 1H), 4.15 (dd, J=9.4, 5.4 Hz, 1H), 4.57-4.58 (m, 1H), 7.28-7.36 (m, 5H).

(263) Step 5

(264) To a solution of Compound xi-40 (0.65 g, 2.8 mmol) in ethanol (20 ml) was added 10 wt % Pd(OH).sub.2/C (65 mg), and the mixture was stirred for 21.5 hours under hydrogen atmosphere. The mixture was filtered off, and the filtrate was concentrated in vacuo. The resulting residue was dissolved in dichloromethane (20 ml). To the mixture were added triethylamine (0.78 mL, 5.6 mmol) and 4-ethoxybenzenesulphonyl chloride (0.74 g, 3.4 mmol) under ice-cooling, and the resulting mixture was stirred for 2 hours at room temperature. The mixture was concentrated in vacuo, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound xi-41 (0.80 g, Yield 87%).

(265) .sup.1H-NMR (DMSO-d6)δ:1.36 (t, J=6.9 Hz, 3H), 2.99 (dd, J=9.9, 2.6 Hz, 1H), 3.26 (dd, J=9.9, 6.1 Hz, 1H), 3.40 (d, J=10.0 Hz, 1H), 4.13 (q, J=6.9 Hz, 2H), 4.19 (dd, J=8.8, 5.3 Hz, 1H), 4.28-4.34 (m, 2H), 4.50 (dd, J=8.3, 8.3 Hz, 1H), 5.83 (d, J=3.8 Hz, 1H), 7.15 (d, J=8.3 Hz, 2H), 7.74 (d, J=8.3 Hz, 2H).

(266) LC/MS (Condition B) RT=1.37, [M+H].sup.+=328.

(267) Step 6

(268) To a solution of Compound xi-41 (100 mg, 0.31 mmol) in THF (0.5 ml) were added hexamethyldisiloxane (0.26 ml, 1.2 mmol), benzaldehyde (0.062 ml, 0.61 mmol), and trimethylsilyl triflate (0.083 ml, 0.46 mmol) at −20° C. After the mixture was stirred for 2 hours at −20° C., triethylsilane (0.15 ml, 0.92 mmol) was added to the mixture, and the resulting mixture was stirred for 1.5 hours (−20° C. to room temperature). To the reaction mixture was added saturated aqueous sodium bicarbonate, and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound xi-42 (101 mg, Yield 80%).

(269) .sup.1H-NMR (CDCl.sub.3)δ:1.46 (t, J=7.0 Hz, 3H), 3.14 (dd, J=10.8, 3.8 Hz, 1H), 3.23 (dd, J=9.8, 6.3 Hz, 1H), 3.73 (d, J=10.8 Hz, 1H), 4.10 (q, J=7.3 Hz, 2H), 4.23 (brm, 1H), 4.39-4.47 (m, 2H), 4.56-4.62 (m, 3H), 6.99 (d, J=8.5 Hz, 2H), 7.29-7.36 (m, 5H), 7.74 (d, J=8.5 Hz, 2H).

(270) LC/MS (Condition B) RT=2.09, [M+H].sup.+=418.

(271) Step 7

(272) To a solution of Compound xi-42 (665 mg, 1.59 mmol) in THF (7 ml) was added lithium aluminium hydride (121 mg, 3.19 mmol) under ice-cooling, and the mixture was stirred for 1 hour at 0° C. To the resulting mixture was added aqueous saturated potassium sodium tartrate, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound xi-43 (637 mg, Yield 95%).

(273) .sup.1H-NMR (CDCl.sub.3)δ:1.45 (t, J=6.9 Hz, 3H), 2.00-2.03 (m, 1H), 2.50-2.53 (m, 1H), 3.14-3.17 (m, 2H), 3.73 (d, J=11.8 Hz, 1H), 3.76-3.81 (m, 1H), 3.85-3.93 (m, 4H), 4.02 (t, J=4.8 Hz, 1H), 4.09 (q, J=6.7 Hz, 2H), 4.35 (d, J=11.8 Hz, 1H), 4.65 (d, J=11.5 Hz, 1H), 6.97 (d, J=8.5 Hz, 2H), 7.31-7.37 (m, 5H), 7.77 (d, J=8.8 Hz, 2H).

(274) LC/MS (Condition B) RT=1.83, [M+H].sup.+=422.

(275) Step 8

(276) To a solution of Compound xi-43 (562 mg, 1.33 mmol) in THF (10 ml) were added triphenylphosphine (770 mg, 2.94 mmol) and bis(2-methoxyethyl)azodicarboxylate (686 mg, 2.94 mmol) under ice-cooling, and the mixture was stirred for 1 hour. The mixture was concentrated in vacuo, and the resulting residue was dissolved in diethyl ether. The organic layer was washed by water, dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound xi-44 (521 mg, Yield 97%).

(277) .sup.1H-NMR (CDCl.sub.3)δ:1.46 (t, J=6.9 Hz, 3H), 2.83-2.90 (m, 1H), 3.19 (dd, J=9.7, 9.7 Hz, 1H), 3.51 (dd, J=9.7, 9.7 Hz, 1H), 3.61-3.66 (m, 2H), 3.71 (ddd, J=7.5, 7.5, 7.5 Hz, 1H), 4.04-4.11 (m, 3H), 4.24 (dd, J-9.4, 3.9 Hz, 1H), 4.33 (dd, J=5.9, 5.9 Hz, 1H), 4.39 (d, J=12.0 Hz, 1H), 4.44 (d, J=12.0 Hz, 1H), 6.94 (d, 8.3 Hz, 2H), 7.24-7.36 (m, 5H), 7.71 (d, J=8.3 Hz, 2H).

(278) LC/MS (Condition B) RT=2.20, [M+H].sup.+=404.

(279) Step 9

(280) To a solution of Compound xi-44 (530 mg, 1.29 mmol) in THF (5 ml)-methanol (5 ml), was added 10 wt % Pd(OH).sub.2 (52 mg), and the mixture was stirred for 4.5 hours under hydrogen atmosphere. The mixture was filtered off, and the filtrate was concentrated in vacuo. The resulting residue was dissolved in dichloromethane (4 ml). To the mixture was added a mixture of triethylamine (0.35 mL, 2.49 mmol), trimethylamine hydrochloride (36 mg, 0.37 mmol), TsCl (355 mg, 1.86 mmol) and dichloromethane (2 ml) under ice-cooling, and the resulting mixture was stirred for 1 hour at 0° C. The mixture was concentrated in vacuo, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound XI-13 (529 mg, Yield 88%).

(281) .sup.1H-NMR (DMSO-d6)δ:1.37 (t, J=6.9 Hz, 3H), 2.44 (s, 3H), 2.94-2.97 (m, 1H), 3.18 (dd, J=11.8. 5.3 Hz, 1H), 3.24-3.29 (m, 2H), 3.54 (dd, J=9.7, 4.6 Hz, 1H), 3.81 (d, J=10.0 Hz, 1H), 3.91 (d, J=9.8 Hz, 1H), 4.00-4.03 (m, 1H), 4.14 (q, J=6.9, 2H), 4.49 (dd, J=11.7, 5.4 Hz, 1H), 7.12 (d, J=8.3 Hz, 2H), 7.49 (d, J=7.8 Hz, 2H), 7.70 (d, J=8.3 Hz, 2H), 7.75 (d, J=8.0 Hz, 2H).

(282) LC/MS (Condition B) RT=2.16, [M+H].sup.+=468.

REFERENCE EXAMPLE 25

(283) ##STR00104## ##STR00105##
Step 1

(284) To a solution of Compound xi-45 (1.58 g, 3.81 mmol) in dichloromethane (20 mL) were added triethylamine (1.27 mL, 9.15 mmol), trimethylamine hydrochloride (109 mg, 1.14 mmol), and p-toluenesulfonyl chloride (1017 mg, 5.33 mmol) under ice-cooling, and the mixture was stirred for 4 hours at room temperature. To the reaction mixture was added 10% aqueous citric acid, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed by brine, dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound xi-46 (2.05 g, Yield 95%).

(285) .sup.1H-NMR (CDCl.sub.3) δ: −0.09 (3H, s), −0.07 (3H, s), 0.73 (9H, s), 1.45 (3H, t, J=6.9 Hz), 1.76-1.85 (1H, m), 1.92-2.02 (1H, m), 2.46 (3H, s), 3.00 (1H, d, J=10.3 Hz), 3.51 (1H, dd, J=10.7, 4.0 Hz), 3.79 (1H, s), 4.02-4.10 (3H, m), 4.26-4.28 (1H, m), 4.42 (1H, d, J=9.8 Hz), 6.93 (2H, d, J=8.7 Hz), 7.37 (2H, d, J=7.8 Hz), 7.68 (2H, d, J=8.5 Hz), 7.82 (2H, d, J=8.0 Hz).

(286) Step 2

(287) Under nitrogen atmosphere, to a solution of dimethyl malonate (1.89 mL, 16.5 mmol) in DMF (20 mL) was added sodium hydride (658 mg, 16.5 mmol) under ice-cooling, and the resulting mixture was stirred for 1 hour at room temperature. To the reaction mixture was added a solution of Compound xi-46 (1.87 g, 3.29 mmol) in DMF (10 mL), and the resulting mixture was stirred for 5 hours at 100° C. After the mixture was cooled, to the reaction mixture was added saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate. The organic layer was washed by water and brine, dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound xi-47 (1.40 g, Yield 80%).

(288) .sup.1H-NMR (CDCl.sub.3) δ: −0.08 (3H, s), −0.05 (3H, s), 0.74 (9H, s), 1.26 (1H, t, J=7.0 Hz), 1.44 (3H, t, J=6.9 Hz), 1.49-1.56 (1H, m), 1.64-1.72 (1H, m), 2.09-2.19 (1H, m), 2.32-2.42 (1H, m), 3.04 (1H, dd, J=11.0, 4.3 Hz), 3.58 (1H, dd, J=11.0, 5.2 Hz), 3.70 (1H, t, J=7.3 Hz), 3.76 (3H, s), 3.77 (3H, s), 4.03-4.10 (2H, m), 4.31-4.34 (1H, m), 6.95 (2H, d, J=8.2 Hz), 7.73 (2H, d, J=8.3 Hz).

(289) Step 3

(290) Under nitrogen atmosphere, to a suspension of lithium aluminium hydride (401 mg, 10.6 mmol) in THF (15 mL) was added dropwise a solution of Compound xi-47 (1.40 g, 2.64 mmol) in THF (15 mL) over 20 minutes under ice-cooling. Then, the mixture was stirred for 2 hours at room temperature. To the reaction mixture was added aqueous saturated potassium sodium tartrate, and the mixture was extracted with ethyl acetate. The organic layer was washed by water and brine, dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound xi-48 (739 mg, Yield 59%).

(291) .sup.1H-NMR (CDCl.sub.3) δ: −0.07 (3H, s), −0.05 (3H, s), 0.75 (9H, s), 1.45 (3H, t, J=6.9 Hz), 1.66-1.85 (2H, m), 1.93-2.02 (1H, m), 2.33 (1H, t, J=5.1 Hz), 2.41 (1H, t, J=5.3 Hz), 3.08 (1H, dd, J=10.8, 3.6 Hz), 3.59 (1H, dd, J=10.9, 5.0 Hz), 3.68-3.86 (5H, m), 4.08 (2H, q, J=7.0 Hz), 4.27-4.34 (1H, m), 6.96 (2H, d, J=8.0 Hz), 7.74 (2H, d, J=7.8 Hz).

(292) Step 4

(293) Under nitrogen atmosphere, to a solution of Compound xi-48 (739 mg, 1.56 mmol) in THF (8 mL) was added 1.65 mol/L n-butyllithium in hexane (0.95 mL, 1.56 mmol) under ice-cooling, and the mixture was stirred for 30 minutes. To the mixture was added a solution of p-toluenesulfonyl chloride (297 mg, 1.56 mmol) in THF (8 mL), and the resulting mixture was allowed to warm to room temperature and stirred for 1 hour. To the reaction mixture was added 1.65 mol/L n-butyllithium in hexane (0.95 mL, 1.56 mmol) under ice-cooling, and the resulting mixture was stirred for 2 hours at 60° C. After the mixture was cooled, to the reaction mixture was added saturated aqueous ammonium chloride, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed by brine, dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound xi-49 (637 mg, Yield 90%).

(294) .sup.1H-NMR (CDCl.sub.3) δ: −0.07 (3H, s), −0.06 (3H, s), 0.75 (9H, s), 1.45 (3H, t, J=6.9 Hz), 1.58-1.61 (1H, m), 1.93-2.02 (1H, m), 2.29-2.39 (1H, m), 3.08 (1H, dd, J=10.8, 3.8 Hz), 3.12-3.19 (1H, m), 3.50-3.60 (2H, m), 4.04-4.16 (3H, m), 4.24-4.30 (1H, m), 4.44-4.53 (2H, m), 4.76-4.83 (2H, m), 6.95 (2H, d, J=8.5 Hz), 7.71-7.79 (2H, m).

(295) Step 5

(296) To a solution of Compound xi-49 (342 mg, 0.749 mmol) in THF (7 mL) was added 1 mol/L tetra-butylammonium fluoride in THF (1.12 mL, 1.12 mmol) under ice-cooling, and the mixture was stirred for 1 hour at room temperature. To the reaction mixture was added saturated aqueous ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was washed by brine, dried over anhydrous sodium sulphate, and concentrated in vacuo to give a crude product.

(297) The obtained Compound was dissolved in dichloromethane (7 mL), and the solution was cooled under ice-cooling. To the reaction mixture were added triethylamine (0.54 mL, 3.90 mmol), trimethylamine hydrochloride (21 mg, 0.23 mmol), and p-toluenesulfonyl chloride (372 mg, 1.94 mmol), and the resulting mixture was stirred for 12 hours at room temperature. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed by brine, dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound XI-14 (263 mg, Yield 71%).

(298) .sup.1H-NMR (CDCl.sub.3) δ: 1.46 (3H, t, J=6.9 Hz), 1.61-1.70 (1H, m), 1.88-1.99 (2H, m), 2.30-2.40 (1H, m), 2.46 (3H, s), 3.01-3.12 (1H, m), 3.47-3.56 (3H, m), 4.10 (2H, q, J =6.8 Hz), 4.39-4.48 (2H, m), 4.71-4.81 (3H, m), 6.95 (2H, d, J=8.5 Hz), 7.32 (2H, d, J =7.9 Hz), 7.56 (2H, d, J=7.9 Hz), 7.69 (2H, d, J=8.5 Hz).

REFERENCE EXAMPLE 26

(299) ##STR00106##
Step 1

(300) To a solution of Compound xi-50 (3.43 g, 6.57 mmol) which was synthesized in a similar manner as described in Tetrahedron: Asymmetry, vol. 13, p. 1103-1113, in THF (35 mL), was added Pd/C (699 mg), and the mixture was stirred overnight under hydrogen atmosphere at room temperature. The reaction mixture was filtered using Celite, and the filtrate was washed by THF. The filtrate was concentrated in vacuo to give Compound xi-51 (2.53 g, Yield 99%).

(301) .sup.1H-NMR (CDCl.sub.3) δ: 4.48 (1H, dd, J=10.4, 4.6 Hz), 3.80 (1H, dd, J=10.4, 5.1 Hz), 3.68-3.63 (1H, m), 3.17-3.09 (2H, m), 3.06-3.01 (2H, m), 2.88-2.82 (1H, m), 2.04-1.96 (1H, m), 1.86-1.72 (3H, m), 1.07-1.04 (18H, m), 0.89 (9H, s), 0.05 (6H, d, J=1.8 Hz).

(302) Step 2

(303) To a solution of Compound xi-51 (1 g, 2.58 mmol) in dichloromethane (10 mL) were added triethylamine (536 μL, 3.87 mmol) and 4-isopropoxybenzenesulfonyl chloride (726 mg, 3.09 mmol) under ice-cooling, and the mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated in vacuo. To the residue were added hydrochloric acid and water, and the mixture was extracted with ethyl acetate. The organic layer was washed by water and brine, dried over anhydrous magnesium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give a crude product (1.61 g).

(304) To a solution of the obtained crude product (1.61 g) in THF (20 mL) was added 2 mol/L aqueous hydrochloric acid (4.12 mL, 8.24 mmol), and the mixture was stirred for 2 hours at 50° C. The reaction mixture was concentrated in vacuo. To the residue was added saturated aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed by water and brine, dried over anhydrous magnesium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound xi-52 (1.03 g, 2 Step Yield 85%).

(305) .sup.1H-NMR (CDCl.sub.3) δ: 7.77 (2H, d, J=8.8 Hz), 6.96 (2H, d, J=8.8 Hz), 4.66-4.60 (1H, m), 4.10-4.04 (1H, m), 3.96-3.89 (1H, m), 3.83-3.77 (1H, m), 3.69-3.64 (1H, m), 3.57-3.51 (1H, m), 3.22-3.15 (1H, m), 2.87-2.83 (1H, m), 1.97-1.82 (2H, m), 1.37 (6H, d, J=6.0 Hz), 1.00 (21H, s).

(306) Step 3

(307) To a solution of Compound xi-52 (820 mg, 1.74 mmol) in dichloromethane (10 mL) were added triethylamine (361 μL, 2.61 mmol) and methanesulfonyl chloride (163 μL, 2.09 mmol) under ice-cooling, and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was concentrated in vacuo. To the residue were added hydrochloric acid and water, and the mixture was extracted with ethyl acetate. The organic layer was washed by brine, dried over anhydrous magnesium sulphate, and concentrated in vacuo. The resulting residue was used in the next step without purification.

(308) The resulting residue was dissolved in THF (10 mL). To the solution was added 1 mol/L lithium triethylborohydride in THF (8.69 mL, 8.69 mmol), and the mixture was heated at reflux at 2 hours. To the reaction mixture was added hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed by water and brine, dried over anhydrous magnesium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound xi-53 (719 mg, 2 Steps Yield 91%).

(309) .sup.1H-NMR (CDCl.sub.3) δ: 7.74 (2H, d, J=8.7 Hz), 6.94 (2H, d, J=8.7 Hz), 4.65-4.59 (1H, m), 3.94-3.88 (1H, m), 3.74-3.67 (1H, m), 3.48-3.42 (1H, m), 3.19-3.11 (1H, m), 1.89-1.78 (2H, m), 1.37 (6H, d, J=6.0 Hz), 1.23 (3H, d, J=6.8 Hz), 0.99 (21H, s).

(310) Step 4

(311) To a solution of Compound xi-53 (710 mg, 1.56 mmol) in THF (5 mL) was added 1 mol/L tetrabutylammonium fluoride in THF (1.87 mL, 1.87 mmol), and the mixture was stirred for 1 hour at room temperature. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed by water and brine, dried over anhydrous magnesium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound XI-15 (458 mg, Yield 98%).

(312) .sup.1H-NMR (CDCl.sub.3) δ: 7.74 (2H, d, J=8.5 Hz), 6.95 (2H, d, J=8.5 Hz), 4.67-4.58 (1H, m), 4.07-4.01 (1H, m), 3.63-3.50 (2H, m), 3.31-3.24 (1H, m), 1.85-1.67 (2H, m), 1.37 (6H, d, J=6.0 Hz), 1.34 (3H, d, J=6.7 Hz).

REFERENCE EXAMPLE 27

(313) ##STR00107##
Step 1

(314) Benzyltriphenylphosphonium chloride (100 mg, 0.257 mmol) was dissolved in THF (1.0 mL). To the solution was added NaOtBu (24.7 mg, 0.257 mmol), and the mixture was stirred for 30 minutes at −78° C. To the reaction mixture was added dropwise gradually a solution of Compound xi-54 (100 mg, 0.234 mmol) in THF (0.5 mL) at −78° C., and the mixture was stirred for 2 hours. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed by water and brine and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound xi-55 (83.1 mg, diastereomer ratio 3:1, Yield 71%).

(315) .sup.1H-NMR (CDCl.sub.3) δ: 7.76 (2H, d, J=8.3 Hz), 7.38-7.30 (5H, m), 6.92 (2H, d, J=8.3 Hz), 6.51 (1H, d, J=15.8 Hz), 6.17 (1H, dd, J=15.9, 7.4 Hz), 4.63-4.57 (1H, m), 4.34 (1H, s), 4.26 (1H, dd, J=14.7, 7.2 Hz), 3.70 (1H, dd, J=10.9, 4.6 Hz), 3.30 (1H, d, J=11.3 Hz), 1.93 (2H, t, J=5.6 Hz), 1.38 (6H, d, J=5.8 Hz), 0.80 (9H, s), 0.01 (6H, d, J=8.3 Hz).

(316) Step 2

(317) Compound xi-55 (67 mg, 0.134 mmol) was dissolved in 2 mol/L hydrochloric acid in dioxane (0.5 mL), and the reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was concentrated in vacuo to give Compound XI-16 (51.7 mg, Yield 100%).

(318) LC/MS (Condition B) RT=2.14, [M+H].sup.+=388.

REFERENCE EXAMPLE 28

(319) ##STR00108##
Step 1

(320) To a solution of 2-bromopyridine (0.647 mL, 6.75 mmol) in diethyl ether (40.0 mL) was added dropwise gradually 1.6 mol/L n-butyllithium in hexane (4.22 mL, 6.75 mmol) at −78° C., and the mixture was stirred for 30 minutes. To the reaction mixture was added dropwise gradually a solution of Compound xi-56 (2.13 g, 6.75 mmol) in THF (4.0 mL) at −78° C., and the mixture was stirred for 2 hours. To the reaction mixture was added 2 mol/L aqueous hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed by water and brine, and concentrated in vacuo to give crude product of Compound xi-57 (2.51 g).

(321) .sup.1H-NMR (CDCl.sub.3) δ: 8.67 (1H, d, J=4.3 Hz), 8.03 (1H, d, J=7.8 Hz), 7.83 (1H, t, J=7.7 Hz), 7.46 (1H, t, J=6.0 Hz), 3.38 (2H, t, J=5.0 Hz), 3.27 (2H, d, J=5.8 Hz), 2.55 (1H, dd, J=9.9, 6.1 Hz), 2.41 (1H, dd, J=12.0, 7.3 Hz), 1.41 (9H, s), 0.87 (9H, s), 0.09 (6H, s).

(322) Step 2

(323) To a solution of Compound xi-57 (2.51 g, 6.36 mmol) in methanol (20.0 mL) was added sodium borohydride (289 mg, 7.63 mmol) at −10° C., and the mixture was stirred for 30 minutes. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed by water and brine, and concentrated in vacuo to give crude product of Compound xi-58 (2.46 g).

(324) LC/MS (Condition B) RT=2.01, 2.06 [M+H].sup.+=397.

(325) Step 3

(326) To a solution of Compound xi-58 (2.46 g, 6.20 mmol) in dichloromethane (3.0 mL) were added methanesulfonyl chloride (0.58 mL, 7.44 mmol) and triethylamine (2.58 mL, 18.61 mmol) at 0° C., and the mixture was stirred for 1 hour at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed by water and brine, and concentrated in vacuo to give crude product (2.70 g).

(327) To a solution of the obtained compound (2.70 g) in DMF (30.0 mL) was added sodium hydride (0.25 mg, 6.26 mmol) at 0° C., and the mixture was stirred for 30 minutes at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed by water and brine, and concentrated in vacuo to give crude product of Compound xi-59 (2.36 g).

(328) LC/MSMS (Condition RT=2.30, 2.54 [M+H].sup.+=379.

(329) Step 4

(330) Compound xi-59 (2.15 g, 5.68 mmol) was dissolved in 2 mol/L hydrochloric acid in dioxane (22.5 mL), and the solution was stirred for 30 minutes at room temperature. The reaction mixture was concentrated in vacuo.

(331) To a solution of the obtained Compound (1.14 g) in dichloromethane (11.0 mL) were added 4-isopropoxybenzenesulfonyl chloride (1.467 g, 6.25 mmol) and triethylamine (2.36 mL, 17.04 mmol), and the mixture was stirred for 1 hour at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed by water and brine, and concentrated in vacuo to give crude product of Compound xi-60 (2.06 g).

(332) LC/MSMS (Condition B) RT=1.25, 1.34 [M+H].sup.+=363.

(333) Step 5

(334) To a solution of Compound xi-60 (2.06 g) in dichloromethane (15.0 mL) were added methanesulfonyl chloride (0.53 mL, 6.82 mmol) and triethylamine (2.36 mL, 17.05 mmol), and the mixture was stirred for 1 hour at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed by water and brine, and concentrated in vacuo.

(335) The obtained compound (2.38 g) was dissolved in DMA (20.0 mL). To the solution was added cesium acetate (2.07 g, 10.79 mmol), and the mixture was stirred for 5 hours at 85° C. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed by water and brine, and concentrated in vacuo.

(336) The obtained compound (1.95 g) was dissolved in methanol (20.0 mL). To the solution was added potassium carbonate (1.33 g, 9.65 mmol), and the mixture was stirred for 1 hour at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed by water and brine, and concentrated in vacuo to give crude product of Compound XI-17 (1.39 g).

(337) LC/MS (Condition B) RT=1.25, 1.35 [M+H].sup.+=363.

(338) The following compound was synthesized by the method in a similar manner to the above.

(339) ##STR00109##

REFERENCE EXAMPLE 29

(340) ##STR00110##
Step 1

(341) Hydrazine monohydrate (10 mL) was slowly added to Compound xii-1 (5 g, 35.2 mmol), and the mixture was stirred for 3 hours at 150° C. The reaction mixture was concentrated in vacuo, and water was added to the mixture. The precipitated solids were collected by filtration to give Compound xii-2 (1.98 g, Yield 41%).

(342) .sup.1H-NMR (CDCl.sub.3) δ: 10.40 (1H, br s), 7.32-7.28 (1H, m), 7.18-7.12 (2H, m).

(343) Step 2

(344) Compound xii-2 (500 mg, 3.67 mmol) was dissolved in dimethylformamide (5 mL). To the solution were added potassium hydroxide (721 mg, 12.86 mmol) and iodine (1.63 g, 6.43 mmol), and the mixture was stirred for 1 hour at room temperature. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed by water, aqueous sodium hydrogensulfate, and brine, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound XII-1 (852 mg, Yield 89%).

(345) .sup.1H-NMR (CDCl.sub.3) δ: 10.20 (1H, s), 8.11 (1H, d, J=3.51 Hz), 7.54-7.50 (1H, m), 7.10-7.08 (2H, m).

(346) The following indazole derivative was synthesized by the method in a similar manner described in the above.

(347) ##STR00111##
Compound XII-2

(348) .sup.1H-NMR (CDCl.sub.3) δ: 10.53 (1H, br s), 7.44 (2H, ddd, J=7.70, 6.25, 0.76 Hz), 7.18 (1H, dd, J=8.08, 7.47 Hz).

EXAMPLE 1

(349) ##STR00112##
Step 1

(350) Compound 1 (150 mg, 0.660 mmol) was dissolved in dichloromethane (2 mL) under nitrogen atmosphere. To the solution were added triethylamine (183 μL, 1.32 mmol) and methanesulfonyl chloride (77 μL, 0.990 mmol) under ice-cooling, and the mixture was stirred for 80 minutes at room temperature. To the reaction mixture was added saturated aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed by brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resulting residue was used in Step 2 without purification.

(351) Step 2

(352) Compound III-1 (171 mg, 0.726 mmol) was dissolved in DMF (1 mL) under nitrogen atmosphere. To the solution was added 60% sodium hydride (29.0 mg, 0.726 mmol) under ice-cooling, and the mixture was stirred for 10 minutes. To the reaction mixture was added a solution of Compound 2 obtained in Step 1 in DMF (1 mL). The mixture was heated at 85° C. and stirred for 6 hours. After the reaction mixture was allowed to cool to room temperature, 1 mol/L aqueous hydrochloric acid was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed by water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 3 (88 mg, Yield 30%).

(353) LC/MS (Condition B) RT=2.85, [M+H].sup.+=446.

(354) Step 3

(355) Compound 4 (85 mg, 0.191 mmol) was dissolved in ethyl acetate (2 mL) under nitrogen atmosphere. To the solution was added 4 mol/L hydrochloric acid in ethyl acetate (0.24 mL, 0.954 mmol) at room temperature, and the resulting mixture was stirred for 1 hour. After the reaction was completed, the mixture was concentrated in vacuo to give Compound 4 (73 mg).

(356) LC/MS (Condition B) RT=1.43, [M+H].sup.+=346.

(357) Step 4

(358) Compound 4 (28 mg, 0.073 mmol) was dissolved in dichloromethane (2 mL) under nitrogen atmosphere. To the solution were added triethylamine (30 μL, 0.220 mmol) and 4-isopropoxybenzenesulfonyl chloride (18.9 mg, 0.081 mmol) under ice-cooling, and the mixture was stirred for 15 hours at room temperature. After the reaction mixture was concentrated until the amount of solvent was to be half amount, the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 5 (40 mg, Yield 100%).

(359) LC/MS (Condition B) RT=2.91, [M+H].sup.+=544.

(360) Step 5

(361) Compound 5 (40 mg, 0.074 mmol) was dissolved in DMSO (1 mL). To the solution was added 2 mol/L aqueous sodium hydroxide (74 μL, 0.147 mmol) at room temperature, and the mixture was stirred for 1 hour. After the reaction was completed, 2 mol/L aqueous hydrochloric acid (74 μL, 0.147 mmol) and distilled water (20 mL) were added dropwise gradually to the mixture. The precipitation was gathered by filtration and dried by heating to give Compound I-41 (33.2 mg, Yield 89%).

(362) LC/MS (Condition B) RT=2.35, [M+H].sup.+=502.

EXAMPLE 2

(363) ##STR00113##
Step 1

(364) Compound XI-4 (64 mg, 0.191 mmol) was dissolved in dichloromethane (1.5 mL). To the solution were added triethylamine (0.053 mL, 0.382 mmol) and methanesulfonyl chloride (0.022 mL, 0.287 mmol) under ice-cooling, and the mixture was stirred for 35 minutes. To the mixture was added saturated aqueous sodium bicarbonate, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed by water and brine, dried over magnesium sulphate, and concentrated in vacuo. The obtained Compound 6 was used in next step without purification.

(365) Step 2

(366) Compound 6 (0.191 mmol) was dissolved in DMF (1.5 mL). To the solution were added Compound 9 (54 mg, 0.229 mmol) and cesium carbonate (125 mg, 0.382 mmol), and the mixture was heated and stirred at 80° C. for 2 hours. The mixture was allowed to cool to room temperature, and water was added to the mixture. The resulting mixture was extracted with ethyl acetate. The organic layer was washed by water and brine, dried over magnesium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate). The obtained compound was hydrolyzed according to the method described in the general synthetic procedures to give Compound I-22 (18 mg, 2 steps, Yield 18%).

(367) .sup.1H-NMR (CDCl.sub.3) δ: 7.83 (2H, d, J=8.90 Hz), 7.60 (1H, dd, J=8.73, 5.04 Hz), 7.05 (2H, d, J=8.90 Hz), 6.97-6.88 (1H, m), 6.75 (1H, dd, J=9.23, 1.68 Hz), 6.17 (1H, ddd, J=57.75, 56.07, 2.52 Hz), 4.75-4.62 (1H, m), 4.41-4.16 (2H, m), 4.01-3.86 (3H, m), 3.70-3.59 (1H, m), 2.87-2.73 (1H, m), 2.51-2.38 (1H, m), 1.41 (6H, dd, J=5.96, 1.43 Hz).

EXAMPLE 3

(368) ##STR00114## ##STR00115##
Step 1

(369) Compound XII-1 (300 mg, 1.145 mmol) was dissolved in DMF (3 mL). To the solution was added 60% sodium hydride (55 mg, 1.374 mmol), and the mixture was stirred for 10 minutes at room temperature. To the mixture was added Compound 7 (623 mg, 1.374 mmol) which was obtained by sulfonylation of Compound XI-3, the mixture was heated and stirred at 80° C. for 1 hour. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed by water and brine, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 8 (466.3 mg, Yield 75%).

(370) .sup.1H-NMR (CDCl.sub.3) δ: 7.86 (2H, d, J=8.90 Hz), 7.74 (1H, d, J=9.06 Hz), 7.20 (1H, t, J=4.45 Hz), 7.04 (2H, t, J=9.06 Hz), 6.94 (1H, d, J=8.73 Hz), 5.38 (1H, t, J =5.71 Hz), 4.71-4.63 (1H, m), 4.07 (1H, d, J=7.22 Hz), 3.96-3.86 (2H, m), 3.70 (1H, t, J=8.14 Hz), 3.24 (1H, t, J=9.90 Hz), 2.68 (1H, dd, J=10.58, 7.05 Hz), 1.40 (6H, d, J =6.04 Hz), 0.52 (3H, d, J=6.71 Hz).

(371) Step 2

(372) Compound 8 (466 mg, 0.858 mmol) was dissolved in dioxane (3 mL) and water (0.3 mL). To the solution were added cesium fluoride (391 mg, 2.57 mmol), allyltributyltin (0.321 mL, 1.029 mmol), and PdCl.sub.2 (dppf) (70 mg, 0.086 mmol), and the mixture was heated and stirred at 85° C. for 3 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed by brine, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 9 (195.8 mg, Yield 50%).

(373) .sup.1H-NMR (CDCl.sub.3) δ: 7.84 (2H, dt, J=9.46, 2.52 Hz), 7.74 (1H, dt, J=9.51, 2.52 Hz), 7.35 (1H, ddd, J=8.44, 4.74, 3.15 Hz), 7.01-6.92 (3H, m), 5.89-5.82 (1H, m), 5.36-5.31 (1H, m), 5.10-5.06 (1H, m), 5.03 (1H, t, J=1.59 Hz), 4.63 (1H, td, J=12.30, 6.15 Hz), 4.06-4.03 (1H, m), 3.95 (1H, s), 3.90 (1H, dd, J=11.08, 2.52 Hz), 3.70-3.64 (1H, m), 3.38 (2H, dt, J=6.38, 1.51 Hz), 3.25 (1H, dd, J=10.74, 8.73 Hz), 2.68-2.58 (0H, m), 1.39 (6H, d, J=6.04 Hz), 0.48 (3H, d, J=6.88 Hz).

(374) Step 3

(375) Compound 9 (190 mg, 0.415 mmol) was dissolved in acetonitrile (1.5 mL) and water (0.75 mL). To the solution were added sodium periodate (266 mg, 1.246 mmol) and 10% osmium tetroxide (106 mg, 0.042 mmol), and the mixture was stirred for 1 hour at room temperature. The reaction mixture was filtered by using Celite, and the filtrate was concentrated in vacuo. To the mixture was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed by brine, and concentrated in vacuo. The residue was used in the next step without purification.

(376) .sup.1H-NMR (CDCl.sub.3) δ: 9.60 (1H, s), 7.83 (2H, t, J=4.39 Hz), 7.71 (1H, d, J=9.06 Hz), 7.05-6.94 (4H, m), 5.37 (1H, d, J=4.67 Hz), 4.69-4.62 (2H, m), 4.09 (1H, dd, J=16.48, 12.64 Hz), 3.91 (1H, dd, J=8.10, 5.63 Hz), 3.69 (2H, dt, J=15.20, 6.52 Hz), 3.23 (1H, t, J=10.03 Hz), 2.66 (1H, d, J=18.95 Hz), 1.40 (6H, d, J=6.04 Hz), 0.50 (3H, d, J=6.87 Hz).

(377) Step 4

(378) Compound 10 (190 mg, 0.415 mmol) was dissolved in tert-butanol (2 mL) and water (1 mL). To the solution were added sodium dihydrogenphosphate (50 mg, 0.416 mmol), 2-methylbutene (0.286 ml, 2.7 mmol), and sodium chlorite (132 mg, 1.455 mmol), and the mixture was stirred for 1 hour at room temperature. To the reaction mixture was added 2 mol/L aqueous hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed by brine, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound I-59 (87.6 mg, Yield 44%).

(379) .sup.1H-NMR (CDCl.sub.3) δ: 7.82 (2H, d, J=8.24 Hz), 7.37 (1H, s), 6.98 (4H, d, J=8.54 Hz), 5.35 (1H, s), 4.65 (1H, t, J=5.72 Hz), 4.13-4.01 (1H, m), 3.91 (1H, d, J=11.13 Hz), 3.71 (2H, s), 3.65 (1H, t, J=8.08 Hz), 3.22 (1H, t, J=9.30 Hz), 2.63 (1H, s), 1.38 (6H, d, J=5.64 Hz), 0.48 (3H, d, J=6.25 Hz).

EXAMPLE 4

(380) ##STR00116##
Step 1

(381) 60% sodium hydride (27.9 mg, 0.698 mmol) was suspended in DMF (1 mL) under nitrogen atmosphere. To the suspension was added a solution of Compound III-1 (150 mg, 0.635 mmol) in DMF (1 mL), and the mixture was stirred for 10 minutes at room temperature. To the reaction mixture was added Compound 11 (129 mg, 0.698 mmol), and the mixture was stirred for 4 hours at 60° C. The reaction mixture was allowed to cool to room temperature, saturated aqueous ammonium chloride was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed by water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 12 (41 mg, Yield 15%).

(382) LC/MS (Condition B) RT=2.36, [M+H].sup.+=422.

(383) Step 2 and after Step 2

(384) Compound I-25 was obtained in a similar manner to those described in Steps 3 to 5 in Example 1.

