4-OXOQUINOLINE COMPOUND AND USE THEREOF AS PHARMACEUTICAL AGENT

Abstract

An anti-HIV agent containing, as an active ingredient, ex, 4-oxoquinoline compound represented by the following formula [I]

##STR00001##

wherein each symbol is as defined in the specification, or a pharmaceutically acceptable salt thereof. The compound of the present invention has HIV integrase inhibitory action and is useful as an anti-HIV agent for the prophylaxis or therapy of AIDS. Moreover, by a combined use with other anti-HIV agents such as protease inhibitors, reverse transcriptase inhibitors and the like, the compound can become a more effective anti-HIV agent. Since the compound has high inhibitory activity specific for integrases, it can provide a safe pharmaceutical agent with a fewer side effects for human.

Claims

1-41. (canceled)

42. A method for the prophylaxis of a Human Immunodeficiency Virus (HIV) infection which comprises administering a compound of formula (III) or a solvate or a stereoisomer thereof or a tautomer thereof or a pharmaceutically acceptable salt thereof to a mammal ##STR00346## wherein ring Cy is a C.sub.3-10 carbon ring group optionally substituted by 1 to 5 substituents selected from the following group A or a heterocyclic group optionally substituted by 1 to 5 substituents selected from the following group A wherein the heterocyclic group is a saturated or unsaturated ring containing, besides carbon atom(s), at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom, group A is a group consisting of cyano group, phenyl group, nitro group, halogen atom, C.sub.1-4 alkyl group, halo C.sub.1-4 alkyl group, halo C.sub.1-4 alkyloxy group, —OR.sup.a1, —SR.sup.a1, —NR.sup.a1R.sup.a2, —CONR.sup.a1R.sup.a2, —SO.sub.2NR.sup.a1R.sup.a2, —COR.sup.a3, —NR.sup.a1 COR.sup.a3, —SO.sub.2R.sup.a3, —NR.sup.a1 SO.sub.2R.sup.a3, —COOR.sup.a1 and —NR.sup.a2COOR.sup.a3 wherein R.sup.a1 and R.sup.a2 are the same or different and each is selected from a hydrogen atom or C.sub.1-4 alkyl group and R.sup.a3 is C.sub.1-4 alkyl group; R.sup.1 is a substituent selected from the following group B or a C.sub.1-6 alkyl group optionally substituted by 1 to 3 substituents selected from halogen atom and the following group B wherein group B is a group consisting of C.sub.3-10 carbon ring group optionally substituted by 1 to 5 substituents selected from the above-mentioned group A, heterocyclic group (as defined above) optionally substituted by 1 to 5 substituents selected from the above-mentioned group A, —OR.sup.a4, —SR.sup.a4, —NR.sup.a4R.sup.a5, —CONR.sup.a4R.sup.a5, —SO.sub.2NR.sup.a4R.sup.a5, —COR.sup.a6, —NR.sup.a4COR.sup.a6, —SO.sub.2R.sup.a6, —NR.sup.a4SO.sub.2R.sup.a6, —COOR.sup.a4 and —NR.sup.a5COOR.sup.a6 wherein R.sup.a4 and R.sup.as are the same or different and each is selected from a hydrogen atom, C.sub.1-4 alkyl group, C.sub.3-10 carbon ring group optionally substituted by 1 to 5 substituents selected from the above-mentioned group A or heterocyclic group (as defined above) optionally substituted by 1 to 5 substituents selected from the above-mentioned group A, and R.sup.a6 is selected from C.sub.1-4 alkyl group, C.sub.3-10 carbon ring group optionally substituted by 1 to 5 substituents selected from the above-mentioned group A or heterocyclic group (as defined above) optionally substituted by 1 to 5 substituents selected from the above-mentioned group A; R.sup.2 is selected from a hydrogen atom or a C.sub.1-4 alkyl group; R.sup.3 is selected from a cyano group, a hydroxy group, an amino group, a nitro group, a halogen atom, a C.sub.1-4 alkyl group, a C.sub.1-4 alkoxy group, a C.sub.1-4 alkylsulfanyl group, a halo C.sub.1-4 alkyl group or a halo C.sub.1-4 alkyloxy group; n is selected from 0 or an integer of 1 to 3 and when n is 2 or 3, R.sup.3 each may be the same or different.

43. The method according to claim 42, wherein the compound is administered at a dosage for inhibiting activity specific for integrases.

44. A compound of the formula: ##STR00347##

45. A compound of the formula: ##STR00348##

Description

REFERENCE EXAMPLE 1

[0267] Preparation of a solution of 2,3-dichlorobenzylzinc chloride in THF

##STR00025##

[0268] Under an argon stream, to a suspension of zinc powder (55.1 g, 843 mmol) in tetrahydrofuran (THF; 56 ml) was added 1,2-dibromoethane (2.9 ml, 33.8 mmol) and the mixture was heated under reflux for 5 min. Then, trimethylsilyl chloride (8.6 ml, 67.5 mmol) was added at 0° C. and the mixture was stirred at 0° C. for 5 min, after which a solution of 2,3-dichlorobenzyl chloride (82.4 g, 421.7 mmol) in THF (330 ml) was added dropwise with ice-cooling. After completion of the dropwise addition, the mixture was warmed to room temperature and stirred for 1 hr to give a solution of 2,3-dichlorobenzylzinc chloride in THF.

Example 1-1 Synthesis of 6-(2,3-dichlorobenzyl)-1,4-dihydro-1-(2-hydroxyethyl)-4-oxo-3-quinolinecarboxylic acid Step 1 Synthesis of 1,2-dichloro-3-(4-nitrobenzyl)benzene

##STR00026##

[0269] Under an argon stream, bis (dibenzylideneacetone)palladium (0) (3.2 g, 5.6 mmol) and tri (2-furyl)phosphine (2.6 g, 11.2 mmol) were dissolved in THF (310 ml). To this solution was added dropwise a solution of 2,3-dichlorobenzylzinc chloride (421.7 mmol) in THF obtained in Reference Example 1 with ice-cooling through a cannula, and then a solution of 4-iodonitrobenzene (70.0 g, 281 mmol) in THF (700 ml) was added dropwise. After stirring at room temperature for 2 hrs, saturated aqueous ammonium chloride solution was added to the reaction solution and the mixture was filtered through Celite. The filtrate was concentrated under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the solid precipitated during the concentration was collected by filtration. The filtrate was again concentrated under reduced pressure and the solid precipitated during the concentration was collected by filtration. The solids obtained by filtration were combined, washed with n-hexane and vacuum-dried to give an object product (60.2 g, yield 76%) as a pale-brown solid. .sup.1H NMR (CDCl.sub.3 400 MHz) (δ) ppm: 4.24(2H,$), 7.09 (1H, d, J=7.7 Hz), 7.18(1H,dd,J=7.8 Hz,7.9 Hz), 7.32 (2H, d, J=8.9 Hz), 7.40 (1H, d, J=8.0 Hz), 8.15 (2H, d, J=8.7 Hz) MS(ESI): M-280

Step 2 Synthesis of 4-(2,3-dichlorobenzyl)phenylamine

##STR00027##

[0270] 1,2-Dichloro-3-(4-nitrobenzyl)benzene (25.0 g, 88.6 mmol) obtained in Step 1 was dissolved in acetic acid (400 ml) and zinc powder (70 g, 1.1 mol) was added by portions at 0° C. The mixture was stirred at room temperature for 1 hr. The reaction mixture was filtered through Celite and washed with ethanol. The filtrate was concentrated under reduced pressure and the solid precipitated during concentration was collected by filtration. The solid obtained by the filtration was washed with diethyl ether, and dissolved in ethyl acetate (500 ml) and water (500 ml). A 4N aqueous sodium hydroxide solution was added to neutralize the aqueous layer. The organic layer was separated, and the aqueous layer was further extracted with ethyl acetate. The organic layers were combined, washed with water and saturated brine, and dried over sodium sulfate. After the filtration, the filtrate was concentrated under reduced pressure and the solid precipitated during the concentration was collected by filtration. The solid obtained by filtration was washed with n-hexane and vacuum-dried to give an object product (18.1 g, yield 81%) as a pale-brown solid.

.sup.1H NMR (CDCl.sub.3 400 MHz) (δ) ppm: 3.52 (2H, brs), 4.01(2H,$), 6.63 (2H, d, J=8.2 Hz), 6.97 (2H, d, J=8.1 Hz), 7.02 (1H, d, J=7.6 Hz), 7.09(1H,dd,J=7.8 Hz,7.8 Hz), 7.31 (1H, d, J=7.8 Hz) MS(ESI): M+252
Step 3 Synthesis of ethyl 6-(2,3-dichlorobenzyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylate

##STR00028##

[0271] 4-(2,3-Dichlorobenzyl)phenylamine (10.0 g, 39.7 mmol) obtained in Step 2 was dissolved in toluene (100 ml) and diethyl ethoxymethylenemalonate (8.8 ml, 43.7 mmol) was added. The mixture was heated under reflux for 3 hrs. The reaction solution was concentrated under reduced pressure, and diphenyl ether (100 ml) was added to dissolve the residue. The mixture was stirred with heating at 250° C. for 3 hrs. After allowing the mixture to cool, n-hexane was added to the reaction solution and the precipitate was collected by filtration, washed with chloroform and vacuum-dried to give an object product (10.1 g, yield 68%) as a pale-yellow solid.

[0272] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 1.27 (3H, t, J=7.1 Hz), 4.20(2H,q,J=7.1 Hz), 4.27(2H,$), 7.34-7.41 (2H, m), 7.55-7.57 (3H, m), 7.90(1H,$), 8.49 (1H, d, J=6.6 Hz), 12.26 (1H, brs) MS(ESI): M+376

Step 4 Synthesis of ethyl 1-(2-acetoxyethyl)-6-(2,3-dichlorobenzyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylate

##STR00029##

[0273] Ethyl 6-(2,3-dichlorobenzyl)-1,4-dihydro-4-oxo quinolinecarboxylate obtained in Step 3 (400 mg, 1.1 mmol) was suspended in dimethylformamide (DMF; 8 ml) and 2-bromoethyl acetate (152 μl, 1.4 mmol) and potassium carbonate (440 mg, 3.2 mmol) were added. The mixture was stirred with heating at 80° C. During the stirring, 2-bromoethyl acetate (152 μl, 1.4 mmol) was added twice and the mixture was stirred with heating at 80° C. for the total of 1.5 hrs. After allowing the mixture to cool, saturated aqueous ammonium chloride was added to the reaction solution, and the precipitate was collected by filtration, washed with water and vacuum-dried to give an object product (468 mg, yield 95%) as a white solid.

.sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 1.25 (3H, t, J=9.3 Hz), 1.88(3H,$), 4.20(2H,q,J=9.3 Hz), 4.27(2H,$), 4.33-4.41 (2H, m), 4.59-4.62 (2H, m), 7.32-7.41 (3H, m), 7.54(1H,dd,J=2.9 Hz,10.2 Hz), 7.64(1H,dd,J=2.4 Hz,11.2 Hz), 7.81 (1H, d, J=11.7 Hz), 7.88 (1H, d, J=2.4 Hz), 8.57 (1H, s)
Step 5 Synthesis of 6-(2,3-dichlorobenzyl)-1,4-dihydro-1-(2-hydroxyethyl)-4-oxo-3-quinolinecarboxylic acid

##STR00030##

[0274] Ethyl 1-(2-acetoxyethyl)-6-(2,3-dichlorobenzyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylate obtained in Step 4 (6.0 g, 13.0 mmol) was suspended in ethanol (480 ml) and 4N aqueous sodium hydroxide solution (84 ml, 21 mmol) was added. The mixture was heated under reflux for 30 min. After allowing the mixture to cool, the reaction solution was partly concentrated under reduced pressure. Hydrochloric acid was added and the precipitate was collected by filtration, washed with water and ethanol and vacuum-dried to give an object product (4.5 g, yield 85%) as a white solid.

.sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 3.75 (2H, t, J=4.7 Hz), 4.36 (2H, s), 4.60 (2H, t, J=4.8 Hz), 4.98 (1H, brs), 7.37-7.39 (1H, m), 7.45 (1H, dd, J=1.4, 7.6 Hz), 7.57 (1H, dd, J=1.5, 8.0 Hz), 7.81 (1H, dd, J=2.1, 8.9 Hz), 8.02 (1H, d, J=8.8 Hz), 8.15 (1H, d, J=1.8 Hz), 8.86 (1H, s), 15.18 (1H, brs)

MS (ESI): M+392

m.p.: 247-249° C.

[0275] Example 1-2 Synthesis of 6-(2,3-dichlorobenzyl)-1,4-dihydro-8-fluoro-1-(2-hydroxyethyl)-4-oxo-3-quinolinecarboxylic acid Step 1 Synthesis of 2,3-difluoro-5-iodobenzoic acid

##STR00031##

[0276] 2,3-Difluorobenzoic acid (5.0 g, 31.6 mmol) was dissolved in trifluoromethanesulfonic acid (25 ml), and N-iodosuccinimide (8.55 g, 38.0 mmol) was added by portions at 0° C. under an argon stream. The mixture was stirred at room temperature for 3 hrs., and the reaction solution was poured into sodium sulfite in ice water. The mixture was stirred and the precipitate was collected by filtration, washed with water and vacuum-dried to give an object product (7.5 g, yield 84%) as a pale-pink solid.

.sup.1H NMR (CDCl.sub.3 300 MHz) (δ) ppm: 7.74 (1H, m), 8.11 (1H, m) MS(ESI): M-283
Step 2 Synthesis of ethyl 2-(2,3-difluoro-5-iodobenzoyl)-3-(2-hydroxyethylamino)acrylate

##STR00032##

[0277] 2,3-Difluoro-5-iodobenzoic acid (3.0 g, 10.6 mmol) obtained in Step 1 was dissolved in toluene, and thionyl chloride (3.0 ml, 41.1 mmol) and DMF (catalytic amount) were added. The mixture was heated under reflux for 3 hrs. The reaction solution was concentrated under reduced pressure and THF (15 ml) was added to dissolve the residue. The resulting solution was added dropwise to a solution of ethyl 3-dimethylaminoacrylate (1.66 g, 11.6 mmol) and triethylamine (1.77 ml, 12.7 mmol) in THF (10 ml) and the mixture was stirred with heating at 50° C. for 2.5 hrs. After allowing the mixture to cool, the reaction mixture was filtered and washed with THF (10 ml). Aminoethanol (0.77 ml, 12.7 mmol) was added to the filtrate and the mixture was stirred with heating at 40° C. for 1 hr. After allowing the mixture to cool, water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate:hexane=2:1) to give an object product (3.8 g, yield 85%) of a mixture of E form and Z form as a yellow solid.

.sup.1H NMR (CDCl.sub.3 400 MHz) (δ) ppm: 0.91-1.09 (3H, m), 1.80-1.89 (1H, m), 3.52-3.63 (2H, m), 3.83-3.91 (2H, m), 3.98-4.09 (2H, m), 7.36-7.52 (2H, m), 8.15 (1H, d, J=14.4 Hz), 9.6(0.22H,brs), 11.0(0.78H,brs)

MS(ESI): M+426

[0278] Step 3 Synthesis of ethyl 2-(2,3-difluoro-5-iodobenzoyl)-3-[2-(tert-butyldimethylsilyloxy)ethylamino]acrylate

##STR00033##

[0279] Ethyl 2-(2,3-difluoro-5-iodobenzoyl)-3-(2-hydroxyethylamino)acrylate (2.0 g, 4.7 mmol) obtained in Step 2 was dissolved in DMF (10 ml), imidazole (705 mg, 10.4 mmol) and tert-butyldimethylsilyl chloride (1.49 g, 9.9 mmol) were added, and stirred at room temperature for 4 hrs. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate:hexane=1:4) to give an object product (2.3 g, yield 91%) as a white solid.

.sup.1H NMR (CDCl.sub.3 300 MHz) (δ) ppm: 0.07(6H,$), 0.90(9H,$), 1.07 (3H, t, J=7.1 Hz), 3.45-3.55 (2H, m), 3.70-3.80 (2H, m), 4.04(2H,q,J=7.1 Hz), 7.30-7.50 (2H, m), 8.14 (1H, d, J=14.1 Hz), 10.80-11.10 (1H, m)

MS(ESI): M+540

[0280] Step 4 Synthesis of ethyl 1,4-dihydro-8-fluoro-6-iodo-1-[2-(tert-butyldimethylsilyloxy)ethyl]-4-oxo-3-quinolinecarboxylate

##STR00034##

[0281] Ethyl 2-(2,3-difluoro-5-iodobenzoyl)-3-[2-(tert-butyldimethylsilyloxy)ethylamino]acrylate (2.3 g, 4.3 mmol) obtained in Step 3 was dissolved in THF (25 ml) and sodium hydride (256 mg, 6.4 mmol) was added with ice-cooling. The mixture was stirred at 0° C. for 1 hr. 1N Hydrochloric acid (6.4 ml, 6.4 mmol) was added to neutralize the reaction solution. Water was further added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate:hexane=1:2 to ethyl acetate:hexane=2:1) to give an object product (2.0 g, yield 92%) as a white solid.

.sup.1H NMR (CDCl.sub.3 300 MHz) (δ) ppm: −0.12(6H,$), 0.79(9H,$), 1.38 (3H, t, J=7.1 Hz), 3.90-4.00 (2H, m), 4.37(2H,q,J=7.1 Hz), 4.40-4.50 (2H, m), 7.69(1H,dd,J=2.0 Hz,13.7 Hz), 8.40(1H,$), 8.69 (1H, d, J=2.0 Hz)

MS(ESI): M+520

[0282] Step 5 Synthesis of ethyl 6-(2,3-dichlorobenzyl)-1,4-dihydro-8-fluoro-1-[2-(tert-butyldimethylsilyloxy) ethyl]-4-oxo-3-quinolinecarboxylate

##STR00035##

[0283] Under an argon stream, 1M solution (2.9 ml, 2.9 mmol) of 2,3-dichlorobenzylzinc chloride in THF obtained in the same manner as in Reference Example 1 was added to THF (20 ml), and then bis(dibenzylideneacetone)palladium(0) (22 mg, 0.039 mmol), tri(2-furyl)phosphine (18 mg, 0.077 mmol) and ethyl 1,4-dihydro-8-fluoro-6-iodo-1-[2-(tert-butyldimethylsilyloxy)ethyl]-4-oxo-3-quinolinecarboxylate (1.0 g, 1.9 mmol) obtained in Step 4 were added. The mixture was stirred at room temperature for 17 hrs, and then a solution (1.0 ml, 1.0 mmol) of 2,3-dichlorobenzylzinc chloride in THF was added. The mixture was heated under reflux for 1 hr. After allowing the mixture to cool, saturated aqueous ammonium chloride solution was added to the reaction solution and insoluble materials were filtered off with Celite. The filtrate was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate:hexane=1:1), and then by PTLC (ethyl acetate:chloroform=1:2) to give an object product (562 mg, yield 53%) as a pale-yellow oil.

.sup.1H NMR (CDCl.sub.3 300 MHz) (δ) ppm: −0.13(6H,$), 0.79(9H,$), 1.38 (3H, t, J=7.1 Hz), 3.90-4.00 (2H, m), 4.23(2H,$), 4.37(2H,q,J=7.1 Hz), 4.40-4.50 (2H, m), 7.10-7.50 (4H, m), 8.20-8.30 (1H, m), 8.39(1H,$)

MS(ESI): M+552

[0284] Step 6 Synthesis of ethyl 6-(2,3-dichlorobenzyl)-1,4-dihydro-8-fluoro-1-(2-hydroxyethyl)-4-oxo-3-quinolinecarboxylate

##STR00036##

[0285] Ethyl 6-(2,3-dichlorobenzyl)-1,4-dihydro-8-fluoro-1-[2-(tert-butyldimethylsilyloxy)ethyl]-4-oxo-3-quinolinecarboxylate (350 mg, 0.63 mmol) obtained in Step 5 was dissolved in THF (25 ml) and tetrabutylammonium fluoride (1M THF solution; 1.9 ml, 1.9 mmol) was added. The mixture was stirred at room temperature for 1 hr. Water was added to the reaction solution and the precipitate was collected by filtration, washed with water and vacuum-dried to give an object product (279 mg, yield quant) as a pale-yellow solid.

.sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 1.27 (3H, t, J=7.1 Hz), 3.65-3.80 (2H, m), 4.21(2H,q,J=7.1 Hz), 4.40-4.50 (2H, m), 4.99 (1H, m), 7.30-7.90 (5H, m), 8.47(1H,$)

MS(ESI): M+438

[0286] Step 7 Synthesis of 6-(2,3-dichlorobenzyl)-1,4-dihydro fluoro-1-(2-hydroxyethyl)-4-oxo-3-quinolinecarboxylic acid

##STR00037##

[0287] Ethyl 6-(2,3-dichlorobenzyl)-1,4-dihydro-8-fluoro-1-(2-hydroxyethyl)-4-oxo-3-quinolinecarboxylate (80 mg, 0.18 mmol) obtained in Step 6 was dissolved in a mixture of ethanol (2 ml) and THF (1 ml), and 1N aqueous sodium hydroxide solution (1 ml, 1.0 mmol) was added. The mixture was stirred with heating at 60° C. for 1 hr. After allowing the mixture to cool, 10% aqueous citric acid solution was added to the reaction solution. The precipitate was collected by filtration, washed with 30% aqueous ethanol and vacuum-dried to give an object product (70 mg, yield 93%) as a white solid.

.sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 3.78 (2H, m), 4.35 (2H, s), 4.64 (2H, m), 5.00 (1H, m), 7.39 (2H, m), 7.47 (1H, m), 7.58 (1H, m), 8.00 (1H, m), 8.81 (1H, s), 14.80 (1H, s)

MS (ESI): M+409

Example 3-38

Step 1

[0288] ##STR00038##

[0289] 2-Chloro-3-nitrobenzoic acid (6.00 g, 29.77 mmol) was dissolved in trifluoromethanesulfonic acid (40 ml) and N-iodosuccinimide (7.37 g, 32.76 mmol) was added by portions at 0° C. The mixture was stirred at 40° C. for 4 hrs and the reaction solution was added to ice water. After stirring, the precipitate was collected by filtration, washed with water and vacuum-dried. The obtained solid was dissolved in methanol (50 ml), conc. sulfuric acid (catalytic amount) was added, and the mixture was heated under reflux for 5.5 hrs. The reaction solution was concentrated under reduced pressure and the obtained residue was purified by silica gel chromatography (ethyl acetate:hexane=1:4) to give an object product (5.35 g, yield 53%) as a pale-yellow solid.

1H NMR (CDCl.SUB.3 .300 MHz) (δ) ppm: 3.98 (3H, s), 8.11 (1H, d, J=2.1 Hz), 8.24 (1H, d, J=2.1 Hz)

Step 2

[0290] ##STR00039##

[0291] The compound (5.35 g, 15.67 mmol) obtained in Step 1 was dissolved in methanol (25 ml) and 4N aqueous potassium hydroxide solution (10.00 ml, 4.00 mmol) was added. The mixture was heated under reflux for 30 min. After allowing the mixture to cool, 1N hydrochloric acid was added to the reaction solution and the precipitated solid was collected by filtration and vacuum-dried to give an object product (4.99 g, yield 97%) as a white solid.

.sup.1H NMR (CDCl.sub.3 300 MHz) (δ) ppm: 8.14 (1H, d, J=2.0 Hz), 8.39 (1H, d, J=2.1 Hz)

Step 3

[0292] ##STR00040##

[0293] The compound (4.99 g, 15.24 mmol) obtained in Step 2 was dissolved in toluene (50 ml), and thionyl chloride (5.00 ml, 68.54 mmol) and dimethylformamide (catalytic amount) were added. The mixture was heated under reflux for 1 hr. The reaction solution was concentrated under reduced pressure and tetrahydrofuran (80 ml) was added to dissolve the residue. The resulting solution was added dropwise to a solution of ethyl 3,3-dimethylaminoacrylate (2.29 g, 16.00 mmol) and triethylamine (2.55 ml, 18.30 mmol) in tetrahydrofuran (50 ml) and the mixture was stirred with heating at 50° C. for 10 hrs. After allowing the mixture to cool, aminoethanol (1.10 ml, 18.23 mmol) was added to the reaction mixture and the mixture was stirred with heating at 40° C. for 1.5 hrs. After allowing the mixture to cool, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate:hexane=2:1) to give an object product (5.35 g, yield 75%) of a mixture of E form and Z form as a yellow solid.

.sup.1H NMR (CDCl.sub.3 300 MHz) (δ) ppm: 0.82-1.01 (3H, m), 3.63 (2H, br), 3.85-4.06 (4H, m), 7.65-7.68 (1H, m), 8.02-8.06 (1H, m), 8.21 8.36 (1H, m), 9.78 (0.16H, br), 11.15 (0.84H, br)

Step 4

[0294] ##STR00041##

[0295] The compound (5.35 g, 11.42 mmol) obtained in Step 3 was dissolved in dimethylformamide (50 ml), and imidazole (1.71 g, 25.12 mmol) and tert-butyldimethylsilyl chloride (3.62 g, 24.02 mmol) were added. The mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over sodium sulfate. After filtration, concentration under reduced pressure gave a crude product (7.10 g) as a pale-yellow solid.

Step 5

[0296] ##STR00042##

[0297] The crude product (7.10 g) obtained in Step 4 was dissolved in tetrahydrofuran (70 ml) and sodium hydride (731 mg, 18.27 mmol) was added with ice-cooling. The mixture was stirred at 0° C. for 45 min. 1N Hydrochloric acid (18.3 ml) and water were added to the reaction solution and stirred, after which the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel chromatography (ethyl acetate:hexane=1:4 to 1:2) to give an object product (5.58 g, yield 84%) as a yellow solid.

.sup.1H NMR (CDCl.sub.3 300 MHz) (δ) ppm: −0.14 (6H, s), 0.73 (9H, s), 1.39 (3H, t, J=7.1 Hz), 3.74 (2H, t, J=4.6 Hz), 4.02 (2H, t, J=4.6 Hz), 4.39 (2H, q, J=7.1 Hz), 8.13 (1H, d, J=2.2 Hz), 8.50 (1H, s), 9.02 (1H, d, J=2.2 Hz)

Step 6

[0298] ##STR00043##

[0299] The compound (5.00 g, 9.15 mmol) obtained in Step 5 was dissolved in tetrahydrofuran (100 ml) and bis(dibenzylideneacetone)palladium(0) (105 mg, 0.18 mmol) and tri(2-furyl)phosphine (85 mg, 0.37 mmol) were added under an argon stream. A solution of 3-chloro-2-fluorobenzylzinc bromide (11.90 mmol) in tetrahydrofuran prepared as mentioned in Example 4-32, Step 4 was added dropwise at 60° C. After completion of the addition, the mixture was heated under reflux for 4 hrs. After allowing the mixture to cool, saturated aqueous ammonium chloride solution was added to the reaction solution and insoluble material was filtered off with Celite. The filtrate was extracted with ethyl acetate, and the organic layer was washed successively with water and saturated brine and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate:hexane=1:2 to 1:1) to give an object product (2.67 g, yield 52%) as a brown oil.

.sup.1H NMR (CDCl.sub.3 300 MHz) (δ) ppm: −0.19 (6H, s), 0.70 (9H, s), 1.39 (3H, t, J=7.1 Hz), 3.73 (2H, t, J=4.6 Hz), 4.03 (2H, t, J=4.6 Hz), 4.14 (2H, s), 4.38 (2H, q, J=7.1 Hz), 7.02-7.14 (2H, m), 7.29-7.35 (1H, m), 7.73 (1H, d, J=2.2 Hz), 8.50 (1H, s), 8.59 (1H, s)

Step 7

[0300] ##STR00044##

[0301] The compound (1.00 g, 1.79 mmol) obtained in Step 6 was dissolved in acetic acid (20 ml) and zinc powder (1.16 g, 17.76 mmol) was added. The mixture was stirred at room temperature for 4 hrs. The reaction mixture was filtered through Celite and saturated aqueous sodium hydrogen carbonate was added to the filtrate. The mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate). To the residue obtained was added ethyl ether and the mixture was sonicated. After filtration, it was vacuum-dried to give an object product (730 mg, yield 77%) as a pale-orange solid.

.sup.1H NMR (CDCl.sub.3 300 MHz) (δ) ppm: −0.06 (6H, s), 0.77 (9H, s), 1.41 (3H, t, J=7.1 Hz), 4.01 (2H, s), 4.08 (2H, t, J=4.7 Hz), 4.39 (2H, q, J=7.1 Hz), 4.50 (2H, brs), 4.75 (2H, t, J=4.7 Hz), 6.81 (1H, s), 6.94-7.08 (2H, m), 7.20-7.26 (1H, m), 7.91 (1H, s), 8.34 (1H, s)

Step 8

[0302] ##STR00045##

[0303] The compound (100 mg, 0.19 mmol) obtained in Step 7 was dissolved in dimethylformamide (2 ml), and methyl iodide (0.029 ml, 0.47 mmol) and sodium hydride (23 mg, 0.56 mmol) were added. The mixture was stirred at room temperature for 2 hrs. A 10% aqueous citric acid solution was added to the reaction mixture, and the mixture was stirred and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and subjected to silica gel chromatography (ethyl acetate:hexane=2:1) to give a crudely purified product (45 mg) as a pale-red solid.

.sup.1H NMR (CDCl.sub.3 300 MHz) (δ) ppm: −0.33-0.29 (6H, m), 0.64-0.69 (9H, m), 1.23-1.41 (3H, m), 2.66-2.70 (6H, m), 3.55-3.59 (2H, m), 4.36-4.4.2 (4H, m), 4.82-4.96 (2H, m), 6.96-7.11 (2H, m), 7.23-7.30 (2H, m), 8.16-8.15 (1H, m), 8.40-8.66 (1H, m)

Step 9

[0304] ##STR00046##

[0305] The crudely purified product (45 mg) obtained in Step 8 was dissolved in tetrahydrofuran (1 ml), and 1M solution of tetrabutylammonium fluoride (1.00 ml, 1.00 mmol) in THF was added. The mixture was stirred at room temperature for 5 min. To the reaction solution were added ethanol (1 ml) and 1N aqueous sodium hydroxide solution (1 ml, 1.00 mmol), and the mixture was heated under reflux for 2 hrs. After allowing the mixture to cool, 10% aqueous citric acid solution was added to the reaction solution. The mixture was stirred and extracted twice with chloroform. The organic layer was washed with saturated brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and subjected to silica gel chromatography (chloroform:methanol:acetic acid=10:1:0.1) to give a crudely purified product. To the crudely purified product was added aqueous ethanol and the mixture was sonicated. After filtration, the filtrate was vacuum-dried to give an object product (22 mg, yield 27%) as a beige solid.

.sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 2.67 (6H, s), 3.39 (2H, m), 4.21 (2H, s), 4.72 (1H, t), 4.97 (2H, t), 7.20-7.22 (1H, m), 7.40-7.50 (2H, m), 7.65 (1H, s), 7.84 (1H, s), 15.10 (1H, s) MS(ESI): M+419

Example 3-62

Step 1

[0306] ##STR00047##

[0307] 2,4-Difluoro-5-iodobenzoic acid (3.00 g, 10.60 mmol) obtained in Example 4-33, Step 1 was dissolved in toluene (10 ml), and thionyl chloride (3.00 ml, 41.10 mmol) and dimethylformamide (catalytic amount) were added. The mixture was heated under reflux for 1.5 hrs. The reaction solution was concentrated under reduced pressure and tetrahydrofuran (15 ml) was added to dissolve the residue. The resulting solution was added dropwise to a solution of ethyl 3,3-dimethylaminoacrylate (1.66 g, 11.60 mmol) and triethylamine (1.77 ml, 12.70 mmol) in tetrahydrofuran (10 ml), and the mixture was stirred with heating at 50° C. for 2.5 hrs. After allowing the mixture to cool, the reaction mixture was filtered and washed with tetrahydrofuran (10 ml). To the filtrate was added aminoethanol (0.77 ml, 12.76 mmol) and the mixture was stirred with heating at 40° C. for 1 hr. After allowing the mixture to cool, water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate:hexane=2:1) to give a crudely purified product (3.00 g, yield 67%) of a mixture of E form and Z form as a yellow solid.