(385) .sup.1H-NMR (DMSO-d6) δ: 7.69 (2H, d, J=8.8 Hz), 7.67 (1H, d, J=10.1 Hz), 7.46 (1H, dd, J=10.1, 2.0 Hz), 7.08 (2H, d, J=8.8 Hz), 6.99 (1H, dt, J=12.8, 4.6 Hz), 5.69-5.58 (1H, m), 5.01-4.91 (1H, m), 4.80-4.67 (1H, m), 4.38-4.25 (1H, m), 3.84-3.69 (1H, m), 3.76 (2H, s), 3.55 (1H, dd, J=10.3, 6.0 Hz), 3.49-3.40 (1H, m), 3.11 (1H, dd, J =10.2, 5.0 Hz), 1.31 (6H, d, J=6.1 Hz).

(386) LC/MS (Condition B) RT=1.92, [M+H].sup.+=478.

EXAMPLE 5

(387) ##STR00117##

(388) To a solution of Compound 13 (90 mg, 0.178 mmol) in dichloromethane (1 mL) was added DAST (35 μl, 0.267 mmol) dropwise at 0° C. under nitrogen atmosphere. The mixture was allowed to warm to room temperature gradually and stirred for 3.5 hours. To the mixture was added saturated aqueous sodium bicarbonate under ice-cooling, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed by water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate). The obtained compound (22 mg) was hydrolyzed according to the method described in the general synthetic procedures to give Compound I-26 (11 mg, 2 steps, Yield 14%).

(389) .sup.1H-NMR (CDCl3) δ: 7.73 (2H, d, J=8.7 Hz), 7.61 (1H, dd, J=9.0, 4.8 Hz), 7.02-6.89 (2H, m), 6.94 (2H, d, J=8.6 Hz), 5.33 (1H, dd, J=52.4, 2.5 Hz), 5.09-4.95 (1H, m), 4.70-4.58 (1H, m), 3.98 (1H, dd, J=10.7, 7.7 Hz), 3.86 (2H, s), 3.82 (1H, d, J =3.4 Hz), 3.75-3.62 (2H, m), 1.38 (6H, d, J=6.0 Hz).

(390) LC/MS (Condition B) RT=2.16, [M+H].sup.+=480.

EXAMPLE 6

(391) ##STR00118##

(392) To a solution of Compound I-25 (23 mg, 0.048 mmol) in dichloromethane (2 mL) was added Dess-Martin Periodinane (30.6 mg, 0.072 mmol) at room temperature under nitrogen atmosphere, and the mixture was stirred for 4.5 hours. To the reaction mixture were added 1 mol/L aqueous sodium thiosulfate and 1 mol/L aqueous hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed by water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound I-27 (18 mg, Yield 80%).

(393) .sup.1H-NMR (CDCl3) δ: 7.79 (2H, d, J=8.7 Hz), 7.63 (1H, dd, J=8.9, 5.0 Hz), 7.03 (2H, d, J=8.7 Hz), 6.97 (1H, t, J=9.7 Hz), 6.88 (1H, d, J=9.1 Hz), 5.13 (1H, t, J=9.2 Hz), 4.71-4.63 (1H, m), 4.38 (1H, t, J=9.5 Hz), 4.10 (2H, d, J=17.6 Hz), 3.94 (2H, d, J=1.2 Hz), 3.73 (1H, t, J=10.2 Hz), 3.56 (1H, d, J=18.0 Hz), 1.40 (6H, d, J=6.0 Hz).

(394) LC/MS (Condition B) RT=2.07, [M+H].sup.+=476.

EXAMPLE 7

(395) ##STR00119##
Step 1

(396) To a solution of Intermediate 14 (25 mg, 0.048 mmol), which is an intermediate of the synthesis method of Compound I-25 described in Example 4, in dichloromethane (2 mL) were added triethylamine (13 μL, 0.096 mmol) and methanesulfonyl chloride (5.6 μL, 0.072 mmol) in turn under ice-cooling, and the resulting mixture was stirred for 30 minutes. To the mixture was added saturated aqueous sodium bicarbonate and the resulting mixture was extracted with ethyl acetate. The organic layer was washed by water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resulting residue was used in Step 2 without purification.

(397) Step 2

(398) To the resulting residue was added 1 mol/L sodium methoxide (0.481 mL, 0.481 mmol) at room temperature. After the residue was dissolved, the mixture was stirred for 2 hours at 60° C. The mixture was allowed to cool to room temperature, and 1 mol/L aqueous hydrochloric acid was added to the mixture. The resulting mixture was extracted with ethyl acetate. The organic layer was washed by water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (chloroform-methanol) to give Compound I-28 (8.7 mg, Yield 39%).

(399) .sup.1H-NMR (DMSO-d6) δ: 7.94-7.61 (4H, m), 7.26-7.04 (3H, m), 6.10-5.99 (1H, m), 4.78-4.51 (3H, m), 4.36-4.21 (2H, m), 4.03-3.88 (2H, m), 1.31-1.20 (6H, m).

(400) LC/MS (Condition B) RT=2.19, [M+H].sup.+=460.

EXAMPLE 8

(401) ##STR00120##
Step 1

(402) Intermediate 16 (290 mg, 0.548 mmol) which is an intermediate of the synthesis method of Compound I-38 was dissolved in acetonitrile (3 mL). To the solution was added a solution of sodium periodate (351 mg, 1.643 mmol) in water (3 mL) at room temperature. Additionally, 10% osmium tetroxide (139 mg, 0.055 mmol) was added to the mixture, and the resulting mixture was stirred for 6 hours. The mixture was left standing for 1 day. After the reaction mixture was diluted by water (5 mL) and ethyl acetate (5 mL), the insoluble was removed by filtration using Celite. The filtrate was extracted with ethyl acetate. The organic layer was washed by water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The obtained Compound 17 (280 mg) was used in the next step without purification.

(403) Step 2

(404) The obtained Compound 17 (200 mg) was dissolved in THF (4 mL). To the solution was added sodium borohydride (14.2 mg, 0.376 mmol) at room temperature. The mixture was stirred for 6 hours at room temperature, and left standing overnight. To the mixture was added 1 mol/L aqueous hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed by brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 18 (74 mg).

(405) LC/MS (Condition B) RT=2.44, [M+H].sup.+=534.

(406) Step 3

(407) The obtained Compound 18 was hydrolyzed by the method described in the general synthetic procedures to give Compound I-64.

(408) LC/MS (Condition B) RT=1.93, [M+H].sup.+=492.

EXAMPLE 9

(409) ##STR00121##
Step 1

(410) Compound 17 (80 mg) was dissolved in ethanol (2 mL) under nitrogen atmosphere. To the solution were added methanolamine hydrochloride (15.1 mg, 0.181 mmol) and sodium acetate (14.8 mg, 0.181 mmol) at room temperature. After the mixture was stirred for 10 hours at room temperature, the mixture was left standing overnight. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed by brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 19 (34 mg).

(411) LC/MS (Condition B) RT=2.70, [M+H].sup.+=561.

(412) Step 2

(413) Compound 19 was hydrolyzed by the method described in the general synthetic procedures to give Compound I-65.

(414) LC/MS (Condition B) RT=2.20, [M+H].sup.+=519.

EXAMPLE 10

(415) ##STR00122##
Step 1

(416) Compound 20, which was synthesized in a similar manner as described in Tetrahedron, 1996, vol. 52, no. 47, p. 15017-15030, was reacted with Compound III-1 according to the similar manner described in the general method in the specification to give Compound 21.

(417) .sup.1H-NMR (CDCl.sub.3) δ: 7.67 (2H, d, J=7.58 Hz), 7.61-7.54 (1H, m), 7.45-7.33 (5H, m), 6.93-6.79 (4H, m), 5.28 (1H, d, J=12.13 Hz), 5.21 (1H, d, J=12.13 Hz), 5.13-4.96 (2H, m), 4.66-4.54 (2H, m), 4.00-3.92 (1H, m), 3.78-3.66 (3H, m), 2.95-2.84 (1H, m), 2.44-2.35 (1H, m), 1.37 (6H, d, J=6.06 Hz), 1.22 (6H, d, J=6.06 Hz).

(418) Step 2

(419) Compound 21 (120 mg, 0.188 mmol) was dissolved in ethanol (2 mL). To the solution was added Pd-Carbon (12 mg) under hydrogen atmosphere at room temperature, and the mixture was stirred for 4 hours. After the reaction mixture was diluted with ethyl acetate, the mixture was filtered by using Celite. The filtrate was concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (chloroform-methanol) to give Compound 22 (102.7 mg, Yield 100%).

(420) .sup.1H-NMR (CDCl.sub.3) δ: 7.67 (2H, d, J=8.08 Hz), 7.56-7.49 (1H, m), 7.11-7.04 (1H, m), 6.88-6.76 (3H, m), 5.27-5.18 (1H, m), 5.06-4.95 (1H, m), 4.64-4.52 (2H, m), 4.17-4.02 (1H, m), 3.72 (2H, s), 3.67-3.60 (1H, m), 2.92-2.79 (1H, m), 2.72-2.62 (1H, m), 1.34 (6H, d, J=6.06 Hz), 1.20 (6H, d, J=6.06 Hz).

(421) Step 3

(422) Compound 22 (35 mg, 0.064 mmol) was dissolved in DMF (1 mL). To the solution were added diisopropylethylamine (0.056 mL, 0.320 mmol), HATU (36.5 mg, 0.096 mmol), and ammonium chloride (5.1 mg, 0.096 mmol), and the mixture was stirred for 5 hours at room temperature. To the mixture was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed by water and brine, dried over magnesium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 23 (29 mg, Yield 83%).

(423) .sup.1H-NMR (CDCl.sub.3) δ: 7.72 (2H, d, J=8.59 Hz), 7.62-7.56 (1H, m), 7.01 (1H, br s), 6.95-6.87 (4H, m), 5.68-5.62 (1H, m), 5.08-4.96 (2H, m), 4.69-4.59 (1H, m), 4.38 (1H, d, J=6.06 Hz), 4.01-3.92 (1H, m), 3.80-3.73 (3H, m), 2.70-2.62 (1H, m), 2.57-2.46 (1H, m), 1.43-1.36 (6H, m), 1.23 (6H, d, J=6.06 Hz).

(424) Step 4

(425) Compound 23 was hydrolyzed by the method described in the general synthetic procedures in the specification to give Compound I-2.

(426) .sup.1H-NMR (DMSO-d.sub.6) δ: 7.68-7.52 (4H, m), 7.42 (1H, d, J=10.61 Hz), 7.26-7.21 (1H, br m), 7.02-6.93 (1H, br m), 6.89 (2H, d, J=8.08 Hz), 5.30-5.22 (1H, m), 4.73-4.61 (1H, m), 4.37-4.29 (1H, m), 3.98-3.89 (1H, m), 3.72-3.15 (3H, m), 2.69-2.14 (2H, m), 1.33-1.19 (6H, m).

EXAMPLE 11

(427) ##STR00123##
Step 1

(428) Compound 23 (26 mg, 0.048 mmol) was dissolved in THF (1 mL). To the solution were added triethylamine (0.021 mL, 0.155 mmol) and trifluoroacetic anhydride (0.011 mL, 0.077 mmol) under ice-cooling, and the mixture was stirred for 1.5 hours. Additionally, triethylamine (0.021 mL, 0.155 mmol) and trifluoroacetic anhydride (0.011 mL, 0.077 mmol) were added to the mixture under ice-cooling, and the resulting mixture was stirred for 3 hours. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed by water and brine, dried over sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 24 (19 mg, Yield 76%).

(429) .sup.1H-NMR (CDCl.sub.3) δ: 7.69 (2H, d, J=8.59 Hz), 7.65-7.58 (1H, m), 6.99-6.90 (2H, m), 6.85 (2H, d, J=8.59 Hz), 5.16-4.99 (2H, m), 4.94-4.88 (1H, m), 4.65-4.56 (1H, m), 3.88-3.71 (4H, m), 3.18-3.09 (1H, m), 2.74-2.65 (1H, m), 1.38 (6H, d, J=4.55 Hz), 1.24 (6H, d, J=6.06 Hz).

(430) Step 2

(431) To a solution of Compound 24 (18 mg, 0.035 mmol) in THF was added 0.1 mol/L aqueous lithium hydroxide (0.348 mL, 0.035 mmol), and the mixture was stirred for 2 hours at room temperature. To the mixture was added 0.1 mol/L aqueous lithium hydroxide (0.174 mL, 0.017 mmol), and the resulting mixture was stirred for 1 hour at room temperature. Additionally, 0.1 mol/L aqueous lithium hydroxide (0.384 mL, 0.035 mmol) was added to the mixture. The reaction mixture was stirred for 6 hours and left standing overnight. To the mixture were added water and 10% aqueous citric acid, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed by brine, dried over sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (chloroform-methanol) to give Compound I-7 (12 mg, Yield 71%).

(432) .sup.1H-NMR (DMSO-d.sub.6) δ: 7.89-7.54 (4H, m), 7.20-6.92 (3H, m), 5.49-5.41 (1H, m), 5.06-4.99 (1H, m), 4.76-4.64 (1H, m), 3.96-3.61 (4H, m), 2.89-2.72 (2H, m), 1.31 (6H, d, J=5.56 Hz).

EXAMPLE 12

(433) ##STR00124##

(434) A solution of Compound 22 (21 mg, 0.038 mmol) in dichloromethane (1 mL) was cooled to −10° C. To the solution were added triethylamine (6.4 μL, 0.046 mmol) and ethyl chlorocarbonate (4.0 μL, 0.042 mmol), and the mixture was stirred for 35 minutes. Additionally, tetrabutylammonium bromide (1.2 mg, 3.8 μmol) and sodium borohydride (3.2 mg, 0.084 mmol) were added to the mixture, and the resulting mixture was stirred for 35 minutes at −5° C. vigorously. To the mixture were added 2 mol/L aqueous hydrochloric acid (0.070 mL), water, and ethyl acetate, and the resulting mixture was stirred for 30 minutes at −5° C. The reaction mixture was extracted with ethyl acetate. The organic layer was washed by saturated aqueous sodium bicarbonate and brine, dried over sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate). The obtained compound was hydrolyzed by the method described in the general synthetic procedures in the specification to give Compound I-9 (14 mg, Yield 75%).

(435) .sup.1H-NMR (CDCl.sub.3) δ: 7.61-7.51 (3H, m), 6.96-6.88 (2H, m), 6.78 (2H, d, J=8.59 Hz), 5.06-4.97 (1H, m), 4.63-4.54 (1H, m), 4.07-3.91 (3H, m), 3.82-3.66 (4H, m), 3.52-3.44 (1H, m), 2.68-2.57 (1H, m), 2.40-2.28 (1H, m), 1.40-1.34 (6H, m).

EXAMPLE 13

(436) ##STR00125##

(437) Intermediate 25 (25 mg, 0.047 mmol), which is an intermediate of the synthesis method of Compound I-9, was dissolved in dichloromethane (1 mL). To the solution was added DAST (6.2 μL, 0.047 mmol) under ice-cooling, and the mixture was stirred for 1 hour. To the mixture was added DAST (6.2 μL, 0.047 mmol), and the mixture was stirred for additional 20 minutes. The mixture was allowed to warm to room temperature gradually, and left standing overnight. To the mixture was added saturated aqueous sodium bicarbonate, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed by brine, dried over sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate). The obtained compound was hydrolyzed by the method described in the general synthetic procedures in the specification to give Compound I-12 (16 mg, Yield 74%).

(438) .sup.1H-NMR (CDCl.sub.3) δ: 7.74-7.57 (3H, m), 7.06-6.89 (4H, m), 5.14-4.91 (1H, m), 4.82-4.70 (1H, m), 4.69-4.57 (1H, m), 4.26-4.15 (1H, m), 4.02-3.92 (3H, m), 2.91-2.61 (2H, m), 2.50-2.22 (2H, m), 1.38 (6H, d, J=5.56 Hz).

EXAMPLE 14

(439) ##STR00126##
Step 1

(440) Compound 23 (44 mg, 0.082 mmol) was dissolved in dichloromethane (1 mL). To the solution were added triethylamine (0.017 mL, 0.123 mmol) and methanesulfonyl chloride (7.6 μL, 0.098 mmol) under ice-cooling, and the mixture was stirred for 1 hour.

(441) To the mixture was added saturated aqueous sodium bicarbonate, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed by brine, dried over sodium sulphate, and concentrated in vacuo. The obtained Compound 26 was used in the next step without purification.

(442) Step 2

(443) Compound 26 was dissolved in DMSO (1.5 mL). To the solution was added sodium cyanide (12 mg, 0.240 mmol), and the mixture was heated at 90° C. and stirred for 5 hours. The mixture was allowed to cool to room temperature, and left standing overnight. The mixture was diluted with ethyl acetate, and water was added to the mixture. The resulting mixture was extracted with ethyl acetate. The organic layer was washed by water and brine, dried over sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate). The obtained compound was hydrolyzed by the method described in the general synthetic procedures in the specification to give Compound I-14 (9.4 mg, Yield 23%).

(444) LC/MS (Condition B) RT=2.04, [M+H].sup.+=501.

EXAMPLE 15

(445) ##STR00127##

(446) Compound 26 (0.058 mmol) was dissolved in methanol (1 mL). To the solution was added 1.02 mol/L sodium methoxide in methanol (0.285 mL, 0.291 mmol), and the mixture was stirred for 4 hours at reflux. After the mixture was allowed to cool to room temperature, 1.02 mol/L sodium methoxide in methanol (0.571 mL, 0.583 mmol) was added to the reaction mixture. Additionally, the mixture was stirred for 2.5 hours at reflux. After the reaction mixture was allowed to cool to room temperature, water and 2 mol/L aqueous hydrochloric acid were added to the mixture. The resulting mixture was extracted with ethyl acetate. The organic layer was washed by water and brine, dried over sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (chloroform-methanol) to give Compound I-16 (14 mg, Yield 47%).

(447) .sup.1H-NMR (CDCl.sub.3) δ: 7.67 (2H, d, J=8.08 Hz), 7.61-7.52 (1H, m), 6.96-6.81 (4H, m), 5.18-5.07 (1H, m), 4.66-4.55 (1H, m), 4.16-3.99 (1H, m), 3.92-3.83 (3H, m), 3.73-3.56 (3H, m), 3.44 (3H, s), 2.58-2.46 (1H, m), 2.39-2.29 (1H, m), 1.38-1.34 (6H, m).

EXAMPLE 16

(448) ##STR00128##
Step 1

(449) Intermediate 27 (20 mg, 0.038 mmol), which is an intermediate of the synthesis method of Compound I-11 was dissolved in dichloromethane (1 mL). To the solution was added Dess-Martin Periodinane (24 mg, 0.057 mmol) under ice-cooling, and the mixture was stirred for 1 hour at room temperature. Dess-Martin Periodinane (24 mg, 0.057 mmol) was added to the mixture, and stirred for additional 5 hours at room temperature. The mixture was left standing overnight. To the mixture were added 6% aqueous sodium thiosulfate and water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed by saturated aqueous sodium bicarbonate and brine, dried over sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 28 (16 mg, Yield 79%).

(450) .sup.1H-NMR (CDCl.sub.3) δ: 9.83 (1H, s), 7.80 (2H, d, J=8.08 Hz), 7.70-7.61 (1H, m), 7.06-6.81 (4H, m), 5.09-4.98 (1H, m), 4.84-4.75 (1H, m), 4.73-4.60 (1H, m), 4.09-4.01 (1H, m), 3.90-3.84 (3H, br m), 3.69-3.61 (1H, m), 2.81-2.70 (1H, m), 2.50-2.39 (1H, m), 1.40 (6H, d, J=5.56 Hz), 1.24 (6H, d, J=6.06 Hz).

(451) Step 2

(452) Compound 28 (16 mg, 0.030 mmol) was dissolved in ethanol (1 mL). To the solution was added methanolamine hydrochloride (3 mg, 0.036 mmol) under ice-cooling, and the mixture was stirred for 4 hours at room temperature. The mixture was left standing overnight. To the mixture was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed by water and brine, dried over sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate). The obtained compound was hydrolyzed by the method described in the general synthetic procedures in the specification to give Compound I-19 (13 mg, Yield 87%).

(453) LC/MS (Condition B) RT=2.24, [M+H].sup.+=519.

EXAMPLE 17

(454) ##STR00129##
Step 1

(455) Compound 27 (32 mg, 0.060 mmol) was dissolved in dichloromethane (1 mL). To the solution were added triethylamine (0.013 mL, 0.091 mmol) and p-toluenesulfonyl chloride (15 mg, 0.078 mmol) under ice-cooling, and the mixture was stirred for 1 hour. Triethylamine (0.013 mL, 0.091 mmol) and p-toluenesulfonyl chloride (15 mg, 0.078 mmol) were added to the mixture, and the resulting mixture was allowed to warm to room temperature and stirred for additional 55 minutes. DMAP (0.7 mg, 6.0 μmol) was added to the mixture, and the resulting mixture was stirred for additional 9 hours. To the reaction mixture was added saturated aqueous sodium bicarbonate, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed by brine, dried over sodium sulphate, and concentrated in vacuo. The resulting mixture was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 29 (20 mg, Yield 48%).

(456) LC/MS (Condition B) RT=2.86, [M+H].sup.+=688.

(457) Step 2

(458) Imidazole (2.8 mg, 0.041 mmol) was dissolved in DMF (1 mL). To the solution was added sodium hydride (1.7 mg, 0.041 mmol), and the mixture was stirred for 10 minutes. A solution of Compound 29 (19 mg, 0.028 mmol) in DMF (1 mL) was added dropwise to the mixture, and the resulting mixture was stirred for 4 hours at 60° C. After the mixture was allowed to cool to room temperature, water and saturated aqueous ammonia were added to the mixture. The resulting mixture was extracted with ethyl acetate. The organic layer was washed by water and brine, dried over sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate). The obtained compound was hydrolyzed by the method described in the general synthetic procedures in the specification to give Compound I-20 (5.5 mg, Yield 25%).

(459) LC/MS (Condition B) RT=1.51, [M+H].sup.+=542.

EXAMPLE 18

(460) ##STR00130##
Step 1

(461) To a solution of allylamine (3.35 mL, 44.7 mmol) in dichloromethane (50 mL) was added Compound 30 (5.0 g, 21.3 mmol) under ice-cooling, and the mixture was stirred under ice-cooling. The reaction mixture was washed by diluted hydrochloric acid, water, and brine, dried over sodium sulfate, and concentrated in vacuo to give oil (6.22 g). To a solution of the obtained oil (2.4 g) in DMF (20 mL) were added cesium carbonate (4.59 g, 14.1 mmol) and 3-bromo-2-methyl-1-propene (1.14 mL, 11.28 mmol), and the mixture was stirred for 4 hours. To the reaction mixture was added hydrochloric acid under ice-cooling, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed by water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resulting crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 31 (2.81 g, Yield 20%) as colorless oil.

(462) Step 2

(463) To a solution of the obtained Compound 31 (3.8 g, 12.3 mmol) in dichloromethane (120 mL) was added (1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(phenylmethylene)(tri-cyclohexyl phosphine)ruthenium (313 mg, 0.368 mmol) under nitrogen atmosphere, and the mixture was stirred for 1 hour at room temperature. The reaction mixture was filtered by using silica gel pad. The filtrate was concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 32 (3.01 g, Yield 87%) as white solid.

(464) Step 3

(465) To a solution of Compound 32 (0.85 g, 3.02 mmol) in dichloromethane (8.5 mL) was added m-chloroperbenzoic acid (1.49 g, 6.04 mmol), and the mixture was stirred over night. To the reaction mixture was added aqueous sodium bicarbonate and the resulting mixture was extracted with ethyl acetate. The extract layer was washed by water and brine, dried over sodium sulfate, and concentrated in vacuo. The obtained crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 33 (608 mg, Yield 68%) as pale yellow solid.

(466) .sup.1H-NMR (CDCl.sub.3) δ: 1.36 (6H, d, J=6.03 Hz), 1.45 (3H, s), 3.25 (1H, d, J=11.75 Hz), 3.35-3.40 (2H, m), 3.55 (2H, d, J=11.75 Hz), 3.65 (2H, d, J=11.75 Hz), 4.62 (1H, m), 6.91-6.96 (2H, m), 7.66-7.71 (2H, m).

(467) Step 4

(468) A suspension of Compound 33 (230 mg, 0.773 mmol), Compound III-1 (219 mg, 0.927 mmol), and cesium carbonate (605 mg, 1.856 mmol) in DMA (2 mL) was stirred for 5 hours at 120° C. under nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature. To the mixture were added ethyl acetate and diluted hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract layer was washed by water and brine, dried over sodium sulfate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (chloroform-methanol) to give Compound 34 (183 mg, Yield 44%) as pale brown amorphous.

(469) .sup.1H-NMR (CDCl.sub.3) δ: 1.21 (6H, dd, J=6.32, 3.85 Hz), 1.40 (6H, dd, J=6.04, 1.65 Hz), 1.54 (3H, s), 2.34 (1H, br s), 3.51 (2H, dd, J=22.25, 10.44 Hz), 3.65 (2H, dd, J=23.00, 16.00 Hz), 3.89 (1H, dd, J=11.12, 3.71 Hz), 4.17 (1H, dd, J=10.99, 7.97 Hz), 4.63-4.78 (2H, m), 4.97-5.05 (1H, m), 6.90 (1H, td, J=8.93, 2.11 Hz), 7.01 (2H, d, J=9.06 Hz), 7.05 (1H, dd, J=9.20, 1.79 Hz), 7.57 (1H, dd, J=8.93, 5.08 Hz), 7.82-7.87 (2H, m).

(470) Step 5

(471) To a solution of Compound 34 (50 mg, 0.094 mmol) in dichloromethane (1 mL) was added DAST (30 mg, 0.19 mmol) under ice-cooling. After the reaction mixture was stirred for 1.5 hours at room temperature, aqueous sodium bicarbonate was added to the reaction mixture under ice-cooling. The mixture was extracted with dichloromethane, and the extract layer was concentrated in vacuo. The resulting crude product was purified by silica gel column chromatography (chloroform-ethyl acetate) to give Compound 35 (37 mg, Yield 73%) as colorless oil.

(472) LC/MS (Condition C) RT=2.63, [M+H].sup.+=536.

(473) Step 6

(474) To a solution of Compound 35 (37 mg, 0.069 mmol) in THF-methanol (1:1.2 mL) was added 4 mol/L aqueous lithium hydroxide (69 μL, 0.28 mmol). After the mixture was stirred at room temperature, diluted hydrochloric acid was added to the mixture. The resulting mixture was extracted with dichloromethane. The extract layer was concentrated in vacuo to give Compound I-85 (32.8 mg, Yield 96%) as pale brown amorphous.

(475) LC/MS (Condition C) RT=2.15, [M+H].sup.+=494.

EXAMPLE 19

(476) ##STR00131##

(477) Compound 34 was hydrolyzed by the method described in the general synthetic procedures in the present specification to give Compound I-84.

EXAMPLE 20

(478) ##STR00132##

(479) Compound 36 was synthesized by the method described in the general method in the specification by using Compound III-1 as a starting material. Compound 36 (50 mg, 0.10 mmol) and cesium carbonate (99 mg, 0.30 mmol) were dissolved in ethanol (2 mL), and the solution was stirred for 5 hours at reflux. To the reaction mixture were added water and 2 mol/L aqueous hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed by brine, and concentrated in vacuo. The resulting residue was dissolved in ethyl acetate. The solution was filtered and concentrated to give Compound I-56 (31 mg, Yield 66.4%).

(480) .sup.1H-NMR (DMSO-d6) δ: 12.45 (1H, s), 8.63 (1H, d, J=2.01 Hz), 8.11 (1H, dd, J =8.73, 1.34 Hz), 7.65 (1H, dd, J=8.64, 5.29 Hz), 7.52 (1H, d, J=9.57 Hz), 6.94-7.01 (2H, m), 5.31 (1H, t, J=6.63 Hz), 4.43 (2H, q, J=7.05 Hz), 3.93 (1H, dd, J=11.58, 7.05 Hz), 3.48-3.65 (4H, m), 3.13 (1H, t, J=9.90 Hz), 2.54-2.62 (1H, m), 1.38 (3H, t, J =6.97 Hz), 0.32 (3H, d, J=6.55 Hz).

(481) LC/MS (Condition A) RT=1.99, [M+H].sup.+=463.

EXAMPLE 21

(482) ##STR00133##
Step 1

(483) Compound 38 was synthesized by the similar manner as described in WO2004/112793. Compound 38 (405 mg, 2.01 mmol) was dissolved in pyridine (4 mL). To the solution were added p-toluenesulfonyl chloride (460 mg, 2.42 mmol) and catalytic amount of DMAP, and the resulting mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed by water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20) to give sulfonyl derivative as colorless oil.

(484) Commercially available Compound 37 (164 mg, 0.63 mmol) was dissolved in DMF (6 mL). To the solution were added the obtained sulfonyl derivative (340 mg, 0.75 mmol) and cesium carbonate (611 mg, 1.87 mmol), and the mixture was stirred for 3 hours at 100° C. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed by water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20) to give Compound 39 (292 mg, Yield 86%) as colorless oil.

(485) .sup.1H-NMR (CDCl.sub.3) δ: 7.86-7.82 (2H, m), 7.37 (1H, dd, J=8.7, 5.1 Hz), 7.04-6.92 (4H, m), 4.94 (1H, td, J=6.9, 2.7 Hz), 4.71-4.63 (1H, m), 4.13-4.04 (1H, m), 3.82 (1H, dd, J=11.3, 2.7 Hz), 3.71 (1H, t, J=8.1 Hz), 3.26 (1H, t, J=9.9 Hz), 2.74-2.64 (1H, m), 1.40 (6H, d, J=6.0 Hz), 0.50 (3H, d, J=6.9 Hz).

(486) Step 2

(487) (E)-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane2-yl)acrylate (182 mg, 0.81 mmol) was dissolved in DME (4 mL) and ethanol (1.5 mL). To the solution were added Compound 39 (292 mg, 0.54 mmol), PdCl.sub.2 (dppf) (21.9 mg, 0.027 mmol), and 2 mol/L aqueous sodium carbonate (0.81 mL, 1.61 mmol), and the mixture was stirred for 2 hours at 80° C. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed by brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=75/25) to give Compound 40 (246 mg, Yield 89%) as colorless oil.

(488) .sup.1H-NMR (CDCl.sub.3) δ: 7.87-7.79 (3H, m), 7.67 (1H, d, J=16.2 Hz), 7.05-6.97 (4H, m), 6.56 (1H, d, J=16.2 Hz), 5.03-4.92 (1H, m), 4.98 (1H, td, J=7.1, 3.0 Hz), 4.71-4.63 (1H, m), 4.32 (2H, q, J=7.2 Hz), 4.07 (1H, dd, J=11.3, 7.5 Hz), 3.83-3.72 (2H, m), 3.37 (1H, t, J=9.8 Hz), 2.78-2.66 (1H, m), 1.43-1.34 (9H, m), 0.51 (3H, d, J=6.9 Hz).

(489) Step 3

(490) Compound I-100 was synthesized from Compound 40 by the similar manner as described in the general synthetic procedures in the present specification.

(491) .sup.1H-NMR (DMSO-d.sub.6) δ: 8.09 (1H, dd, J=8.9, 5.1 Hz), 7.78 (2H, d, J=8.7 Hz), 7.68 (1H, dd, J=9.8, 2.0 Hz), 7.54 (1H, d, J=16.3 Hz), 7.15-7.09 (3H, m), 6.57 (1H, d, J=16.3 Hz), 5.47-5.40 (1H, m), 4.80-4.70 (1H, m), 3.92-3.86 (1H, m), 3.65-3.59 (2H, m), 3.28-3.19 (1H, m), 2.63-2.51 (1H, m), 1.30 (6H, dd, J=7.6, 6.2 Hz), 0.36 (3H, d, J =6.7 Hz).

EXAMPLE 22

(492) ##STR00134##
Step 1

(493) Compound 40 (70 mg, 0.14 mmol) was dissolved in THF (1.5 mL) and ethanol (1.5 mL). To the solution was added Pd-Carbon (14 mg), and the mixture was stirred overnight under hydrogen atmosphere at atmospheric pressure. After the reaction was completed, the insoluble was removed by filtration using Celite. The filtrate was concentrated in vacuo to give Compound 41. Compound 41 was used in the next step without further purification.

(494) Step 2

(495) Compound I-101 was synthesized from the hydrolysis of Compound 41 by the similar manner as described in the general synthetic procedures in the specification.

(496) .sup.1H-NMR (DMSO-d.sub.6) δ: 7.78-7.71 (3H, m), 7.48 (1H, dd, J=10.2, 2.0 Hz), 7.12 (2H, d, J=8.5 Hz), 6.94 (m, td, J=9.0, 1.8 Hz), 5.30-5.25 (1H, m), 4.79-4.71 (1H, m), 3.89-3.83 (1H, m), 3.62-3.52 (2H, m), 3.20-3.13 (1H, m), 3.05-2.95 (1H, m), 2.88-2.78 (1H, m), 2.54-2.40 (1H, m), 1.32 (6H, dd, J=6.0, 3.4 Hz), 0.29 (3H, d, J=6.6 Hz).

EXAMPLE 23

(497) ##STR00135##

(498) Compound 42 (15.5 mg, 0.024 mmol), which was synthesized from Compound III-1 and Compound XI-11 by the similar manner as described in the general synthetic procedures in the specification, was subjected to the same reactions described in Steps 2 and 3 of Example 10 and Example 11 in sequence to give Compound I-104 (2.8 mg, 6 steps, Yield 26%).

(499) .sup.1H-NMR (CDCl.sub.3) δ: 7.83 (2H, d, J=8.85 Hz), 7.62-7.51 (1H, m), 6.92 (5H, d, J =8.85 Hz), 5.11-4.99 (1H, m), 4.67-4.57 (1H, m), 4.06-3.96 (1H, m), 3.84 (2H, s), 3.69-3.57 (1H, m), 3.28-3.15 (1H, m), 2.64-2.52 (1H, m), 2.01 (3H, s), 1.36 (6H, dd, J=6.10, 1.53 Hz).

EXAMPLE 24

(500) ##STR00136##

(501) Compound 43, which was synthesized from Compound III-1 and Compound IV-6 by the similar manner as described in the general synthetic procedures in the specification, was subjected to the same reaction described in Example 23 to give Compound I-105 (7.5 mg, 7 steps, Yield 8.1%).

(502) .sup.1H-NMR (CDCl.sub.3) δ: 7.84 (2H, d, J=9.06 Hz), 7.66-7.59 (1H, m), 7.03-6.89 (4H, m), 5.12-5.04 (1H, m), 4.69-4.60 (1H, m), 3.96 (2H, br s), 3.88-3.82 (2H, m), 2.92-2.84 (2H, m), 2.01 (3H, s), 1.38 (6H, d, J=6.04 Hz).

EXAMPLE 25

(503) ##STR00137##
Step 1

(504) To a solution of Compound I-37 (120 mg, 0.25 mmol) in DMF (2 mL) were added ammonium chloride (20.3 mg, 0.38 mmol), triethylamine (52 μL, 0.38 mmol), EDC (53 mg, 0.28 mmol), HOBt (43 mg, 0.28 mmol), and catalytic amount of DMAP under ice-cooling, and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and precipitated solid was filtered off. The obtained solid was well washed by water to give Compound 44 (120 mg, Yield 100%).

(505) .sup.1H-NMR (CDCl.sub.3) δ: 7.85-7.81 (2H, m), 7.64 (1H, dd, J=8.8, 5.0 Hz), 7.02-6.90 (4H, m), 6.34 (1H, brs), 5.44 (1H, brs), 4.95-4.89 (1H, m), 4.72-4.63 (1H, m), 4.01-3.96 (1H, m), 3.90-3.85 (1H, m), 3.74-3.64 (3H, m), 3.27 (1H, t, J=9.9 Hz), 2.68-2.62 (1H, m), 1.42-1.38 (6H, m), 0.51 (3H, d, J=6.8 Hz).

(506) Step 2

(507) To a solution of Compound 44 (117 mg, 0.25 mmol) in dichloromethane (2 mL) and pyridine (0.2 mL) was added trifluoroacetic anhydride (84 μL, 0.60 mmol), and the mixture was stirred for 7 hours at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed by water and brine, dried over anhydrous magnesium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate).

(508) To a solution of the obtained compound (93 mg, 0.20 mmol) in DMF (2 mL) were added sodium azide (66 mg, 1.02 mmol) and triethylamine hydrochloride (140 mg, 1.02 mmol), and the mixture was stirred for 8 hours at 110° C. To the reaction mixture was added hydrochloric acid under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed by water and brine, dried over anhydrous magnesium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (chloroform -methanol) to give Compound I-157 (42 mg, Yield 42%).

(509) .sup.1H-NMR (DMSO-d.sub.6) δ: 7.77 (2H, d, J=8.9 Hz), 7.58-7.49 (2H, m), 7.10 (2H, d, J =8.9 Hz), 6.97 (1H, td, J=9.1, 2.1 Hz), 5.33-5.29 (1H, m), 4.74-4.65 (1H, m), 4.40 (2H, s), 3.84 (1H, dd, J=11.2, 7.3 Hz), 3.69 (1H, dd, J=11.3, 2.5 Hz), 3.58 (1H, dd, J =9.3, 7.4 Hz), 3.17 (1H, t, J=10.0 Hz), 2.45-2.33 (1H, m), 1.27 (6H, d, J=5.3 Hz), 0.32 (3H, d, J=6.7 Hz).

EXAMPLE 26

(510) ##STR00138##
Step 1

(511) Compound 45 was synthesized from Compound I-97 in a similar manner as described in Example 25.

(512) .sup.1H-NMR (DMSO-d.sub.6) δ: 7.83-7.77 (3H, m), 7.69 (1H, d, J=8.7 Hz), 7.42 (1H, t, J =7.3 Hz), 7.20-7.16 (3H, m), 5.43-5.38 (1H, m), 4.20-4.04 (4H, m), 3.90-3.85 (1H, m), 3.65-3.57 (2H, m), 3.16 (1H, t, J=10.0 Hz), 2.51-2.43 (1H, m), 1.39 (3H, t, J=6.9 Hz), 0.28 (3H, d, J=6.8 Hz).

(513) Step 2

(514) To a suspension of Compound 45 (110 mg, 0.26 mmol), hydroxylamine hydrochloride (43.2 mg, 0.62 mmol) and ethanol (3 mL), 28% sodium methoxide in methanol (120 mg, 0.62 mmol) was added, and the mixture was stirred for 4 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed by water and brine, dried over anhydrous magnesium sulphate, and concentrated in vacuo.

(515) The resulting residue was dissolved in 1, 4-dioxane (2 mL). To the solution were added carbonyldiimidazole (35 mg, 0.22 mmol) and diazabicycloundecene (32 μL, 0.22 mmol), and the mixture was stirred for 2 hours at 105° C. Then, to the reaction mixture was added phenyl chlorocarbonate (27 μL, 0.22 mmol), and the mixture was stirred for 2 hours at 105° C. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed by water and brine, dried over anhydrous magnesium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (chloroform-methanol) to give Compound I-296 (22 mg, 2 Steps Yield 18%).

(516) LC/MS (Condition B) RT=2.09, [M+H].sup.+=484.

EXAMPLE 27

(517) ##STR00139##
Step 1

(518) To a suspension of Compound I-97 (200 mg, 0.45 mmol) in dichloromethane were added catalytic amount of DMF and oxalyl chloride (47 μL, 0.54 mmol) under ice-cooling, and the mixture was stirred for 30 minutes at 0° C. The reaction mixture was concentrated in vacuo, and dichloromethane (2 mL) was added to the resulting residue. To the reaction mixture were added Meldrum's Acid (72 mg, 0.50 mmol) and N,N-diisopropylethylamine (173 μL, 0.99 mmol) under ice-cooling, and the mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated in vacuo. To the residue was added ethanol (4 mL), and the mixture was heated at reflux for 2 hours. The reaction mixture was concentrated in vacuo. To the residue was added hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed by brine, dried over anhydrous magnesium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 46 (43 mg, Yield 19%).

(519) LC/MS (Condition B) RT=2.37, [M+H].sup.+=514.

(520) Step 2

(521) To a suspension of Compound 46 (40 mg, 0.078 mmol) in ethanol (1 mL) was added hydrazine monohydrate (5.7 μL, 0.12 mmol). The mixture was stirred for 1 hour at room temperature, and heated at reflux for 3 hours. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed by brine, dried over anhydrous magnesium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (chloroform-methanol) to give Compound I-297 (27 mg, Yield 71%).

(522) .sup.1H-NMR (DMSO-D.sub.6) δ: 11.44 (1H, brs), 9.35 (0.4H, brs), 7.81 (2H, d, J=8.9 Hz), 7.59 (1H, d, J=8.5 Hz), 7.47 (1H, d, J=8.2 Hz), 7.31 (1H, t, J=7.5 Hz), 7.13 (2H, d, J=8.8 Hz), 7.03 (1H, t, J=7.5 Hz), 5.37-5.32 (1H, m), 5.04 (1H, brs), 4.07 (2H, q, J=6.9 Hz), 3.92-3.81 (3H, m), 3.72-3.67 (1H, m), 3.61-3.56 (1H, m), 3.19 (1H, t, J=10.0 Hz), 2.51-2.42 (1H, m), 1.33 (3H, t, J=7.0 Hz), 0.28 (3H, d, J=6.8 Hz).

(523) LC/MS (Condition B) RT=1.82, [M+H].sup.+=482.

EXAMPLE 28

(524) ##STR00140##

(525) To a suspension of Compound I-97 (80 mg, 0.18 mmol) in dichloromethane (2 mL) were added catalytic amount of DMF and oxalyl chloride (19 μL, 0.22 mmol) under ice-cooling, and the mixture was stirred for 1 hour at 0° C. The reaction mixture was concentrated in vacuo.

(526) To a solution of hydroxylamine hydrochloride (50 mg, 0.72 mmol) in water (0.5 mL) were added triethylamine (100 μL, 0.72 mmol) and acetonitrile (2.5 mL) under ice-cooling, and the mixture was stirred for 1 hour at 0° C. To the resulting reaction mixture was added a solution of the resulting residue of the above process in dichloromethane (2 mL), and the mixture was stirred for 1 hour at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed by water and brine, dried over anhydrous magnesium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (chloroform-methanol) to give Compound I-311 (36 mg, Yield 43%).

(527) .sup.1H-NMR (DMSO-d.sub.6) δ: 10.77 (1H, brs), 8.93 (1H, brs), 7.81 (2H, d, J=8.5 Hz), 7.72 (1H, d, J=8.2 Hz), 7.59 (1H, d, J=8.4 Hz), 7.34 (1H, t, J=7.5 Hz), 7.17-7.07 (3H, m), 5.35-5.30 (1H, m), 4.15 (2H, q, J=6.8 Hz), 3.87-3.82 (1H, m), 3.70-3.46 (4H, m), 3.20 (1H, t, J=9.9 Hz), 2.43-2.32 (1H, m), 1.38 (3H, t, J=6.8 Hz), 0.28 (3H, d, J=6.5 Hz).

(528) LC/MS (Condition B) RT=1.78, [M+H].sup.+=459.

EXAMPLE 29

(529) ##STR00141##

(530) To a solution of Compound I-37 (100 mg, 0.210 mmol) in dichloromethane were added methanesulfonamide (40 mg, 0.421 mmol), DMAP (25.7 mg, 0.21 mmol) and DCC (47.7 mg, 0.231 mmol), and the mixture was stirred overnight. To the resulting suspension was added diluted hydrochloric acid, and the mixture was extracted with dichloromethane. The organic layer was concentrated in vacuo, and the resulting residue was purified by silica gel column chromatography (methanol-chloroform) to give Compound I-138 (106 mg).

(531) .sup.1H-NMR (DMSO-D6) δ: 1.32 (6H, br s), 2.35 (1H, m), 3.15-3.27 (2H, m), 3.25 (3H, s), 3.59 (1H, m), 3.68 (1H, m), 3.77-3.84 (1H, m), 3.84 (2H, s), 4.76 (1H, m), 5.39 (1H, m), 5.75 (1H, br s), 7.01 (1H, m), 7.09-7.17 (2H, m), 7.49-7.57 (1H, m), 7.66-7.75 (2H, m), 7.75-7.84 (2H, m).

EXAMPLE 30

(532) ##STR00142##

(533) To a solution of Compound 48 (100 mg, 0.21 mmol) in THF (2 ml) was added 1.0 mol/L sodium bis(trimethylsilyl)amide in THF (0.41 ml, 0.41 mmol) at −78° C., and the mixture was stirred for 30 minutes at −78° C. To the resulting mixture was added N-fluorobenzenesulfonimide (130 mg, 0.41 mmol) at −78° C., and the mixture was allowed to warm gradually to room temperature from −78° C. over 1.5 hours. To the mixture was added 2 mol/L aqueous hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated in vacuo.

(534) To a solution of the resulting residue in DMSO (1 ml) was added 2 mol/L aqueous sodium hydroxide (0.19 ml, 0.38 mmol), and the mixture was stirred for 1 hour. To the mixture were added 2 mol/L aqueous hydrochloric acid (0.19 ml, 0.38 mmol) and water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed by water, dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by HPLC for isolation to give Compound I-290 (49.7 mg, Yield 50%).

(535) .sup.1H-NMR (DMSO-d.sub.6) δ: 0.26 (d, J=6.8 Hz, 3H), 1.37 (t, J=6.8 Hz, 3H), 2.33-2.42 (m, 1H), 3.15-3.88 (m, 4H), 4.15 (q, J=6.8 Hz, 2H), 5.50-5.53 (m, 1H), 7.15 (d, J=8.8 Hz, 2H), 7.29 (d, J=7.6 Hz, 1H), 7.49 (d, J=7.6 Hz, 1H), 7.78-7.81 (m, 2H), 7.81 (d, J=8.8 Hz, 2H).

EXAMPLE 31

(536) ##STR00143##

(537) To a solution of Compound 48 (200 mg, 0.41 mmol) in THF (4 ml) was added 2.0 mol/L lithium diisopropylamide in THF (0.21 ml, 0.41 mmol) at −78° C., and the mixture was stirred for 30 minutes at −78° C. To the reaction mixture was added carbon tetrachloride (0.10 ml, 1.03 mmol), and the mixture was stirred for 1 hour at −78° C. To the reaction mixture was added saturated aqueous ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate, and concentrated in vacuo. To a solution of the resulting residue in DMSO (2 ml) was added 2 mol/L aqueous sodium hydroxide (0.82 ml, 1.65 mmol), and the mixture was stirred for 19 hours at room temperature. To the reaction mixture were added 2 mol/L aqueous hydrochloric acid (0.82 ml, 1.65 mmol) and water, and the mixture was extracted with ethyl acetate. The organic layer was washed by water, dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by preparative HPLC to give Compound I-306 (38.5 mg, Yield 20%) and Compound I-307 (12.3 mg, Yield 7%). The absolute configuration of these two compounds is not identified.

(538) Compound I-306

(539) .sup.1H-NMR (DMSO-d6)δ:0.26 (d, J=6.8 Hz, 3H), 1.37 (t, J=6.9 Hz, 3H), 2.39-2.46 (m, 1H), 3.17 (dd, J=9.9, 9.9 Hz, 1H), 3.58 (dd, J=9.0, 7.5 Hz, 1H), 3.67 (dd, J=11.3, 2.5 Hz, 1H), 3.88 (dd, J=11.2, 7.4 Hz, 1H), 4.14 (q, J=6.9 Hz, 2H), 5.06 (s, 1H), 5.35-5.39 (m, 1H), 7.09 (dd, J=7.4, 7.4 Hz, 1H), 7.15 (d, J=8.8 Hz, 2H), 7.35 (dd, J=7.5, 7.5 Hz, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.71 (d, J=8.0 Hz, 1H), 7.81 (d, J=8.8 Hz, 2H).

(540) LC/MS (Condition B) RT=1.74, [M+H].sup.+=460.

(541) Compound I-307

(542) .sup.1H-NMR (DMSO-d6)δ:0.24 (d, J=6.8 Hz, 3H), 1.38 (t, J=7.0 Hz, 3H), 2.33-2.44 (m, 1H), 3.17 (dd, J=9.9, 9.9 Hz, 1H), 3.57 (dd, J=8.4, 8.4 Hz, 1H), 3.69 (dd, J=11.0, 2.5 Hz, 1H), 3.87 (dd, J=11.2, 7.4 Hz, 1H), 4.13-4.19 (m, 2H), 5.09 (s, 1H), 5.35-5.38 (m, 1H), 7.09 (dd, J=7.5, 7.5 Hz, 1H), 7.16 (d, J=8.8 Hz, 2H), 7.34 (dd, J=7.7, 7.7 Hz, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.75 (d, J=8.3 Hz, 1H), 7.81 (d, J=8.8 Hz, 2H).

(543) LC/MS (Condition B) RT=1.75, [M+H].sup.+=460.

EXAMPLE 32

(544) ##STR00144##

(545) To a solution of Compound 48 (129.7 mg, 0.27 mmol) in THF (2 ml) was added 2.0 mol/L lithium diisopropylamide in THF (0.26 ml, 0.52 mmol) at −78° C., and the mixture was stirred for 30 minutes at −78° C. To the mixture was added 1,2-dibromoethane (0.138 ml, 1.60 mmol), and the resulting mixture was allowed gradually to room temperature from −78° C. To the reaction mixture was added saturated aqueous ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by preparative HPLC to give Compound 49 (44.7 mg, Yield 33%).

(546) LC/MS (Condition B) RT=2.69, [M+H].sup.+=512.

(547) Step 2

(548) Compound 49 was hydrolyzed according to the method described in the general synthetic procedures to give Compound I-336.

(549) .sup.1H-NMR (DMSO-d6)δ:0.22 (d, J=6.8 Hz, 3H), 0.93 (dd, J=9.2, 4.1 Hz, 1H), 1.06-1.11 (m, 1H), 1.38 (t, J=6.9 Hz, 3H), 1.42-1.44 (m, 2H), 2.44-2.48 (m, 1H), 3.06 (t, J=9.9 Hz, 1H), 3.53-3.61 (m, 2H), 3.90 (dd, J=10.9, 7.7 Hz, 1H), 4.14 (q, J=6.9 Hz, 2H), 5.36-5.40 (m, 1H), 7.09 (dd, 7.7, 7.7 Hz, 1H), 7.15 (d, J=9.0 Hz, 2H), 7.34 (dd, J=7.7, 7.7 Hz, 1H), 7.61 (d, J=8.3 Hz, 2H), 7.79 (d, J=9.0 Hz, 2H), 12.37 (brs, 1H).

(550) LC/MS (Condition B) RT=2.13, [M+H].sup.+=470.

EXAMPLE 33

(551) ##STR00145##
Step 1

(552) To the mixture of Compound 50 (500 mg, 0.93 mmol), dimethoxyethane (8 mL), and ethanol (4 mL) were added 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (215 mg, 1.40 mmol), PdCl.sub.2 (dppf) (68 mg, 0.093 mmol), and 2 mol/L aqueous sodium carbonate (1.40 ml, 2.80 mmol), and the resulting mixture was stirred for 8 hours at 80° C. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed by water and brine, dried over anhydrous magnesium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 51 (280 mg, Yield 62%).

(553) LC/MS (Condition B) RT=2.51 [M+H].sup.+=484.

(554) Step 2

(555) To the mixture of Compound 51 (100 mg, 0.21 mmol), acetonitrile (3 mL), and water (0.75 mL) were added 7% osmium tetroxide (75 mg, 0.021 mmol) and sodium periodate (133 mg, 0.62 mmol), and the resulting mixture was heated with reflux at 4 hours. The reaction mixture was filtered, and washed by ethyl acetate. To the filtrate was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed by water and brine, dried over anhydrous magnesium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 52 (35 mg, Yield 35%).

(556) LC/MS (Condition B) RT=2.45 [M+H].sup.+=486.

(557) Step 3

(558) To a mixture of Compound 52 (100 mg, 0.072 mmol), THF (1 mL), and water (0.5 mL) were added O-methylhydroxylamine hydrochloride (9.0 mg, 0.11 mmol) and sodium acetate (8.9 mg, 0.11 mmol), and the mixture was stirred for 30 minutes at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed by water and brine, dried over anhydrous magnesium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate).

(559) The obtained compound (33 mg, 0.064 mmol) was dissolved in THF (0.75 mL) and methanol (0.75 mL). To the solution was added 2 mol/L aqueous sodium hydroxide (192 μL, 0.38 mmol), and the mixture was stirred for 1 hour at room temperature. To the reaction mixture was added hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed by brine, dried over anhydrous magnesium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (chloroform-methanol) to give Compound I-181 (18 mg, Yield 56%).

(560) .sup.1H-NMR (DMSO-D.sub.6) δ: 8.88 (1H, s), 8.00 (1H, d, J=9.0 Hz), 7.64 (2H, t, J=9.4 Hz), 7.45 (1H, d, J=2.5 Hz), 7.35 (1H, t, J=7.5 Hz), 7.19 (1H, dd, J=8.9, 2.6 Hz), 7.09 (1H, t, J=7.4 Hz), 5.43-5.38 (1H, m), 4.17 (2H, q, J=6.9 Hz), 3.96-3.89 (4H, m), 3.70 (2H, d, J=2.8 Hz), 3.63-3.58 (2H, m), 3.16 (1H, t, J=9.7 Hz), 2.72-2.63 (1H, m), 1.38 (3H, t, J=6.9 Hz), 0.33 (3H, d, J=6.5 Hz).

(561) LC/MS (Condition B) RT=2.27 [M+H].sup.+=501.

EXAMPLE 34

(562) ##STR00146##

(563) To a solution of Compound 53 (168 mg, 0.33 mmol) which was synthesized by the similar manner as described in Example 33 in THF (2 mL) was added 0.5 mol/L 9-borabicyclo[3.3.1]nonane in THF (0.99 mL, 0.49 mmol) under ice-cooling, and the mixture was stirred for 1 hour at room temperature. To the reaction mixture was added 2 mol/L dimethyl sulfide borane in toluene (0.25 mL, 0.49 mmol), and the mixture was stirred overnight at room temperature. Then, water (0.5 mL) and 30% hydrogen peroxide solution (0.5 mL) were added to the mixture, and the resulting mixture was stirred for 1 hour at room temperature. Further, 2 mol/L aqueous sodium hydroxide (0.49 mL, 0.99 mmol) was added to the mixture, and the resulting mixture was stirred for 1 hour at room temperature. To the reaction mixture was added 10% aqueous sodium hydrogensulfite, and the mixture was extracted with ethyl acetate. The organic layer was washed by water and brine, dried over anhydrous magnesium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate).

(564) The obtained compound (48 mg, 0.064 mmol) was dissolved in THF (1 mL) and methanol (1 mL). To the solution was added 2 mol/L aqueous sodium hydroxide (204 μL, 0.41 mmol), and the resulting mixture was stirred for 90 minutes at room temperature. The reaction mixture was back extracted with 0.1 mol/L aqueous sodium hydroxide. To the water layer was added hydrochloric acid and the mixture was made acidic. The resulting mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (chloroform-methanol) to give Compound I-314 (23.1 mg, 2 Steps Yield 16%).

(565) .sup.1H-NMR (DMSO-d.sub.6) δ: 7.98 (1H, d, J=8.5 Hz), 7.71-7.63 (2H, m), 7.37 (1H, t, J =7.4 Hz), 7.11 (1H, t, J=7.3 Hz), 7.02 (1H, s), 6.96 (1H, d, J=8.3 Hz), 5.47-5.42 (1H, m), 4.16-4.09 (2H, m), 3.99-3.93 (1H, m), 3.80 (2H, s), 3.71-3.58 (4H, m), 3.25-3.11 (3H, m), 2.74-2.64 (1H, m), 1.36 (3H, t, J=6.5 Hz), 0.36 (3H, d, J=6.3 Hz).

(566) LC/MS (Condition B) RT=1.87, [M+H].sup.+=488.

EXAMPLE 35

(567) ##STR00147##
Step 1

(568) To the mixture of Compound 52 (174 mg, 0.36 mmol), methanol (1.5 mL), and THF (1.5 mL) was added sodium borohydride (13.56 mg, 0.36 mmol) under ice-cooling, and the mixture was stirred for 15 minutes at 0° C. To the reaction mixture was added 2 mol/L aqueous hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed by brine, dried over anhydrous magnesium sulphate, and concentrated in vacuo to give crude product of Compound 54 (151 mg).

(569) Step 2

(570) To a solution of Compound 54 (48 mg, 0.098 mmol) in dichloromethane (1.5 mL) was added DAST (20 μL, 0.15 mmol) at −78° C., and the mixture was stirred for 1 hour at −78° C. To the reaction mixture was added saturated aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed by brine, dried over anhydrous magnesium sulphate, and concentrated in vacuo.

(571) The resulting residue was dissolved in THF (0.75 mL) and methanol (0.75 mL). To a solution was added 2 mol/L aqueous sodium hydroxide (140 μL, 0.28 mmol), and the mixture was stirred for 2 hours at room temperature. To the reaction mixture was added 2 mol/L aqueous hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed by brine, dried over anhydrous magnesium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (chloroform-methanol) to give Compound I-258 (15.6 mg, 2 Steps Yield 34%).

(572) .sup.1H-NMR (DMSO-d.sub.6) δ: 7.96 (1H, d, J=8.8 Hz), 7.65 (2H, t, J=9.2 Hz), 7.36 (1H, t, J=7.7 Hz), 7.20 (1H, s), 7.14-7.08 (2H, m), 5.91 (1H, s), 5.79 (1H, s), 5.42 (1H, t, J=6.3 Hz), 4.17 (2H, q, J=6.8 Hz), 3.96-3.91 (1H, m), 3.76-3.58 (4H, m), 3.13 (1H, t, J=9.7 Hz), 2.72-2.64 (1H, m), 1.38 (3H, t, J=6.8 Hz), 0.34 (3H, d, J=6.7 Hz).

(573) LC/MS (Condition B) RT=2.19 [M+H].sup.+=476.

EXAMPLE 36

(574) ##STR00148##
Step 1

(575) To a solution of Compound 54 (40 mg, 0.082 mmol) in THF (1 mL) were added diphenylphosphoryl azide (43 μL, 0.196 mmol) and diazabicycloundecene (30 μL, 0.196 mmol), and the mixture was stirred for 2 days at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed by brine, dried over anhydrous magnesium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 55 (63 mg).

(576) LC/MS (Condition RT=2.59 [M+H].sup.+=513.

(577) Step 2

(578) To the mixture of Compound 55 (63 mg), THF (1 mL), and methanol (1 mL) was added Pd-Carbon (13 mg), and the mixture was stirred for 4 hours under hydrogen atmosphere at room temperature. The reaction mixture was filtered by using Celite, and washed by methanol. The filtrate was concentrated in vacuo.

(579) The resulting residue was dissolved in dichloromethane (1.5 mL). To the solution were added triethylamine (30 μL, 0.22 mmol) and acetyl chloride (12.4 μL, 0.172 mmol) under ice-cooling, and the mixture was stirred for 2 hours at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed by brine, dried over anhydrous magnesium sulphate, and concentrated in vacuo.

(580) The resulting residue was dissolved in THF (1.5 mL) and methanol (1.5 mL). To the solution was added 2 mol/L aqueous sodium hydroxide (70 μL, 0.14 mmol), and the mixture was stirred overnight at room temperature. To the reaction mixture was added 2 mol/L aqueous hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed by brine, dried over anhydrous magnesium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (chloroform-methanol) to give Compound I-259 (18.5 mg, 4 Steps Yield 44%).

(581) .sup.1H-NMR (DMSO-d.sub.6) δ: 8.39 (1H, brs), 7.99 (1H, d, J=8.8 Hz), 7.71-7.64 (2H, m), 7.37 (1H, t, J=7.5 Hz), 7.11 (1H, t, J=7.4 Hz), 7.01 (1H, dd, J=8.8, 2.5 Hz), 6.98-6.96 (1H, m), 5.48-5.42 (1H, m), 4.69 (2H, d, J=6.0 Hz), 4.12 (2H, q, J=6.9 Hz), 3.96 (1H, dd, J=10.7, 7.2 Hz), 3.82 (2H, s), 3.70 (1H, d, J=10.8 Hz), 3.62 (1H, t, J=8.2 Hz), 3.20 (1H, t, J=9.5 Hz), 2.74-2.65 (1H, m), 1.94 (3H, s), 1.36 (3H, t, J=6.9 Hz), 0.36 (3H, d, J=6.5 Hz).

(582) LC/MS (Condition B) RT=1.81 [M+H].sup.+=515.

EXAMPLE 37

(583) ##STR00149##

(584) To a mixture of Compound 56 (95 mg, 0.193 mmol), THF (1.5 mL), and deuteromethanol (1.5 mL) was added dried 10% Pd-Carbon (62 mg), and the mixture was stirred overnight under deuterium atmosphere at room temperature. The reaction mixture was filtered by using Celite, and washed by ethanol. The filtrate was concentrated in vacuo, and the resulting residue was purified by silica gel column chromatography (acetonitrile including 0.1% formic acid −0.1% aqueous formic acid).

(585) The obtained compound (8 mg, 0.017 mmol) was dissolved in THF (0.5 mL) and methanol (0.5 mL). To the solution was added 2 mol/L aqueous sodium hydroxide (52 μL, 0.104 mmol), and the mixture was stirred for 2 hours at room temperature. To the reaction mixture was added 2 mol/L aqueous hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed by brine, dried over anhydrous magnesium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (chloroform-methanol) to give Compound I-264 (7.8 mg, Yield 10%).

(586) LC/MS (Condition B) RT=2.04 [M+H].sup.+=445.

EXAMPLE 38

(587) ##STR00150##

(588) To a solution of Compound 57 (50 mg, 0.093 mmol) in NMP (2 mL) were added Zn(CN).sub.2 (10.94 mg, 0.093 mmol), Zn (1.22 mg, 0.019 mmol) and bis(tri-tert-butylphosphine) palladium (4.76 mg, 9.32 μmol) at room temperature, and the mixture was stirred for 30 minutes at 130° C. by using the microwave reactor. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed by water and brine, dried over anhydrous magnesium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate).

(589) The obtained compound was hydrolyzed according to the method described in the general synthetic procedures to give Compound I-172 (33 mg, 2 Steps Yield 80%).

(590) .sup.1H-NMR (DMSO-D.sub.6) δ: 8.37 (1H, s), 7.85 (1H, d, J=8.4 Hz), 7.78 (2H, d, J=8.9 Hz), 7.43 (1H, dd, J=8.3, 1.2 Hz), 7.14 (2H, d, J=9.0 Hz), 5.46 (1H, t, J=5.8 Hz), 4.15 (2H, q, J=6.9 Hz), 3.90 (1H, dd, J=11.4, 7.4 Hz), 3.75-3.55 (4H, m), 3.10 (1H, t, J=10.0 Hz), 2.5 (1H, m), 1.39 (3H, t, J=7.0 Hz), 0.27 (3H, d, J=6.7 Hz).

(591) LC/MS (Condition B) RT=1.98, [M+H].sup.+=469.

EXAMPLE 39

(592) ##STR00151##

(593) To a solution of Compound 57 (25 mg, 0.047 mmol) in toluene (2 mL) were added morpholine (0.012 ml, 0.140 mmol), cesium carbonate (45.6 mg, 0.140 mmol), BINAP (1.94 mg, 3.12 μmol) and palladium acetate (2.09 mg, 9.32 μmol) at room temperature, and the mixture was stirred for 7.5 hours under nitrogen atmosphere at 110° C. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed by water and brine, dried over anhydrous magnesium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate).

(594) The obtained compound was hydrolyzed according to the method described in the general synthetic procedures to give Compound I-219 (14.3 mg, 66%).

(595) .sup.1H-NMR (CDCl.sub.3) δ: 7.83 (2H, d, J=8.9 Hz), 7.46 (1H, d, J=8.9 Hz), 7.02 (2H, d, J=8.9 Hz), 6.89 (1H, dd, J=9.0, 1.8 Hz), 6.64 (1H, d, J=1.6 Hz), 5.00 (1H, dt, J=10.2, 3.6 Hz), 4.13 (2H, ddd, J=14.1, 7.1, 2.6 Hz), 4.01 (1H, dd, J=11.1, 7.6 Hz), 3.89 (4H, t, J=4.8 Hz), 3.82-3.76 (3H, m), 3.69 (1H, dd, J=9.0, 7.4 Hz), 3.24-3.18 (5H, m), 2.66 (1H, ddd, J=15.4, 8.7, 5.4 Hz), 1.47 (3H, t, J=7.0 Hz), 0.50 (3H, d, J=6.8 Hz).

(596) LC/MS (Condition B) RT=1.95, [M+H].sup.+=529.

EXAMPLE 40

(597) ##STR00152##

(598) To the mixture of Compound 57 (25 mg, 0.047 mmol), toluene (2 mL), and purified water (0.1 mL) were added 2-cyclohexyl-4,4,5,5-tetramethyl-1,3,2-dioxyborolane (12.61 mg, 0.061 mmol), potassium phosphate (34.6 mg, 0.163 mmol), triphenylphosphine (1.22 mg, 4.66 μmol), and palladium acetate (0.523 mg, 2.330 μmol) at room temperature, and the resulting mixture was stirred for 7.5 hours under nitrogen atmosphere at 100° C. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed by water and brine, dried over anhydrous magnesium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate).

(599) The obtained compound was hydrolyzed according to the method described in the general synthetic procedures to give Compound I-220 (20.9 mg, 98%).

(600) .sup.1H-NMR (CDCl.sub.3) δ: 7.84 (2H, d, J=8.9 Hz), 7.51 (1H, d, J=8.4 Hz), 7.26-7.23 (2H, m), 7.02 (2H, d, J=8.9 Hz), 6.19 (1H, s), 5.07 (1H, td, J=7.0, 2.8 Hz), 4.15-4.03 (3H, m), 3.82-3.68 (4H, m), 3.22 (1H, t, J=9.7 Hz), 2.68 (1H, dt, J=17.2, 6.9 Hz), 2.49-2.42 (2H, m), 2.27-2.21 (2H, m), 1.84-1.78 (2H, m), 1.71-1.65 (2H, q, J=6.0 Hz), 1.47 (3H, t, J=7.0 Hz), 0.47 (3H, d, J=6.9 Hz).

(601) LC/MS (Condition B) RT=2.60, [M+H].sup.+=523.

EXAMPLE 41

(602) ##STR00153##

(603) To a solution of Compound 18 (60.0 mg, 0.112 mmol) in THF (0.5 mL) were added pyridine 2-ol (26.7 mg, 0.281 mmol), 2.2 mol/L DEAD in toluene (0.051 mL, 0.112 mmol), and triphenylphosphine (29.5 mg, 0.112 mmol) at 0° C., and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed by brine, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate).

(604) The obtained compound was hydrolyzed according to the method described in the general synthetic procedures to give Compound I-339.

(605) LC/MS (Condition B) RT=2.27, [M+H].sup.+=569.

EXAMPLE 42

(606) ##STR00154##

(607) To a solution of Compound 58 (181 mg, 0.359 mmol) in methanol (2.0 mL) were added 8.8 mol/L aqueous glyoxal (0.41 mL, 3.59 mmol) and 28% aqueous ammonia (0.28 mL, 3.59 mmol), and the mixture was stirred for overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed by brine, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate).

(608) The obtained compound was hydrolyzed according to the method described in the general synthetic procedures to give Compound I-363.

(609) .sup.1H-NMR (DMSO-D6) δ: 7.75-7.73 (4H, m), 7.34 (1H, d, J=9.8 Hz), 7.13 (2H, d, J=8.5 Hz), 7.03 (1H, t, J=9.2 Hz), 6.94 (1H, s), 4.81-4.77 (3H, m), 3.92 (3H, s), 3.80 (1H, t, J=9.9 Hz), 2.72 (2H, dt, J=22.8, 8.8 Hz), 1.33 (6H, d, J=5.8 Hz).

EXAMPLE 43

(610) ##STR00155## ##STR00156##
Step 1

(611) To a solution of Compound 59 (996 mg, 5.79 mmol) in NMP (23 ml) was added sodium hydride (347 mg, 8.68 mmol) at 0° C., and the mixture was stirred for 30 minutes at room temperature. Then, Compound 60 (2 g, 5.79 mmol) was added to the mixture, and the resulting mixture was stirred for 2 hours at 80° C. The reaction mixture was diluted with ethyl acetate, and washed by brine. The organic layer was dried over anhydrous magnesium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 61 (1.05 g, Yield 53%).

(612) LC/MS (Condition B) RT=1.54, [M+H].sup.+=345.

(613) Step 2

(614) The solution of Compound 61 (1 g, 2.90 mmol), (1-propynyl)tributylstannane (0.881 ml, 2.90 mmol) and tetrakis(triphenylphosphine) palladium (167 mg, 0.145 mmol) in toluene (10 ml) was stirred for 2 hours at 140° C. by using the microwave reactor. The reaction mixture was diluted with ethyl acetate, and washed by saturated aqueous potassium fluoride. The organic layer was dried over anhydrous magnesium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 62 (742 mg, Yield 84%).

(615) LC/MS (Condition B) RT=1.58, [M+H].sup.+=305.

(616) Step 3

(617) The solution of Compound 62 (616 mg, 2.02 mmol) and copper iodide (39 mg, 0.20 mmol) in DMF (5 ml) was stirred for 4 hours at 160° C. by using the microwave reactor. The reaction mixture was diluted with ethyl acetate, and washed by brine. The organic layer was dried over anhydrous magnesium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 63 (322 mg, Yield 52%).

(618) LC/MS (Condition B) RT=1.60, [M+H].sup.+=305.

(619) Step 4

(620) To a solution of Compound 63 (322 mg, 1.06 mmol) in THF (4 ml) was added oxalyl chloride (116 ml, 1.32 mmol) at 0° C., and the mixture was stirred for 1 hour at room temperature. To the mixture was added ethanol (1.2 ml, 21 mmol), and the resulting mixture was stirred for additional 1 hour at room temperature. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate, and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 64 (335 mg, Yield 78%).

(621) LC/MS (Condition B) RT=1.71, [M+H].sup.+=405.

(622) Step 5

(623) To a solution of Compound 64 (139 mg, 0.34 mmol) in dichloromethane (2 ml) were added triethylsilane (165 ml, 1.03 mmol) and trifluoroacetic acid (0.529 ml, 6.87 mmol), and the mixture was stirred for 3 hours at room temperature. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulphate, and the concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 65 (118 mg, Yield 88%).

(624) LC/MS (Condition B) RT=1.69, [M+H].sup.+=391.

(625) Step 6

(626) To a solution of Compound 65 (118 mg, 0.30 mmol) in THF (4 ml) was added Pd-Carbon (32 mg), and the mixture was stirred for 5 hours under hydrogen atmosphere at atmospheric pressure. The insoleble was filtered off and the filtrate was concentrated in vacuo to give Compound 66 (90 mg, Yield 99%).

(627) LC/MS (Condition A) RT=1.36, [M+H].sup.+=301.

(628) Step 7

(629) Compound I-329 was synthesized according to the method described in the general synthetic procedures from Compound 66.

(630) .sup.1H-NMR (DMSO-D.sub.6) δ: 0.33 (d, J=7.0 Hz, 3H), 1.39 (t, J=7.0 Hz, 3H), 2.28 (s, 3H), 2.44-2.46 (m, 1H), 2.99 (t, J=10.0 Hz, 1H), 3.56 (s, 2H), 3.65 (dd, J=10.2, 8.2 Hz, 1H), 3.77-3.82 (m, 2H), 4.16-4.20 (m, 2H), 5.16-5.19 (m, 1H), 6.79 (t, J=7.7 Hz, 1H), 6.94-6.96 (m, 2H), 7.21 (d, J=9.0 Hz, 2H), 7.40 (d, J=7.8 Hz, 1H), 7.85 (d, J=8.8 Hz, 2H), 12.11 (s, 1H).

(631) According to the similar manner as described in the above Examples or in the general synthetic procedures, the following Examples were synthesized by using the commercially available compounds or the intermediates described in the above Reference Examples. The chemical structures and physical properties of the Examples are shown in the Tables 1 to 81.