Step 2

[0308] ##STR00048##

[0309] The compound (3.00 g, 7.06 mmol) obtained in Step 1 was dissolved in dimethylformamide (15 ml) and imidazole (1.06 g, 15.52 mmol) and tert-butyldimethylsilyl chloride (2.23 g, 14.82 mmol) were added. The mixture was stirred at room temperature for 14 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate:hexane=1:4) to give an object product (3.22 g, yield 85%) as a white solid.

.sup.1H NMR (CDCl.sub.3 300 MHz) (δ) ppm: 0.06 (6H, s), 0.90 (9H, s), 1.08 (3H, t, J=7.1 Hz), 3.51 (2H, br), 3.79 (2H, t, J=4.9 Hz), 4.05(2H, q, J=7.1 Hz), 6.78 (1H, dd, J=7.9, 9.4 Hz), 7.71 (1H, dd, J=7.3, 7.3 Hz), 8.11 (1H, d, J=14.0 Hz), 10.91 (1H, br)

Step 3

[0310] ##STR00049##

[0311] The compound (3.22 g, 5.97 mmol) obtained in Step 2 was dissolved in tetrahydrofuran (35 ml) and sodium hydride (358 mg, 8.95 mmol) was added with ice-cooling. The mixture was stirred at 0° C. for 2.5 hrs. 1N Hydrochloric acid (8.90 ml, 8.90 mmol) and water (35 ml) were added to the reaction mixture and the mixture was stirred. The precipitate was collected by filtration, and purified by silica gel chromatography (ethyl acetate:hexane=1:2 to 2:1) to give an object product (2.52 g, yield 81%) as a pale-yellow solid.

.sup.1H NMR (CDCl.sub.3 300 MHz) (δ) ppm: −0.11 (6H, s), 0.79 (9H, s), 1.39 (3H, t, J=7.1 Hz), 3.96 (2H, t, J=4.8 Hz), 4.23 (2H, t, J=4.8 Hz), 4.38(2H, q, J=7.1 Hz), 7.14 (1H, d, J=9.3 Hz), 8.47 (1H, s), 8.93 (1H, d, J=7.2 Hz)

Step 4

[0312] ##STR00050##

[0313] The compound (1.00 g, 1.93 mmol) obtained in Step 3 was dissolved in tetrahydrofuran (20 ml). Under an argon stream, bis(dibenzylideneacetone)palladium(0) (22 mg, 0.039 mmol) and tri(2-furyl)phosphine (18 mg, 0.077 mmol) were added. To this mixture was added a solution of 3-chloro-2-fluorobenzylzinc bromide (2.89 mmol) in tetrahydrofuran prepared as mentioned above dropwise at 60° C. After completion of the addition, the mixture was heated under reflux for 1 hr. After allowing the mixture to cool, saturated aqueous ammonium chloride solution was added to the reaction solution. Insoluble material was filtered off with Celite. The filtrate was extracted with ethyl acetate, and the organic layer was washed successively with water and saturated brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate:hexane=2:1) to give an object product (573 mg, yield 55%) as a pale-yellow solid.

.sup.1H NMR (CDCl.sub.3 300 MHz) (δ) ppm: −0.12 (6H, s), 0.78 (9H, s), 1.38 (3H, t, J=7.1 Hz), 3.99 (2H, t), 4.13 (2H, s), 4.23 (2H, t), 4.37 (2H, q, J=7.1 Hz), 6.96-7.13 (3H, m), 7.25-7.31 (1H, m), 8.39 (1H, d), 8.46 (1H, s)

Step 5

[0314] ##STR00051##

[0315] The compound (170 mg, 0.32 mmol) obtained in Step 4 was dissolved in tetrahydrofuran (1 ml) and 2N aqueous sodium hydroxide solution (4.00 ml, 2.00 mmol) was added. The mixture was heated under reflux for 3.5 hrs. After allowing the mixture to cool, 10% aqueous citric acid solution was added to the reaction solution, and the precipitate was collected by filtration, washed with 50% aqueous ethanol and vacuum-dried to give an object product (117 mg, yield 94%) as a white solid.

.sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 3.73 (2H, br), 4.25 (2H, s), 4.58 (2H, br), 4.96 (1H, br), 7.19-7.22 (1H, m), 7.30-7.36 (1H, m), 7.49-7.54 (1H, m), 8.03 (1H, d), 8.30 (1H, d), 8.88 (1H, s), 15.42 (1H, brs)

Step 6

[0316] ##STR00052##

[0317] The compound (65 mg, 0.17 mmol) obtained in Step 5 was dissolved in dimethyl sulfoxide (2.5 ml) and microwave was irradiated thereon at 50W and 120° C. or below for 20 min. After allowing the mixture to cool, 10% aqueous citric acid solution was added to the reaction mixture, and the precipitate was collected by filtration, washed with water and vacuum-dried to give an object product (66 mg, yield 96%) as a white solid.

.sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 2.88 (6H, s), 3.70-3.80 (2H, m), 4.22 (2H, s), 4.60-4.70 (2H, m), 5.05 (1H, t), 7.20-7.31 (3H, m), 7.50-7.60 (1H, m), 7.80 (1H, s), 8.78 (1H, s), 15.30-15.40 (1H, brs)

MS(ESI): M+419

Example 3-73

Step 1

[0318] ##STR00053##

[0319] 2,4-Difluoro-5-iodobenzoic acid (5.00 g, 17.60 mol) was dissolved in toluene (25 ml), and oxalyl chloride (2.00 ml, 22.93 mmol) and dimethylformamide (catalytic amount) were added. The mixture was stirred at room temperature for 12 hrs. After filtering the reaction solution, the filtrate was concentrated under reduced pressure and toluene (20 ml) was added. Insoluble material was filtered with Celite. The filtrate was concentrated under reduced pressure and tetrahydrofuran (20 ml) was added to dissolve the obtained residue. The resulting solution was added dropwise to a solution of ethyl 3,3-dimethylaminoacrylate (3.28 g, 22.91 mmol) and triethylamine (3.70 ml, 26.55 mmol) in tetrahydrofuran (20 ml). The mixture was heated under reflux for 1 hr. After allowing the mixture to cool, water and ethyl acetate (50 ml) were added to the reaction mixture. The mixture was stirred and partitioned. The organic layer was washed successively with 1N hydrochloric acid (20 ml) and water (200 ml), and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give a crude product (7.24 g) as a brown oil.

Step 2

[0320] ##STR00054##

[0321] The crude product (7.24 g) obtained in Step 1 was dissolved in tetrahydrofuran (20 ml) and (S)-2-amino-1-butanol (1.89 g, 21.24 mmol) was added. The mixture was stirred with heating at 60° C. for 1.5 hrs. After allowing the mixture to cool, the reaction solution was concentrated under reduced pressure and the obtained residue was dissolved in dimethylformamide (20 ml). Potassium carbonate (7.33 g, 53.02 mmol) was added and the mixture was stirred with heating at 70° C. for 1 hr. After allowing the mixture to cool, the reaction mixture was concentrated under reduced pressure. Water (150 ml) was added to the residue and the mixture was stirred at room temperature for 30 min. The precipitate was collected by filtration. The obtained solid was washed with water (50 ml), and then with a mixture (50 ml) of hexane:diethyl ether=7:3, and vacuum-dried to give an object product (4.69 g, yield 61%) as a white solid.

.sup.1H NMR (CDCl.sub.3 300 MHz) (δ) ppm: 0.97 (3H, t, J=7.4 Hz), 1.40 (3H, t, J=7.1 Hz), 1.95-2.05 (1H, m), 2.11-2.21 (1H, m), 4.05 (1H, br), 4.34-4.39 (5H, m), 5.59 (1H, br), 7.30 (1H, d, J=10.0 Hz), 8.04 (1H, d, J=7.1 Hz), 8.58 (1H, s)

Step 3

[0322] ##STR00055##

[0323] The compound (4.69 g, 10.82 mmol) obtained in Step 2 was dissolved in dimethylformamide (20 ml), and imidazole (950 mg, 13.95 mmol) and tert-butyldimethylsilyl chloride (1.95 g, 12.96 mmol) were added. The mixture was stirred at room temperature for 14.5 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate (50 ml). The organic layer was washed 3 times with water and then with saturated brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate:hexane=3:7) to give an object product (5.06 g, yield 86%) as a yellow oil.

.sup.1H NMR (CDCl.sub.3 300 MHz) (δ) ppm: −0.08 (3H, s), -0.05 (3H, s), 0.77 (9H, s), 0.98 (3H, t, J=7.5 Hz), 1.40 (3H, t, J=7.2 Hz), 1.94-2.10 (2H, m), 3.90 (2H, br), 4.35-4.43 (3H, m), 7.26 (1H, d, J=9.9 Hz), 8.59 (1H, s), 8.95 (1H, d, J=7.2 Hz)

Step 4

[0324] ##STR00056##

[0325] The compound (5.06 g, 9.24 mmol) obtained in Step 3 was dissolved in tetrahydrofuran (20 ml), and bis(dibenzylideneacetone)palladium(0) (266 mg, 0.46 mmol) and tri(2-furyl)phosphine (215 mg, 0.92 mmol) were added under an argon stream. A solution of 3-chloro-2-fluorobenzylzinc bromide (18.50 mmol) in tetrahydrofuran prepared as mentioned above was added dropwise. After completion of the addition, the mixture was stirred with heating at 60° C. for 1 hr. After allowing the mixture to cool, water and ethyl acetate were added to the reaction solution and the mixture was stirred and partitioned. The organic layer was washed successively with 1N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (ethyl acetate:hexane=1:1 to 2:1) to give an object product (3.86 g, yield 74%) as a brown oil.