(632) TABLE-US-00001 TABLE 1 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-1 (DMSO-d.sub.6) δ: 7.85-7.71 (3H, m), 7.40 (1H, d, J = 8.4 Hz), 7.15 (2H, d, J = 8.5 Hz), 6.99 (1H, t, J = 8.8 Hz), 5.02 (1H, q, J = 6.7 Hz), 4.81-4.73 (1H, m), 3.97-3.79 (4H, m), 3.41- 3.33 (2H, m), 1.99-1.93 (1H, m), 1.33 (6H, d, J = 6.0 Hz), 0.67 (3H, d, J = 6.3 Hz). 476 2.21 P I-2 (DMSO-d.sub.6) δ: 7.68-7.52 (4H, m), 7.42 (1H, d, J = 10.61 Hz), 7.26-7.21 (1H, br m), 7.02-6.93 (1H, br m), 6.89 (2H, d, J = 8.08 Hz), 5.30-5.22 (1H, m), 4.73-4.61 (1H, m), 4.37- 4.29 (1H, m), 3.98-3.89 (1H, m), 3.72-3.15 (3H, m), 2.69-2.14 (2H, m), 1.33-1.19 (6H, m). 505 1.74 B I-3 (CDCl.sub.3) δ: 7.88 (2H, d, J = 8.59 Hz), 7.56-7.48 (1H, m), 7.47-7.40 (1H, m), 7.34-7.29 (1H, m), 7.04 (2H, d, J = 8.59 Hz), 6.93-6.82 (2H, m), 4.90-4.84 (1H, m), 4.75-4.67 (1H, m), 4.45-4.38 (1H, m), 4.31-4.24 (1H, m), 3.93-3.83 (1H, m), 3.80- 3.73 (1H, m), 3.71-3.63 (1H, m), 2.67-2.59 (1H, m), 2.57-2.49 (1H, m), 1.44-1.38 (6H, m). 505 1.87 B I-4 0 519 1.81 B I-5 533 1.84 B

(633) TABLE-US-00002 TABLE 2 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-6 547 2.02 B I-7 (DMSO-d.sub.6) δ: 7.89-7.54 (4H, m), 7.20-6.92 (3H, m), 5.49-5.41 (1H, m), 5.06-4.99 (1H, m), 4.76-4.64 (1H, m), 3.96-3.61 (4H, m), 2.89- 2.72 (2H, m), 1.31 (6H, d, J = 5.56 Hz). 487 2.09 B I-8 (CDCl.sub.3) δ: 7.83 (2H, d, J = 8.08 Hz), 7.64-7.56 (1H, m), 7.02 (2H, d, J = 8.08 Hz), 6.96-6.88 (1H, m), 6.79 (1H, d, J = 8.08 Hz), 4.73-4.62 (1H, m), 4.41-4.29 (1H, m), 4.01- 3.81 (4H, m), 3.75-3.66 (1H, m), 2.52-2.41 (1H, m), 2.36-2.25 (1H, m), 1.49 (3H, d, J = 5.56 Hz), 1.40 (6H, d, J = 5.56 Hz). 476 2.26 B I-9 (CDCl.sub.3) δ: 7.61-7.51 (3H, m), 6.96- 6.88 (2H, m), 6.78 (2H, d, J = 8.59 Hz), 5.06-4.97 (1H, m), 4.63-4.54 (1H, m), 4.07-3.91 (3H, m), 3.82- 3.66 (4H, m), 3.52-3.44 (1H, m), 2.68-2.57 (1H, m), 2.40-2.28 (1H, m), 1.40-1.34 (6H, m). 492 1.87 B I-10 (CDCl.sub.3) δ: 7.62-7.50 (3H, m), 6.97- 6.88 (2H, m), 6.78 (2H, d, J = 8.59 Hz), 5.01-4.91 (1H, m), 4.62-4.53 (1H, m), 4.06-3.98 (1H, m), 3.97- 3.90 (1H, m), 3.83 (2H, s), 3.66-3.58 (1H, m), 3.53-3.44 (1H, m), 2.74- 2.63 (1H, m), 2.09-2.00 (1H, m), 1.51 (3H, d, J = 6.06 Hz), 1.39-1.32 (6H, m). 476 2.17 B

(634) TABLE-US-00003 TABLE 3 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-11 (CDCl.sub.3) δ: 7.83 (2H, d, J = 8.08 Hz), 7.63-7.56 (1H, m), 7.04 (2H, d, J = 8.08 Hz), 6.94-6.85 (1H, m), 6.76 (1H, d, J = 8.59 Hz), 4.73-4.64 (1H, m), 4.39-4.27 (1H, m), 3.98- 3.67 (8H, m), 2.56-2.45 (1H, m), 2.44-2.32 (1H, m), 1.40 (6H, d, J = 5.56 Hz). 492 2   B I-12 (CDCl.sub.3) δ: 7.74-7.57 (3H, m), 7.06- 6.89 (4H, m), 5.14-4.91 (1H, m), 4.82-4.70 (1H, m), 4.69-4.57 (1H, m), 4.26-4.15 (1H, m), 4.02-3.92 (3H, m), 2.91-2.61 (2H, m), 2.50- 2.22 (2H, m), 1.38 (6H, d, J = 5.56 Hz). 494 2.18 B I-13 (CDCl.sub.3) δ: 7.84 (2H, d, J = 8.59 Hz), 7.63-7.57 (1H, m), 7.03 (2H, d, J = 8.59 Hz), 6.96-6.87 (1H, m), 6.78 (1H, d, J = 8.59 Hz), 4.71-4.58 (3H, m), 4.47-4.34 (1H, m), 4.24- 4.08 (1H, m), 3.97 (2H, s), 3.91-3.82 (1H, m), 3.74-3.60 (1H, m), 2.70- 2.57 (1H, m), 2.52-2.39 (1H, m), 1.40 (6H, d, J = 5.05 Hz). 494 2.22 B I-14 0 501 2.04 B I-15 (CDCl.sub.3) δ: 7.61-7.51 (3H, m), 7.35- 7.15 (2H, m), 6.74 (2H, d, J = 8.59 Hz), 5.05-4.94 (1H, m), 4.62-4.50 (1H, m), 4.07-3.89 (2H, m), 3.80 (2H, s), 3.66-3.58 (1H, m), 2.78-2.66 (1H, m), 2.10-1.98 (1H, m), 1.51 (3H, d, J = 6.06 Hz), 1.40-1.31 (6H, m). 492 2.25 B

(635) TABLE-US-00004 TABLE 4 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-16 (CDCl.sub.3) δ: 7.67 (2H, d, J = 8.08 Hz), 7.61-7.52 (1H, m), 6.96-6.81 (4H, m), 5.18-5.07 (1H, m), 4.66- 4.55 (1H, m), 4.16-3.99 (1H, m), 3.92-3.83 (3H, m), 3.73-3.56 (3H, m), 3.44 (3H, s), 2.58-2.46 (1H, m), 2.39-2.29 (1H, m), 1.38-1.34 (6H, m). 506 2.15 B I-17 (CDCl.sub.3) δ: 7.83 (2H, d, J = 7.58 Hz), 7.64-7.54 (1H, m), 7.03 (2H, d, J = 7.58 Hz), 6.94-6.77 (2H, m), 4.73-4.62 (1H, m), 4.37-4.26 (1H, m), 4.16-3.53 (7H, m), 3.38 (3H, s), 2.62-2.50 (1H, m), 2.47-2.31 (1H, m), 1.39 (6H, d, J = 5.56 Hz). 506 2.21 B I-18 501 2.05 B I-19 519 2.24 B I-20 542 1.51 B

(636) TABLE-US-00005 TABLE 5 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-21 (CDCl.sub.3) δ: 7.84 (2H, d, J = 8.85 Hz), 7.62-7.50 (3H, m), 7.04 (2H, d, J = 8.85 Hz), 6.95-6.86 (1H, m), 6.64 (1H, dd, J = 9.15, 1.98 Hz), 6.29-6.26 (1H, m), 4.73-4.59 (3H, m), 4.40-4.17 (2H, m), 3.97 (2H, s), 3.85-3.74 (1H, m), 3.62-3.53 (1H, m), 2.55-2.43 (1H, m), 2.31-2.20 (1H, m), 1.42 (6H, d, J = 6.10 Hz). 542 2.17 B I-22 (CDCl.sub.3) δ: 7.83 (2H, d, J = 8.90 Hz), 7.60 (1H, dd, J = 8.73, 5.04 Hz), 7.05 (2H, d, J = 8.90 Hz), 6.97-6.88 (1H, m), 6.75 (1H, dd, J = 9.23, 1.68 Hz), 6.17 (1H, ddd, J = 57.75, 56.07, 2.52 Hz), 4.75-4.62 (1H, m), 4.41- 4.16 (2H, m), 4.01-3.86 (3H, m), 3.70-3.59 (1H, m), 2.87-2.73 (1H, m), 2.51-2.38 (1H, m), 1.41 (6H, dd, J = 5.96, 1.43 Hz). 512 2.29 B I-23 583 2.12 B I-24 0 (CDCl.sub.3) δ: 7.67-7.57 (3H, m), 7.02- 6.90 (2H, m), 6.84 (2H, d, J = 8.73 Hz), 5.05-4.94 (1H, m), 4.69-4.59 (1H, m), 3.97-3.87 (3H, m), 3.70 (1H, dd, J = 10.66, 5.96 Hz), 2.69-2.57 (1H, m), 2.23-2.05 (2H, m), 1.42 (6H, d, J = 6.04 Hz), 1.33-1.27 (3H, m), 1.09-1.01 (3H, m). 490 2.29 B I-25 (DMSO-d.sub.6) δ: 7.69 (2H, d, J = 8.8 Hz), 7.67 (1H, d, J = 10.1 Hz), 7.46 (1H, dd, J = 10.1, 2.0 Hz), 7.08 (2H, d, J = 8.8 Hz), 6.99 (1H, dt, J = 12.8, 4.6 Hz), 5.69-5.58 (1H, m), 5.01-4.91 (1H, m), 4.80-4.67 (1H, m), 4.38-4.25 (1H, m), 3.84-3.69 (1H, m), 3.76 (2H, s), 3.55 (1H, dd, J = 10.3, 6.0 Hz), 3.49-3.40 (1H, m), 3.11 (1H, dd, J = 10.2, 5.0 Hz), 1.31 (6H, d, J = 6.1 Hz). 478 1.92 B

(637) TABLE-US-00006 TABLE 6 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-26 (CDCl.sub.3) δ: 7.73 (2H, d, J = 8.7 Hz), 7.61 (1H, dd, J = 9.0, 4.8 Hz), 7.02- 6.89 (2H, m), 6.94 (2H, d, J = 8.6 Hz), 5.33 (1H, dd, J = 52.4, 2.5 Hz), 5.09-4.95 (1H, m), 4.70-4.58 (1H, m), 3.98 (1H, dd, J = 10.7, 7.7 Hz), 3.86 (2H, s), 3.82 (1H, d, J = 3.4 Hz), 3.75-3.62 (2H, m), 1.38 (6H, d, J = 6.0 Hz). 480 2.16 B I-27 (CDCl.sub.3) δ: 7.79 (2H, d, J = 8.7 Hz), 7.63 (1H, dd, J = 8.9, 5.0 Hz), 7.03 (2H, d, J = 8.7 Hz), 6.97 (1H, t, J = 9.7 Hz), 6.88 (1H, d, J = 9.1 Hz), 5.13 (1H, t, J = 9.2 Hz), 4.71-4.63 (1H, m), 4.38 (1H, t, J = 9.5 Hz), 4.10 (2H, d, J = 17.6 Hz), 3.94 (2H, d, J = 1.2 Hz), 3.73 (1H, t, J = 10.2 Hz), 3.56 (1H, d, J = 18.0 Hz), 1.40 (6H, d, J = 6.0 Hz). 476 2.07 B I-28 (DMSO-d.sub.6) δ: 7.94-7.61 (4H, m), 7.26-7.04 (3H, m), 6.10-5.99 (1H, m), 4.78-4.51 (3H, m), 4.36-4.21 (2H, m), 4.03-3.88 (2H, m), 1.31- 1.20 (6H, m). 460 2.19 B I-29 (DMSO-d.sub.6) δ: 7.75 (2H, d, J = 8.5 Hz), 7.65 (1H, dd, J = 9.1, 5.4 Hz), 7.50 (1H, d, J = 9.8 Hz), 7.11 (2H, d, J = 8.1 Hz), 6.95 (1H, t, J = 9.1 Hz), 5.28 (1H, t, J = 5.9 Hz), 4.79-4.71 (1H, m), 3.85 (1H, dd, J = 11.0, 7.6 Hz), 3.61 (4H, dt, J = 31.7, 11.8 Hz), 3.11 (1H, t, J = 9.7 Hz), 1.33 (6H, d, J = 5.9 Hz), 0.29 (3H, d, J = 6.6 Hz). 476 2.22 B I-30 (DMSO-d.sub.6) δ: 7.80 (2H, d, J = 8.9 Hz), 7.69 (1H, dd, J = 8.7, 5.5 Hz), 7.49 (1H, d, J = 9.4 Hz), 7.14 (2H, d, J = 9.1 Hz), 7.02-6.95 (1H, m), 5.33-5.24 (1H, m), 4.83-4.71 (1H, m), 4.15-4.05 (1H, m), 3.86-3.69 (3H, m), 3.59 (1H, dd, J = 10.0, 5.3 Hz). 492 2.07 B

(638) TABLE-US-00007 TABLE 7 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-31 (CDCl.sub.3) δ: 7.75 (2H, d, J = 8.4 Hz), 7.59 (1H, dd, J = 8.6, 4.8 Hz), 7.00- 6.85 (2H, m), 6.97 (2H, d, J = 8.4 Hz), 4.69-4.61 (1H, m), 4.41 (1H, q, J = 7.9 Hz), 3.92 (2H, s), 3.79 (1H, t, J = 8.8 Hz), 3.74-3.55 (2H, m), 3.06 (1H, t, J = 9.1 Hz), 2.85-2.71 (1H, m), 1.39 (6H, d, J = 5.9 Hz), 0.99 (3H, d, J = 6.7 Hz). 476 2.23 B I-32 (CDCl.sub.3) δ: 7.80 (2H, d, J = 8.4 Hz), 7.56 (1H, dd, J = 8.8, 5.0 Hz), 7.00- 6.86 (2H, m), 6.98 (2H, d, J = 8.7 Hz), 5.49 (1H, td, J = 16.8, 6.6 Hz), 4.97 (1H, t, J = 6.4 Hz), 4.86 (1H, d, J = 10.4 Hz), 4.73-4.60 (2H, m), 4.03 (1H, dd, J = 11.2, 7.2 Hz), 3.78-3.67 (2H, m), 3.75 (2H, s), 3.35 (1H, t, J = 9.8 Hz), 2.72-2.55 (1H, m), 1.70-1.57 (1H, m), 1.53-1.43 (1H, m), 1.39 (6H, dd, J = 5.9, 2.1 Hz). 502 2.33 B I-33 (CDCl.sub.3) δ: 7.81 (2H, d, J = 8.7 Hz), 7.53 (1H, d, J = 8.5 Hz), 7.33 (1H, s), 7.10 (1H, t, J = 4.3 Hz), 6.99 (2H, d, J = 8.8 Hz), 4.95 (1H, td, J = 7.1, 2.7 Hz), 4.72-4.60 (1H, m), 4.04 (1H, dd, J = 11.2, 7.2 Hz), 3.81 (1H, dd, J = 11.3, 2.9 Hz), 3.74 (2H, d, J = 2.1, Hz), 3.68 (1H, dd, J = 9.0, 7.3 Hz), 3.23 (1H, t, J = 9.6 Hz), 2.76-2.58 (1H, m), 1.39 (6H, dd, J = 6.1, 1.8 Hz), 0.47 (3H, d, J = 6.9 Hz). 492 2.33 B I-34 0 (DMSO-d.sub.6) δ: 7.75 (2H, d, J = 7.9 Hz), 7.64 (1H, dd, J = 9.0, 5.5 Hz), 7.50 (1H, d, J = 9.2 Hz), 7.10 (2H, d, J = 8.1 Hz), 6.95 (1H, t, J = 9.2 Hz), 5.33 (1H, t, J = 6.3 Hz), 4.80-4.68 (1H, m), 3.89-3.80 (1H, m), 3.70- 3.15 (5H, m), 1.32 (6H, dd, J = 5.6, 3.4 Hz), 2.39-2.22 (1H, m), 1.13- 0.62 (3H, m), 0.57 (3H, t, J = 7.4 Hz), 0.52-0.37 (1H, m). 504 2.4  B I-35 (DMSO-d.sub.6) δ: 7.78 (2H, d, J = 8.1 Hz), 7.62 (1H, dd, J = 12.6, 8.6 Hz), 7.34 (1H, t, J = 7.3 Hz), 7.19-7.04 (3H, m), 5.41-5.30 (1H, m), 4.83- 4.69 (1H, m), 3.95-3.82 (1H, m), 3.73-3.50 (4H, m), 3.20-3.07 (1H, m), 2.39-2.10 (1H, m), 1.34 (6H, d, J = 5.6 Hz), 0.29 (3H, d, J = 6.6 Hz). 458 2.16 B

(639) TABLE-US-00008 TABLE 8 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-36 (DMSO-d.sub.6) δ: 7.75 (2H, d, J = 8.4 Hz), 7.65 (1H, dd, J = 8.9, 5.4 Hz), 7.50 (1H, d, J = 9.9 Hz), 7.11 (2H, d, J = 8.4 Hz), 6.95 (1H, t, J = 8.9 Hz), 5.33-5.23 (1H, m), 4.82-4.67 (1H, m), 3.92-3.79 (1H, m), 3.73- 3.49 (3H, m), 3.17-3.04 (1H, m), 2.52-2.35 (1H, m), 1.32 (6H, d, J = 5.6 Hz), 0.29 (3H, d, J = 6.4 Hz). 476 2.23 B I-37 (DMSO-d.sub.6) δ: 7.75 (2H, d, J = 8.8 Hz), 7.65 (1H, dd, J = 8.8, 5.3 Hz), 7.50 (1H, dd, J = 10.1, 2.1 Hz), 7.11 (2H, d, J = 8.8 Hz), 6.95 (1H, td, J = 9.0, 2.1 Hz), 5.32-5.22 (1H, m), 4.83-4.67 (1H, m), 3.90-3.80 (1H, m), 3.73-3.49 (4H, m), 3.17- 3.05 (1H, m), 1.33 (6H, dd, J = 5.9, 1.8 Hz), 0.29 (3H, d, J = 6.7 Hz). 476 2.23 B I-38 (CDCl.sub.3) δ: 7.82 (2H, d, J = 8.7 Hz), 7.55 (1H, dd, J = 8.2, 4.8 Hz), 6.99 (2H, d, J = 9.0 Hz), 6.96-6.85 (2H, m), 5.08-4.96 (2H, m), 4.93-4.76 (2H, m), 4.74-4.60 (1H, m), 4.10- 4.00 (1H, m), 3.83 (1H, dd, J = 11.8, 2.5 Hz), 3.74 (2H, d, J = 2.3 Hz), 3.70 (1H, d, J = 7.8 Hz). 3.48 (1H, t, J = 9.8 Hz), 3.28-3.13 (1H, m), 1.40 (6H, dd, J = 6.1, 2.3 Hz). 488 2.27 B I-39 490 2.32 B I-40 506 1.94 B

(640) TABLE-US-00009 TABLE 9 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-41 502 2.35 B I-42 494 2.17 B I-43 474 2.18 B I-44 00 526 2.24 B I-45 01 508 2.21 B

(641) TABLE-US-00010 TABLE 10 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-46 02 (CDCl.sub.3) δ: 7.82 (2H, d, J = 8.69 Hz), 7.59 (1H, dd, J = 8.92, 5.11 Hz), 7.02 (2H, d, J = 8.85 Hz), 6.94 (1H, d, J = 7.02 Hz), 6.79 (1H, d, J = 9.00 Hz), 4.71-4.63 (1H, m), 4.35 (1H, t, J = 8.46 Hz), 4.00 (2H, s), 3.95 (1H, d, J = 7.47 Hz), 3.85 (1H, dd, J = 11.06, 7.24 Hz), 3.70 (1H, t, J = 10.45 Hz), 2.47 (1H, dd, J = 13.57, 7.02 Hz), 2.33 (1H, t, J = 9.07 Hz), 1.50 (3H, d, J = 6.25 Hz), 1.40 (6H, d, J = 6.10 Hz). 476 2.24 B I-47 03 531 1.44 B I-48 04 (DMSO-d.sub.6) δ: 7.94 (2H, dd, J = 8.39, 5.04 Hz), 7.67 (1H, dd, J = 8.64, 5.12 Hz), 7.44-7.52 (3H, m), 6.97 (1H, t, J = 8.14 Hz), 5.28-5.33 (1H, m), 3.88-3.95 (1H, m), 3.65- 3.53 (4H, m), 3.14 (1H, t, J = 10.16 Hz), 2.55-2.57 (1H, m), 0.31 (3H, d, J = 6.71 Hz). 436 1.93 A I-49 05 (DMSO-d.sub.6) δ: 12.40 (1H, s), 7.88 (2H, dd, J = 8.31, 1.43 Hz), 7.73- 7.64 (3H, m), 7.51 (1H, d, J = 10.07 Hz), 6.96 (1H, t, J = 8.98 Hz), 5.30 (1H, t, J = 6.29 Hz), 3.88-3.95 (1H, m), 3.51-3.67 (4H, m), 3.14 (1H, t, J = 9.57 Hz), 2.53-2.58 (1H, m), 0.31 (3H, d, J = 6.71 Hz). 452 2.03 A I-50 06 (DMSO-d.sub.6) δ: 12.46 (1H, s), 7.78 (2H, d, J = 8.90 Hz), 7.66 (1H, dd, J = 8.73, 5.20 Hz), 7.50 (1H, d, J = 10.07 Hz), 7.13 (2H, d, J = 8.73 Hz), 6.96 (1H, dt, J = 12.48, 4.70 Hz), 5.28 (1H, t, J = 6.38 Hz), 4.15 (2H, q, J = 6.94 Hz), 3.86 (1H, dd, J = 11.16, 7.30 Hz), 3.52-3.63 (4H, m), 3.11 (1H, t, J = 9.82 Hz), 2.41-2.47 (1H, m), 1.29 (3H, q, J = 23.44 Hz), 0.29 (3H, d, J = 6.71 Hz). 462 2.01 A

(642) TABLE-US-00011 TABLE 11 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-51 07 (DMSO-d.sub.6) δ: 12.44 (1H, s), 7.94 (2H, d, J = 8.23 Hz), 7.67 (1H, dd, J = 8.81, 5.46 Hz), 7.51 (1H, d, J = 10.07 Hz), 7.43 (1H, t, J = 72.52 Hz), 7.41 (2H, d, J = 8.73 Hz), 6.97 (1H, t, J = 8.64 Hz), 5.30 (1H, t, J = 6.13 Hz), 3.89 (1H, t, J = 5.62 Hz), 3.53-3.69 (4H, m), 3.15 (1H, t, J = 9.90 Hz), 2.54-2.56 (1H, m), 0.31 (3H, d, J = 6.71 Hz). 484 2.02 A I-52 08 (DMSO-d.sub.6) δ: 12.43 (1H, s), 7.79 (1H, t, J = 8.64 Hz), 7.70 (1H, dd, J = 8.73, 5.20 Hz), 7.56 (1H, d, J = 9.90 Hz), 6.94-7.09 (3H, m), 5.37 (1H, t, J = 5.96 Hz), 4.85-4.76 (1H, m), 3.96 (1H, dd, J = 11.16, 7.30 Hz), 3.58-3.77 (4H, m), 3.25 (1H, t, J = 9.82 Hz), 2.65 (1H, dt, J = 17.63, 6.67 Hz), 1.36 (6H, d, J = 6.04 Hz), 0.38 (3H, d, J = 6.55 Hz). 494 2.16 A I-53 09 (DMSO-d.sub.6) δ: 12.48 (1H, s), 8.00 (1H, d, J = 8.23 Hz), 7.72 (1H, dd, J = 8.48, 5.46 Hz), 7.55 (1H, d, J = 10.07 Hz), 7.41 (1H, s), 7.23 (1H, d, J = 8.23 Hz), 6.99 (1H, t, J = 9.06 Hz), 5.38 (1H, t, J = 6.04 Hz), 4.04-3.95 (11H, m), 3.82-3.65 (4H, m), 2.73-2.60 (1H, m), 2.09-2.00 (1H, m), 1.09 (2H, d, J = 7.05 Hz), 0.86 (2H, d, J = 4.87 Hz), 0.39 (3H, d, J = 6.55 Hz). 492 2.19 A I-54 0 (CDCl.sub.3) δ: 7.90 (2H, d, J = 7.39 Hz), 7.69-7.58 (1H, m), 7.03 (2H, d, J = 7.39 Hz), 6.99-6.87 (2H, m), 5.07-4.91 (1H, m), 4.76-4.63 (1H, m), 4.30-4.12 (1H, m), 4.10-3.95 (3H, m), 2.14-1.86 (2H, m), 1.45- 0.71 (10H, m). 488 2.32 B I-55 529 1.85 B

(643) TABLE-US-00012 TABLE 12 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-56 (DMSO-d.sub.6) δ: 12.45 (1H, s), 8.63 (1H, d, J = 2.01 Hz), 8.11 (1H, dd, J = 8.73, 1.34 Hz), 7.65 (1H, dd, J = 8.64, 5.29 Hz), 7.52 (1H, d, J = 9.57 Hz), 6.94-7.01 (2H, m), 5.31 (1H, t, J = 6.63 Hz), 4.43 (2H, q, J = 7.05 Hz), 3.93 (1H, dd, J = 11.58, 7.05 Hz), 3.48-3.65 (4H, m), 3.13 (1H, t, J = 9.90 Hz), 2.54-2.62 (1H, m), 1.38 (3H, t, J = 6.97 Hz), 0.32 (3H, d, J = 6.55 Hz). 463 1.99 A I-57 (DMSO-d.sub.6) δ: 12.41 (1H, s), 8.63 (1H, s), 8.09 (1H, d, J = 8.90 Hz), 7.66 (1H, t, J = 6.80 Hz), 7.52 (1H, d, J = 10.24 Hz), 6.93-6.99 (2H, m), 5.29-5.41 (2H, m), 3.92 (1H, dd, J = 11.25, 6.88 Hz), 3.46-3.67 (4H, m), 3.13 (1H, t, J = 9.99 Hz), 2.54-2.65 (1H, m), 1.34-1.37 (6H, m), 0.33 (2.9H, d, J = 6.55 Hz). 477 2.12 A I-58 (DMSO-d.sub.6) δ: 12.46 (1H, s), 8.00 (1H, d, J = 7.22 Hz), 7.66-7.69 (2H, m), 7.54 (1H, d, J = 10.24 Hz), 7.42 (1H, d, J = 9.06 Hz), 6.98 (1H, t, J = 9.06 Hz), 5.35 (1H, t, J = 6.13 Hz), 4.90-4.83 (1H, m), 4.01 (1H, dd, J = 11.75, 7.05 Hz), 3.78 (1H, d, J = 11.08 Hz), 3.45-3.67 (3H, m), 3.22 (1H, t, J = 9.74 Hz), 2.63-2.77 (1H, m), 1.35 (6H, d, J = 5.88 Hz), 0.36 (3H, d, J = 5.88 Hz). 501 2.11 A I-59 (CDCl.sub.3) δ: 7.82 (2H, d, J = 8.24 Hz), 7.37 (1H, s), 6.98 (4H, d, J = 8.54 Hz), 5.35 (1H, s), 4.65 (1H, t, J = 5.72 Hz), 4.13-4.01 (1H, m), 3.91 (1H, d, J = 11.13 Hz), 3.71 (2H, s), 3.65 (1H, t, J = 8.08 Hz), 3.22 (1H, t, J = 9.30 Hz), 2.63 (1H, s), 1.38 (6H, d, J = 5.64 Hz), 0.48 (3H, d, J = 6.25 Hz). 476 2.29 B I-60 (CDCl.sub.3) δ: 7.81 (2H, d, J = 8.85 Hz), 7.40 (1H, d, J = 7.02 Hz), 7.01 (4H, t, J = 7.70 Hz), 4.76 (1H, s), 4.65 (1H, dd, J = 12.05, 6.10 Hz), 4.01 (2H, s), 3.96-3.90 (4H, m), 2.43 (1H, t, J = 12.58 Hz), 1.50 (3H, d, J = 6.25 Hz), 1.40 (6H, d, J = 5.95 Hz). 476 2.3  B

(644) TABLE-US-00013 TABLE 13 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-61 (CDCl.sub.3) δ: 7.82 (2H, d, J = 7.78 Hz), 7.51 (1H, d, J = 8.08 Hz), 7.32 (1H, d, J = 7.93 Hz), 7.05 (1H, d, J = 7.63 Hz), 6.98 (2H, d, J = 7.47 Hz), 6.04 (1H, s), 5.29 (2H, d, J = 1.37 Hz), 4.65 (1H, s), 3.99 (1H, t, J = 10.60 Hz), 3.71 (1H, s), 3.64 (2H, d, J = 7.47 Hz), 3.20 (1H, t, J = 9.61 Hz), 2.64 (1H, s), 1.38 (6H, d, J = 5.95 Hz), 0.47 (3H, d, J = 6.56 Hz). 492 2.4 B I-62 472 2.3 B I-63 472 2.3 B I-64 0 492 1.93 B I-65 519 2.2 B

(645) TABLE-US-00014 TABLE 14 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-66 476 2.25 B I-67 458 2.09 C I-68 494 2.15 A I-69 476 2.12 A I-70 (CDCl.sub.3) δ: 7.75 (2H, d, J = 8.69 Hz), 7.38 (1H, dd, J = 13.95, 9.53 Hz), 7.05 (2H, t, J = 6.25 Hz), 6.96 (2H, d, J = 8.85 Hz), 4.83 (1H, q, J = 7.57 Hz), 4.69-4.61 (1H, m), 3.93 (2H, s), 3.87 (1H, t, J = 8.69 Hz), 3.67 (2H, t, J = 7.40 Hz), 3.08 (1H, t, J = 8.69 Hz), 2.80 (1H, t, J = 6.79 Hz), 1.39 (6H, t, J = 3.05 Hz), 1.01 (3H, d, J = 6.71 Hz). 476 2.27 B

(646) TABLE-US-00015 TABLE 15 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-71 488 2.23 B I-72 (DMSO-d.sub.6) δ: 7.79 (2H, d, J = 8.23 Hz), 7.69 (1H, s), 7.46 (1H, d, J = 10.74 Hz), 7.11 (2H, d, J = 8.73 Hz), 6.98 (1H, t, J = 8.48 Hz), 4.98 (1H, s), 4.78-4.75 (2H, m), 4.11- 4.08 (1H, m), 3.84-3.81 (3H, m), 3.80- 3.76 (2H, m), 3.59-3.49 (1H, m), 2.00- 1.96 (1H, m), 1.94-1.80 (1H, m), 1.74-1.71 (1H, m), 1.31 (6H, d, J = 5.20 Hz). 506 1.93 B I-73 504 2.32 B I-74 0 490 2.31 B I-75 490 2.3 B

(647) TABLE-US-00016 TABLE 16 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-76 490 2.29 B I-77 450 2.08 B I-78 490 2.27 B I-79 450 2.06 B

(648) TABLE-US-00017 TABLE 17 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-80 462 2.1  B I-81 502 2.32 B I-82 462 2.15 B I-83 502 2.35 B

(649) TABLE-US-00018 TABLE 18 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-84 0 492.45 1.86 A I-85 494.26 2.15 A I-86 474.12 1.81 A I-87 488.15 1.9  A I-88 476.16 2.09 A

(650) TABLE-US-00019 TABLE 19 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-89 290.17 2.19 A I-90 494 2.26 B I-91 458 2.21 B I-92 508 2.35 B I-93 528 2.41 B

(651) TABLE-US-00020 TABLE 20 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-94 0 472 2.32 B I-95 492 2.39 B I-96 (DMSO-d.sub.6) δ: 8.64 (1H, d, J = 1.8 Hz), 8.11 (1H, dd, J = 8.7, 1.4 Hz), 7.61 (2H, d, J = 8.4 Hz), 7.34 (1H, t, J = 7.7 Hz), 7.08 (1H, t, J = 7.7 Hz), 7.00 (1H, d, J = 8.9 Hz), 5.37 (1H, t, J = 6.0 Hz), 4.43 (2H, q, J = 7.0 Hz), 3.95 (1H, dd, J= 10.6, 7.1 Hz), 3.67-3.49 (4H, m), 3.19-3.11 (1H, m), 2.65-2.54 (1H, m), 1.39 (3H, t, J = 6.7 Hz), 0.29 (3H, d, J = 6.4 Hz). 445.3 1.99 P I-97 (DMSO-d.sub.6) δ: 7.79 (2H, d, J = 8.5 Hz), 7.61 (2H, t, J = 7.3 Hz), 7.33 (1H, t, J = 7.7 Hz), 7.15-7.05 (3H, m), 5.34 (2H, s), 4.16 (2H, q, J = 6.8 Hz), 3.93-3.86 (1H, m), 3.70-3.53 (4H, m), 3.17-3.10 (1H, m), 1.39 (3H, t, J = 6.7 Hz), 0.28 (3H, d, J = 6.6 Hz). 444.3 2.03 P I-98 (DMSO-d.sub.6) δ: 7.94 (2H, d, J = 8.7 Hz), 7.68-7.59 (2H, m), 7.43-7.31 (4H, m), 7.08 (1H, t, J = 7.5 Hz), 5.36 (1H, t, J = 5.9 Hz), 3.97-3.89 (1H, m), 3.70-3.54 (4H, m), 3.21- 3.14 (1H, m), 0.29 (3H, d, J = 6.7 Hz). 466.3 2.03 P

(652) TABLE-US-00021 TABLE 21 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-99 (DMSO-d.sub.6) δ: 8.63 (1H, d, J = 2.4 Hz), 8.09 (1H, dd, J = 8.8, 2.5 Hz), 7.61 (2H, d, J = 8.7 Hz), 7.34 (1H, t, J = 7.9 Hz), 7.08 (1H, t, J = 7.7 Hz), 6.95 (1H, d, J = 8.8 Hz), 5.41-5.33 (2H, m), 3.98-3.91 (1H, m), 3.68- 3.47 (4H, m), 3.19-3.12 (1H, m), 2.65-2.53 (1H, m), 1.36 (6H, dd, J = 6.1, 3.4 Hz), 0.30 (3H, d, J = 6.7 Hz). 459.3 2.14 P I-100 (DMSO-d.sub.6) δ: 8.09 (1H, dd, J = 8.9, 5.1 Hz), 7.78 (2H, d, J = 8.7 Hz), 7.68 (1H, dd, J = 9.8, 2.0 Hz), 7.54 (1H, d, J = 16.3 Hz), 7.15-7.09 (3H, m), 6.57 (1H, d, J = 16.3 Hz), 5.47-5.40 (1H, m), 4.80-4.70 (1H, m), 3.92-3.86 (1H, m), 3.65-3.59 (2H, m), 3.28-3.19 (1H, m), 2.63- 2.51 (1H, m), 1.30 (6H, dd, J = 7.6, 6.2 Hz), 0.36 (3H, d, J = 6.7 Hz). 488.3 2.24 P I-101 (DMSO-d.sub.6) δ: 7.78-7.71 (3H, m), 7.48 (1H, dd, J = 10.2, 2.0 Hz), 7.12 (2H, d, J = 8.5 Hz), 6.94 (1H, td, J = 9.0, 1.8 Hz), 5.30-5.25 (1H, m), 4.79-4.71 (1H, m), 3.89-3.83 (1H, m), 3.62-3.52 (2H, m), 3.20-3.13 (1H, m), 3.05-2.95 (1H, m), 2.88- 2.78 (1H, m), 2.54-2.40 (1H, m), 1.32 (6H, dd, J = 6.0, 3.4 Hz), 0.29 (3H, d, J = 6.6 Hz). 490.3 2.28 P I-102 (CDCl.sub.3) δ: 7.87-7.81 (2H, m), 7.64 (1H, dd, J = 8.73, 5.04 Hz), 7.07- 7.01 (2H, m), 7.00-6.88 (2H, m), 6.04-5.90 (1H, m), 5.33 (1H, d, J = 16.95 Hz), 5.18 (1H, d, J = 10.24 Hz), 4.78-4.55 (2H, m), 4.34 (1H, dd, J = 15.61, 7.72 Hz), 4.03-3.91 (3H, m), 3.77 (1H, dd, J = 11.25, 8.56 Hz), 2.64-2.47 (2H, m), 1.44 (6H, d, J = 6.21 Hz). 488 2.29 B I-103 (CDCl.sub.3) δ: 7.87 (2H, d, J = 8.90 Hz), 7.67-7.57 (1H, br m), 7.07 (2H, d, J = 8.90 Hz), 6.96-6.85 (1H, br m), 6.74 (1H, d, J = 8.73 Hz), 4.78- 4.67 (1H, m), 4.33-4.19 (1H, m), 4.02-3.82 (4H, m), 3.71-3.60 (1H, m), 2.51-2.24 (2H, m), 1.85-1.58 (2H, m), 1.45 (6H, dd, J = 6.04, 1.85 Hz), 1.04-0.83 (3H, m). 490 2.37 B

(653) TABLE-US-00022 TABLE 22 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-104 0 (CDCl.sub.3) δ: 7.83 (2H, d, J = 8.85 Hz), 7.62-7.51 (1H, m), 6.92 (5H, d, J = 8.85 Hz), 5.11-4.99 (1H, m), 4.67-4.57 (1H, m), 4.06-3.96 (1H, m), 3.84 (2H, s), 3.69-3.57 (1H, m), 3.28-3.15 (1H, m), 2.64-2.52 (1H, m), 2.01 (3H, s), 1.36 (6H, dd, J = 6.10, 1.53 Hz). 501 2.15 B I-105 (CDCl.sub.3) δ: 7.84 (2H, d, J = 9.06 Hz), 7.66-7.59 (1H, m), 7.03-6.89 (4H, m), 5.12-5.04 (1H, m), 4.69- 4.60 (1H, m), 3.96 (2H, br s), 3.88- 3.82 (2H, m), 2.92-2.84 (2H, m), 2.01 (3H, s), 1.38 (6H, d, J = 6.04 Hz). 501 2.24 B I-106 462 2.12 B I-107 484 2.11 B I-108 463 2.09 B

(654) TABLE-US-00023 TABLE 23 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-109 458 2.19 B I-110 480 2.17 B I-111 459 2.16 B I-112 448 1.99 B I-113 458  2.2 B

(655) TABLE-US-00024 TABLE 24 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-114 0 472 2.3 B I-115 458 2.2 B I-116 449 1.95 B I-117 432 2.08 B I-118 446 2.21 B

(656) TABLE-US-00025 TABLE 25 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-119 486 2.24 B I-120 502 2.28 B I-121 452 2.08 B I-122 452 2.15 B I-123 477 2.23 B

(657) TABLE-US-00026 TABLE 26 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-124 0 443 1.92 B I-125 498 2.17 B I-126 496 2.38 B I-127 534 2.28 B I-128 498 2.19 B

(658) TABLE-US-00027 TABLE 27 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-129 512 2.3 B I-130 526 2.4 B I-131 527 2.41 B I-132 513 2.29 B

(659) TABLE-US-00028 TABLE 28 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-133 (CDCl.sub.3) δ: 8.00 (1H, d, J = 8.39 Hz), 7.84 (2H, t, J = 5.95 Hz), 7.42 (1H, d, J = 7.78 Hz), 7.04 (3H, d, J = 9.00 Hz), 6.20 (1H, t, J = 57.50 Hz), 4.92-4.89 (1H, m), 4.76-4.73 (1H, m), 4.69 (1H, t, J = 6.10 Hz), 4.24- 4.07 (1H, m), 4.03 (2H, s), 3.79-3.70 (1H, m), 2.94-2.91 (1H, m), 2.46 (1H, s), 1.42 (6H, dd, J = 5.95, 0.76 Hz). 512 2.3 B I-134 0 (CDCl.sub.3) δ: 7.93 (2H, d, J = 8.54 Hz), 7.54 (1H, d ,J = 8.69 Hz), 7.31 (3H, t, J = 7.24 Hz), 7.10 (1H, d, J = 10.07 Hz), 6.68 (1H, t, J = 73.51 Hz), 4.99-4.95 (1H, m), 4.09 (1H, dd, J = 10.98, 6.86 Hz), 3.78 (1H, dd, J = 12.12, 9.84 Hz), 3.71 (1H, d, J = 7.93 Hz), 3.67 (2H, s), 3.24 (1H, t, J = 9.84 Hz), 2.75-2.71 (1H, m), 1.25- 1.24 (1H, m), 0.47 (3H, d, J = 7.17 Hz). 500 2.2 B I-135 (CDCl.sub.3) δ: 7.81 (2H, d, J = 7.78 Hz), 7.53 (1H, d, J = 8.54 Hz), 7.33 (1H, s), 7.09 (1H, d, J = 8.39 Hz), 6.98 (2H, d, J = 7.93 Hz), 4.97-4.93 (1H, m), 4.67-4.63 (1H, m), 4.03 (1H, dd, J = 10.90, 7.55 Hz), 3.82 (1H, t, J = 7.17 Hz), 3.73 (2H, s), 3.68 (1H, t, J = 8.31 Hz), 3.23 (1H, t, J = 9.46 Hz), 2.68-2.64 (1H, m), 1.39 (6H, d, J = 6.25 Hz), 0.47 (3H, d, J = 6.86 Hz). 492 2.33 B I-136 484 2.11 B

(660) TABLE-US-00029 TABLE 29 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-137 478 2.23 B I-138 1H-NMR (DMSO-D6) δ: 1.32 (6H, br s), 2.35 (1H, m), 3.15-3.27 (2H, m), 3.25 (3H, s), 3.59 (1H, m), 3.68 (1H, m), 3.77-3.84 (1H, m), 3.84 (2H, s), 4.76 (1H, m), 5.39 (1H, m), 5.75 (1H, br s), 7.01 (1H, m), 7.09- 7.17 (2H, m), 7.49-7.57 (1H, m), 7.66-7.75 (2H, m), 7.75-7.84 (2H, m). I-139 1H-NMR (DMSO-D6) δ: 0.31 (3H, d, J = 5.6 Hz), 1.32 (6H, s), 2.38 (1H, br s), 3.17-3.90 (m), 4.75 (1H, m), 5.31 (1H, br), 5.75 (1H, br s), 7.01 (1H, t, J = 8.6 Hz), 7.13 (2H, d, J = 7.6 Hz), 7.54 (1H, d, J = 9.6 Hz), 7.72 (1H, m), 7.79 (2H, d, J = 8.1 Hz). I-140 464 2.1 B I-141 462 2.31 B

(661) TABLE-US-00030 TABLE 30 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-142 518 2.36 B I-143 479 2.19 B I-144 00 1H-NMR (CDCl3) δ: 0.51 (d, J = 6.9 Hz, 3H), 1.38 (s, 3H), 1.40 (s, 3H), 2.46-2.56 (m, 1H), 3.07 (t, J = 10.1 Hz, 1H), 3.60-3.66 (m, 3H), 3.73-3.83 (m, 2H), 4.62-4.71 (m, 1H), 4.74-4.78 (m, 1H), 6.67 (s, 1H), 6.88 (ddd, J = 18.0, 9.2, 2.0 Hz, 2H), 7.00-7.04 (m, 2H), 7.47 (dd, J = 8.6, 5.4 Hz, 1H), 7.81-7.84 (m, 2H). I-145 01 .sup.1H-NMR (CDCl.sub.3) δ: 8.48 (1H, d, J = 3.4 Hz), 8.05 (1H, d, J = 6.9 Hz), 7.86 (2H, d, J = 8.9 Hz), 7.15-7.08 (1H, m), 7.03 (2H, d, J = 8.9 Hz), 5.65-5.57 (1H, m), 4.75-4.66 (1H, m), 4.10-4.01 (1H, m), 3.88-3.79 (3H, m), 3.76-3.66 (1H, m), 3.39- 3.30 (1H, m), 2.75-2.62 (1H, m), 1.46-1.41 (6H, m), 0.51 (3H, d, J = 6.7 Hz). I-146 02 1H-NMR (CDCl3) δ: 8.76 (1H, t, J = 4.19 Hz), 8.05-7.99 (1H, m), 7.55 (1H, d, J = 8.54 Hz), 7.35 (1H, s), 7.10 (1H, d, J = 8.69 Hz), 6.80 (1H, d, J = 8.85 Hz), 5.39-5.35 (1H, m), 5.00 (1H, t, J = 5.49 Hz), 4.05 (1H, s), 3.87 (1H, d, J = 10.83 Hz), 3.74 (2H, s), 3.72-3.70 (1H, m), 3.27 (1H, t, J = 9.84 Hz), 2.75 (1H, dd, J = 10.68, 6.71 Hz), 1.40 (6H, d, J = 6.25 Hz), 0.49 (4H, d, J = 6.71 Hz).

(662) TABLE-US-00031 TABLE 31 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-147 03 I-148 04 1H-NMR (CDCl3) δ: 8.24 (1H, dd, J = 4.7, 1.5 Hz), 7.90 (1H, dd, J = 7.8, 1.5 Hz), 7.83 (2H, d, J = 8.6 Hz), 7.08-7.00 (3H, m), 6.91 (1H, s), 5.58-5.52 (1H, m), 4.72-4.62 (1H, m), 3.82-3.67 (4H, m), 3.60 (1H, dd, J = 9.9, 8.2 Hz), 3.12 (1H, dd, J = 9.9, 9.9 Hz), 2.60-2.48 (1H, m), 1.40 (6H, d, J = 6.0 Hz), 0.52 (3H, d, J = 6.9 Hz). I-149 05 477 2.06 B I-150 06 .sup.1H-NMR (DMSO-D.sub.6) δ: 7.83-7.71 (2H, m), 7.78 (2H, d, J = 8.8 Hz), 7.48-7.44 (1H, m), 7.35-7.29 (1H, m), 7.14 (2H, d, J = 8.8 Hz), 6.84- 6.79 (1H, m), 5.39-5.28 (1H, m), 4.14 (2H, q, J = 6.9 Hz), 3.92-3.82 (1H, m), 3.64-3.51 (3H, m), 3.10 (1H, t, J = 9.9 Hz), 1.39 (3H, t, J = 6.9 Hz), 0.29 (3H, t, J = 5.3 Hz). 462 2.07 B I-151 07 472 2.36 B

(663) TABLE-US-00032 TABLE 32 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-152 08 456 2.16 B I-153 09 456 2.02 B I-154 0 .sup.1H-NMR (CDCl.sub.3) δ: 7.87 (2H, d, J = 8.8 Hz), 7.60-7.51 (1H, m), 7.05 (2H, d, J = 8.8 Hz), 7.02-6.86 (2H, m), 5.87-5.82 (1H, m), 5.02-4.96 (1H, m), 4.32-4.25 (1H, m), 4.19- 4.00 (3H, m), 3.81-3.61 (4H, m), 3.00-2.91 (1H, m), 1.47 (3H, t, J = 7.0 Hz), 0.26 (3H, d, J = 7.0 Hz). 505 1.66 B I-155 .sup.1H-NMR (CDCl.sub.3) δ: 7.86 (2H, d, J = 8.7 Hz), 7.62-7.56 (1H, m), 7.07- 6.89 (4H, m), 4.98-4.91 (1H, m), 4.53 (1H, d, J = 9.4 Hz), 4.16-4.03 (3H, m), 4.02-3.85 (1H, m), 3.71- 3.60 (2H, m), 3.07-2.94 (1H, m), 1.46 (3H, t, J = 6.8 Hz), 0.70 (3H, d, J = 6.8 Hz). 487 2.05 B I-156 1H-NMR (CDCl3) δ: 7.82 (3H, d, J = 8.66 Hz), 7.09 (1H, d, J = 8.66 Hz), 7.00 (2H, d, J = 8.78 Hz), 4.91-4.88 (1H, m), 4.68-4.65 (1H, m), 4.05 (1H, dd, J = 10.98, 7.72 Hz), 3.83 (1H, d, J = 11.04 Hz), 3.70 (2H, s), 3.68-3.66 (1H, m), 3.21 (1H, t, J = 9.85 Hz), 2.64 (1H, s), 1.40 (6H, dd, J = 5.83, 2.57 Hz), 0.45 (3H, d, J = 6.78 Hz). 554 556 2.38 B

(664) TABLE-US-00033 TABLE 33 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-157 .sup.1H-NMR (DMSO-d.sub.6) δ: 7.77 (2H, d, J = 8.9 Hz), 7.58-7.49 (2H, m), 7.10 (2H, d, J = 8.9 Hz), 6.97 (1H, td, J = 9.1, 2.1 Hz), 5.33-5.29 (1H, m), 4.74-4.65 (1H, m), 4.40 (2H, s), 3.84 (1H, dd, J = 11.2, 7.3 Hz), 3.69 (1H, dd, J = 11.3, 2.5 Hz), 3.58 (1H, dd, J = 9.3, 7.4 Hz), 3.17 (1H, t, J = 10.0 Hz), 2.45-2.33 (1H, m), 1.27 (6H, d, J = 5.3 Hz), 0.32 (3H, d, J = 6.7 Hz). 500 2.46 B I-158 1H-NMR (DMSO-D6) δ: 7.96- 7.91 (2H, m), 7.67-7.56 (2H, m), 7.48-7.33 (3H, m), 7.09 (1H, t, J = 7.5 Hz), 5.38 (1H, s), 5.03-4.97 (1H, m), 4.07-3.99 (1H, m), 3.70- 3.62 (3H, m), 0.53 (3H, s). C I-159 1H-NMR (CDCl3) δ: 8.79 (1H, d, J = 2.01 Hz), 8.07 (1H, s), 8.05 (1H, dd, J = 8.53, 2.51 Hz), 7.59 (1H, dd, J = 8.78, 1.51 Hz), 7.45 (1H, d, J = 8.53 Hz), 6.88 (1H, d, J = 8.78 Hz), 5.13-5.11 (1H, m), 4.49 (2H, q, J = 6.94 Hz), 4.19 (1H, dd, J = 11.42, 7.15 Hz), 3.89 (1H, d, J = 11.29 Hz), 3.80 (2H, d, J = 3.76 Hz), 3.77-3.75 (1H, m), 3.27 (1H, t, J = 10.04 Hz), 2.82-2.79 (1H, m), 1.46 (3H, t, J = 7.03 Hz), 0.48 (3H, d, J = 6.78 Hz). 470 1.93 B I-160 1H-NMR (CDCl3) δ: 8.05 (1H, s), 7.84 (2H, d, J = 8.78 Hz), 7.56 (1H, dd, J = 8.78, 1.51 Hz), 7.42 (2H, d, J = 8.53 Hz), 7.02 (2H, d, J = 8.78 Hz), 5.06 (1H, d, J = 4.77 Hz), 4.14 (2H, q, J = 6.94 Hz), 4.07 (1H, dd, J = 11.54, 7.28 Hz), 3.82 (1H, dd, J = 11.54, 2.51 Hz), 3.75 (2H, s), 3.70 (1H, t, J = 8.16 Hz), 3.22 (1H, t, J = 10.04 Hz), 2.72-2.70 (1H, m), 1.48 (3H, t, J = 6.90 Hz), 0.45 (3H, d, J = 6.78 Hz). 469 1.96 B

(665) TABLE-US-00034 TABLE 34 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-161 1H-NMR (DMSO-d6) δ: 7.78 (2H, d, J = 8.8 Hz), 7.73 (1H, d, J = 1.8 Hz), 7.68 (1H, d, J = 9.0 Hz), 7.37 (1H, dd, J = 9.0, 1.9 Hz), 7.14 (2H, d, J = 8.9 Hz), 5.36 (1H, t, J = 5.8 Hz), 4.15 (2H, q, J = 6.9 Hz), 3.88 (1H, dd, J = 11.3, 7.4 Hz), 3.70- 3.53 (4H, m), 3.09 (1H, t, J = 10.0 Hz), 1.39 (3H, t, J = 6.9 Hz), 0.25 (3H, d, J = 6.8 Hz). 478 2.19 B I-162 1H-NMR (DMSO-d6) δ: 8.64 (1H, d, J = 2.5 Hz), 8.12 (1H, dd, J = 8.7, 2.5 Hz), 7.73-7.68 (2H, m), 7.38 (1H, dd, J = 9.0, 1.9 Hz), 7.01 (1H, d, J = 8.7 Hz), 5.39 (1H, t, J = 6.0 Hz), 4.43 (2H, q, J = 7.0 Hz), 3.99-3.92 (1H, m), 3.66-3.50 (4H, m), 3.13-3.07 (1H, m), 2.65-2.55 (1H, m), 1.38 (3H, t, J = 7.0 Hz), 0.27 (3H, d, J = 6.8 Hz). 479 2.16 B I-163 1H-NMR (DMSO-d6) δ: 7.78- 7.67 (4H, m), 7.37 (1H, dd, J = 8.9, 1.9 Hz), 7.13 (2H, d, J = 8.9 Hz), 5.37 (1H, t, J = 5.8 Hz), 4.80-4.74 (1H, m), 3.90-3.85 (1H, m), 3.73- 3.53 (4H, m), 3.10 (1H, t, J = 10.0 Hz), 1.34 (6H, dd, J = 6.0, 3.3 Hz), 0.26 (3H, d, J = 6.7 Hz). 492 2.3 B I-164 0 1H-NMR (DMSO-d6) δ: 0.31 (d, J = 6.7 Hz, 3H), 1.38 (t, J = 7.0 Hz, 3H), 2.43-2.45 (m, 1H), 2.93 (t, J = 10.0 Hz, 1H), 3.51 (s, 2H), 3.56- 3.59 (m, 3H), 3.78 (dd, J = 11.4, 6.8 Hz, 1H), 4.16 (q, J = 6.9 Hz, 2H), 5.12-5.14 (m, 1H), 6.52 (s, 1H), 7.00 (t, J = 7.5 Hz, 1H), 7.11 (t, J = 7.5 Hz, 1H), 7.20 (d, J = 8.9 Hz, 2H), 7.46 (t, J = 6.7 Hz, 2H), 7.86 (d, J = 8.8 Hz, 2H). 443 2.18 P I-165 1H-NMR (DMSO-d6) δ: 0.32 (d, J = 6.4 Hz, 3H), 1.33 (d, J = 5.6 Hz, 6H), 2.44 (t, J = 7.1 Hz, 1H), 2.94 (t, J = 9.8 Hz, 1H), 3.52-3.62 (m, 5H), 3.77 (dd, J = 10.9, 6.7 Hz, 1H), 4.77-4.80 (m, 1H), 5.14 (s, 1H), 6.61 (s, 1H), 7.00 (t, J = 7.3 Hz, 1H), 7.10 (t, J = 7.5 Hz, 1H), 7.18 (d, J = 7.7 Hz, 2H), 7.45 (t, J = 7.9 Hz, 2H), 7.84 (d, J = 7.7 Hz, 2H). 457 2.3 P

(666) TABLE-US-00035 TABLE 35 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-166 469 2.07 B I-167 1H-NMR (CDCl3) δ: 8.01 (1H, d, J = 6.02 Hz), 7.81 (2H, d, J = 8.78 Hz), 7.13 (1H, d, J = 9.03 Hz), 7.00 (2H, d, J = 8.78 Hz), 4.92 (1H, t, J = 5.77 Hz), 4.70-4.64 (1H, m), 4.05 (1H, dd, J = 11.42, 7.40 Hz), 3.82 (1H, dd, J = 11.42, 2.38 Hz), 3.74 (2H, s), 3.69 (1H, t, J = 8.28 Hz), 3.21 (1H, t, J = 9.91 Hz), 2.68 (2H, dd, J = 11.04, 7.53 Hz), 1.40 (6H, dd, J = 6.02, 2.76 Hz), 0.48 (3H, d, J = 6.78 Hz). 501 2.15 B I-168 451 2.01 B I-169 468 2.12 B I-170 465 2.14 B

(667) TABLE-US-00036 TABLE 36 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-171 464 2.19 B I-172 1H-NMR (DMSO-D6) δ: 8.37 (1H, s), 7.85 (1H, d, J = 8.4 Hz), 7.78 (2H, d, J = 8.9 Hz), 7.43 (1H, dd, J = 8.3, 1.2 Hz), 7.14 (2H, d, J = 9.0 Hz), 5.46 (1H, t, J = 5.8 Hz), 4.15 (2H, q, J = 6.9 Hz), 3.90 (1H, dd, J = 11.4, 7.4 Hz), 3.75- 3.55 (4H, m), 3.10 (1H, t, J = 10.0 Hz), 2.5 (1H, m), 1.39 (3H, t, J = 7.0 Hz), 0.27 (3H, d, J = 6.7 Hz). 469 1.98 B I-173 470 1.94 B I-174 0 502 2.1 B I-175 488 1.99 B

(668) TABLE-US-00037 TABLE 37 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-176 489 2 B I-177 450 2.07 B I-178 436 1.93 B I-179 454 1.98 B I-180 450 2.06 B

(669) TABLE-US-00038 TABLE 38 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-181 .sup.1H-NMR (DMSO-D.sub.6) δ: 8.88 (1H, s), 8.00 (1H, d, J = 9.0 Hz), 7.64 (2H, t, J = 9.4 Hz), 7.45 (1H, d, J = 2.5 Hz), 7.35 (1H, t, J = 7.5 Hz), 7.19 (1H, dd, J = 8.9, 2.6 Hz), 7.09 (1H, t, J = 7.4 Hz), 5.43-5.38 (1H, m), 4.17 (2H, q, J = 6.9 Hz), 3.96- 3.89 (4H, m), 3.70 (2H, d, J = 2.8 Hz), 3.63-3.58 (2H, m), 3.16 (1H, t, J = 9.7 Hz), 2.72-2.63 (1H, m), 1.38 (3H, t, J = 6.9 Hz), 0.33 (3H, d, J = 6.5 Hz). 501 2.27 B I-182 1H-NMR (DMSO-d6) δ: 7.94 (1H, d, J = 8.8 Hz), 7.67 (1H, d, J = 8.0 Hz), 7.63 (1H, d, J = 8.4 Hz), 7.43 (1H, d, J = 15.8 Hz), 7.36 (1H, t, J = 7.6 Hz), 7.24 (1H, s), 7.10 (1H, t, J = 7.4 Hz), 7.03 (1H, d, J = 8.5 Hz), 6.34 (1H, td, J = 10.5, 5.4 Hz), 5.41-5.37 (1H, m), 4.18 (2H, q, J = 6.8 Hz), 4.03- 4.00 (2H, m), 3.92-3.86 (1H, m), 3.79-3.69 (3H, m), 3.59 (1H, t, J = 8.1 Hz), 3.24-3.19 (4H, m), 2.62-2.55 (1H, m), 1.38 (3H, t, J = 6.8 Hz), 0.32 (3H, d, J = 6.5 Hz). 514 2.2 B I-183 .sup.1H-NMR (DMSO-d.sub.6) δ: 7.97 (1H, d, J = 8.5 Hz), 7.71-7.64 (2H, m), 7.37 (1H, t, J = 7.6 Hz), 7.11 (1H, t, J = 7.3 Hz), 6.99-6.94 (2H, m), 5.48-5.43 (1H, m), 4.13 (2H, q, J = 6.8 Hz), 3.98-3.93 (1H, m), 3.79 (2H, s), 3.68 (1H, d, J = 10.9 Hz), 3.60 (1H, t, J = 7.9 Hz), 3.24-3.17 (4H, m), 2.99 (2H, t, J = 7.9 Hz), 2.73-2.64 (1H, m), 1.91-1.82 (2H, m), 1.36 (3H, t, J = 6.8 Hz), 0.36 (3H, d, J = 6.5 Hz). 516 2.23 B I-184 0 .sup.1H-NMR (DMSO-d.sub.6) δ: 7.95 (1H, d, J = 8.8 Hz), 7.69-7.63 (2H, m), 7.36 (1H, t, J = 7.5 Hz), 7.21 (1H, s), 7.10 (1H, t, J = 7.3 Hz), 7.03 (1H, d, J = 7.0 Hz), 5.46-5.42 (1H, m), 4.83 (2H, s), 4.14 (2H, q, J = 6.9 Hz), 3.98-3.92 (1H, m), 3.80- 3.59 (4H, m), 3.37 (3H, s), 3.16 (1H, t, J = 9.6 Hz), 2.72-2.63 (1H, m), 1.37 (3H, t, J = 6.9 Hz), 0.34 (3H, d, J = 6.7 Hz). 488 2.16 B

(670) TABLE-US-00039 TABLE 39 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-185 .sup.1H-NMR (DMSO-d.sub.6) δ: 8.05-7.97 (2H, m), 7.65 (1H, d, J = 8.2 Hz), 7.58 (1H, d, J = 8.5 Hz), 7.52 (2H, d, J = 7.8 Hz), 7.45 (1H, s), 7.40- 7.20 (7H, m), 7.10-7.05 (2H, m), 5.39-5.34 (1H, m), 4.22 (2H, q, J = 6.8 Hz), 3.93-3.88 (1H, m), 3.76- 3.58 (5H, m), 3.23 (1H, t, J = 9.5 Hz), 2.61-2.53 (1H, m), 1.40 (3H, t, J = 7.0 Hz), 0.27 (3H, d, J = 6.7 Hz). 546 2.52 B I-186 .sup.1H-NMR (DMSO-d.sub.6) δ: 8.01 (1H, d, J = 8.8 Hz), 7.70-7.63 (2H, m), 7.36 (1H, t, J = 7.6 Hz), 7.29 (4H, m), 7.20-7.05 (3H, m), 6.98 (1H, d, J = 8.4 Hz), 5.48-5.43 (1H, m), 4.11 (2H, q, J = 6.8 Hz), 4.01-3.95 (1H, m), 3.78-3.59 (4H, m), 3.27-3.18 (3H, m), 2.97-2.90 (2H, m), 2.74- 2.64 (1H, m), 1.35 (3H, t, J = 6.7 Hz), 0.35 (3H, d, J = 6.5 Hz). 548 2.55 B I-187 .sup.1H-NMR (DMSO-d.sub.6) δ: 8.10 (1H, d, J = 8.9 Hz), 7.71 (1H, d, J = 8.2 Hz), 7.63 (1H, d, J = 8.5 Hz), 7.45- 7.35 (6H, m), 7.16-7.09 (2H, m), 6.82 (1H, s), 5.31-5.24 (1H, m), 4.16 (2H, q, J = 6.8 Hz), 3.86 (2H, s), 3.53-3.45 (2H, m), 3.15 (1H, t, J = 8.0 Hz), 3.01 (1H, t, J = 9.6 Hz), 1.36 (3H, t, J = 6.8 Hz), 0.29 (3H, d, J = 6.7 Hz). 520 2.4 B I-188 489 2.06 B

(671) TABLE-US-00040 TABLE 40 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-189 474 1.9 B I-190 502 2.17 B I-191 488 2.04 B I-192 536 2.31 B I-193 516 2.29 B

(672) TABLE-US-00041 TABLE 41 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-194 0 1H-NMR (DMSO-d6) δ: 0.86 (d, J = 6.7 Hz, 3H), 2.55-2.59 (m, 1H), 2.97 (t, J = 9.2 Hz, 1H), 3.49 (dd, J = 9.7, 7.3 Hz, 1H), 3.70 (t, J = 8.6 Hz, 1H), 3.77 (t, J = 9.0 Hz, 1H), 3.84 (s, 2H), 4.97 (q, J = 7.7 Hz, 1H), 7.13 (t, J = 7.5 Hz, 1H), 7.29-7.47 (m, 4H), 7.61 (d, J = 8.5 Hz, 1H), 7.67 (t, J = 7.6 Hz, 1H), 7.93 (d, J = 8.5 Hz, 2H), 12.52 (s, 1H). 466 2.02 B I-195 1H-NMR (DMSO-d6) δ: 0.86 (d, J = 6.5 Hz, 3H), 2.55-2.59 (m, 1H), 2.97 (t, J = 9.2 Hz, 1H), 3.49 (t, J = 8.4 Hz, 1H), 3.70 (t, J = 8.6 Hz, 1H), 3.77 (t, J = 9.0 Hz, 1H), 3.84 (s, 2H), 4.97 (q, J = 7.5 Hz, 1H), 7.12 (t, J = 7.5 Hz, 1H), 7.29-7.47 (m, 4H), 7.60-7.69 (m, 2H), 7.93 (d, J = 8.4 Hz, 2H), 12.54 (s, 1H). 466 2.02 B I-196 1H-NMR (DMSO-d6) δ: 1.38 (t, J = 6.8 Hz, 6H), 2.08-2.11 (m, 1H), 2.43-2.46 (m, 1H), 3.65-3.70 (m, 2H), 3.81 (dd, J = 11.2, 7.7 Hz, 1H), 3.92 (s, 2H), 4.17 (q, J = 7.0 Hz, 2H), 4.64-4.72 (m, 1H), 7.13 (t, J = 7.1 Hz, 1H), 7.19 (d, J = 8.8 Hz, 2H), 7.36-7.40 (m, 2H), 7.70 (d, J = 8.0 Hz, 1H), 7.86 (d, J = 8.8 Hz, 2H), 12.53 (s, 1H). 444 2.06 B I-197 1H-NMR (DMSO-d6) δ: 0.85 (d, J = 6.7 Hz, 3H), 1.38 (t, J = 6.9 Hz, 3H), 2.93 (t, J = 9.2 Hz, 1H), 3.45 (dd, J = 9.9, 7.3 Hz, 2H), 3.65 (t, J = 8.7 Hz, 1H), 3.71 (t, J = 8.9 Hz, 1H), 3.84 (s, 2H), 4.15 (q, J = 6.9 Hz, 2H), 4.93 (q, J = 7.7 Hz, 1H), 7.11-7.15 (m, 3H), 7.36 (t, J = 7.7 Hz, 1H), 7.60 (d, J = 8.5 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.77 (d, J = 8.7 Hz, 2H). 444 2.04 B I-198 1H-NMR (DMSO-d6) δ: 0.85 (d, J = 6.7 Hz, 3H), 1.38 (t, J = 7.0 Hz, 3H), 2.55 (d, J = 7.4 Hz, 1H), 2.93 (t, J = 9.2 Hz, 1H), 3.45 (dd, J = 9.9, 7.2 Hz, 2H), 3.65 (dd, J = 9.6, 7.7 Hz, 1H), 3.71 (dd, J = 9.6, 8.2 Hz, 1H), 3.84 (s, 2H), 4.15 (q, J = 6.9 Hz, 2H), 4.92- 4.94 (m, 1H), 7.11-7.15 (m, 3H), 7.37 (t, J = 7.6 Hz, 1H), 7.60 (d, J = 8.5 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.77 (d, J = 8.8 Hz, 2H). 444 2.04 B

(673) TABLE-US-00042 TABLE 42 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-199 1H-NMR (DMSO-d6) δ: 0.85 (d, J = 6.5 Hz, 3H), 1.33 (d, J = 5.9 Hz, 6H), 2.56-2.58 (m, 1H), 2.93 (t, J = 9.3 Hz, 1H), 3.45 (dd, J = 9.5, 7.4 Hz, 2H), 3.66 (t, J = 8.7 Hz, 1H), 3.71 (t, J = 9.0 Hz, 1H), 3.84 (s, 2H), 4.74-4.80 (m, 1H), 4.93 (q, J = 7.7 Hz, 1H), 7.11- 7.14 (m, 3H), 7.36 (t, J = 7.7 Hz, 1H), 7.59 (d, J = 8.5 Hz, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.75 (d, J = 8.8 Hz, 2H). 458 2.16 B I-200 .sup.1H-NMR (DMSO-d.sub.6) δ: 8.02 (1H, d, J = 8.9 Hz), 7.70 (1H, d, J = 2.6 Hz), 7.63 (2H, d, J = 8.7 Hz), 7.43 (1H, dd, J = 8.9, 2.5 Hz), 7.36 (1H, t, J = 7.6 Hz), 7.09 (1H, t, J = 7.6 Hz), 5.41 (1H, t, J = 6.1 Hz), 4.23 (2H, q, J = 6.9 Hz), 4.05-4.01 (1H, m), 3.78 (1H, d, J = 11.2 Hz), 3.64 (1H, t, J = 7.8 Hz), 3.58-3.47 (2H, m), 3.22 (1H, t, J = 9.9 Hz), 2.75-2.67 (1H, m), 1.39 (3H, t, J = 6.9 Hz), 0.31 (3H, d, J = 6.8 Hz). 469 2.02 B I-201 1H-NMR (DMSO-d6) δ: 0.89 (d, J = 6.5 Hz, 3H), 1.37 (t, J = 6.8 Hz, 3H), 2.55-2.57 (m, 1H), 2.99 (t, J = 9.0 Hz, 1H), 3.51 (t, J = 8.2 Hz, 1H), 3.70 (t, J = 8.4 Hz, 1H), 3.78-3.81 (m, 3H), 4.43 (q, J = 6.8 Hz, 2H), 4.99 (q, J = 7.2 Hz, 1H), 7.02 (d, J = 8.7 Hz, 1H), 7.12 (t, J = 7.3 Hz, 1H), 7.38 (t, J = 7.5 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 8.11 (d, J = 8.3 Hz, 1H), 8.62 (s, 1H), 12.53 (s, 1H). 445 2 B I-202 458 2.16 B

(674) TABLE-US-00043 TABLE 43 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-203 472 2.26 B I-204 0 488 2.15 B I-205 .sup.1H-NMR (DMSO-d.sub.6) δ: 7.78 (2H, d, J = 8.8 Hz), 7.41 (1H, d, J = 8.5 Hz), 7.21-7.13 (3H, m), 6.80 (1H, d, J = 6.9 Hz), 5.34-5.28 (1H, m), 4.15 (2H, q, J = 6.9 Hz), 3.89 (1H, dd, J = 11.0, 7.5 Hz), 3.66-3.52 (4H, m), 3.11 (1H, t, J = 9.9 Hz), 1.39 (3H, t, J = 6.9 Hz), 0.25 (3H, d, J = 6.7 Hz). 458 2.14 B I-206 1H-NMR (DMSO-d6) δ: 8.65 (1H, d, J = 2.4 Hz), 8.12 (1H, dd, J = 8.8, 2.4 Hz), 7.42 (1H, d, J = 8.5 Hz), 7.20 (1H, t, J = 7.7 Hz), 7.00 (1H, d, J = 8.8 Hz), 6.81 (1H, d, J = 7.0 Hz), 5.37-5.31 (1H, m), 4.43 (2H, q, J = 7.0 Hz), 3.95 (1H, dd, J = 11.2, 7.3 Hz), 3.67-3.55 (4H, m), 3.12 (1H, t, J = 9.9 Hz), 2.68-2.55 (1H, m), 1.39 (3H, t, J = 7.0 Hz), 0.27 (3H, d, J = 6.8 Hz). 459 2.11 B I-207 1H-NMR (DMSO-D6) δ: 0.79 (3H, d, J = 21.6 Hz), 1.37 (3H, t, J = 7.0 Hz), 3.63-3.80 (2H, m), 4.04 (1H, dd, J = 10.9, 7.7 Hz), 4.43 (2H, q, J = 7.0 Hz), 5.43 (1H, dd, J = 12.9, 7.4 Hz), 7.01-7.10 (2.1H, m), 7.36 (1.1H, t, J = 7.7 Hz), 7.69 (2.2H, dd, J = 8.3, 3.5 Hz), 8.14 (1.1H, dd, J = 8.8, 2.8 Hz), 8.65 (1.0H, d, J = 2.3 Hz). 463 2.02 B

(675) TABLE-US-00044 TABLE 44 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-208 1H-NMR (DMSO-D6) δ: 0.77 (3H, d, J = 21.8 Hz), 3.51-3.81 (m), 3.99 (3H, s), 4.06 (1H, dd, J = 10.9, 7.7 Hz), 5.49 (1H, dd, J = 13.3, 7.0 Hz), 7.05 (1H, d, J = 8.8 Hz), 7.14 (1H, t, J = 7.4 Hz), 7.41 (1H, t, J = 7.3 Hz), 7.67 (1H, d, J = 8.3 Hz), 7.77 (1H, t, J = 9.0 Hz), 8.15 (1H, dd, J = 8.8, 2.5 Hz), 8.60 (1H, d, J = 2.5 Hz), 12.51 (1H, br s). 449 1.87 B I-209 1H-NMR (CDCl3) δ: 1.48 (t, J = 6.9 Hz, 3H), 2.44-2.52 (m, 1H), 2.62-2.69 (m, 1H), 3.71 (dd, J = 11.4, 9.3 Hz, 1H), 3.91 (dd, J = 11.7, 7.4 Hz, 1H), 4.00 (s, 2H), 4.12-4.18 (m, 3H), 4.57-4.61 (m, 2H), 4.67-4.75 (m, 1H), 7.04 (d, J = 8.7 Hz, 2H), 7.17 (dd, J = 17.5, 8.2 Hz, 2H), 7.38 (t, J = 7.7 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 8.7 Hz, 2H). 462 2.15 P I-210 1H-NMR (DMSO-d6) δ: 7.64 (1H, dd, J = 8.6, 5.2 Hz), 7.56 (2H, d, J = 8.5 Hz), 7.45 (1H, d, J = 9.8 Hz), 7.02-6.93 (3H, m), 4.94- 4.89 (1H, m), 4.73-4.66 (1H, m), 3.74-3.53 (5H, m), 2.37- 2.29 (1H, m), 2.10-2.02 (1H, m), 1.39 (3H, d, J = 6.3 Hz), 1.32 (6H, d, J = 5.9 Hz). 476 2.14 B I-211 1H-NMR (CDCl3) δ: 1.47 (dd, J = 15.0, 6.8 Hz, 6H), 1.98-2.02 (m, 1H), 2.44-2.51 (m, 1H), 3.59 (dd, J = 11.5, 7.6 Hz, 1H), 3.78-3.82 (m, 4H), 4.13 (q, J = 6.9 Hz, 2H), 4.33-4.41 (m, 1H), 7.04-7.22 (m, 6H), 7.57 (d, J = 7.8 Hz, 1H), 7.84 (d, J = 8.5 Hz, 2H). 443 2.28 P I-212 521 2.03 B

(676) TABLE-US-00045 TABLE 45 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-213 493 2.15 B I-214 0 471 1.86 B I-215 440 1.94 B I-216 1H-NMR (DMSO-d6) δ: 12.46 (1H, brs), 8.11 (1H, d, J = 8.8 Hz), 7.70-7.65 (2H, m), 7.42-7.36 (2H, m), 7.15-7.09 (2H, m), 5.45 (1H, t, J = 5.8 Hz), 4.17 (2H, q, J = 6.9 Hz), 4.03-3.98 (1H, m), 3.85-3.79 (3H, m), 3.68 (1H, t, J = 7.9 Hz), 3.39-3.33 (1H, m), 2.75-2.65 (1H, m), 1.36 (3H, t, J = 7.0 Hz), 0.37 (3H, d, J = 6.8 Hz). 522 524 2.22 B I-217 .sup.1H-NMR (CDCl.sub.3) δ: 7.86 (2H, d, J = 8.8 Hz), 7.59 (1H, dd, J = 8.8, 5.0 Hz), 7.07-6.89 (4H, m), 4.98- 4.92 (1H, m), 4.53 (1H, d, J = 9.5 Hz), 4.18-3.86 (3H, m), 3.72- 3.61 (3H, m), 3.03 (1H, dd, J = 15.9, 6.9 Hz), 1.48-1.43 (3H, m), 0.70 (3H, d, J = 6.8 Hz). 487 2.04 B

(677) TABLE-US-00046 TABLE 46 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-218 1H-NMR (DMSO-D6) δ: 7.80 (2H, d, J = 8.9 Hz), 7.74 (1H, d, J = 1.9 Hz), 7.68 (1H, d, J = 9.0 Hz), 7.37 (1H, dd, J = 8.9, 1.9 Hz), 7.16 (2H, d, J = 8.8 Hz), 5.40-5.33 (1H, m), 3.91- 3.86 (5H, s), 3.70-3.53 (4H, m), 3.10 (1H, t, J = 10.0 Hz), 0.25 (3H, d, J = 6.8 Hz). 464 2.06 B I-219 1H-NMR (CDCl3) δ: 7.83 (2H, d, J = 8.9 Hz), 7.46 (1H, d, J = 8.9 Hz), 7.02 (2H, d, J = 8.9 Hz), 6.89 (1H, dd, J = 9.0, 1.8 Hz), 6.64 (1H, d, J = 1.6 Hz), 5.00 (1H, dt, J = 10.2, 3.6 Hz), 4.13 (2H, ddd, J = 14.1, 7.1, 2.6 Hz), 4.01 (1H, dd, J = 11.1, 7.6 Hz), 3.89 (4H, t, J = 4.8 Hz), 3.82-3.76 (3H, m), 3.69 (1H, dd, J = 9.0, 7.4 Hz), 3.24-3.18 (5H, m), 2.66 (1H, ddd, J = 15.4, 8.7, 5.4 Hz), 1.47 (3H, t, J = 7.0 Hz), 0.50 (3H, d, J = 6.8 Hz). 529 1.95 B I-220 1H-NMR (CDCl3) δ: 7.84 (2H, d, J = 8.9 Hz), 7.51 (1H, d, J = 8.4 Hz), 7.26-7.23 (2H, m), 7.02 (2H, d, J = 8.9 Hz), 6.19 (1H, s), 5.07 (1H, td, J = 7 0, 2.8 Hz), 4.15- 4.03 (3H, m), 3.82-3.68 (4H, m), 3.22 (1H, t, J = 9.7 Hz), 2.68 (1H, dt, J = 17.2, 6.9 Hz), 2.49-2.42 (2H, m), 2.27-2.21 (2H, m), 1.84- 1.78 (2H, m), 1.71-1.65 (2H, q, J = 6.0 Hz), 1.47 (3H, t, J = 7.0 Hz), 0.47 (3H, d, J = 6.9 Hz). 524 2.6 B I-221 525 2.58 B