.sup.1H NMR (CDCl.sub.3 300 MHz) (δ) ppm: −0.10 (3H, s), -0.06 (3H, s), 0.752 (9H, s), 0.98 (3H, t, J=7.4 Hz), 1.403H, t, J=7.1 Hz), 1.90-2.12 (2H, m), 3.89 (2H, br), 4.12 (2H, s), 4.35-4.49 (3H, m), 6.97-7.08 (2H, m), 7.22-7.29 (2H, m), 8.40 (1H, d, J=8.7 Hz), 8.58 (1H, s)

Step 5

[0326] ##STR00057##

[0327] To the compound (3.86 g, 6.85 mmol) obtained in Step 4 were added 28% sodium methoxide in methanol (40.00 ml, 0.20 mol) and water (2.00 ml, 0.11 mol), and the mixture was heated under reflux for 5.5 hrs. After allowing the mixture to cool, the reaction solution was concentrated under reduced pressure and 6N hydrochloric acid was added to the obtained residue.

[0328] The mixture was stirred, and extracted twice with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was recrystallized from ethanol (200 ml) to give an object product (2.03 g, yield 68%) as a white solid.

.sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 0.87 (3H, t, J=7.3 Hz), 1.80-2.10 (2H, m), 3.70-3.90 (2H, m), 4.02 (3H, s), 4.11 (2H, s), 5.00-5.19 (2H, m), 7.16-7.24 (2H, m), 7.44-7.48 (2H, m), 8.04 (1H, s), 8.78 (1H, s), 15.44 (1H, s)

MS(ESI): M+434

Example 3-75

Step 1

[0329] ##STR00058##

[0330] 2-Fluoro-5-iodobenzoic acid (6.60 g, 24.81 mmol) was dissolved in chloroform (70 ml) and oxalyl chloride (4.30 ml, 49.29 mmol) and dimethylformamide (catalytic amount) were added. The mixture was stirred at room temperature for 3 hrs. The reaction solution was concentrated under reduced pressure and chloroform (35 ml), was added to dissolve the residue. The obtained solution was added dropwise to a solution of ethyl 3,3-dimethylaminoacrylate (4.26 g, 29.75 mmol) and triethylamine (5.19 ml, 37.24 mmol) in chloroform (35 ml), and the mixture was stirred at room temperature for 15 hrs. Water was added to partition the reaction solution, and the organic layer was washed with saturated brine and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel chromatography (ethyl acetate:hexane=1:2 to 1:1) to give an object product (6.40 g, yield 66%) of a mixture of E form and Z form as an orange solid.

.sup.1H NMR (CDCl.sub.3 400 MHz) (δ) ppm: 0.94 (3H, t, J=7.2 Hz), 2.88 (3H, brs), 3.31 (3H, brs), 3.97 (2H, q), 6.78 (1H, dd, J=8.4, 10.0 Hz), 7.65-7.67 (1H, m), 7.78 (1H, s), 7,85 (1H, brs) MS(ESI): M+392

Step 2

[0331] ##STR00059##

[0332] The compound (300 mg, 0.77 mmol) obtained in Step 1 was dissolved in tetrahydrofuran (1.5 ml) and (S)-(+)-tert-leucinol (0.12 ml, 0.92 mmol) was added. The mixture was stirred with heating at 60° C. for 1 hr. The reaction solution was concentrated under reduced pressure and the obtained residue was dissolved in dimethylformamide (1.2 ml). Potassium carbonate (318 mg, 2.30 mmol) was added and the mixture was stirred with heating at 70° C. for 5.5 hrs. After cooling, 1N hydrochloric acid (5 ml) was added to the reaction mixture and the mixture was stirred with ice-cooling for 30 min. The precipitate was collected by filtration and the obtained solid was washed with 30% aqueous ethanol (6 ml), and then with a mixture (5 ml) of hexane:diethyl ether=2:1 and vacuum-dried to give an object product (276 mg, yield 81%) as a pale-yellow solid.

.sup.1H NMR (CDCl.sub.3 300 MHz) (δ) ppm: 0.98 (9H, s), 1.41 (3H, t, J=7.0 Hz), 4.25-4.41 (4H, m), 4.64-4.70 (1H, m), 5.14 (1H, br), 7.46 (1H, d, J=9.0 Hz), 7.89 (1H, dd, J=2.2, 9.1 Hz), 8.06 (1H, d, J=2.1 Hz), 8.69 (1H, s)

Step 3

[0333] ##STR00060##

[0334] The compound (276 mg, 0.62 mmol) obtained in Step 2 was dissolved in dimethylformamide (1 ml) and imidazole (51 mg, 0.75 mmol) and tert-butyldimethylsilyl chloride (122 mg, 0.81 mmol) were added. The mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture and the mixture was extracted twice with ethyl acetate, and the organic layer was washed twice with water and then with saturated brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate:hexane=3:5) to give an object product (314 mg, yield 91%) as a white amorphous form.

.sup.1H NMR (CDCl.sub.3 300 MHz) (δ) ppm: −0.09 (3H, s), -0.01 (3H, s), 0.66 (9H, s), 1.04 (9H, s), 1.41 (3H, t, J=7.2 Hz), 4.10-4.14 (2H, m), 4.40 (2H, q, J=7.0 Hz), 4.58-4.63 (1H, m), 7.39 (1H, d, J=9.3 Hz), 7.89 (1H, dd, J=2.2, 8.8 Hz), 8.67 (1H, s), 8.87 (1H, d, J=2.1 Hz)

Step 4

[0335] ##STR00061##

[0336] The compound (314 mg, 0.56 mmol) obtained in Step 3 was dissolved in tetrahydrofuran (1.2 ml), and bis(dibenzylideneacetone)palladium(0) (16 mg, 0.028 mmol) and tri(2-furyl)phosphine (13 mg, 0.056 mmol) were added under an argon stream. A solution of 3-chloro-2-fluorobenzylzinc bromide (1.13 mmol) in tetrahydrofuran prepared as mentioned above was added dropwise. After completion of the addition, the mixture was stirred with heating at 50° C. for 1.5 hrs. After allowing the mixture to cool, water and ethyl acetate were added to the reaction solution and the mixture was stirred. Insoluble material was filtered with Celite. The filtrate was partitioned and the organic layer was washed successively with water and saturated brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel chromatography (ethyl acetate:hexane=1:1) to give an object product (283 mg, yield 87%) as a brown amorphous form.

.sup.1H NMR (CDCl.sub.3 400 MHz) (δ) ppm: −0.11 (3H, s), -0.01 (3H, s), 0.63 (9H, s), 1.06 (9H, s), 1.41 (3H, t, J=7.0 Hz), 4.08-4.16 (4H, m), 4.38 (2H, q, J=7.0 Hz), 4.61-4.67 (1H, m), 6.95-7.08 (2H, m), 7.23-7.27 (1H, m), 7.47-7.49 (1H, m), 7.53-7.55 (1H, m), 8.41 (1H, d, J=2.0 Hz), 8.68 (1H, s)

Step 5

[0337] ##STR00062##

[0338] The compound (283 mg, 0.49 mmol) obtained in Step 4 was dissolved in ethanol (2 ml) and 1N aqueous sodium hydroxide solution (1.00 ml, 1.00 mmol) was added. The mixture was heated under reflux for 1 hr. After allowing the mixture to cool, acetic acid (0.35 ml) was added to the reaction solution and the mixture was stirred. The precipitate was collected by filtration and the solid was suspended in diethyl ether (10 ml). After filtration, the mixture was vacuum-dried to give an object product (157 mg, yield 74%) as a white solid.

.sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 1.00 (9H, s), 4.07-4.12 (2H, m), 4.30 (2H, s), 5.12-5.14 (2H, m), 7.20-7.25 (1H, m), 7.40-7.45 (1H, m), 7.51-7.53 (1H, m), 7.87 (1H, d), 8.25 (1H, s), 8.41 (1H, d, J=9.2 Hz), 8.85 (1H, s), 15.20-15.21 (1H, br)

MS(ESI): M+432

Example 4-20

Step 1

[0339] ##STR00063##

[0340] 2-Chloro-4-hydroxybenzoic acid (5.18 g, 30.02 mmol) was dissolved in trifluoromethanesulfonic acid (25 g) and N-iodosuccinimide (6.75 g, 30.00 mmol) was added by portions at 0° C. The mixture was stirred at room temperature for 15 hrs and trifluoromethanesulfonic acid (25 g) was further added. N-Iodosuccinimide (2.02 g, 8.98 mmol) was added by portions at 0° C. The mixture was stirred at room temperature for 13.5 hrs and the reaction mixture was added to ice water (300 ml). The mixture was stirred for 2 hrs. The precipitate was collected by filtration, washed with water and vacuum-dried to give an object product as a mixture of 2-chloro-4-hydroxy-5-iodobenzoic acid and 2-chloro-3,5-diiodo-4-hydroxybenzoic acid (8:2) (5.76 g).

Step 2

[0341] ##STR00064##

[0342] The mixture (3.89 g) obtained in Step 1 was dissolved in dimethylformamide (20 ml) and potassium carbonate (8.97 g, 64.90 mmol) and isopropyl iodide (6.50 ml, 65.15 mmol) were added. The mixture was stirred with heating at 80° C. for 2.5 hrs. The reaction mixture was added to 1N hydrochloric acid (100 ml), and toluene (100 ml) was further added. The mixture was stirred and insoluble material was filtered through Celite. The filtrate was partitioned and the organic layer was washed with water three times, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel chromatography (ethyl acetate:hexane=1:9) to give an object product as a mixture (4.08 g).

Step 3

[0343] ##STR00065##

[0344] The mixture (4.08 g) obtained in Step 2 was dissolved in ethanol (20 ml) and 1N aqueous sodium hydroxide solution (20.00 ml, 20.00 mmol) was added. The mixture was heated under reflux for 24 hrs. After allowing the mixture to cool, 1N hydrochloric acid (30 ml) was added to the reaction solution and the mixture was stirred. The mixture was extracted with ethyl acetate three times. The organic layer was washed successively with water and saturated brine, and dried over sodium sulfate. After filtration, concentration under reduced pressure gave an object product as a mixture (3.40 g).

Step 4

[0345] ##STR00066##

[0346] The mixture (3.40 g) obtained in Step 3 was dissolved in toluene (35 ml) and thionyl chloride (3.40 ml, 46.61 mmol) and dimethylformamide (catalytic amount) were added. The mixture was heated under reflux for 1.5 hrs. The reaction solution was concentrated under reduced pressure and tetrahydrofuran (25 ml) was added to dissolve the residue. The obtained solution was added dropwise to a solution of ethyl 3,3-dimethylaminoacrylate (4.29 g, 30.00 mmol) and triethylamine (4.17 ml, 30.00 mmol) in tetrahydrofuran (10 ml) and the mixture was heated under reflux for 14 hrs. After allowing the mixture to cool, water and ethyl acetate were added to the reaction mixture, and the mixture was stirred and partitioned. The organic layer was washed successively with water and saturated brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate:hexane=1:1.5 to 1.5:1) to give an object product as a mixture (2.71 g).