(678) TABLE-US-00047 TABLE 47 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-222 514 2.33 B I-223 1H-NMR (CDCl3) δ: 7.83 (2H, d, J = 8.9 Hz), 7.51 (1H, d, J = 8.2 Hz), 7.14 (1H, s), 7.03 (3H, dd, J = 11.7, 8.7 Hz), 5.06 (1H, td, J = 7.0, 2.5 Hz), 4.13 (2H, q, J = 6.9 Hz), 4.05 (1H, dd, J = 11.2, 7.5 Hz), 3.82-3.68 (4H, m), 3.22 (1H, t, J = 9.7 Hz), 2.72-2.62 (2H, m), 1.91-1.76 (5H, m), 1.57-1.25 (5H, m), 1.47 (3H, t, J = 7.0 Hz), 0.49 (3H, t, J = 7.8 Hz). 526 2.66 B I-224 0 527 2.65 B I-225 1H-NMR (CDCl.sub.3) δ: 7.84 (2H, d, J = 8.8 Hz), 7.47 (1H, d, J = 8.8 Hz), 7.02 (2H, d, J = 8.8 Hz), 6.81 (1H, dd, J = 8.8, 1.9 Hz), 6.71 (1H, d, J = 1.9 Hz), 5.03-4.97 (1H, m), 4.14 (2H, q, J = 7.0 Hz), 4.03 (1H, dd, J = 11.2, 7.5 Hz), 3.88 (3H, s), 3.84-3.76 (3H, m), 3.73-3.61 (1H, m), 3.24-3.17 (1H, m), 2.72-2.63 (1H, m), 1.47 (3H, t, J = 7.0 Hz), 0.50 (3H, d, J = 6.9 Hz). 474 2.03 B I-226 475 2.01 B

(679) TABLE-US-00048 TABLE 48 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-227 1H-NMR (DMSO-D6) δ: 7.98-7.94 (2H, m), 7.76-7.65 (2H, m), 7.51-7.36 (3H, m), 7.13 (1H, t, J = 7.4 Hz), 5.52-5.43 (1H, m), 4.08-4.01 (1H, m), 3.81-3.50 (6H, m), 0.78 (3H, d, J = 21.7 Hz). I-228 1H-NMR (CDCl3) δ: 0.90 (3H, d, J = 21.6 Hz), 1.46 (3H, t, J = 7.0 Hz), 3.60 (1H, dd, J = 34.9, 11.5 Hz), 3.76-3.85 (3H, m), 3.89 (1H, dd, J = 11.0, 3.1 Hz), 4.08-4.17 (3H, m), 5, 04 (1H, ddd, J = 14.3, 7.6, 3.0 Hz), 6.98-7.04 (2H, m), 7.16-7.20 (1H, m), 7.39-7.44 (2H, m), 7.62-7.67 (1H, m), 7.80-7.86 (2H, m). 462 2.05 B I-229 473 2.3  B I-230 444 2.06 B I-231 498 2.34 B

(680) TABLE-US-00049 TABLE 49 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-232 442 2.27 B I-233 466 2.04 B I-234 0 449 1.8  B I-235 463 1.95 B I-236 462 2.11 B

(681) TABLE-US-00050 TABLE 50 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-237 476 2.23 B I-238 406 2.01 B I-239 424 2.07 B I-240 431 1.88 B I-241 430 1.92 B

(682) TABLE-US-00051 TABLE 51 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-242 484 2.22 B I-243 428 2.15 B I-244 00 448 1.98 B I-245 01 462 2.12 B I-246 02 431 1.74 B

(683) TABLE-US-00052 TABLE 52 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-247 03 445 1.88 B I-248 04 459 2.01 B I-249 05 420 2.14 B I-250 06 1H-NMR (DMSO-d6) δ: 7.77 (2H, d, J = 8, 8 Hz), 7.41 (1H, d, J = 8.4 Hz), 7.19 (1H, t, J = 7.7 Hz), 7.12 (2H, d, J = 8.7 Hz), 6.81 (1H, d, J = 6.9 Hz), 5.32 (1H, t, J = 5.8 Hz), 4.79-4.73 (1H, m), 3.91-3.85 (1H, m), 3.75-3.52 (4H, m), 3.12 (1H, t, J = 9.9 Hz), 1.34 (6H, dd, J = 5.9, 1.9 Hz), 0.27 (3H, d, J = 6.8 Hz). 472 2.23 B I-251 07 1H-NMR (DMSO-d6) δ: 0.27 (d, J = 6.8 Hz, 3H), 2.55-2.56 (m, 1H), 3.14 (t, J = 10.0 Hz, 1H), 3.58-3.63 (m, 4H), 3.92 (dd, J = 11.3, 7.3 Hz, 1H), 5.38 (t, J = 5.8 Hz, 1H), 7.25-7.28 (m, 1H), 7.41-7.46 (m, 4H), 7.64-7.70 (m, 1H), 7.95 (d, J = 8.8 Hz, 2H), 12.48 (s, 1H). 484 2.05 B

(684) TABLE-US-00053 TABLE 53 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-252 08 1H-NMR (DMSO-d6) δ: 0.26 (d, J = 6.8 Hz, 3H), 1.39 (t, J = 7.0 Hz, 3H), 2.46-2.47 (m, 1H), 3.10 (t, J = 9.9 Hz, 1H), 3.53-3.67 (m, 4H), 3.88 (dd, J = 11.2, 7.3 Hz, 1H), 4.15 (q, J = 6.9 Hz, 2H), 5.34-5.38 (m, 1H), 7.14 (d, J = 8.8 Hz, 2H), 7.26 (td, J = 9.1, 2.4 Hz, 1H), 7.41 (dd, J = 9.1, 2.3 Hz, 1H), 7.67 (dd, J = 9.2, 4.1 Hz, 1H), 7.78 (d, J = 8.8 Hz, 2H), 12.47 (s, 1H). 462 2.06 B I-253 09 518 1.91 B I-254 0 450 1.97 B I-255 450 1.92 B I-256 1H-NMR (DMSO-d6) δ: 0.32 (d, J = 6.9 Hz, 3H), 1.38 (t, J = 6.9 Hz, 3H), 2.42-2.46 (m, 1H), 2.95 (t, J = 9.9 Hz, 1H), 3.59-3.64 (m, 4H), 3.75 (dd, J = 11.5, 6.7 Hz, 1H), 4.16 (q, J = 6.9 Hz, 2H), 5.25 (td, J = 6.2, 2.7 Hz, 1H), 6.91 (s, 1H), 7.20 (d, J = 8.9 Hz, 2H), 7.36 (dd, J = 8.2, 1.2 Hz, 1H), 7.66 (d, J = 8.3 Hz, 1H), 7.86 (dd, J = 9.4, 2.4 Hz, 2H), 8.16 (s, 1H). 468 2.16 P

(685) TABLE-US-00054 TABLE 54 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-257 1H-NMR (DMSO-d6) δ: 7.79 (2H, d, J = 8.8 Hz), 7.62 (2H, d, J = 8.7 Hz), 7.35 (1H, t, J = 8.1 Hz), 7.16-7.07 (3H, m), 5.39-5.34 (1H, m), 4.92-4.85 (1H, m), 4.16 (2H, q, J = 7.0 Hz), 3.92-3.86 (1H, m), 3.77 (1H, d, J = 16.3 Hz), 3.66-3.54 (3H, m), 3.12 (1H, t, J = 10.0 Hz), 2.51-2.44 (1H, m), 1.40 (3H, t, J = 7.0 Hz), 1.15 (6H, dd, J = 8.3, 6.3 Hz). 486 2.61 B I-258 1H-NMR (DMSO-d6) δ: 7.96 (1H, d, J = 8.8 Hz), 7.65 (2H, t, J = 9.2 Hz), 7.36 (1H, t, J = 7.7 Hz), 7.20 (1H, s), 7.14-7.08 (2H, m), 5.91 (1H, s), 5.79 (1H, s), 5.42 (1H, t, J = 6.3 Hz), 4, 17 (2H, q, J = 6.8 Hz), 3.96-3.91 (1H, m), 3.76-3.58 (4H, m), 3.13 (1H, t, J = 9.7 Hz), 2.72-2.64 (1H, m), 1.38 (3H, t, J = 6.8 Hz), 0.34 (3H, d, J = 6.7 Hz). 476 2.19 B I-259 1H-NMR (DMSO-d6) δ: 8.39 (1H, brs), 7.99 (1H, d, J = 8.8 Hz), 7.71-7.64 (2H, m), 7.37 (1H, t, J = 7.5 Hz), 7.11 (1H, t, J = 7.4 Hz), 7.01 (1H, dd, J = 8.8, 2.5 Hz), 6.98-6.96 (1H, m), 5.48-5.42 (1H, m), 4.69 (2H, d, J = 6.0 Hz), 4.12 (2H, q, J = 6.9 Hz), 3.96 (1H, dd, J = 10.7, 7.2 Hz), 3.82 (2H, s), 3.70 (1H, d, J = 10.8 Hz), 3, 62 (1H, t, J = 8.2 Hz), 3.20 (1H, t, J = 9.5 Hz), 2.74-2.65 (1H, m), 1.94 (3H, s), 1.36 (3H, t, J = 6.9 Hz), 0.36 (3H, d, J = 6.5 Hz). 515 1.81 B I-260 1H-NMR (DMSO-d6) δ: 7.97 (1H, d, J = 8.9 Hz), 7.89 (1H, brs), 7.70-7.64 (2H, m), 7.37 (1H, t, J = 7.3 Hz), 7.11 (1H, t, J = 7.4 Hz), 7.01 (1H, d, J = 2.5 Hz), 6.95 (1H, dd, J = 8.9, 2.5 Hz), 5.48-5.43 (1H, m), 4.13 (2H, q, J = 6.9 Hz), 3.97-3.92 (1H, m), 3.78 (2H, s), 3.69 (1H, d, J = 10.7 Hz), 3.59 (1H, t, J = 8.0 Hz), 3.19 (1H, t, J = 9.6 Hz), 3.08 (2H, dd, J = 12.8, 6.8 Hz), 2.96 (2H, t, J = 7.7 Hz), 2.73-2.64 (1H, m), 1.79-1.71 (5H, m), 1.36 (3H, t, J = 6.9 Hz), 0.35 (3H, d, J = 6.8 Hz). 543 1.89 B

(686) TABLE-US-00055 TABLE 55 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-261 1H-NMR (DMSO-d6) δ: 7.74 (1H, d, J = 8. 7 Hz), 7.70-7.64 (2H, m), 7.36 (1H, t, J = 7.6 Hz), 7.11 (1H, t, J = 7.4 Hz), 6.74 (1H, d, J = 2.0 Hz), 6.65 (1H, d, J = 8.8 Hz), 5.41-5.36 (1H, m), 4.15 (2H, q, J = 6.9 Hz), 3.95-3.75 (7H, m), 3.59 (1H, t, J = 8.3 Hz), 3.25 (1H, t, J = 9.9 Hz), 1.37 (3H, t, J = 6.9 Hz), 0.32 (3H, d, J = 6.7 Hz). 474 2   B I-262 1H-NMR (CDCl3) δ: 8.06 (1H, s), 7.83 (2H, t, J = 4.52 Hz), 7.56 (1H, dd, J = 8.78, 1.25 Hz), 7.42 (1H, d, J = 9.03 Hz), 7.01 (2H, d, J = 9.03 Hz), 5.06 (1H, t, J = 7.40 Hz), 4.69 (1H, q, J = 6.02 Hz), 4.07 (1H, dd. J = 11.29, 7.28 Hz), 3.83 (1H, dd, J = 11.42, 2.64 Hz), 3.77 (2H, d, J = 2.26 Hz), 3.70 (1H, t, J = 8.28 Hz), 3.23 (1H, t, J = 9.79 Hz), 2.70 (1H, dd, J = 10.79, 7.03 Hz), 1.41 (6H, dd, J = 6.02, 2.51 Hz), 0.46 (3H, d, J = 7.03 Hz). 483 2.07 B I-263 1H-NMR (DMSO-d6) δ: 12.50 (1H, s), 7.76 (2H, d, J = 8.9 Hz), 7.46 (1H, d, J = 8.5 Hz), 7.35-7.30 (1H, m), 7.13 (2H, d, J = 8.9 Hz), 6.82 (1H, dd, J = 10.5, 7.7 Hz), 5.37 (1H, t, J = 5.8 Hz), 4.78-4.72 (1H, m), 3.89 (1H, dd, J = 11.3, 7.4 Hz), 3.65-3.54 (4H, m), 3.10 (1H, t, J = 10.0 Hz), 1.34 (6H, dd, J = 6.0, 2.4 Hz), 0.29 (3H, d, J = 6.8 Hz). 476 2.18 B I-264 0 445 2.04 B

(687) TABLE-US-00056 TABLE 56 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-265 459 2.12 B I-266 406 2   B I-267 1H-NMR (CDCl3) δ: 7.83 (2H, d, J = 8.78 Hz), 7.23 (1H, s), 7.05 (1H, t, J = 5.65 Hz), 7.00 (2H, d, J = 8.78 Hz), 6.92 (1H, d, J = 2.01 Hz), 5.01 (1H, s), 4.67 (1H, t, J = 6.02 Hz), 4.03 (1H, dd, J = 11.17, 7.40 Hz), 3.85 (1H, t, J = 3.01 Hz), 3.83 (3H, s), 3.79 (2H, d, J = 4.77 Hz), 3.69 (1H, t, J = 8.28 Hz), 3.22 (1H, t, J = 9.79 Hz), 2.67-2.64 (1H, m), 1.40 (6H, dd, J = 6.02, 2.76 Hz), 0.46 (3H, d, J = 6.78 Hz). 488 2.15 B I-268 462 2.04 B

(688) TABLE-US-00057 TABLE 57 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-269 466 1.97 B I-270 448 1.92 B I-271 1H-NMR (DMSO-d6) δ: 0.32 (d, J = 6.8 Hz, 3H), 1.38 (t, J = 6.9 Hz, 3H), 2.37 (s, 3H), 2.42-2.46 (m, 1H), 2.92 (t, J = 9.9 Hz, 1H), 3.46 (s, 2H), 3.54-3.58 (m, 2H), 3.76 (dd, J = 11.3, 6.9 Hz, 1H), 4.16 (q, J = 6.9 Hz, 2H), 5.07-5.08 (m, 1H), 6.42 (s, 1H), 6.83 (d, J = 8.2 Hz, 1H), 7.20-7.23 (m, 3H), 7.34 (d, J = 8.0 Hz, 1H), 7.86 (d, J = 8.8 Hz, 2H), 12.20 (s, 1H). 457 2.23 B I-272 1H-NMR (DMSO-d6) δ: 0.37 (d, J = 6.8 Hz, 3H), 1.37 (t, J = 7.1 Hz, 3H), 2.38 (s, 3H), 2.44-2.46 (m, 1H), 3.02 (t, J = 9.7 Hz, 1H), 3.53 (s, 2H), 3.61-3.65 (m, 2H), 3.77 (dd, J = 11.1, 6.8 Hz, 1H), 4.43 (q, J = 7.0 Hz, 2H), 5.09 (dd, J = 9.0, 6.3 Hz, 1H), 6.80 (s, 1H), 6.85 (d, J = 8.0 Hz, 1H), 7.06 (d, J = 8.8 Hz, 1H), 7.26 (s, 1H), 7.36 (d, J = 8.2 Hz, 1H), 8.20 (dd, J = 8.8, 2.5 Hz, 1H), 8.70 (d, J = 2.3 Hz, 1H), 12.21 (s, 1H). 458 2.2  B

(689) TABLE-US-00058 TABLE 58 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-273 502 2.16 B I-274 0 488 2.03 B I-275 1H-NMR (DMSO-d6) δ: 1.38 (t, J = 7.0 Hz, 3H), 2.33-2.45 (m, 2H), 3.66 (t, J = 9.9 Hz, 1H), 3.86 (s, 2H), 3.97-4.08 (m, 2H), 4.45 (q, J = 7.0 Hz, 2H), 4.57 (dd, J = 13.6, 4.1 Hz, 1H), 4.69 (dd, J = 14.6, 4.0 Hz, 1H), 4.81 (t, J = 8.1 Hz, 1H), 7.06-7.14 (m, 2H), 7.35-7.42 (m, 2H), 7.71 (d, J = 8.0 Hz, 1H), 8.26 (d, J = 8.5 Hz, 1H), 8.74 (s, 1H). 463 2.08 P I-276 1H-NMR (DMSO-d6) δ: 12.48 (1H, brs), 7.96 (1H, d, J = 8.8 Hz), 7.68-7.54 (3H, m), 7.35 (1H, t, J = 7.7 Hz), 7.12-7.04 (2H, m), 5.85 (1H, d, J = 17.3 Hz), 5.44-5.38 (2H, m), 4.19 (2H, q, J = 6.9 Hz), 3.95-3.88 (1H, m), 3.78-3.70 (3H, m), 3.58 (1H, t, J = 8.0 Hz), 3.20 (1H, t, J = 9.7 Hz), 2.66-2.57 (1H, m), 1.38 (3H, t, J = 6.9 Hz), 0.32 (3H, d, J = 6.8 Hz). 470 2.23 B

(690) TABLE-US-00059 TABLE 59 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-277 1H-NMR (DMSO-d6) δ: 7.91 (1H, d, J = 8.8 Hz), 7.69-7.63 (2H, m), 7.37 (2H, t, J = 7.6 Hz), 7.10 (1H, t, J = 7.5 Hz), 6.96 (1H, d, J = 8.9 Hz), 5.46-5.40 (1H, m), 4.93 (2H, s), 4.14 (2H, q, J = 6.9 Hz), 3.95-3.89 (1H, m), 3.79 (2H, s), 3.65-3.57 (2H, m), 3.16 (1H, t, J = 9.6 Hz), 2.72-2.64 (1H, m), 1.37 (3H, t, J = 6.9 Hz), 0.36 (3H, d, J = 6.7 Hz). 474 1.89 B I-278 1H-NMR (DMSO-d6) δ: 12.48 (1H, brs), 7.93 (1H, d, J = 8.8 Hz), 7.65 (2H, t, J = 8.4 Hz), 7.36 (1H, t, J = 7.5 Hz), 7.23 (1H, d, J = 2.8 Hz), 7.15 (1H, dd, J = 8.9, 2.6 Hz), 7.10 (1H, t, J = 7.5 Hz), 5.40 (1H, m), 4.55 (1H, s), 4.16 (2H, q, J = 6.9 Hz), 4.00-3.94 (1H, m), 3.86-3.81 (1H, m), 3.71-3.63 (3H, m), 3.32-3.26 (1H, m), 2.68-2.57 (1H, m), 1.37 (3H, t, J = 6.9 Hz), 0.32 (3H, d, J = 6.8 Hz). 468 2.1  B I-279 1H-NMR (DMSO-d6) δ: 7.93 (1H, d, J = 8.8 Hz), 7.68-7.62 (2H, m), 7.43 (1H, d, J = 15.6 Hz), 7.36 (1H, t, J = 7.7 Hz), 7.20 (1H, s), 7.10 (1H, t, J = 7.4 Hz), 7.00 (1H, d, J = 8.7 Hz), 6.41-6.33 (1H, m), 5.42-5.35 (1H, m), 4.17 (2H, q, J = 6.9 Hz), 4.10 (2H, s), 3.91-3.71 (4H, m), 3.59 (1H, t, J = 8.2 Hz), 3.22 (1H, t, J = 9.7 Hz), 1.37 (3H, t, J = 6.9 Hz), 0.32 (3H, d, J = 6.7 Hz). 500 1.92 B I-280 1H-NMR (DMSO-d6) δ: 7.97 (1H, d, J = 8.5 Hz), 7.69 (1H, d, J = 8.0 Hz), 7.65 (1H, d, J = 8.5 Hz), 7.37 (1H, t, J = 7.5 Hz), 7.11 (1H, t, J = 7.5 Hz), 6.99-6.93 (2H, m), 5.48-5.42 (1H, m), 4.13 (2H, q, J = 6.9 Hz), 3.98-3.93 (1H, m), 3.80 (2H, s), 3.72-3.68 (1H, m), 3.60 (1H, t, J = 8.2 Hz), 3.45 (2H, t, J = 6.4 Hz), 3.20 (1H, t, J = 9.5 Hz), 2.99 (2H, t, J = 7.9 Hz), 2.72-2.63 (1H, m), 1.82-1.74 (2H, m), 1.36 (3H, t, J = 6.9 Hz), 0.36 (3H, d, J = 6.8 Hz). 502 1.93 B

(691) TABLE-US-00060 TABLE 60 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-281 1H-NMR (CDCl3) δ: 7.77 (2H, d, J = 8.8 Hz), 7.61 (1H, t, J = 7.0 Hz), 7.45 (1H, d, J = 9.3 Hz), 6.98- 6.95 (3H, m), 4.69-4.63 (3H, m), 4.00-3.93 (3H, m), 3.49-3.47 (2H, m), 3.40-3.37 (1H, m), 3.24-3.22 (1H, m), 3.10-3.08 (3H, m), 2.84- 2.81 (1H, m), 2.11-2.08 (1H, m), 1.66-1.63 (1H, m), 1.37 (6H, d, J = 6.0 Hz). 566 1.74 B I-282 1H-NMR (DMSO-D6) δ: 0.34 (d, J = 6.8 Hz, 3H), 1.39 (t, J = 7.0 Hz, 3H), 2.95 (t, J = 10.0 Hz, 1H), 3.58-3.63 (m, 4H), 3.78 (dd, J = 11.4, 6.8 Hz, 1H), 4.17 (q, J = 7.0 Hz, 2H), 5.31 (t, J = 5.1 Hz, 1H), 6.69 (s, 1H), 7.21 (d, J = 8.9 Hz, 2H), 7.34 (d, J = 0.8 Hz, 1H), 7.60 (d, J = 8.3 Hz, 1H), 7.68 (dd, J = 8.3, 1.3 Hz, 1H), 7.87 (d, J = 8.9 Hz, 2H), 8.12 (s, 1H), 8.18 (d, J = 0.8 Hz, 1H). 510 2.14 P I-283 1H-NMR (CDCl3) δ: 0.44 (d, J = 6.8 Hz, 3H, minor), 0.47 (d, J = 6.8 Hz, 3H, major), 1.45-1.50 (m, mixture), 1.81 (s, 3H, minor), 1.85 (s, 3H, major), 2.65-2.73 (m, 1H, mixture), 3.16-3.33 (m, 1H, mixture), 3.59-3.67 (m, 1H, mixture), 3.74-3.78 (m, 1H, minor), 3.88-3.92 (m, 1H, major), 3.97-4.18 (m, 3H, mixture), 5.05-5.12 (m, 1H, mixture), 7.02 (d, J = 8.8 Hz, 2H, major), 7.05 (d, J = 8.8 Hz, 2H, minor), 7.16-7.21 (m, 1H, mixture), 7.32-7.35 (m, 1H, mixture), 7.38-7.42 (m, 1H, mixture), 7.84 (d, J = 8.8 Hz, 2H, major), 7.85 (d, J = 8.8 Hz, 2H, minor), 8.046-8.083 (m, 1H, mixture). 474 1.89 B

(692) TABLE-US-00061 TABLE 61 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-284 0 1H-NMR (CDCl3) δ: 0.40-0.40 (m, 3H, mixture), 1.41-1.50 (m, 6H, mixture), 2.65-2.66 (m, 1H, mixture), 3.19-3.28 (m, 1H, mixture), 3.66-3.68 (m, 1H, mixture), 3.80-3.84 (m, 1H, mixture), 3.86-3.89 (m, 1H, major), 3.95-3.97 (m, 1H, minor), 4.04- 4.15 (m, 3H, mixture), 5.04-5.09 (m, 1H, mixture), 7.00-7.02 (m, 2H, mixture), 7.09-7.12 (m, 1H, mixture), 7.32-7.34 (m, 2H, mixture), 7.67-7.71 (m, 1H, mixture), 7.83-7.85 (m, 2H, mixture). 458 2.12 B I-285 1H-NMR (CDCl3) δ: 0.42 (d, J = 6.8 Hz, 3H), 1.47 (t, J = 6.9 Hz, 3H), 1.69 (s, 3H), 2.61-2.68 (m, 1H), 3.12 (s, 3H), 3.26 (dd, J = 9.8, 9.8 Hz, 1H), 3.69 (dd, J = 8.2, 8.2 Hz, 1H), 3.81 (dd, J = 10.8, 2.8 Hz, 1H), 4.06-4.15 (m, 3H), 5.13 (brm, 1H), 7.01 (d, J = 8.8 Hz, 2H), 7.13-7.15 (m, 1H), 7.33-7.40 (m, 2H), 7.77 (d, J = 8.3 Hz, 1H), 7.84 (d, J = 7.8 Hz, 2H). 488 2.03 B I-286 1H-NMR (CDCl3) δ: 0.44 (d, J = 7.0 Hz, 3H), 1.45 (t, J = 6.9 Hz, 3H), 1.69 (s, 3H), 2.64-2.75 (m, 1H), 3.11 (s, 3H), 3.26 (dd, J = 9.7, 9.7 Hz, 1H), 3.71 (dd, J = 9.0, 7.3 Hz, 1H), 3.88 (dd, J = 10.9, 3.4 Hz, 1H), 4.06-4.15 (m, 3H), 5.11-5.16 (m, 1H), 7.02 (d, J = 8.8 Hz, 2H), 7.14-7.17 (m, 1H), 7.37-7.40 (m, 2H), 7.75 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 8.8 Hz, 2H). 488 2.04 B I-287 1H-NMR (DMSO-D6) δ: 0.34 (d, J = 6.9 Hz, 3H), 2.28 (s, 3H), 2.44- 2.46 (m, 1H), 3.03 (t, J = 10.2 Hz, 1H), 3.57 (d, J = 0.9 Hz, 2H), 3.71 (dd, J = 10.4, 8.2 Hz, 1H), 3.84 (d, J = 6.3 Hz, 2H), 5.19 (dd, J = 14.0, 6.6 Hz, 1H), 6.80 (t, J = 7.5 Hz, 1H), 6.95 (t, J = 7.2 Hz, 2H), 7.41 (d, J = 7.5 Hz, 1H), 7.55-7.60 (m, 2H), 8.00-8.04 (m, 2H), 12.15 (br s, 1H). 431 2.17 P

(693) TABLE-US-00062 TABLE 62 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-288 1H-NMR (DMSO-D6) δ: 0.32 (d, J = 7.0 Hz, 3H), 2.27 (s, 3H), 2.42- 2.44 (m, 1H), 2.48 (s, 3H), 3.00 (t, J = 10.1 Hz, 1H), 3.56 (s, 2H), 3.67 (dd, J = 10.4, 8.2 Hz, 1H), 3.78- 3.84 (m, 2H), 5.18 (dd, J = 12.7, 7.8 Hz, 1H), 6.77 (t, J = 7.6 Hz, 1H), 6.94 (t, J = 7.2 Hz, 2H), 7.40 (d, J = 7.5 Hz, 1H), 7.53 (d, J = 8.0 Hz, 2H), 7.82 (d, J = 8.2 Hz, 2H), 12.14 (br s, 1H). 427 2.23 P I-289 1H-NMR (CDCl3) δ: 7.76 (2H, d, J = 8.8 Hz), 7.61 (1H, dd, J = 8.8, 5.0 Hz), 7.46 (1H, d, J = 9.3 Hz), 7.26-7.24 (2H, m), 7.00-6.91 (4H, m), 6.81 (2H, d, J = 8.3 Hz), 4.79 (1H, dd, J = 14.6, 3.0 Hz), 4.59 (2H, td, J = 12.2, 6.2 Hz), 4.02 (2H, s), 3.92 (1H, d, J = 4.8 Hz), 3.76 (2H, t, J = 5.8 Hz), 3.57 (1H, t, J = 4.3 Hz), 3.33 (1H, dd, J = 11.3, 4.3 Hz), 3.25-3.19 (3H, m), 2.15-2.09 (1H, m), 1.78 (1H, s), 1.62 (1H, t, J = 6.1 Hz), 1.34 (6H, d, J = 5.8 Hz). 626 2.52 B I-290 1H-NMR (DMSO-d6) δ: 0.26 (d, J = 6.8 Hz, 3H), 1.37 (t, J = 6.8 Hz, 3H), 2.33-2.42 (m, 1H), 3.15-3.88 (m, 4H), 4.15 (q, J = 6.8 Hz, 2H), 5.50-5.53 (m, 1H), 7.15 (d, J = 8.8 Hz, 2H), 7.29 (d, J = 7.6 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.78- 7.81 (m, 2H), 7.81 (d, J = 8.8 Hz, 2H). 480 2.21 B I-291 594 2.07 B

(694) TABLE-US-00063 TABLE 63 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-292 1H-NMR (CDCl3) δ: 7.80 (2H, d, J = 8.8 Hz), 7.66 (1H, dd, J = 9.0, 5.0 Hz), 6.95 (4H, d, J = 8.5 Hz), 6.91-6.87 (1H, m), 6.82-6.78 (3H, m), 4.65-4.59 (3H, m), 4.50 (1H, d, J = 9.5 Hz), 4.13 (2H, s), 3.99 (3H, ddd, J = 23.7, 14.7, 8.2 Hz), 2.70- 2.62 (2H, m), 1.37 (6H, dd, J = 6.0, 4.0 Hz). 584 2.32 B I-293 1H-NMR (CDCl3) δ: 8.74 (1H, d, J = 2.5 Hz), 8.04 (1H, dd, J = 8.8, 2.5 Hz), 7.65 (1H, d, J = 8.2 Hz), 7.44-7.38 (1H, m), 7.31 (1H, d, J = 8.5 Hz), 7.20-7.15 (1H, m), 6.84 (1H, d, J = 8.8 Hz), 5.11-5.06 (1H, m), 4.57 (1H, d, J = 9.9 Hz), 4.47 (2H, q, J = 7.0 Hz), 4.18-4.09 (1H, m), 3.96-3.91 (1H, m), 3.78-3.67 (2H, m), 3.12-3.01 (1H, m), 1.43 (3H, t, J = 7.0 Hz), 0.67 (3H, d, J = 6.9 Hz). 470 1.93 B I-294 0 .sup.1H-NMR (CDCl.sub.3) δ: 7.83 (2H, d, J = 8.9 Hz), 7.68 (1H, d, J = 8.0 Hz), 7.46-7.40 (1H, m), 7.38-7.30 (1H, m), 7.23-7.17 (1H, m), 7.00 (2H, d, J = 8.9 Hz), 4.87-4.78 (2H, m), 4.15-4.03 (2H, m), 3.99 (2H, s), 3.82-3.70 (2H, m), 3.21-3.11 (1H, m), 1.46 (3H, t, J = 7.0 Hz), 1.14 (3H, d, J = 6.8 Hz). 469 2.01 B I-295 1H-NMR (CDCl3) δ: 7.83 (2H, d, J = 9.0 Hz), 7.64 (2H, ddd, J = 18.5, 8.8, 5.1 Hz), 7.10 (1H, d, J = 8.8 Hz), 7.02-6.81 (8H, m), 4.68- 4.61 (1H, m), 4.43 (1H, dd, J = 15.8, 8.0 Hz), 4.35 (1H, dd, J = 9.0, 3.8 Hz), 4.26-4.24 (1H, m), 4.06 (2H, s), 3.99 (2H, s), 3.92 (1H, dd, J = 11.4, 7.2 Hz), 3.80 (1H, dd, J = 11.5, 8.8 Hz), 2.72-2.65 (1H, m), 2.54 (1H, dd, J = 13.9, 6.9 Hz), 1.40 (6H, d, J = 6.0 Hz) 694 2.66 B

(695) TABLE-US-00064 TABLE 64 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-296 484 2.09 B I-297 1H-NMR (DMSO-D6) δ: 11.44 (1H, brs), 9.35 (0.4H, brs). 7.81 (2H, d, J = 8.9 Hz), 7.59 (1H, d, J = 8.5 Hz), 7.47 (1H, d, J = 8.2 Hz), 7.31 (1H, t, J = 7.5 Hz), 7.13 (2H, d, J = 8.8 Hz), 7.03 (1H, t, J = 7.5 Hz), 5.37-5.32 (1H, m), 5.04 (1H, brs), 4.07 (2H, q, J = 6.9 Hz), 3.92-3.81 (3H, m), 3.72-3.67 (1H, m), 3.61-3.56 (1H, m), 3.19 (1H, t, J = 10.0 Hz), 2.51-2.42 (1H, m), 1.33 (3H, t, J = 7.0 Hz), 0.28 (3H, d, J = 6.8 Hz). 482 1.82 B I-298 .sup.1H-NMR (CDCl.sub.3) δ: 7.74 (2H, d, J = 8.8 Hz), 7.71-7.06 (4H, m), 6.95 (2H, d, J = 8.8 Hz), 4.95-4.83 (1H, m), 4.33-4.24 (2H, m), 4.20-3.87 (5H, m), 3.86-3.75 (1H, m), 3.70- 3.61 (1H, m), 2.97-2.86 (1H, m), 1.29-1.24 (3H, m), 0.93 (3H, d, J = 6.9 Hz). 487 487 1.59 1.71 B I-299 1H-NMR (CDCl3) δ: 8.52 (1H, s), 7.85 (2H, d, J = 8.9 Hz), 7.67-7.61 (2H, m), 7.04 (2H, d, J = 8.8 Hz), 6.77 (1H, d, J = 8.8 Hz), 5.23 (1H, d, J = 5.0 Hz), 5.16-5.14 (1H, m), 4.68-4.67 (1H, m), 4.54-4.52 (1H, m), 4.08 (1H, s), 4.01 (2H, s), 3.83- 3.81 (1H, m), 3.76-3.74 (1H, m), 2.50-2.49 (1H, m), 2.37-2.35 (1H, m), 1.40 (6H, d, J = 6.0 Hz). 544 2.05 B

(696) TABLE-US-00065 TABLE 65 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-300 1H-NMR (CDCl3) δ: 7.71 (2H, d, J = 9.0 Hz), 7.62 (1H, d, J = 8.5 Hz), 7.55 (1H, dd, J = 8.8, 5.0 Hz), 7.48 (2H, t, J = 6.7 Hz), 7.25-7.23 (1H, m), 7.03 (1H, d, J = 7.3 Hz), 6.93 (1H, t, J = 8.9 Hz), 6.88 (2H, d, J = 8.8 Hz), 5.13-5.11 (1H, m), 4.61-4.60 (1H, m), 4.49 (1H, dd, J = 14.3, 9.8 Hz), 4.34-4.32 (1H, m), 4.27-4.25 (1H, m), 3.91 (1H, dd, J = 9.9, 6.9 Hz), 3.86 (2H, s), 3.67 (1H, t, J = 8.8 Hz), 2.48 (1H, s), 2.31 (1H, t, J = 10.8 Hz), 1.37 (6H, dd, J = 6.0, 4.3 Hz) 625 2.37 B I-301 1H-NMR (CDCl3) δ: 7.60-7.58 (4H, m), 7.32-7.29 (1H, m), 7.20 (1H, t, J = 7.3 Hz), 7.04 (1H, t, J = 9.7 Hz), 6.95 (1H, t, J = 8.9 Hz), 6.90 (1H, d, J = 9.0 Hz), 6.79 (2H, d, J = 8.8 Hz), 5.32 (1H, t, J = 6.5 Hz), 5.01 (1H, t, J = 6.3 Hz), 4.60 (1H, t, J = 6.0 Hz), 4.14 (1H, dd, J = 11.9, 6.7 Hz), 3.91 (2H, s), 3.88 (1H, t, J = 5.3 Hz), 2.98 (1H, dd, J = 13.4, 7.2 Hz), 2.39 (1H, t, J = 7.0 Hz), 1.38 (6H, d, J = 6.0 Hz). 556 2.27 B I-302 1H-NMR (CDCl3) δ: 7.71 (2H, d, J = 8.8 Hz), 7.60-7.55 (2H, m), 7.26-7.20 (1H, m), 7.11 (1H, t, J = 7.4 Hz), 6.95-6.91 (4H, m), 6.82 (1H, d, J = 9.0 Hz), 5.18 (1H, t, J = 8.5 Hz), 4.68-4.62 (1H, m), 4.52- 4.47 (1H, m), 4.11 (1H, t, J = 8.4 Hz), 3.93-3.90 (1H, m), 3.93 (2H, s), 2.85-2.79 (1H, m), 2.66 (1H, dd, J = 22.7, 10.4 Hz), 1.39 (6H, d, J = 6.0 Hz). 556 2.37 B I-303 1H-NMR (CDCl3) δ: 7.83 (2H, d, J = 8.5 Hz), 7.60 (1H, t, J = 6.7 Hz), 7.21 (1H, t, J = 7.5 Hz), 7.01 (2H, d, J = 8.7 Hz), 6.92 (1H, t, J = 8.8 Hz), 6.81 (1H, d, J = 8.9 Hz), 6.68 (2H, t, J = 7.2 Hz), 6.62 (1H, t, J = 9.1 Hz), 4.67 (1H, q, J = 6.0 Hz), 4.43 (1H, t, J = 8.0 Hz), 4.36 (1H, d, J = 9.0 Hz), 4.26-4.24 (1H, m), 4.18-4.12 (1H, m), 3.96 (2H, s), 3.91 (1H, t, J = 9.3 Hz), 3.79 (1H, t, J = 10.4 Hz), 2.66 (1H, d, J = 8.3 Hz), 2.55 (1H, dd, J = 13.9, 6.7 Hz), 1.40 (6H, d, J = 5.9 Hz). 586 2.47 B

(697) TABLE-US-00066 TABLE 66 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-304 0 .sup.1H-NMR (CDCl.sub.3) δ: 7.83 (2H, d, J = 8.8 Hz), 7.72-7.67 (1H, m), 7.47- 7.41 (1H, m), 7.39-7.31 (1H, m), 7.24-7.18 (1H, m), 7.01 (2H, d, J = 8.8 Hz), 4.88-4.79 (2H, m), 4.12 (2H, q, J = 7.0 Hz), 4.02-3.99 (2H, m), 3.80 (2H, d, J = 8.0 Hz), 3.20- 3.10 (1H, m), 1.47 (3H, t, J = 6.9 Hz), 1.15 (3H, d, J = 6.8 Hz). 469 2.04 B I-305 536 1.78 B I-306 1H-NMR (DMSO-d6) δ: 0.26 (d, J = 6.8 Hz, 3H), 1.37 (t, J = 6.9 Hz, 3H), 2.39-2.46 (m, 1H), 3.17 (dd, J = 9.9, 9.9 Hz, 1H), 3.58 (dd, J = 9.0, 7.5 Hz, 1H), 3.67 (dd, J = 11.3, 2.5 Hz, 1H), 3.88 (dd, J = 11.2, 7.4 Hz, 1H), 4.14 (q, J = 6.9 Hz, 2H), 5.06 (s, 1H), 5.35-5.39 (m, 1H), 7.09 (dd, J = 7.4, 7.4 Hz, 1H), 7.15 (d, J = 8.8 Hz, 2H), 7.35 (dd, J = 7.5, 7.5 Hz, 1H), 7.62 (d, J = 8.5 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 8.8 Hz, 2H). 460 1.74 B I-307 1H-NMR (DMSO-d6) δ: 0.24 (d, J = 6.8 Hz, 3H), 1.38 (t, J = 7.0 Hz, 3H), 2.33-2.44 (m, 1H), 3.17 (dd, J = 9.9, 9.9 Hz, 1H), 3.57 (dd, J = 8.4, 8.4 Hz, 1H), 3.69 (dd, J = 11.0, 2.5 Hz, 1H), 3.87 (dd, J = 11.2, 7.4 Hz, 1H), 4.13-4.19 (m, 2H), 5.09 (s, 1H), 5.35-5.38 (m, 1H), 7.09 (dd, J = 7.5, 7.5 Hz, 1H), 7.16 (d, J = 8.8 Hz, 2H), 7.34 (dd, J = 7.7, 7.7 Hz, 1H), 7.62 (d, J = 8.5 Hz, 1H), 7.75 (d, J = 8.3 Hz, 1H), 7.81 (d, J = 8.8 Hz, 2H). 460 1.75 B

(698) TABLE-US-00067 TABLE 67 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-308 504 2.24 B I-309 462 2.07 B I-310 462 2.07 B I-311 1H-NMR (DMSO-d6) δ: 10.77 (1H, brs), 8.93 (1H, brs), 7.81 (2H, d, J = 8.5 Hz), 7.72 (1H, d, J = 8.2 Hz), 7.59 (1H, d, J = 8.4 Hz), 7.34 (1H, t, J = 7.5 Hz), 7.17-7.07 (3H, m), 5.35-5.30 (1H, m), 4.15 (2H, q, J = 6.8 Hz), 3.87-3.82 (1H, m), 3.70-3.46 (4H, m), 3.20 (1H, t, J = 9.9 Hz), 2.43-2.32 (1H, m), 1.38 (3H, t, J = 6.8 Hz), 0.28 (3H, d, J = 6.5 Hz). 459 1.78 B I-312 488 1.96 B

(699) TABLE-US-00068 TABLE 68 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-313 1H-NMR (CDCl3) δ: 1.24 (6H, d, J = 6.3 Hz), 1.49 (9H, d, J = 7.5 Hz), 3.72-3.85 (1H, m), 3.90-4.11 (5H (include 3.93 ppm (2H, s), m. ), 5.05 (1H, qq, J = 6.3 Hz, 6.3 Hz), 5.15-5.25 (1H, m), 5.36 (1H, d, J = 51.4 Hz), 7.19 (1H, m), 7.39-7.45 (2H, m), 7.69-7.75 (1.0H, m). 448 1.99 B I-314 0 1H-NMR (DMSO-d6) δ: 7.98 (1H, d, J = 8.5 Hz), 7.71-7.63 (2H, m), 7.37 (1H, t, J = 7.4 Hz), 7.11 (1H, t, J = 7.3 Hz), 7.02 (1H, s), 6.96 (1H, d, J = 8.3 Hz), 5.47-5.42 (1H, m), 4.16-4.09 (2H, m), 3.99-3.93 (1H, m), 3.80 (2H, s), 3.71-3.58 (4H, m), 3.25-3.11 (3H, m), 2.74-2.64 (1H, m), 1.36 (3H, t, J = 6.5 Hz), 0.36 (3H, d, J = 6.3 Hz). 488 1.87 B I-315 457 2.3  P I-316 479 2.27 P

(700) TABLE-US-00069 TABLE 69 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-317 431 2.19 P I-318 427 2.25 P I-319 .sup.1H-NMR (CDCl.sub.3) δ: 7.92 (2H, d, J = 8.0 Hz), 7.71 (1H, d, J = 7.9 Hz), 7.60 (1H, s), 7.41-7.38 (2H, br m), 7.28-7.12 (4H, m), 4.69-4.59 (1H, m), 4.23-4.12 (3H, m), 3.94-3.86 (3H, m), 3.75-3.67 (1H, m), 2.56-2.47 (2H, m), 1.40 (3H, t, J = 6.7 Hz). 473 1.62 B I-320 .sup.1H-NMR (CDCl.sub.3) δ: 7.92 (2H, d, J = 8.0 Hz), 7.71 (1H, d, J = 7.9 Hz), 7.60 (1H, s), 7.41-7.38 (2H, br m), 7.28-7.12 (4H, m), 4.69-4.59 (1H, m), 4.23-4.12 (3H, m), 3.94-3.86 (3H, m), 3.75-3.67 (1H, m), 2.56-2.47 (2H, m), 1.40 (3H, t, J = 6.7 Hz). 455 1.84 B I-321 .sup.1H-NMR (CDCl.sub.3) δ: 7.70 (2H, d, J = 8.8 Hz), 7.62 (1H, d, J = 7.8 Hz), 7.44-7.38 (1H, m), 7.21-7.16 (1H, m), 7.04 (1H, s), 6.93 (2H, d, J = 8.8 Hz), 5.69-5.63 (1H, m), 5.16- 5.10 (1H, m), 4.40 (1H, d, J = 8.0 Hz), 4.17-4.08 (3H, m), 4.03-3.91 (3H, m), 3.80-3.73 (1H, m), 2.73- 2.64 (1H, m), 2.50-2.40 (1H, m), 1.48 (3H, t, J = 7.0 Hz). 473 1.47 B

(701) TABLE-US-00070 TABLE 70 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-322 .sup.1H-NMR (CDCl.sub.3) δ: 7.89 (2H, d, J = 8.8 Hz), 7.69 (1H, d, J = 7.9 Hz), 7.47-7.42 (1H, m), 7.35 (1H, d, J = 8.5 Hz), 7.29-7.19 (1H, m), 7.03 (2H, d, J = 8.8 Hz), 5.20-5.15 (1H, m), 4.91-4.85 (1H, m), 4.15- 4.05 (3H, m), 4.00 (2H, s), 3.76 (1H, dd, J = 10.2, 6.7 Hz), 2.92 (2H, t, J = 6.7 Hz), 1.46 (3H, t, J = 7.0 Hz). 455 1.86 B I-323 1H-NMR (CDCl3) δ: 7.77 (2H, d, J = 8.8 Hz), 7.61 (1H, dd, J = 8.8, 5.0 Hz), 7.46 (1H, d, J = 7.3 Hz), 6.98 (1H, t, J = 5.6 Hz), 6.93 (2H, d, J = 8.8 Hz), 5.52 (1H, dt, J = 17.1, 5.3 Hz), 5.00 (2H, t, J = 11.5 Hz), 4.84 (1H, dd, J = 14.6, 2.8 Hz), 4.60 (2H, dt, J = 18.9, 6.5 Hz), 4.03 (2H, s), 3.96 (1H, d, J = 4.5 Hz), 3.68 (1H, d, J = 4.3 Hz), 3.56 (2H, t, J = 6.0 Hz), 3.35 (1H, dd, J = 11.2, 4.1 Hz), 3.18 (1H, d, J = 11.0 Hz), 2.15 (1H, dd, J = 15.9, 8.2 Hz), 1.80-1.77 (1H, m), 1.36 (6H, d, J = 6.0 Hz). 532 2.24 B I-324 0 1H-NMR (DMSO-D6) δ: 8.07 (1H, d, J = 9.0 Hz), 7.66 (2H, d, J = 8.8 Hz), 7.59 (1H, d, J = 2.5 Hz), 7.39- 7.34 (2H, m), 7.10 (1H, t, J = 7.7 Hz), 5.46-5.41 (1H, m), 4.22 (2H, q, J = 6.9 Hz), 4.03-3.98 (1H, m), 3.86 (1H, d, J = 10.7 Hz), 3.67- 3.57 (4H, m), 2.75-2.66 (1H, m), 1.38 (3H, t, J = 7.0 Hz), 0.35 (3H, d, J = 6.7 Hz). 489 2.13 B I-325 1H-NMR (DMSO-D6) δ: 7.64 (2H, t, J = 8.6 Hz), 7.45 (1H, d, J = 8.8 Hz), 7.35 (1H, t, J = 7.5 Hz), 7.09 (1H, t, J = 7.3 Hz), 6.39 (1H, d, J = 2.3 Hz), 6.26 (1H, dd, J = 9.1, 2.3 Hz), 6.06 (2H, brs), 5.41-5.35 (1H, m), 4.02 (2H, q, J = 7.0 Hz), 3.92- 3.87 (1H, m), 3.81-3.71 (3H, m), 3.56 (1H, t, J = 8.2 Hz), 3.20 (1H, t, J = 9.7 Hz), 1.34 (3H, t, J = 6.9 Hz), 0.31 (3H, d, J = 6.8 Hz). 459 1.93 B

(702) TABLE-US-00071 TABLE 71 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-326 544 2.23 B I-327 1H-NMR (CDCl3) δ: 7.78 (2H, d, J = 8.8 Hz), 7.66 (1H, ddd, J = 21.6, 8.8, 5.0 Hz), 7.44 (1H, d, J = 9.3 Hz), 7.10 (1H, d, J = 9.0 Hz), 6.94-6.93 (2H, m), 5.05 (2H, dt, J = 11.5, 4.6 Hz), 4.83 (1H, dd, J = 14.3, 3.0 Hz), 4.62-4.52 (2H, m), 3.94 (4H, d, J = 21.3 Hz), 3.64 (1H, s), 3.35 (1H, dd, J = 11.0, 4.5 Hz), 3.18 (1H, s), 3.01-2.94 (2H, m), 2.17 (2H, s), 1.36 (6H, dd, J = 6.0, 3.0 Hz), 534 2.33 B I-328 1H-NMR (DMSO-D6) δ: 0.36 (d, J = 6.8 Hz, 3H), 1.39 (t, J = 6.9 Hz, 3H), 2.94 (t, J = 9.9 Hz, 1H), 3.49 (s, 2H), 3.56-3.61 (m, 2H), 3.80- 3.85 (m, 4H), 4.16 (q, J = 6.9 Hz, 2H), 5.18-5.19 (m, 1H), 6.46 (s, 1H), 7.21 (t, J = 7.8 Hz, 3H), 7.42 (d, J = 8.3 Hz, 1H), 7.70 (s, 1H), 7.86 (t, J = 8.3 Hz, 3H), 8.07 (s, 1H). 523 2.04 P I-329 1H-NMR (DMSO-D6) δ: 0.33 (d, J = 7.0 Hz, 3H), 1.39 (t, J = 7.0 Hz, 3H), 2.28 (s, 3H), 2.44-2.46 (m, 1H), 2.99 (t, J = 10.0 Hz, 1H), 3.56 (s, 2H), 3.65 (dd, J = 10.2, 8.2 Hz, 1H), 3.77-3.82 (m, 2H), 4.16-4.20 (m, 2H), 5.16-5.19 (m, 1H), 6.79 (t, J = 7.7 Hz, 1H), 6.94-6.96 (m, 2H), 7.21 (d, J = 9.0 Hz, 2H), 7.40 (d, J = 7.8 Hz, 1H), 7.85 (d, J = 8.8 Hz, 2H), 12.11 (s, 1H). 457 2.27 P

(703) TABLE-US-00072 TABLE 72 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-330 1H-NMR (DMSO-D6) δ: 0.36 (d, J = 6.8 Hz, 3H), 1.38 (t, J = 7.0 Hz, 3H), 2.29 (s, 3H), 2.45-2.47 (m, 1H), 3.05 (t, J = 10.2 Hz, 1H), 3.57 (s, 2H), 3.72 (dd, J = 10.4, 8.2 Hz, 1H), 3.82-3.87 (m, 2H), 4.45 (q, J = 7.0 Hz, 2H), 5.20 (td, J = 8.0, 3.4 Hz, 1H), 6.85 (t, J = 7.5 Hz, 1H), 6.96 (t, J = 7.4 Hz, 1H), 7.09 (dd, J = 8.4, 3.9 Hz, 2H), 7.42 (d, J = 7.8 Hz, 1H), 8.20 (dd, J = 8.8, 2.5 Hz, 1H), 8.70 (d, J = 2.5 Hz, 1H). 458 2.25 P I-331 1H-NMR (CDCl3) δ: 7.84 (2H, d, J = 8.9 Hz), 7.55 (1H, dd, J = 8.9, 8.9 Hz), 7.03 (2H, d, J = 8.9 Hz), 6.98-6.88 (2H, m), 4.50 (1H, dd, J = 7.6, 3.8 Hz), 4.16-4.09 (2H, m), 4.05 (1H, dd, J = 11.0, 7.6 Hz), 3.90 (1H, dd, J = 11.0, 3.8 Hz), 3.75 (2H, d, J = 1.6 Hz), 3.35 (1H, d, J = 9.0 Hz), 3.29 (1H, d, J = 9.0 Hz), 1.47 (3H, t, J = 7.0 Hz), 1.22 (3H, s), 0.48 (3H, s). 476 2.19 P I-332 1H-NMR (CDCl3) δ: 7.87 (2H, d, J = 8.8 Hz), 7.65 (1H, d, J = 8.3 Hz), 7.45-7.39 (1H, m), 7.33 (1H, d, J = 8.8 Hz), 7.21-7.16 (1H, m), 7.02 (2H, d, J = 8.8 Hz), 5.13-5.07 (1H, m), 4.56 (1H, d, J = 9.5 Hz), 4.17-4.00 (3H, m), 3.97 (1H, dd, J = 11.0, 2.7 Hz), 3.81-3.71 (2H, m), 3.08-3.02 (1H, m), 1.48 (3H, t, J = 7.0 Hz), 0.70 (3H, d, J = 6.8 Hz). 469 1.95 B I-333 1H-NMR (CDCl3) δ: 7.99 (2H, d, J = 8.8 Hz), 7.69 (1H, d, J = 8.4 Hz), 7.45-7.39 (1H, m), 7.34 (1H, d, J = 8.4 Hz), 7.22-7.17 (1H, m), 7.06 (2H, d, J = 8.8 Hz), 5.20-5.15 (1H, m), 4.97 (1H, d, J = 8.7 Hz), 4.18-4.10 (3H, m), 4.03-3.98 (1H, m), 3.95 (2H, d, J = 4.0 Hz), 3.07- 3.00 (1H, m), 1.46 (3H, t, J = 7.0 Hz), 0.77 (3H, d, J = 6.8 Hz). 469 1.89 B

(704) TABLE-US-00073 TABLE 73 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-334 0 1H-NMR (CDCl3) δ: 7.78 (2H, d, J = 8.8 Hz), 7.63 (1H, dd, J = 8.8, 5.0 Hz), 7.48 (1H, d, J = 8.2 Hz), 7.39 (2H, dd, J = 17.3, 8.0 Hz), 7.19 (1H, t, J = 7.6 Hz), 6.98 (3H, d, J = 9.0 Hz), 6.74 (1H, d, J = 9.0 Hz), 4.65 (1H, t, J = 6.0 Hz), 4.44 (3H, dd, J = 13.6, 7.8 Hz), 4.33 (1H, s), 4.03 (2H, s), 3.89 (2H, d, J = 7.7 Hz), 2.51 (1H, d, J = 6.4 Hz), 2.41 (1H, s), 1.39 (6H, dd, J = 6.0, 1.6 Hz) 625 2.37 B I-335 1H-NMR (DMSO-d6) δ: 0.23 (d, J = 6.8 Hz, 3H), 1.37 (s, 3H), 1.38 (t, J = 6.8 Hz, 3H), 1.39 (s, 3H), 2.46- 2.54 (m, 1H), 3.11 (t, J = 9.8 Hz, 1H), 3.55-3.63 (m, 2H), 3.93 (dd, J = 10.8, 8.0 Hz, 1H), 4.13 (q, J = 6.8 Hz, 2H), 5.40-5.44 (m, 1H), 7.06 (dd, J = 7.5, 7.5 Hz, 1H), 7.14 (d, J = 8.8 Hz, 2H), 7.33 (dd, J = 7.5, 7.5 Hz), 7.59 (d, J = 9.3 Hz, 1H), 7.61 (d, J = 9.3 Hz, 1H), 7.79 (d, J = 8.8 Hz, 2H), 12.41 (brs, 1H). 472 2.21 B I-336 1H-NMR(DMSO-d6) δ: 0.22 (d, J = 6.8 Hz, 3H), 0.93 (dd, J = 9.2, 4.1 Hz, 1H), 1.06-1.11 (m, 1H), 1.38 (t, J = 6.9 Hz, 3H), 1.42-1.44 (m, 2H), 2.44-2.48 (m, 1H), 3.06 (t, J = 9.9 Hz, 1H), 3.53-3.61 (m, 2H), 3.90 (dd, J = 10.9, 7.7 Hz, 1H), 4.14 (q, J = 6.9 Hz, 2H), 5.36-5.40 (m, 1H), 7.09 (dd, 7.7, 7.7 Hz, 1H), 7.15 (d, J = 9.0 Hz, 2H), 7.34 (dd, J = 7.7, 7.7 Hz, 1H), 7.61 (d, J = 8.3 Hz, 2H), 7.79 (d, J = 9.0 Hz, 2H), 12.37 (brs, 1H). 470 2.13 B I-337 1H-NMR (DMSO-d6) δ: 0.25 (d, J = 6.8 Hz, 3H), 1.38 (t, J = 6.9 Hz, 3H), 2.47-2.55 (m, 1H), 3.15 (t, J = 9.9 Hz, 1H), 3.60 (dd, J = 8.9, 7.7 Hz, 1H), 3.66 (dd, J = 11.3, 2.3 Hz, 1H), 3.91 (dd, J = 11.3, 7.3 Hz, 1H), 4.14 (q, J = 6.9 Hz, 2H), 5.44-5.46 (m, 1H), 5.82 (d, JHF = 47.4 Hz, 1H), 7.17 (d, J = 8.8 Hz, 2H), 7.21 (dd, J = 7.5, 7.5 Hz, 1H), 7.43 (dd, J = 7.7, 7.7 Hz, 1H), 7.65 (d, 8.0 Hz, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.81 (d, J = 8.8 Hz, 2H). 462 1.96 B

(705) TABLE-US-00074 TABLE 74 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-338 1H-NMR (DMSO-d6) δ: 0.25 (d, J = 6.8 Hz, 3H), 1.37 (t, J = 6.9 Hz, 3H), 2.45-2.47 (m, 1H), 3.15 (t, J = 10.0 Hz, 1H), 3.59-3.67 (m, 2H), 3.89 (dd, J = 11.4, 7.4 Hz, 1H), 4.14 (q, J = 6.9 Hz, 2H), 5.45-5.48 (m, 1H), 5.87 (d, JHF = 47.7 Hz, 1H), 7.16 (d, J = 8.8 Hz, 2H), 7.20 (dd, J = 7.7, 7.7 Hz, 1H), 7.43 (dd, J = 7.8, 7.8 Hz, 1H), 7.66 (d, 8.3 Hz, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.82 (d, J = 9.0 Hz, 2H). 462 1.99 B I-339 569 2.27 B I-340 586 2.44 B I-341 1H-NMR (CDCl3) δ: 7.86-7.82 (2H, m), 7.52 (1H, d, J = 8.2 Hz), 7.38-7.32 (2H, m), 7.13-7.09 (1H, m), 7.01-6.97 (2H, m), 5.47 (1H, s), 5.09-5.03 (1H, m), 4.12-4.02 (3H, m), 3.97 (2H, s), 3.84 (1H, dd, J = 11.2, 2.6 Hz), 3.70 (1H, t, J = 8.0 Hz), 3.24 (1H, dd, J = 10.6, 9.0 Hz), 2.74-2.65 (1H, m), 1.44 (3H, t, J = 7.0 Hz), 0.44 (3H, d, J = 6.9 Hz). 483 2.07 B

(706) TABLE-US-00075 TABLE 75 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-342 550 1.93 B I-343 1H-NMR (CDCl3) δ: 7.65 (2H, s), 7.43 (2H, s), 7.16 (3H, s), 6.95 (2H, s), 6.71-6.63 (3H, m), 4.65-4.62 (1H, m), 4.13 (2H, br s), 3.83 (2H, br s), 3.73 (3H, br s), 2.70 (2H, br s), 2.57 (2H, brs), 2.35 (1H, s), 1.92 (1H, s), 1.38 (6H, s). 566 2.53 B I-344 00 598 2.4 B I-345 01 539 1.6 B

(707) TABLE-US-00076 TABLE 76 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-346 02 584 2.18 B I-347 03 584 2.13 B I-348 04 1H-NMR (DMSO-D6) δ: 7.91 (2H, d, J = 8.4 Hz), 7.74 (1H, dd, J = 8.7. 5.2 Hz), 7.29-7.25 (2H, m), 7.22-7.12 (6H, m), 7.01 (1H, t, J = 8.9 Hz), 4.83-4.76 (1H, m), 4.61- 4.52 (1H, m), 3.92 (2H, s), 3.90- 3.83 (2H, m), 3.74-3.68 (1H, m), 3.31-3.25 (2H, m), 2.94 (1H, t, J = 11.5 Hz), 2.08-2.03 (2H, m), 1.33 (6H, d, J = 5.9 Hz). 552 2.47 B I-349 05 1H-NMR (DMSO-D6) δ: 7.92 (2H, d, J = 8.4 Hz), 7.70 (1H, d, J = 8.2 Hz), 7.34-7.10 (10H, m), 4.85-4.77 (1H, m), 4.61-4.53 (1H, m), 3.93- 3.84 (4H, m), 3.72-3.67 (1H, m), 3.30-3.25 (1H, m), 2.95 (1H, t, J = 11.5 Hz), 2.12-2.07 (2H, m), 1.33 (6H, d, J = 5.9 Hz). 534 2.43 B

(708) TABLE-US-00077 TABLE 77 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-350 06 1H-NMR (CDCl3) δ: 8.59 (1H, d, J = 4.8 Hz), 7.81 (1H, t, J = 7.7 Hz), 7.74 (2H, t, J = 7.4 Hz), 7.62 (1H, dd, J = 8.8, 5.0 Hz), 7.53 (2H, d, J = 8.5 Hz), 6.91 (1H, t, J = 9.0 Hz), 6.85 (1H, d, J = 9.0 Hz), 6.74 (2H, d, J = 8.5 Hz), 5.28 (1H, t, J = 6.8 Hz), 5.10-5.03 (1H, m), 4.61- 4.55 (1H, m), 4.09 (1H, dd, J = 10.8, 6.0 Hz), 3.88 (2H, d, J = 8.0 Hz), 3.09-3.02 (1H, m), 2.43-2.36 (1H, m), 1.39 (6H, dd, J = 11.0, 6.0 Hz). I-351 07 1H-NMR (CDCl3) δ: 8.53 (1H, d, J = 5.0 Hz), 7.90 (2H, d, J = 7.5 Hz), 7.79 (2H, d, J = 8.5 Hz), 7.60 (1H, dd, J = 8.8, 5.0 Hz), 7.35 (1H, d, J = 5.8 Hz), 7.01 (2H, d, J = 8.8 Hz), 6.88 (1H, t, J = 9.0 Hz), 6.76 (1H, d, J = 9.0 Hz), 5.22 (1H, t, J = 8.0 Hz), 4.71-4.65 (1H, m), 4.46 (1H, dd, J = 15.3, 7.5 Hz), 3.97 (1H, t, J = 9.7 Hz), 3.90 (1H, t, J = 5.8 Hz), 3.86 (2H, s), 2.80-2.73 (2H, m), 1.41 (6H, d, J = 5.8 Hz). I-352 08 500 1.89 B I-353 09 1H-NMR(CDCl3) δ: 1.43 (t, J = 6.9 Hz, 3H), 2.79 (dd, d = 13.3, 6.3 Hz, 1H), 3.06 (dd, J = 13.3, 5.0 Hz, 1H), 3.73 (dd, J = 10.2, 4.4 Hz, 1H), 3.81 (d, J = 16.7 Hz, 1H), 3.86 (d, J = 16.7 Hz, 1H), 4.06 (dd, J = 10.2, 6.4 Hz, 1H), 4.06 (q, J = 6.9 Hz, 2H), 4.44 (d, J = 6.8 Hz, 1H), 4.55 (d, J = 6.0 Hz, 1H), 5.00- 5.06 (m, 1H), 5.34 (d, J = 6.8 Hz, 1 H), 5.56 (d, J = 6.0 Hz, 1H), 6.88 (d, J = 8.5 Hz, 2H), 7.16 (dd, J = 7.4, 7.4 Hz, 1H), 7.32 (d, J = 8.5 Hz, 1H), 7.39 (dd, J = 7.7, 7.7 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 8.5 Hz, 2H). 472 1.78 B

(709) TABLE-US-00078 TABLE 78 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-354 0 1H-NMR (DMSO-D6) δ: 7.87 (2H, d, J = 8.4 Hz), 7.77-7.72 (1H, m), 7.21-7.16 (3H, m), 7.02 (1H, t, J = 8.9 Hz), 4.85-4.76 (1H, m), 4.60- 4.52 (1H, m), 3.93-3.82 (4H m), 3.71-3.66 (1H, m), 3.00-2.85 (2H, m), 2.48-2.41 (1H, m), 2.33-2.24 (1H, m), 2.11 (3H, s), 1.33 (6H, d, J = 5.8 Hz). 522 2.28 B I-355 1H-NMR (DMSO-D6) δ: 7.76- 7.58 (3H, m), 7.44 (1H, d, J = 9.7 Hz), 7.04-6.99 (3H, m), 6.08 (1H, dd, J = 15.4, 7.3 Hz), 5.77-5.69 (1H, m), 5.29 (1H, q, J = 6.9 Hz), 4.72-4.65 (1H, m), 3.94-3.80 (5H, m), 2.84 (3H, s), 1.28 (6H, d, J = 5.9 Hz). 554 1.76 B I-356 458 2.09 B I-357 539 1.49 B

(710) TABLE-US-00079 TABLE 79 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-358 539 1.6 B I-359 538 2.3 P I-360 1H-NMR (CDCl3) δ: 7.60 (3H, d, J = 8.4 Hz), 7.37 (2H, d, J = 7.5 Hz), 7.30 (3H, t, J = 7.4 Hz), 6.96- 6.89 (4H, m), 4.97 (1H, t, J = 8.5 Hz), 4.65 (2H, dd, J = 15.4, 9.3 Hz), 4.20-4.12 (1H, m), 3.98 (2H, s), 3.88 (1H, t, J = 10.4 Hz), 2.85-2.78 (1H, m), 2.71 (1H, dd, J = 22.2, 11.0 Hz), 1.39 (6H, d, J = 5.9 Hz). 538 2.37 P I-361 1H-NMR (CDCl3) δ: 8.59 (2H, s), 7.61 (2H, d, J = 8.0 Hz), 7.49 (3H, t, J = 6.0 Hz), 6.90 (1H, t, J = 8.4 Hz), 6.82 (1H, d, J = 8.8 Hz), 6.72 (2H, d, J = 8.3 Hz), 5.11-5.09 (1H, m), 4.88 (1H, s), 4.55 (1H, t, J = 5.9 Hz), 4.11 (1H, dd, J = 12.5, 5.8 Hz), 3.85 (1H, d, J = 11.3 Hz), 3.82 (2H, s), 3.06 (1H, s), 2.20 (1H, t, J = 6.5 Hz), 1.36 (6H, s). 539 1.4 B

(711) TABLE-US-00080 TABLE 80 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] RT condition I-362 1H-NMR (CDCl3) δ: 8.47 (2H, s), 7.72 (2H, d, J = 7.3 Hz), 7.63 (1H, s), 7.39 (2H, s), 6.97 (2H, d, J = 7.5 Hz), 6.89 (1H, s), 6.80 (1H, d, J = 7.8 Hz), 4.98 (2H, s), 4.66 (2H, s), 4.05 (2H, s), 3.86 (2H, s), 2.75 (1H, s), 2.60 (1H, s), 1.38 (6H, s) 539 1.52 B I-363 1H-NMR (DMSO-D6) δ: 7.75- 7.73 (4H, m), 7.34 (1H, d, J = 9.8 Hz), 7.13 (2H, d, J = 8.5 Hz), 7.03 (1H, t, J = 9.2 Hz), 6.94 (1H, s), 4.81-4.77 (3H, m), 3.92 (3H, s), 3.80 (1H, t, J = 9.9 Hz), 2.72 (2H, dt, J = 22.8, 8.8 Hz), 1.33 (6H, d, J = 5.8 Hz). 528 1.37 B I-364 0 1H-NMR (CDCl3) δ: 7.62 (2H, t, J = 6.4 Hz), 7.58 (1H, t, J = 4.4 Hz), 7.00-6.93 (2H, m), 6.83 (2H, d, J = 8.8 Hz), 5.34 (1H, dd, J = 8.0, 5.0 Hz), 5.28 (1H, t, J = 6.0 Hz), 4.61 (1H, td, J = 12.3, 6.2 Hz), 4.09 (1H, dd, J = 10.4, 6.7 Hz), 3.85 (2H, s), 3.08-3.01 (1H, m), 2.62-2.56 (1H, m), 2.42 (3H, s), 1.38 (6H, d, J = 6.5 Hz). 544 2.01 B I-365 1H-NMR (CDCl3) δ: 7.83 (2H, d, J = 8.4 Hz), 7.59 (1H, t, J = 6.8 Hz), 7.28 (3H, t, J = 6.9 Hz), 7.01- 6.90 (5H, m), 6.81 (1H, d, J = 9.0 Hz), 4.66 (1H, t, J = 6.0 Hz), 4.41 (2H, d, J = 8.5 Hz), 4.26 (1H, s), 4.18 (1H, t, J = 8.7 Hz), 3.95 (2H, s), 3.89 (1H, d, J = 7.2 Hz), 3.80 (1H, t, J = 10.5 Hz), 2.73-2.67 (1H, m), 2.58-2.52 (1H, m), 1.40 (6H, d, J = 5.8 Hz). 568 2.46 B

(712) TABLE-US-00081 TABLE 81 LC/MS No. compound .sup.1H-NMR δ ppm [M + H] condition RT I-366 1H-NMR (CDCl3) δ: 7.82 (2H, d, J = 8.3 Hz), 7.60 (1H, dd, J = 8.8, 5.0 Hz), 7.01-6.81 (8H, m), 4.68- 4.62 (1H, m), 4.42 (1H, dd, J = 16.3, 8.3 Hz), 4.34 (1H, dd, J = 9.0, 3.5 Hz), 4.26 (1H, d. J = 7.5 Hz), 4.14 (1H, dd, J = 14.9, 7.4 Hz), 3.96 (2H, s), 3.91 (1H, dd, J = 11.8, 7.3 Hz), 3.79 (1H, t, J = 10.3 Hz), 2.73-2.66 (1H, m), 2.57-2.49 (1H, m), 1.39 (6H, d, J = 6.0 Hz). 586 2.46 B I-367 1H-NMR(CDCl3) δ: 1.47 (t, J = 6.9 Hz, 3H), 3.37 (t, J = 9.0 Hz, 1H), 3.46-3.54 (m, 2H), 3.68 (dd, J = 10.3, 5.0 Hz, 1H), 33.85-3.92 (m, 2H), 3.94 (s. 2H), 4.11 (q, J = 6.9 Hz, 2H), 4.19-4.23 (m, 1H), 4.43 (m, 1H), 4.93-4.99 (m, 1H), 6.95 (d, J = 8.3 Hz, 2H), 7.17-7.20 (m, 1H), 7.39-7.45 (m, 2H), 7.65 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 8.5 Hz, 2H). 472 1.81 B

(713) According to the similar manner as described in the above Examples or in the general synthetic procedures, the compounds in the following Table 82 to 97 can be synthesized by using the commercially available compounds or the intermediates described in the art.

(714) TABLE-US-00082 TABLE 82 No. compound II-1 II-2 II-3 II-4 II-5 II-6 II-7 0 II-8 II-9 II-10

(715) TABLE-US-00083 TABLE 83 No. compound II-11 II-12 II-13 II-14 II-15 II-16 II-17 0 II-18 II-19 II-20

(716) TABLE-US-00084 TABLE 84 No. compound II-21 II-22 II-23 II-24 II-25 II-26 II-27 0 II-28 II-29 II-30

(717) TABLE-US-00085 TABLE 85 No. compound II-31 II-32 II-33 II-34 II-35 II-36 II-37 0 II-38 II-39 II-40

(718) TABLE-US-00086 TABLE 86 No. compound II-41 II-42 II-43 II-44 II-45 II-46 II-47 0 II-48 II-49 II-50

(719) TABLE-US-00087 TABLE 87 No. compound II-51 II-52 II-53 II-54 II-55 II-56 II-57 0 II-58 II-59 II-60

(720) TABLE-US-00088 TABLE 88 No. compound II-61 II-62 II-63 II-64 II-65 II-66 II-67 0 II-68 II-69 II-70

(721) TABLE-US-00089 TABLE 89 No. compound II-71 II-72 II-73 II-74 II-75 II-76 II-77 00 II-78 01 II-79 02 II-80 03

(722) TABLE-US-00090 TABLE 90 No. compound II-81 04 II-82 05 II-83 06 II-84 07 II-85 08 II-86 09 II-87 0 II-88 II-89 II-90

(723) TABLE-US-00091 TABLE 91 No. compound II-91 II-92 II-93 II-94 II-95 II-96 II-97 0 II-98 II-99 II-100

(724) TABLE-US-00092 TABLE 92 No. compound II-101 II-102 II-103 II-104 II-105 II-106 II-107 0 II-108 II-109 II-110

(725) TABLE-US-00093 TABLE 93 No. compound II-111 II-112 II-113 II-114 II-115 II-116 II-117 0 II-118 II-119 II-120

(726) TABLE-US-00094 TABLE 94 No. compound II-121 II-122 II-123 II-124 II-125 II-126 II-127 0 II-128 II-129 II-130

(727) TABLE-US-00095 TABLE 95 No. compound II-131 II-132 II-133 II-134 II-135 II-136 II-137 0 II-138 II-139 II-140

(728) TABLE-US-00096 TABLE 96 No. compound II-141 II-142 II-143 II-144 II-145 II-146 II-147 0 II-148 II-149 II-150

(729) TABLE-US-00097 TABLE 97 No. compound II-151 II-152 II-153 II-154 II-155 II-156 II-157 0 II-158 II-159

TEST EXAMPLE 1

In Vitro DP Inhibitory Activity

(730) 1) DP Inhibitory Activity in Human Platelets

(731) Thirty milliliter of blood was drown from healthy human into a syringe preloaded with 1/9 volume of 3.8% citrate sodium. The blood was centrifuged with 180 g for 10 min at room temperature and the upper plasma layer was collected as platelet rich plasma (PRP). The PRP was transferred to plate and treated with 3-isobutyl-1-methylxanthin (IBMX; 0.5 nM) for 5 min. Then the compounds of the present invention were added to the plate and after 10 min, 300 nM of PGD2 was added. The reaction was stopped with 1 mmol/l hydrogenchlolide after 2 min of PGD2 addition, and platelet was lysed by adding 12% Triton X-100. The concentration of cAMP in the supernatant of the platelet lysate was quantified using homogenous time resolved fluorescence (HTRF). Inhibition ratio was defined by cAMP increase with and without compound, and 1050 for each compound was calculated from inhibitory curve. Results were shown in Table 98.

(732) 2) Human DP1 Inhibitory Activity in DP1-Expressing Cell

(733) Human DP1 receptor expressing Jurkut cell was suspended in buffer (HBSS, 20 mM HEPES buffer pH 7.4, 0.1 mM IBMX, 0.2 mM (4-(3-butoxy-4-methoxy-benzyl) imidazolidone (RO 20-1724)) at concentration of 1.2×10.sup.6 cells/ml. Compounds of the present invention was added to the cell suspension and the mixture was incubated for 10 min at 37° C. PGD2 was added at final concentration of 60 nM, and the mixture was incubated for 60 min at 37° C. The concentration of cAMP in the cell lysate was measured using the cAMP dynamic 2 kit (Cisbio Bioassays, France) according to the manufacturer's instructions. Inhibition ratio was defined by cAMP increase with and without compound, and IC50 for each compound was calculated from inhibitory curve

(734) Results were shown in Table 98 as cAMP (nM). Compounds were categorized as AA (cAMP is less than 100 nM) and A (cAMP is more than 100 nM and less than 5000 nM) as shown in Table 99 and 100.