Step 5

[0347] ##STR00067##

[0348] The mixture (300 mg) obtained in Step 4 was dissolved in tetrahydrofuran (2 ml), and (S)-(+)-tert leucinol (0.10 ml, 0.77 mmol) was added. The mixture was heated under reflux for 20 min. After allowing the mixture to cool, the reaction solution was concentrated under reduced pressure and the obtained residue was dissolved in dimethylformamide (4 ml). Imidazole (110 mg, 1.61 mmol) and tert-butyldimethylsilyl chloride (214 mg, 1.42 mmol) were added and the mixture was stirred at room temperature for 20 min. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate:hexane=1:4) to give an object product as a mixture (391 mg).

Step 6

[0349] ##STR00068##

[0350] The mixture (391 mg) obtained in Step 5 was dissolved in toluene (5 ml) and sodium hydride (29 mg, 0.73 mmol) was added under ice-cooling. The mixture was stirred at room temperature for 30 min and dimethylformamide (3 ml), potassium carbonate (100 mg, 0.72 mmol) and ethyl iodide (0.058 ml, 0.73 mmol) were added to the reaction mixture. The mixture was stirred with heating at 60° C. for 30 min. After allowing the mixture to cool, the reaction mixture was added to ice water. 1N

[0351] Hydrochloric acid was added for neutralization and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel chromatography (ethyl acetate:hexane=4:5 to 2:1) to give an object product (258 mg, yield 19%) as a pale-white yellow solid.

.sup.1H NMR (CDCl.sub.3 300 MHz) (δ) ppm: −0.09 (3H, s), 0.00 (3H, s), 0.67 (9H, s), 1.05 (9H, s), 1.40 (3H, t, J=7.1 Hz), 1.46 (6H, d, J=6.0 Hz), 4.09-4.20 (2H, m), 4.39 (2H, q, J=7.1 Hz), 4.43-4.49 (1H, m), 4.61-4.69 (1H, m), 6.87 (1H, s), 8.60 (1H, s), 8.94 (1H, s)

Step 7

[0352] ##STR00069##

[0353] Ethyl 1,4-dihydro-1-{2,2-dimethyl-1-[(tert-butyldimethylsilyloxy)methyl]propyl}-6-iodo-7-isopropyloxy oxo-3-quinolinecarboxylate (258 mg, 0.42 mmol) obtained in Step 6 was dissolved in tetrahydrofuran (5 ml). Under an argon stream, bis(dibenzylideneacetone)palladium(0) (9.7 mg, 0.017 mmol) and tri(2-furyl)phosphine (7.8 mg, 0.034 mmol) were added and a solution of 3-chloro-2-fluorobenzylzinc bromide (0.63 mmol) in tetrahydrofuran prepared as mentioned above was added dropwise at 60° C. After completion of the addition, the mixture was heated under reflux for 1 hr. After allowing the mixture to cool, saturated aqueous ammonium chloride solution was added to the reaction solution and the mixture was stirred and filtered through Celite. Water was added to the filtrate and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the obtained residue was crudely purified by silica gel chromatography (ethyl acetate:hexane=1:1 to 2:1) to give a crudely purified product (216 mg) as a pale-yellow oil.

Step 8

[0354] ##STR00070##

[0355] The crudely purified product (216 mg) obtained in Step 7 was dissolved in a mixture of ethanol (2 ml) and tetrahydrofuran (1 ml), and 1N aqueous sodium hydroxide solution (2.00 ml, 2.00 mmol) was added. The mixture was heated under reflux for 1 hr. After allowing the mixture to cool, 10% aqueous citric acid solution was added to the reaction solution and the mixture was stirred. The mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was treated with a mixture of diethyl ether and hexane. After filtration, the solid was vacuum-dried to give an object product (140 mg, yield 68%) as a white solid.

.sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 0.97 (9H, s), 1.18 (3H, d, J=5.9 Hz), 1.26 (3H, d, J=6.0 Hz), 4.04-4.09 (4H, m), 5.09-5.13 (3H, m), 7.12-7.21 (2H, m), 7.43-7.51 (2H, m), 8.19 (1H, s), 8.78 (1H, s), 15.46 (1H, s)

MS(ESI): M+490

Example 4-32

Step 1

[0356] ##STR00071##

[0357] 2,4-Difluoro-5-iodobenzoic acid (650.57 g, 2.29 mol) was dissolved in toluene (1300 ml), and thionyl chloride (184 ml, 2.52 mol) and dimethylformamide (catalytic amount) were added. The mixture was stirred at 90° C. for 2 hrs. After allowing the mixture to cool, the reaction solution was concentrated under reduced pressure. The residue was dissolved in toluene (330 ml) followed by concentration under reduced pressure, and repeated again. The residue was dissolved in toluene (690 ml) and the obtained solution was added dropwise to a solution of ethyl 3,3-dimethylaminoacrylate (361.52 g, 2.525 mol) and diisopropylethylamine (480 ml, 2.75 mol) in toluene (690 ml) and the mixture was stirred with heating at 90° C. for 3 hrs. After allowing the mixture to cool, (S)-(+)-valinol (260.00 g, 2.52 mol) was added to the reaction mixture and the mixture was stirred at room temperature for 1 hr. Water (2600 ml) was added to the reaction mixture and the mixture was partitioned. The aqueous layer was extracted with toluene (680 ml). The organic layers were combined, washed twice with water (2000 ml), and dried over sodium sulfate. After filtration, concentration under reduced pressure gave a crude product (1180 g) as a brown oil.

Step 2

[0358] ##STR00072##

[0359] The crude product (1180 g) obtained in Step 1 was dissolved in dimethylformamide (2500 ml) and finely ground potassium carbonate (292.00 g, 1.06 mol) was added. The mixture was stirred at room temperature for 22 hrs. The reaction mixture was added to ice water (ca. 10 L) and the mixture was stirred for 30 min. The precipitate was collected by filtration and washed with water (2000 ml). The obtained solid was vacuum-dried, and suspended in ethyl acetate (5000 ml). Filtration and vacuum-drying gave an object product (774.63 g, yield 82%) as a white yellow solid.

.sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 0.72 (3H, d, J=6.6 Hz), 1.10 (3H, d, J=6.6 Hz), 1.28 (3H, t, J=7.0 Hz), 2.27 (1H, br), 3.77 (1H, br), 3.86 (1H, br), 4.23 (2H, q, J=7.0 Hz), 4.56 (1H, br), 5.12 (1H, t, J=4.9 Hz), 8.09 (1H, d, J=11.1 Hz), 8.62 (1H, d, J=7.5 Hz), 8.68 (1H, s)

MS(ESI): M+448

Step 3

[0360] ##STR00073##

[0361] The compound (626.15 g, 1.40 mol) obtained in Step 2 was dissolved in chloroform (1250 ml), and pyridine (433 ml, 5.60 mol) and 4-(dimethylamino)pyridine (17.10 g, 0.14 mol) were added. A solution of methyl chloroformate (529.30 g, 5.60 mol) in chloroform (1250 ml) was added dropwise at 10° C. or below. After completion of the addition, the mixture was stirred at the same temperature for 30 min. The reaction mixture was washed successively with water (1250 ml), 2N hydrochloric acid (1250 ml), water (630 ml) and saturated aqueous sodium hydrogen carbonate (630 ml), and dried over sodium sulfate. After filtration, the residue was concentrated under reduced pressure to give a crude object substance (834.02 g) as a brown oil.

Step 4

[0362] ##STR00074##

(Preparation of 3-chloro-2-fluorobenzylzinc bromide tetrahydrofuran solution)

[0363] Under an argon stream, zinc powder (113.02 g, 1.73 mol) was suspended in tetrahydrofuran (350 ml), and 1,2-dibromoethane (1.207 ml, 14.00 mmol) and trimethylsilyl chloride (8.88 ml, 70.00 mmol) were added at 60° C. The mixture was stirred with heating at 30 min. A solution of 3-chloro-2-fluorobenzyl bromide (406.73 g, 1.82 mol) in tetrahydrofuran (700 ml) was added dropwise at 60° C. The mixture was stirred with heating for 1 hr to give a solution of 3-chloro-2-fluorobenzylzinc bromide.

(Main Step)

[0364] The crude product (834.02 g) obtained in Step 3 was dissolved in tetrahydrofuran (1060 ml), and dichlorobis(triphenylphosphine)palladium (II) (19.65 g, 28.00 mmol) was added under an argon stream and a solution of 3-chloro-2-fluorobenzylzinc bromide (1.82 mol) was added dropwise at 60° C. After completion of the addition, the mixture was heated under reflux for 1.5 hrs. After allowing the mixture to cool, toluene (2120 ml) and 20% aqueous ammonium chloride solution (1410 ml) were added to the reaction solution, and the mixture was stirred and partitioned. The organic layer was washed twice with 20% aqueous ammonium chloride solution (710 ml) and twice with saturated aqueous sodium hydrogen carbonate (710 ml) and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give a crude product (849.34 g) as a brown oil.

Step 5

[0365] ##STR00075##

[0366] The crude product (849.34 g) obtained in Step 4 was dissolved in isopropanol (1100 ml) and 4N aqueous sodium hydroxide solution (1050 ml, 4.20 mmol) was added. The mixture was stirred with heating at 50° C. for 1.5 hrs. Activated carbon (37 g) was added to the reaction solution and the mixture was stirred at room temperature for 30 min. The mixture was filtered through Celite and 6N hydrochloric acid (740 ml) and ethyl acetate (3650 ml) were added to the filtrate. The mixture was stirred and partitioned. The organic layer was concentrated under reduced pressure and the residue was suspended in isopropanol (1070 ml). The mixture was stirred at 60° C. for 1 hr. After allowing the mixture to cool, the solid was collected by filtration. The obtained solid was washed with isopropanol (740 ml) and vacuum-dried to give an object product (446.51 g, yield 73%) as a pale-yellow solid.

.sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 0.71 (3H, d, J=6.5 Hz), 1.13 (3H, d, J=6.5 Hz), 2.36 (1H, br), 3.77 (1H, br), 3.94 (1H, br), 4.25 (2H, s), 4.77 (1H, br), 5.16 (1H, t, J=2.4 Hz), 7.19-7.23 (1H, m), 7.32-7.35 (1H, m), 7.48-7.52 (1H, m), 8.24-8.28 (2H, m), 9.00 (1H, s), 15.00 (1H, s)

MS(ESI): M+436

Step 6

[0367] ##STR00076##

[0368] The compound (443.59 g, 1.02 mol) obtained in Step 5 was dissolved in methanol (2400 ml), and a 28% sodium methoxide in methanol (2077 ml, 10.17 mol) and water (44.30 ml, 2.46 mol) were added. The mixture was heated under reflux for 17.5 hrs. Activated carbon (22 g) was added to the reaction solution and the mixture was stirred at room temperature for 1 hr. The mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. Water (1770 ml) was added to the residue and the mixture was stirred with ice-cooling for 1 hr. Then, 6N hydrochloric acid (1790 ml) was further added and the mixture was stirred at room temperature for 2 hrs. Ethyl acetate (1770 ml) was added and to the mixture was stirred and partitioned. The organic layer was washed twice with 10% brine (890 ml), and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and a part of the residue was recrystallized several times (final recrystallization solvent was methanol-water) to give an object product (28.60 g, yield 67%) as a white solid.

.sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 0.72 (3H, d, J=6.5 Hz), 1.16 (3H, d, J=6.5 Hz), 2.30-2.50 (1H, m), 3.70-3.90 (1H, m), 3.90-4.00 (1H, m), 4.03 (3H, s), 4.12 (2H, s), 4.80-4.90 (1H, m), 5.19 (1H, t, J=5.2 Hz), 7.19-7.25 (2H, m), 7.46-7.51 (2H, m), 8.04 (1H, s), 8.88 (1H, s), 15.44 (1H, s)

MS (ESI): M+448

Example 4-33

Step 1

[0369] ##STR00077##

[0370] 2,4-Difluorobenzoic acid (600.00 g, 3.80 mol) was dissolved in conc. sulfuric acid (2400 ml) and N-iodosuccinimide (854.40 g, 3.60 mol) was added by portions at 5° C. or below. After completion of the addition, the mixture was stirred at the same temperature for 3 hrs. The reaction mixture was poured into ice water (ca. 10 L) and 10% aqueous sodium sulfite solution (40 ml) was added. The mixture was stirred for 30 min. The precipitate was collected by filtration. To be suspended in water (ca. 3 L) and filtration were repeated until the filtrate became not less than pH 3. The obtained wet solid (1677 g) were recrystallized from 50% aqueous ethanol (3000 ml) to give an object product (824.70 g, yield 76%) as a white solid.

.sup.1H NMR (CDCl.sub.3 300 MHz) (δ) ppm: 6.94 (1H, dd, J=10.3, 10.3 Hz), 8.46 (1H, d, J=7.5 Hz)

Step 2

[0371] ##STR00078##

[0372] The compound (150.00 g, 0.53 mol) obtained in Step 1 was dissolved in ethyl acetate (750 ml), and oxalyl chloride (51.0 ml, 0.581 mol) and dimethylformamide (catalytic amount) were added. The mixture was stirred at room temperature for 3.5 hrs. After filtering the reaction solution, the filtrate was concentrated under reduced pressure. After the residue was dissolved in toluene (150 ml), the mixture was concentrated under reduced pressure, and repeated again. Tetrahydrofuran (300 ml) was added to dissolve the residue, and the obtained solution was added dropwise to a solution of ethyl 3,3-dimethylaminoacrylate (83.2 g, 0.581 mol) and triethylamine (96 ml, 0.686 mol) in tetrahydrofuran (450 ml). The mixture was heated under reflux for 15 hrs. After allowing the mixture to cool, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Ethyl acetate (750 ml) was added to dissolve the residue. The mixture was washed successively with aqueous ammonium chloride (400 ml), saturated aqueous sodium hydrogen carbonate (200 ml) and saturated brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give a crude object substance (206.50 g) as a brown oil.

Step 3

[0373] ##STR00079##

[0374] The crude product (206.50 g) obtained in Step 2 was dissolved in tetrahydrofuran (800 ml), and (S)-(+)-tert-leucinol hydrochloride (81.10 g, 0.53 mol) and triethylamine (74 ml, 0.53 mol) were added. The mixture was stirred at room temperature for 50 min. After filtration of the reaction mixture, the filtrate was concentrated under reduced pressure and the obtained residue was dissolved in dimethylformamide (1000 ml). Potassium carbonate (146.0 g, 1.06 mol) was added and the mixture was stirred with heating at 90° C. for 3 hrs. With ice-cooling, water (700 ml) was added to the reaction mixture and the precipitate was collected by filtration and washed with water. The solid collected by filtration was suspended in 30% aqueous ethanol (1000 ml) and collected by filtration. This operation was repeated with a mixture of hexane:diethyl ether=1:1. After filtration, the filtrate was vacuum-dried to give an object product (184.74 g, yield 76%) as a white solid.

.sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 0.968 (9H, s), 1.27 (3H, t), 3.96-3.98 (2H, m), 4.18-4.27 (2H, m), 4.80 (1H, t, J=7.0 Hz), 5.05 (1H, br), 8.22 (1H, d, J=11.2 Hz), 8.60 (1H, s), 8.61 (1H. d, J=7.2 Hz)

Step 4

[0375] ##STR00080##

[0376] The compound (150.00 g, 0.33 mol) obtained in Step 3 was dissolved in dimethylformamide (600 ml), and imidazole (28.80 g, 0.42 mol) and tert-butyldimethylsilyl chloride (28.80 g, 0.42 mol) were added. The mixture was stirred at room temperature for 6 hrs. Water (1200 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate (800 ml). The organic layer was washed 3 times with water, and then with saturated brine and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel chromatography (ethyl acetate:hexane=1:3 to 1:2) to give an object product (164.30 g, yield 88%) as a white amorphous form.

.sup.1H NMR (CDCl.sub.3 300 MHz) (δ) ppm: −0.08 (3H, s), 0.00 (3H, s), 0.67 (9H, s), 1.06(9H,$), 1.41 (3H, t, J=7.1 Hz), 4.05-4.18 (2H, m), 4.36-4.43 (3H, m), 7.32 (1H, d, J=10.3 Hz), 8.65 (1H, s), 8.95 (1H, d, J=7.4 Hz)

Step 5

[0377] ##STR00081##

[0378] The compound (75.0 g, 0.13 mol) obtained in Step 4 was dissolved in tetrahydrofuran (580 ml). Under an argon stream, bis(dibenzylideneacetone)palladium(0) (2.99 g, 5.20 mmol) and tri(2-furyl)phosphine (2.41 g, 10.38 mmol) were added, and a solution of 3-chloro-2-fluorobenzylzinc bromide (0.17 mol) in tetrahydrofuran was added dropwise at 60° C. After completion of the addition, the mixture was heated under reflux for 2 hrs. After allowing the mixture to cool, ethyl acetate (75 ml) and saturated aqueous ammonium chloride solution (38 ml) were added to the reaction solution. The mixture was stirred at room temperature for 30 min. and partitioned. The organic layer was washed twice with water (75 ml) and then with saturated brine (200 ml), and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel chromatography (ethyl acetate:hexane=1:2 to 1:1) to give an object product (66.80 g, yield 73%) as a brown amorphous form.

.sup.1H NMR (CDCl.sub.3 300 MHz) (δ) ppm: −0.10 (3H, s), -0.01 (3H, s), 0.64 (9H, s), 1.06 (9H, s), 1.40 (3H, t, J=7.1 Hz), 4.04-4.15 (4H, m), 4.35-4.46 (3H, m), 6.95-7.03 (2H, m), 7.24-7.31 (2H, m), 8.38 (1H, d, J=8.8 Hz), 8.66 (1H, s)

Step 6

[0379] ##STR00082##

[0380] The compound (2.41 g, 4.07 mmol) obtained in Step 5 was dissolved in methanol (20 ml), and 28% sodium methoxide in methanol (8.4 ml, 40.70 mmol) and water (0.15 ml, 8.14 mmol) were added. The mixture was heated under reflux for 18 hrs. Water (1.4 ml) was added to the reaction solution and the mixture was stirred at room temperature for 1.5 hrs and filtered with Celite. The filtrate was concentrated under reduced pressure, and water (25 ml) and 2N hydrochloric acid (20 ml) were added to the residue. The mixture was stirred for 5 min and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over sodium sulfate. After the filtration, the filtrate was concentrated under reduced pressure. The residue was sonicated with hexane (20 ml) and, after standing still, hexane was removed by decantation. This was repeated three times. Diethyl ether (30 ml) was added to the residue and the mixture was sonicated. The solid was collected by filtration and the obtained solid was dissolved by heating in ethyl acetate (15 ml). Hexane (15 ml) was added and recrystallization gave an object product (1.21 g, yield 64%) as a white solid.

.sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 0.99 (9H, s), 3.99-4.11 (7H, m), 5.11-5.20 (2H, m), 7.19-7.25 (2H, m), 7.49-7.52 (2H, m), 8.03 (1H, s), 8.78 (1H, s), 15.39 (1H, s)

MS(ESI): M+462

Example 4-37

Step 1

[0381] ##STR00083##

[0382] 3-Methoxy-2-nitrobenzoic acid (20.00 g, 0.10 mol) was dissolved in dimethylformamide (100 ml), and potassium carbonate (28.10 g, 0.20 mol) and methyl iodide (7.60 ml, 0.12 mol) were added. The mixture was stirred at room temperature for 1 hr. The reaction mixture was added to water (300 ml) and the mixture was stirred. The precipitate was collected by filtration, washed with water (200 ml) and vacuum-dried to give a crude object substance (23.90 g) as a white solid.

Step 2

[0383] ##STR00084##

[0384] The crude product (23.90 g) obtained in Step 1 was suspended in a mixture of tetrahydrofuran (150 ml) and methanol (50 ml), and 5% palladium-carbon (wet) (2.30 g) was added. The mixture was stirred under a hydrogen atmosphere at room temperature for 19.5 hrs. Ethyl acetate (200 ml) was added to the reaction mixture and the mixture was filtered with Celite. The filtrate was concentrated under reduced pressure and the water was removed azeotropically with toluene to give a crude product (18.80 g) as a brown oil.

Step 3

[0385] ##STR00085##

[0386] The crude product (18.80 g) obtained in Step 2 was dissolved in dimethylformamide (200 ml), and N-bromosuccinimide (17.98 g, 0.10 mol) was added by portions at 5° C. After completion of the addition, the mixture was stirred at the same temperature for 30 min. The reaction mixture was poured into water (500 ml) and extracted twice with ethyl acetate (300 ml). The organic layer was washed successively with water (300 ml), saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel chromatography (chloroform) to give an object product (25.11 g, yield 95%) as a yellow oil.