(735) 3) DP Receptor Binding Inhibitory Activity

(736) Cell membrane was prepared from DP-expressing cells by homogenization and ultracentrifuge. Compounds of the present invention and [.sup.3H]-PGD2 were mixed in plate, then cell membrane was added and the mixture was incubated on ice for 2 hr. The concentration of [.sup.3H]-PGD2 was determined as equal to Kd calculated from Scatchard plot. Using cell harvester, the membrane was collected with glass fiber filter, washed 8 times and dried up, and radio activity on the filter was measured with scintillation counter (MicroBeta). Specific binding was defined as difference between total and non-specific binding (radio activity with 10 μM PGD2). Ki values for each compound were calculated from displacement curve.

(737) TABLE-US-00098 TABLE 98 Compound cAMP PRP No. (nM) (nM) I-3  350 I-7  23 26 I-11  99 I-19  56 260 I-21  59 180 I-37  10 71 I-85  19 210 I-96  40 68 I-123 31 120 I-130 10 240 I-131 31 190 I-142 9.9 92 I-144 4.7 82 I-150 20 41 I-156 3 110 I-159 140 68 I-164 13 43 I-166 32 55 I-174 99 I-177 58 44 I-205 13 70 I-220 32 I-222 95 140 I-245 27 68 I-284 50 130 I-288 100 I-316 110 I-322 29 12 I-325 24 210 I-336 35 180 I-353 120 37

(738) TABLE-US-00099 TABLE 99 Compound No. cAMP I-1 A I-2 A I-3 A I-4 A I-5 A I-6 A I-7 AA I-8 A I-9 A I-10 A I-11 AA I-12 A I-13 AA I-14 A I-15 A I-16 A I-17 AA I-18 A I-19 AA I-20 A I-21 AA I-22 AA I-23 A I-24 A I-25 A I-26 A I-27 A I-28 AA I-29 AA I-30 A I-31 AA I-32 AA I-33 AA I-34 AA I-35 AA I-36 A I-37 AA I-38 AA I-39 AA I-40 A I-41 A I-42 A I-43 A I-44 A I-45 A I-46 AA I-47 A I-48 A I-49 A I-50 AA I-51 AA I-52 AA I-53 AA I-54 A I-55 A I-56 AA I-57 AA I-58 AA I-59 A I-60 AA I-61 A I-62 AA I-63 AA I-64 A I-65 A I-66 AA I-67 AA I-68 AA I-69 AA I-72 A I-73 AA I-74 AA I-75 AA I-76 AA I-77 A I-78 A I-79 A I-80 A I-81 A I-82 A I-83 AA I-84 A I-85 AA I-86 A I-87 A I-88 AA I-89 AA I-90 AA I-91 AA I-92 AA I-93 AA I-94 AA I-95 AA I-96 AA I-97 AA I-98 AA I-99 AA I-100 A I-101 A I-102 AA I-103 AA I-104 AA I-105 AA I-106 AA I-107 AA I-108 AA I-109 AA I-110 AA I-111 AA I-112 AA I-113 AA I-114 AA I-115 AA I-116 A I-117 A I-118 AA I-119 A I-120 AA I-121 A I-122 A I-123 AA I-124 A I-125 A I-126 AA I-127 AA I-128 AA I-129 AA I-130 AA I-131 AA I-132 AA I-133 A I-134 AA I-135 AA I-136 A I-137 AA I-138 A I-139 AA I-140 AA I-141 AA I-142 AA I-143 AA I-144 AA I-145 A I-146 AA I-147 AA I-148 A I-149 A I-150 AA I-151 AA I-152 A I-153 AA I-154 A I-155 A I-156 AA I-157 A I-158 A I-159 A I-160 AA I-161 AA I-162 AA I-163 AA I-164 AA I-165 AA I-166 AA I-167 AA I-168 AA I-169 AA I-170 AA I-171 AA I-172 AA I-173 A I-174 AA I-175 A I-176 A I-177 AA I-178 A I-179 AA I-180 A I-181 A I-182 A I-183 A I-184 A I-185 A I-186 A I-187 A I-188 A I-189 A I-190 A I-191 A I-192 A I-193 A I-194 A I-195 A I-196 AA I-197 A I-198 A I-199 A I-200 AA I-201 A I-202 AA I-203 AA I-204 AA I-205 AA I-206 AA I-207 A I-208 A I-209 AA I-210 A I-211 AA I-212 A I-213 A I-214 AA I-215 A I-216 AA I-217 AA I-218 AA I-219 A I-220 AA I-221 AA I-222 AA I-223 A I-224 A I-225 AA I-226 A

(739) TABLE-US-00100 TABLE 100 Compound No. cAMP I-227 A I-228 AA I-229 AA I-230 AA I-231 AA I-232 AA I-233 AA I-234 A I-235 A I-236 AA I-237 AA I-238 A I-239 A I-240 A I-241 AA I-242 AA I-243 AA I-244 AA I-245 AA I-246 A I-247 A I-248 A I-249 A I-250 AA I-251 AA I-252 AA I-253 A I-254 A I-255 A I-256 AA I-257 A I-258 AA I-259 A I-260 A I-261 A I-262 AA I-263 AA I-264 AA I-265 AA I-266 A I-267 AA I-268 AA I-269 AA I-270 AA I-271 AA I-272 AA I-273 A I-274 A I-275 A I-276 AA I-277 AA I-278 A I-279 A I-280 A I-281 A I-282 A I-283 AA I-284 AA I-285 A I-286 AA I-287 A I-288 A I-289 A I-290 AA I-291 A I-292 AA I-293 A I-294 A I-295 AA I-296 A I-297 A I-298 A I-299 A I-300 A I-301 A I-302 A I-303 AA I-304 AA I-305 A I-306 A I-307 A I-308 AA I-309 AA I-310 A I-311 A I-312 AA I-313 A I-314 A I-315 AA I-316 A I-317 A I-318 A I-319 A I-320 AA I-321 A I-322 AA I-323 A I-324 AA I-325 AA I-326 A I-327 A I-328 A I-329 AA I-330 AA I-331 AA I-332 A I-333 AA I-334 AA I-335 AA I-336 AA I-337 A I-338 AA I-339 A I-340 A I-341 A I-342 A I-343 AA I-344 AA I-345 A I-346 AA I-347 AA I-348 AA I-349 AA I-350 A I-351 A I-352 A I-353 A I-354 AA I-355 A I-356 A I-357 A I-358 A I-359 A I-360 AA I-361 A I-362 A I-363 A I-364 A I-365 AA I-366 AA

TEST EXAMPLE 2

In Vitro CRTH2 Inhibitory Activity

(740) 1) CRTH2 Receptor Binding Inhibitory Activity

(741) Cell membrane was prepared from CRTH2-expressing K562 cell. The cell membrane (20 μg/well) was mixed with reaction buffer (50 mM Tris/HCl, pH 7.4, 10 mM MgCl2). Then, [.sup.3H]-PGD.sub.2 was added to the mixture and incubated for 60 min at room temperature. The concentration of [.sup.3H]-PGD.sub.2 was determined as equal to Kd calculated from Scatchard plot. Then, the mixture was filtrated with glass paper immediately. The filter paper was washed several times and radio activity on the filter was measured. Specific binding was defined as difference between total and non-specific binding (radio activity with 10 μM PGD.sub.2). Ki values for each compound were calculated from displacement curve.

(742) Results were shown in Table 101 as Ki (nM). Compounds were categorized to AAAA (Ki is less than 100 nM) and AAA (Ki is more than 100 nM and less than 5000 nM) as shown in Table 102 and 103.

(743) TABLE-US-00101 TABLE 101 Compound Ki No. (nM) I-4  320 I-9  6.2 I-10  8.2 I-15  56 I-19  62 I-21  10 I-30  140 I-33  2.1 I-34  77 I-37  2.4 I-47  16 I-49  0.59 I-52  5.1 I-57  3.8 I-59  23 I-63  3.1 I-74  680 I-77  48 I-85  2.8 I-96  37 I-97  13 I-104 16 I-113 17 I-117 1.6 I-122 2.5 I-123 4.3 I-130 4.7 I-131 7.4 I-138 65 I-139 32 I-142 11 I-144 3.1 I-145 3.1 I-148 5.6 I-149 4.8 I-150 99 I-152 56 I-153 65 I-157 270 I-164 16 I-166 12 I-173 11 I-174 50 I-177 15 I-210 10 I-215 22 I-219 230 I-220 8.1 I-222 100 I-239 4.4 I-247 15 I-255 390 I-260 21 I-280 7.8 I-282 10 I-284 55 I-288 40 I-316 220 I-322 270 I-325 28 I-336 440 I-353 400 I-360 30 I-363 170 I-367 100

(744) TABLE-US-00102 TABLE 102 Compound No. Ki I-1 AAA I-2 AAA I-3 AAA I-4 AAA I-5 AAA I-6 AAA I-7 AAAA I-8 AAAA I-9 AAAA I-10 AAAA I-11 AAA I-12 AAAA I-13 AAAA I-14 AAAA I-15 AAAA I-16 AAAA I-17 AAAA I-18 AAAA I-19 AAAA I-20 AAAA I-21 AAAA I-22 AAAA I-23 AAAA I-24 AAAA I-25 AAAA I-26 AAAA I-27 AAAA I-28 AAA I-29 AAAA I-30 AAA I-31 AAAA I-32 AAAA I-33 AAAA I-34 AAAA I-35 AAAA I-36 AAAA I-37 AAAA I-38 AAAA I-39 AAAA I-40 AAAA I-41 AAAA I-42 AAAA I-43 AAAA I-44 AAAA I-45 AAAA I-46 AAAA I-47 AAAA I-48 AAAA I-49 AAAA I-50 AAAA I-51 AAAA I-52 AAAA I-53 AAAA I-54 AAAA I-55 AAA I-56 AAAA I-57 AAAA I-58 AAAA I-59 AAAA I-60 AAA I-61 AAAA I-62 AAAA I-63 AAAA I-64 AAAA I-65 AAAA I-66 AAAA I-67 AAAA I-68 AAAA I-69 AAA I-70 AAAA I-72 AAA I-73 AAA I-74 AAA I-75 AAA I-76 AAA I-77 AAAA I-78 AAA I-79 AAA I-80 AAA I-81 AAA I-82 AAA I-83 AAA I-84 AAAA I-85 AAAA I-86 AAAA I-87 AAAA I-88 AAAA I-89 AAAA I-90 AAA I-91 AAAA I-92 AAA I-93 AAA I-94 AAAA I-95 AAAA I-96 AAAA I-97 AAAA I-98 AAAA I-99 AAAA I-100 AAAA I-101 AAA I-102 AAAA I-103 AAAA I-104 AAAA I-105 AAAA I-106 AAAA I-107 AAAA I-108 AAAA I-109 AAAA I-110 AAAA I-111 AAAA I-112 AAAA I-113 AAAA I-114 AAAA I-115 AAAA I-116 AAAA I-117 AAAA I-118 AAAA I-119 AAAA I-120 AAAA I-121 AAAA I-122 AAAA I-123 AAAA I-124 AAAA I-125 AAAA I-126 AAAA I-127 AAAA I-128 AAAA I-129 AAAA I-130 AAAA I-131 AAAA I-132 AAAA I-133 AAA I-134 AAAA I-135 AAAA I-136 AAA I-137 AAAA I-138 AAAA I-139 AAAA I-140 AAAA I-141 AAAA I-142 AAAA I-143 AAAA I-144 AAAA I-145 AAAA I-146 AAAA I-147 AAAA I-148 AAAA I-149 AAAA I-150 AAAA I-151 AAAA I-152 AAAA I-153 AAAA I-155 AAA I-156 AAA I-157 AAA I-158 AAAA I-159 AAA I-160 AAA I-161 AAA I-162 AAA I-163 AAA I-164 AAAA I-165 AAAA I-166 AAAA I-167 AAA I-168 AAAA I-169 AAAA I-170 AAAA I-171 AAAA I-172 AAAA I-173 AAAA I-174 AAAA I-175 AAAA I-176 AAAA I-177 AAAA I-178 AAAA I-179 AAAA I-180 AAAA I-181 AAA I-182 AAAA I-183 AAAA I-184 AAAA I-185 AAAA I-186 AAAA I-187 AAAA I-188 AAA I-189 AAAA I-190 AAAA I-191 AAAA I-192 AAAA I-193 AAA I-194 AAAA I-195 AAAA I-196 AAAA I-197 AAA I-198 AAAA I-199 AAA I-200 AAAA I-201 AAAA I-202 AAA I-203 AAA I-204 AAAA I-205 AAA I-206 AAA I-207 AAAA I-208 AAAA I-209 AAA I-210 AAAA I-211 AAA I-212 AAA I-213 AAA I-214 AAA I-215 AAAA I-216 AAAA I-217 AAAA I-218 AAA I-219 AAA I-220 AAAA I-221 AAAA I-222 AAA I-223 AAAA I-224 AAAA I-225 AAAA I-226 AAAA

(745) TABLE-US-00103 TABLE 103 Compound No. Ki I-227 AAAA I-228 AAAA I-229 AAAA I-230 AAAA I-231 AAAA I-232 AAAA I-233 AAAA I-234 AAAA I-235 AAAA I-236 AAAA I-237 AAAA I-238 AAAA I-239 AAAA I-240 AAAA I-241 AAAA I-242 AAAA I-243 AAA I-244 AAAA I-245 AAAA I-246 AAAA I-247 AAAA I-248 AAAA I-249 AAAA I-250 AAA I-251 AAAA I-252 AAAA I-253 AAA I-254 AAA I-255 AAA I-256 AAAA I-258 AAAA I-259 AAAA I-260 AAAA I-261 AAA I-262 AAA I-263 AAAA I-264 AAAA I-265 AAAA I-266 AAA I-267 AAA I-268 AAAA I-269 AAAA I-270 AAAA I-271 AAAA I-272 AAAA I-273 AAA I-274 AAAA I-275 AAA I-276 AAAA I-277 AAAA I-278 AAAA I-279 AAAA I-280 AAAA I-282 AAAA I-283 AAA I-284 AAAA I-285 AAA I-287 AAAA I-288 AAAA I-289 AAA I-290 AAA I-291 AAA I-292 AAA I-293 AAA I-294 AAA I-295 AAA I-296 AAA I-297 AAA I-298 AAA I-299 AAA I-300 AAAA I-301 AAA I-302 AAA I-303 AAA I-304 AAAA I-305 AAA I-306 AAA I-307 AAA I-308 AAAA I-309 AAAA I-310 AAA I-311 AAA I-312 AAAA I-313 AAAA I-314 AAAA I-315 AAA I-316 AAA I-317 AAA I-318 AAA I-319 AAA I-320 AAAA I-322 AAA I-323 AAA I-324 AAAA I-325 AAAA I-326 AAA I-327 AAA I-328 AAA I-329 AAAA I-330 AAAA I-331 AAAA I-332 AAAA I-333 AAAA I-334 AAA I-336 AAA I-338 AAA I-341 AAA I-342 AAA I-343 AAAA I-344 AAA I-345 AAA I-346 AAAA I-347 AAA I-348 AAAA I-349 AAA I-350 AAAA I-351 AAA I-352 AAA I-353 AAA I-354 AAA I-355 AAA I-356 AAAA I-357 AAA I-358 AAA I-359 AAAA I-360 AAAA I-361 AAA I-362 AAA I-363 AAA I-364 AAA I-365 AAA I-366 AAA I-367 AAA

(746) 2) CRTH2 Inhibitory Activity in CRTH2-Expressing Cells

(747) CRTH2 inhibitory activities of compounds were determined as inhibition activity of intra-cellular calcium concentration increase induced by PGD2 in CRTH2-expressing cells.

(748) CRTH2-expressing K562 cells were suspended at concentration of 2×10.sup.6 cells/ml in buffer (10 mM HEPES, pH 7.4, 0.1% Bovine serum albumin). Cells were incubated with Fura-3 AM (4 μM) for 30 min at room temperature. Cells were washed, resuspended and mixed with various concentration of compounds of the present invention. After 2 min, cells were treated with 200 nM of PGD.sub.2. Then intracellular calcium concentration was measured using intracellular ion analyzer (FDSS3000). Inhibition ratio was defined by comparing intracellular calcium concentration increase with and without compound, and IC50 for each compound was calculated from inhibitory curve.

(749) (Result)

(750) Compound No. I-7:33 nM

(751) Compound No. I-37:50 nM

(752) Compound No. I-49:86 nM

(753) Compound No. I-52:140 nM

(754) Compound No. I-57:210 nM

(755) Compound No. I-85:140 nM

(756) Compound No. I-96:230 nM

(757) Compound No. I-97:92 nM

(758) Compound No. I-123:91 nM

(759) Compound No. I-130:73 nM

(760) Compound No. I-131:210 nM

(761) 3) CRTH2 Inhibitory Activity in Human Eosinophil

(762) CRTH2 inhibitory activity in human eosinophil was determined as inhibitory activity of PGD2 induced eosinophil shape change.

(763) Human peripheral blood was mixed with compounds of the present invention at 37° C. After 5 min, the blood was treated with 40 nM of PGD2 for 10 min and fixed. The blood was hemolyzed and centrifuged. Blood cells were resuspended in PBS and measured forward scatter (FS) using flow cytometer (FACSAria). Inhibition ratio was defined by comparing FS with and without compound, and IC50 for each compound was calculated from inhibitory curve.

(764) (Result)

(765) Compound No. I-7: 34 nM

(766) Compound No. I-31: 13 nM

(767) Compound No. I-37: 15 nM

(768) Compound No. I-85: 33 nM

(769) Compound No. I-96: 270 nM

(770) Compound No. I-97:68 nM

(771) Compound No. I-123:60 nM

(772) Compound No. I-130:46 nM

(773) The others of Test Examples are shown below.

TEST EXAMPLE 3

CYP Inhibition Test

(774) Using commercially available pooled human hepatic microsome, and employing, as markers, 7-ethoxyresorufin O-deethylation (CYP1A2), tolbutamide methyl-hydroxylation (CYP2C9), mephenyloin 4′-hydroxylation (CYP2C19), dextromethorphan O-demethylation (CYP2D6), and terfenedine hydroxylation as typical substrate metabolism reactions of human main five CYP enzyme forms (CYP1A2, 2C9, 2C19, 2D6, 3A4), an inhibitory degree of each metabolite production amount by a compound of the present compound was assessed.

(775) The reaction conditions were as follows: substrate, 0.5 μmol/L ethoxyresorufin (CYP1A2), 100 μmol/L tolbutamide (CYP2C9), 50 μmol/L S-mephenyloin (CYP2C19), 5 μmol/L dextromethorphan (CYP2D6), 1 μmol/L terfenedine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37° C.; enzyme, pooled human hepatic microsome 0.2 mg protein/mL; concentration of a compound of the present invention, 1, 5, 10, 20 μmol/L (four points).

(776) Each five kinds of substrates, human hepatic microsome, or a compound of the present invention in 50 mM Hepes buffer as a reaction mixture was added to a 96-well plate at the composition as described above, NADPH, as a cofactor was added to initiate metabolism reactions as markers and. After the incubation at 37° C. for 15 minutes, a methanol/acetonitrile=1/1 (v/v) solution was added to stop the reaction. After the centrifugation at 3000 rpm for 15 minutes, resorufin (CYP1A2 metabolite) in the supernatant was quantified by a fluorescent multilabel counter and tolbutamide hydroxide (CYP2C9 metabolite), mephenyloin 4′ hydroxide (CYP2C19 metabolite), dextrorphan (CYP2D6 metabolite), and terfenadine alcohol (CYP3A4 metabolite) were quantified by LC/MS/MS.

(777) Addition of only DMSO being a solvent dissolving a the compound of the present invention to a reaction system was adopted as a control (100%), remaining activity (%) was calculated at each concentration of a compound of the present invention added as the solution and IC50 was calculated by reverse presumption by a logistic model using a concentration and an inhibition rate.

(778) (Result)

(779) Compound No. I-7: five kinds >20 μmol/L

(780) Compound No. I-9: five kinds >20 μmol/L

(781) Compound No. I-37: five kinds >20 μmol/L

(782) Compound No. I-49: five kinds >20 μmol/L

(783) Compound No. I-52: five kinds >20 μmol/L

(784) Compound No. I-57: five kinds >20 μmol/L

(785) Compound No. I-74: five kinds >20 μmol/L

(786) Compound No. I-96: five kinds >20 μmol/L

TEST EXAMPLE 4

BA Test

(787) An experimental material and a method for examining oral absorbability (1) Animals used: rats or mice were used. (2) Breeding condition: chow and sterilized tap water were allowed to be taken in freely. (3) Setting of a dosage and grouping: a predetermined dosage was administered orally or intravenously. Groups were formed as shown below. (A dosage varied depending on each compound)
Oral administration 1-30 mg/kg (n=2 to 3)
Intravenous administration 0.5-10 mg/kg (n=2 to 3) (4) Preparation of administered liquid: In oral administration, a solution or suspension was administered. In intravenous administration, after solubilization, the administration was performed. (5) Method of Administration: In oral administration, compulsory administration to the stomach was conducted using an oral probe.
In intravenous administration, administration from the caudal vein was conducted using a syringe with an injection needle. (6) Evaluation item: Blood was chronologically collected, and then the concentration of a compound of the present invention blood plasma was measured using a LC/MS/MS. (7) Statistical analysis: With regard to a shift in plasma concentration, the plasma concentration-time area under the curve (AUC) was calculated using a nonlinear least-squares program WinNonlin®. Bioavailability (BA) was calculated from the AUCs of the oral administration group and the intravenous administration group, respectively.

(788) (Result) Rats, Oral administration 1 mg/kg

(789) Compound No. I-37: 71%

(790) Compound No. I-96: 82%

TEST EXAMPLE 5

Metabolism Stability Test

(791) Using a commercially available pooled human hepatic microsomes, a compound of the present invention was reacted for a constant time, a remaining rate was calculated by comparing a reacted sample and an unreacted sample, thereby, a degree of metabolism in liver was assessed.

(792) A reaction was performed (oxidative reaction) at 37° C. for 0 minute or 30 minutes in the presence of 1 mmol/L NADPH in 0.2 mL of a buffer (50 mmol/L Tris-HCl pH 7.4, 150 mmol/L potassium chloride, 10 mmol/L magnesium chloride) containing 0.5 mg protein/mL of human liver microsomes. After the reaction, 50 μL of the reaction mixture was added to 100 μL of a methanol/acetonitrile=1/1 (v/v), mixed and centrifuged at 3000 rpm for 15 minutes. The compound of the present invention in the supernatant was quantified by LC/MS/MS, and a remaining amount of the compound of the present invention after the reaction was calculated, letting a compound amount at 0 minute reaction time to be 100%. Glucuronidation reaction was in the presence of 5 mM UDP-glucuronic acid in place of NADPH, followed by similar operations.

(793) (Result) % inhibition was shown at 0.5 μmol/L of the compound.

(794) Compound No. I-9: 98.7%

(795) Compound No. I-47: 91.8%

(796) Compound No. I-49: 94.7%

(797) Compound No. I-52: 97.2%

(798) Compound No. I-57: 86.9%

(799) Compound No. I-75: 99.2%

(800) Compound No. I-96: 99.3%

TEST EXAMPLE 6

CYP3A4 Fluorescent MBI Test

(801) The CYP3A4 fluorescent MBI test is a test of investigating enhancement of CYP3A4 inhibition of a compound by a metabolism reaction, and the test was performed using, as CYP3A4 enzyme expressed in Escherichia coli and employing, as an index, a reaction in which 7-benzyloxytrifluoromethylcoumarin (7-BFC) is debenzylated by the CYP3A4 enzyme to produce a metabolite, 7-hydroxytrifluoromethylcoumarin (HFC) emitting fluorescent light.

(802) The reaction conditions were as follows: substrate, 5.6 μmol/L 7-BFC; pre-reaction time, 0 or 30 minutes; reaction time, 15 minutes; reaction temperature, 25° C. (room temperature); CYP3A4 content (expressed in Escherichia coli), at pre-reaction 62.5 μmol/mL, at reaction 6.25 μmol/mL (at 10-fold dilution); concentration of a compound of the present, 0.625, 1.25, 2.5, 5, 10, 20 μmol/L (six points).

(803) An enzyme in a K-Pi buffer (pH 7.4) and a compound solution of the present invention as a pre-reaction mixture were added to a 96-well plate at the composition of the pre-reaction, a part of it was transferred to another 96-well plate so that it was 1/10 diluted by a substrate in a K-Pi buffer, NADPH as a co-factor was added to initiate a reaction as an index (without preincubation) and, after a predetermined time of a reaction, acetonitrile/0.5 mol/L Tris(trishydroxyaminomethane)=4/1 (V/V) was added to stop the reaction. In addition, NADPH was added to a remaining preincubation solution to initiate a preincubation (with preincubation) and, after a predetermined time of a preincubation, a part was transferred to another plate so that it was 1/10 diluted with a substrate and a K-Pi buffer to initiate a reaction as an index. After a predetermined time of a reaction, acetonitrile/0.5 mol/L Tris(trishydroxyaminomethane)=4/1 (V/V) was added to stop the reaction. For the plate on which each index reaction had been performed, a fluorescent value of 7-HFC which is a metabolite was measured with a fluorescent plate reader. (Ex=420 nm, Em=535 nm).

(804) Addition of only DMSO which is a solvent dissolving a compound of the present invention to a reaction system was adopted as a control (100%), remaining activity (%) was calculated at each concentration of a compound of the present invention added as the solution, and IC50 was calculated by reverse-presumption by a logistic model using a concentration and an inhibition rate. When a difference between IC50 values is 5 μM or more, this was defined as (+) and, when the difference is 3 μM or less, this was defined as (−).

(805) (Result)

(806) Compound No. I-7: (−)

(807) Compound No. I-9: (−)

(808) Compound No. I-37: (−)

(809) Compound No. I-52: (−)

(810) Compound No. I-57: (−)

(811) Compound No. I-75: (−)

(812) Compound No. I-96: (−)

(813) Compound No. I-256: (−)

(814) Compound No. I-287: (−)

(815) Compound No. I-329: (−)

TEST EXAMPLE 7

Fluctuation Ames Test

(816) 20 μL of freezing-stored rat typhoid bacillus (Salmonella typhimurium TA98 strain, TA100 strain) was inoculated on 10 mL of a liquid nutrient medium (2.5% Oxoid nutrient broth No. 2), and this was cultured before shaking at 37° C. for 10 hours. 9 mL of a bacterial solution of the TA98 strain was centrifuged (2000×g, 10 minutes) to remove a culturing solution. The bacteria was suspended in 9 mL of a Micro F buffer (K.sub.2HPO.sub.4: 3.5 g/L, KH2PO.sub.4: 1 g/L, (NH.sub.4).sub.2SO.sub.4: 1 g/L, trisodium citrate dehydrate: 0.25 g/L, MgSO.sub.4.7H.sub.2O: 0.1 g/L), the suspension was added to 110 mL of an Exposure medium (Micro F buffer containing Biotin: 8 μg/mL, histidine: 0.2 μg/mL, glucose: 8 mg/mL). The TA100 strain was added to 120 mL of the Exposure medium relative to 3.16 mL of the bacterial solution to prepare a test bacterial solution. Each 12 μL of a DMSO solution of the compound of the present invention (8 stage dilution from maximum dose 50 mg/mL at 2-fold ratio), DMSO as a negative control, 50 μg/mL of 4-nitroquinoline-1-oxide DMSO solution for the TA98 strain, 0.25 μg/mL of 2-(furyl)-3-(5-nitro-2-furyl)acrylamide DMSO solution for the TA100 strain under the non-metabolism activating condition, 40 μg/mL of 2-aminoanthracene DMSO solution for the TA98 strain, 20 μg/mL of 2-aminoanthracene DMSO solution for the TA100 strain under the metabolism activating condition as a positive control, and 588 μL of the test bacterial solution (a mixed solution of 498 μl of the test bacterial solution and 90 μL of S9 mix under the metabolism activating condition) were mixed, and this was shaking-cultured at 37° C. for 90 minutes. 460 μL of the bacterial solution exposed to the compound of the present invention was mixed with 2300 μL of an Indicator medium (Micro F buffer containing biotin: 8 μg/mL, histidine: 0.2 μg/mL, glucose: 8 mg/mL, Bromo Cresol Purple: 37.5 μg/mL), each 50 μL was dispensed into microplate 48 wells/dose, and this was subjected to stationary culturing at 37° C. for 3 days. Since a well containing a bacterium which has obtained the proliferation ability by mutation of an amino acid (histidine) synthesizing enzyme gene turns from purple to yellow due to a pH change, the bacterium proliferation well which has turned to yellow in 48 wells per dose is counted, and was assessed by comparing with a negative control group.

(817) (−) means that mutagenicity is negative and (+) is positive.

(818) (Result)

(819) Compound No. I-37: (−)

TEST EXAMPLE 8

hERG Test

(820) For the purpose of assessing risk of an electrocardiogram QT interval prolongation, effects on delayed rectifier K+ current (I.sub.Kr), which plays an important role in the ventricular repolarization process of the compound of the present invention, was studied using HEK293 cells expressing human ether-a-go-go related gene (hERG) channel.

(821) After a cell was retained at a membrane potential of −80 mV by whole cell patch clamp method using an automated patch clamp system (PatchXpress 7000A, Axon Instruments Inc.) and given leakage potential at −50 mV, I.sub.Kr induced by depolarization pulse stimulation at +40 mV for 2 seconds and, further, repolarization pulse stimulation at −50 mV for 2 seconds was recorded. After the generated current was stabilized, extracellular solution (NaCl: 135 mmol/L, KCl: 5.4 mmol/L, NaH.sub.2PO.sub.1: 0.3 mmol/L, CaCl.sub.2.2H.sub.2O: 1.8 mmol/L, MgCl.sub.2.6H.sub.2O: 1 mmol/L, glucose: 10 mmol/L, HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid): 10 mmol/L, pH=7.4) in which a compound of the present invention had been dissolved at an objective concentration was applied to the cell under the room temperature condition for 10 minutes. From the recording I.sub.Kr, an absolute value of the tail peak current was measured based on the current value at the resting membrane potential using an analysis software (DataXpress ver. 2, Molecular Devices Corporation). Further, the % inhibition relative to the tail peak current before application of the compound of the present invention was calculated, and compared with the vehicle-applied group (0.1% dimethyl sulfoxide solution) to assess influence of the compound of the present invention on I.sub.Kr.

(822) (Result) % inhibition was shown at 1 μmol/L of the compound.

(823) Compound No. I-37: 7.1%

TEST EXAMPLE 9

Solubility Test

(824) The solubility of each compound of the present invention is determined under 1% DMSO addition conditions. A 10 mmol/L solution of the compound of the present invention is prepared with DMSO, and 6 μL of the compound solution is added to 594 μL of an artificial intestinal juice (water and 118 mL of 0.2 mol/L NaOH reagent are added to 250 mL of 0.2 mol/L potassium dihydrogen phosphate reagent to reach 1000 mL) with a pH of 6.8. The mixture is left standing for 16 hours at 25° C., and the mixture is vacuum-filtered. The filtrate is two-fold diluted with methanol/water=1/1 (V/V), and the compound concentration in the filtrate is measured with HPLC or LC/MS/MS by the absolute calibration method.

(825) (Result)

(826) Compound No. I-7: >50 μmol/L

(827) Compound No. I-9: >50 μmol/L

(828) Compound No. I-37: >50 μmol/L

(829) Compound No. I-49: >50 μmol/L

(830) Compound No. I-52: >50 μmol/L

(831) Compound No. I-57: >50 μmol/L

(832) Compound No. I-74: >50 μmol/L

(833) Compound No. I-85: >50 μmol/L

(834) Compound No. I-96: >50 μmol/L

TEST EXAMPLE 10

Powder Solubility Test

(835) Appropriate amounts of the compound of the present invention is put into vials and 200 μL of JP-1st Fluid (water is added to 2.0 g of sodium chloride in 7.0 mL of hydrochloride acid to reach 1000 mL), JP-2nd Fluid (water is added to 500 mL of phosphate buffer solution with a pH of 6.8) and 20 mmol/L sodium taurocholate (TCA) /JP-2nd Fluid (JP-2nd Fluid is added to 1.08 g of TCA in JP-2nd Fluid to reach 100 mL) is added to each vial. When the compound is completely dissolved, appropriate amount of compound is added. After shaken for 1 hour at 37° C., the mixture is filtered and 100 μL of methanol is added to 100 μL of each filtrate (double dilution). Dilution magnification is changed if necessary. After it is confirmed whether there are air bubbles and precipitates in the vials, the vials are shaken with tight stopper. The compound concentration is determined with HPLC by the absolute calibration method.

FORMULATION EXAMPLE

(836) The following formulating examples 1-8 are just for illustrative purposes and not intended to limit the range of the present invention. The term of “active ingredient” means the compounds of the present invention or pharmaceutically acceptable salt thereof.

FORMULATION EXAMPLE 1

(837) A hard-gelatin capsule is prepared with the following ingredients;

(838) TABLE-US-00104 Amount (mg/capsule) active ingredient 250 starch (dried) 200 magnesium stearate 10 Total 460 mg

FORMULATION EXAMPLE 2

(839) A tablet is prepared with the following ingredients;

(840) TABLE-US-00105 Amount (mg/tablet) active ingredient 250 253 cellulose(micro crystalline) 400 silicon dioxide (fume) 10 stearic acid 5 Total 665 mg

(841) The ingredients above are mixed and compressed to give a tablet weighing 665 mg/tablet.

FORMULATION EXAMPLE 3

(842) An aerosol solution is prepared with the following ingredients;

(843) TABLE-US-00106 weight active ingredient 0.25 ethanol 25.75 propellant 22(chlorodifluoroethane) 74.00 Total 100.00

(844) The active ingredient and ethanol are mixed and the mixture is added to a part of propellant 22, and the resulting solution is transferred to a filling apparatus after being cooled to −30° C. Next, the necessary amount is provided to a stainless-steel vessel and the content is diluted with the remaining propellant. A valve unit is fitted to the vessel.

FORMULATION EXAMPLE 4

(845) A tablet containing 60 mg of an active ingredient is prepared as follows;

(846) TABLE-US-00107 active ingredient   60 mg starch   45 mg microcrystalline cellulose   35 mg polyvinylpyrrolidone (10% aq. solution)   4 mg sodium carboxymethylstarch  4.5 mg magnesium stearate  0.5 mg talc   1 mg Total  150 mg

(847) The active ingredient, starch and cellulose are put through a sieve of No. 45 mesh US and mixed sufficiently. The resulting powder is mixed with a solution containing polyvinylpyrrolidone and the mixture is put through a sieve of No. 14 mesh US. The granulated powder is dried at 50° C. and put through a sieve of No. 18 mesh US. Sodium carboxymethylstarch, magnesium stearate and talc are put through a sieve of No. 60 mesh US in advance and added to the granulated powder, mixed and compressed by a tableting machine to give a tablet weighing 150 mg/tablet.

FORMULATION EXAMPLE 5

(848) A capsule containing 80 mg of an active ingredient is prepared as follows;

(849) TABLE-US-00108 active ingredient  80 mg starch  59 mg microcrystalline cellulose  59 mg magnesium stearate  2 mg Total 200 mg

(850) The active ingredient, starch, cellulose and magnesium stearate are mixed, put through a sieve of No. 45 mesh US and filled in hard-gelatin capsules to give a capsule formulation containing 200 mg/capsule.

FORMULATION EXAMPLE 6

(851) A suppository containing 225 mg of an active ingredient is prepared as follows;

(852) TABLE-US-00109 active ingredient  225 mg saturated fatty acid gliceride 2000 mg Total 2225 mg

(853) The active ingredient is put through a sieve of No. 60 mesh US and suspended in the saturated fatty acid gliceride melted by the least amount of heating. Then, the mixture was cooled in a mold of 2 g in appearance.

FORMULATION EXAMPLE 7

(854) A suspension containing 50 mg of an active ingredient is prepared as follows;

(855) TABLE-US-00110 active ingredient   50 mg sodium carboxymethylcellulose   50 mg syrup 1.25 ml solution of benzoic acid 0.10 ml flavor q.v. pigment q.v. Total (adding purified water)   5 ml

(856) The active ingredient is put through a sieve of No. 45 mesh US and mixed with sodium carboxymethylcellulose and syrup to give a smooth paste. The solution of benzoic acid and flavor are diluted with a part of water and added to the paste and stirred. A necessary amount of water is added to give the objective suspension.

FORMULATION EXAMPLE 8

(857) A formulation for i.v. injection is prepared as follows;

(858) TABLE-US-00111 active ingredient  100 mg saturated fatty acid gliceride 1000 ml

(859) The solution containing the active ingredient above is usually injected intravenously to a patient at a rate of 1 ml/min.

INDUSTRIAL APPLICABILITY

(860) The present inventors found that novel heterocyclic derivatives have PGD2 receptor antagonistic activity (DP receptor antagonistic activity, CRTH2 receptor antagonistic activity, and/or, antagonistic activity against both the DP receptor and CRTH2 receptor). These compounds are thought to be effective for treating allergic diseases.