.sup.1H NMR (CDCl.sub.3 300 MHz) (δ) ppm: 3.86 (6H, s), 6.02 (2H, brs), 6.90 (1H, s), 7.60 (1H, s)

Step 4

[0387] ##STR00086##

[0388] The compound (25.11 g, 96.54 mmol) obtained in Step 3 was suspended in water (50 ml) and conc. hydrochloric acid (25 ml) was added. An aqueous solution (100 ml) of sodium nitrite (7.33 g, 106.22 mmol) was added dropwise at 5° C. After completion of the addition, the mixture was stirred at the same temperature for 5 min. This reaction solution was added dropwise to a solution of copper (I) chloride (9.55 g, 96.47 mmol) in conc. hydrochloric acid (75 ml) at room temperature. After completion of the addition, the mixture was stirred at room temperature for 13 hrs. Water (200 ml) was added to the reaction solution and the mixture was extracted with ethyl acetate (400 ml). The organic layer was washed successively with water (400 ml) and saturated brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give an object product (15.18 g, yield 56%) as an orange solid.

.sup.1H NMR (CDCl.sub.3 300 MHz) (δ) ppm: 3.92 (3H, s), 3.93 (3H, s), 7.16 (1H, d, J=2.1 Hz), 7.49 (1H, d, J=2.2 Hz)

Step 5

[0389] ##STR00087##

[0390] The compound (74.80 g, 0.27 mol) obtained in Step 4 was dissolved in dichloromethane (300 ml) and 1M boran tribromide/dichloromethane solution (700 ml, 0.70 mol) was added dropwise at 10° C. or below. After completion of the addition, the mixture was stirred at room temperature for 1.5 hrs. The reaction mixture was added to ice water (1500 ml) and the precipitated solid was collected by filtration. The filtrate was partitioned, and the aqueous layer was extracted with ethyl acetate (200 ml). The organic layers were combined and concentrated under reduced pressure. The solid collected by filtration and the residue were dissolved in diethyl ether (1000 ml) and 1N aqueous sodium hydroxide solution (1000 ml) was added for extraction. 2N Hydrochloric acid (500 ml) was added to the aqueous layer. The mixture was stirred and extracted with ethyl acetate (800 ml). The mixture was partitioned and the organic layer was washed successively with water and saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give an object product (63.83 g, yield 95%) as a beige solid.

.sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 7.23 (1H, d, J=2.4 Hz), 7.28 (1H, d, J=2.4 Hz), 10.99 (1H, s), 13.55 (1H, brs)

Step 6

[0391] ##STR00088##

[0392] The compound (63.83 g, 0.25 mol) obtained in Step 5 was dissolved in dimethylformamide (400 ml), and potassium carbonate (87.70 g, 0.64 mol) and ethyl iodide (81.20 ml, 1.02 mol) were added. The mixture was stirred with heating at 50° C. for 3 hrs, and saturated aqueous ammonium chloride (600 ml) and ethyl acetate (400 ml) were added to the reaction mixture. The mixture was partitioned and the aqueous layer was extracted with ethyl acetate (400 ml). The organic layers were combined and washed successively with brine (3 times) and saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give an object product (76.38 g, yield 98%) as a brown solid.

.sup.1H NMR (CDCl.sub.3 400 MHz) (δ) ppm: 1.39 (3H, t, J=7.2 Hz), 1.48 (3H, t), 4.11(2H, q), 4.38 (2H, q, J=7.2 Hz), 7.12 (1H, d, J=2.0 Hz), 7.42 (1H, d, J=2.0 Hz)

Step 7

[0393] ##STR00089##

[0394] The compound (76.38 g, 0.25 mol) obtained in Step 6 was dissolved in ethanol (250 ml), and 8N aqueous sodium hydroxide solution (62.00 ml, 0.50 mol) was added. The mixture was stirred with heating at 50° C. for 30 min. 2N Hydrochloric acid (250 ml) was added to the reaction solution with ice-cooling and the mixture was stirred, and extracted twice with ethyl acetate (350 ml). The organic layer was washed successively with water and saturated brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give an object product (68.79 g, yield 99%) as a pale-brown solid.

.sup.1H NMR (CDCl.sub.3 400 MHz) (δ) ppm: 1.50 (3H, t, J=6.8 Hz), 4.12 (2H, q, J=6.8 Hz), 7.19 (1H, d, J=2.4 Hz), 7.65 (1H, d, J=2.4 Hz)

Step 8

[0395] ##STR00090##

[0396] The compound (85.17 g, 0.31 mol) obtained in Step 7 was dissolved in toluene (450 ml), and thionyl chloride(44.40 ml, 0.61 mol) and dimethylformamide (catalytic amount) were added. The mixture was stirred at 90° C. for 1 hr. After allowing the mixture to cool, the reaction solution was concentrated under reduced pressure. After the residue was dissolved in toluene, the mixture was concentrated under reduced pressure. This was repeated two more times. The residue was dissolved in tetrahydrofuran (250 ml) and the obtained solution was added dropwise to a solution of ethyl 3,3-dimethylaminoacrylate (43.60 g, 0.31 mol) and triethylamine (50.90 ml, 0.37 mol) in tetrahydrofuran (200 ml). The mixture was heated under reflux for 15 hrs. After allowing the mixture to cool, water (300 ml) and ethyl acetate (500 ml) were added to the reaction mixture. The mixture was stirred and partitioned. The organic layer was washed successively with water (300 ml) and saturated brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give a crude object substance (124.80 g) as a brown oil.

Step 9

[0397] ##STR00091##

[0398] The crude product (124.80 g) obtained in Step 8 was dissolved in tetrahydrofuran (500 ml), and (S)-(+)-tert-leucinol hydrochloride (46.80 g, 0.31 mol) and triethylamine (42.50 ml, 0.31 mol) were added. The mixture was stirred at room temperature for 40 min. After filtration of the reaction mixture, the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate (800 ml), washed twice with water, and then with saturated brine, and dried over sodium sulfate. After the filtration, the filtrate was concentrated under reduced pressure to give a crude object substance (131.30 g) as a brown oil.

Step 10

[0399] ##STR00092##

[0400] The crude product (131.30 g) obtained in Step 9 was dissolved in dimethylformamide (400 ml), and imidazole (27.00 g, 0.40 mol) and tert-butyldimethylsilyl chloride (41.30 g, 0.27 mol) were added. The mixture was stirred at room temperature for 14 hrs. Water was added to the reaction solution and the mixture was extracted twice with ethyl acetate (500 ml). The organic layer was washed three times with water and then with saturated brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give a crude object substance (159.80 g) as a brown oil.

Step 11

[0401] ##STR00093##

[0402] The crude product (159.80 g) obtained in Step 10 was dissolved in toluene (1100 ml), and sodium hydride (15.80 g, 0.40 mol) was added. The mixture was stirred with heating at 100° C. for 14 hrs. 1N Hydrochloric acid (400 ml) was added to the reaction solution under ice-cooling and the mixture was stirred and partitioned. The organic layer was washed successively with water and saturated brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the obtained residue was dissolved in dimethylformamide (500 ml). Potassium carbonate (42.10 g, 0.31 mol) and ethyl iodide (24.40 ml, 0.31 mol) was added and the mixture was stirred with heating at 50° C. for 1.5 hrs. A saturated aqueous ammonium chloride solution (400 ml) was added to the reaction solution under ice-cooling, and the mixture was stirred and extracted twice with ethyl acetate. The organic layer was washed successively with water, twice with brine and saturated brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel chromatography (ethyl acetate:hexane=1:3 to 2:3) to give an object product (76.50 g, yield 45%) as a brown oil.

.sup.1H NMR (CDCl.sub.3 400 MHz) (δ) ppm: −0.05 (3H, s), 0.01 (3H, s), 0.73 (9H, s), 0.98 (9H, s), 1.40 (3H, t), 1.53-1.59 (3H, m), 4.10-4.24 (4H, m), 4.34-4.44 (2H, m), 6.10-6.14 (1H, m), 7.22 (1H, s), 8.32 (1H, t, J=2.4 Hz), 8.70 (1H, s)

Step 12

[0403] ##STR00094##

[0404] The compound (76.50 g, 0.14 mol) obtained in Step 11 was dissolved in tetrahydrofuran (500 ml), and under an argon stream, bis(dibenzylideneacetone)palladium(0) (3.17 g, 5.51 mmol) and tri(2-furyl)phosphine (2.56 g, 11.03 mmol) were added. A solution of 3-chloro-2-fluorobenzylzinc bromide (0.28 mol) in tetrahydrofuran was added dropwise at 60° C. After completion of the addition, the mixture was heated under reflux for 2.5 hrs. After allowing the mixture to cool, saturated aqueous ammonium chloride solution (600 ml) was added to the reaction solution. The mixture was stirred at room temperature for 1 hr and filtered with Celite. After the mixture was partitioned, the aqueous layer was extracted with ethyl acetate twice. The organic layer, on the other hand, was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. All ethyl acetate layers were combined and washed successively with 1N hydrochloric acid and saturated brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in dimethylformamide (400 ml) and potassium carbonate (19.00 g, 0.14 mol) and ethyl iodide (11.00 ml, 0.14 mol) were added. The mixture was stirred with heating at 50° C. for 1.5 hrs. A saturated aqueous ammonium chloride solution (400 ml) was added to the reaction mixture with ice-cooling, and the mixture was stirred and extracted with ethyl acetate (500 ml). The organic layer was washed with water, brine (twice) and saturated brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel chromatography (ethyl acetate:hexane=1:2 to 1:1) to give an object product (72.10 g, yield 85%) as a brown oil.

.sup.1H NMR (CDCl.sub.3 400 MHz) (δ) ppm: −0.07 (3H, s), 0.00 (3H, s), 0.70 (9H, s), 1.24 (9H, s), 1.39 (3H, t, J=7.2 Hz), 1.51-1.54 (3H, m), 4.05 (2H, s), 4.07-4.19 (4H, m), 4.33-4.45 (2H, m), 6.12-6.15 (1H, m), 6.99-7.02 (2H, m), 7.04-7.09 (1H, m), 7.19-7.25 (1H, m), 8.06 (1H, d, J=2.4 Hz), 8.69 (1H, s)

Step 13

[0405] ##STR00095##

[0406] The compound (65.80 g, 0.11 mol) obtained in Step 12 was dissolved in ethanol (200 ml) and 1N aqueous sodium hydroxide solution (640 ml, 0.64 mol) was added. The mixture was heated under reflux for 2 hrs. 2N Hydrochloric acid (350 ml) was added to the reaction solution with ice-cooling and the mixture was stirred and extracted twice with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and diethyl ether (500 ml) was added the residue. The mixture was sonicated and the obtained solid was collected by filtration. The collected solid was added to ethyl acetate (250 ml) and dissolved with heating. Hexane (50 ml) was added and the precipitated solid was collected by filtration, vacuum-dried to give an object product (41.10 g, yield 81%) as a white solid.

.sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 0.93 (9H, s), 1.49 (3H, t, J=6.9 Hz), 4.00 (2H, t, J=6.4 Hz), 4.20 (2H, s), 4.22-4.33 (2H, m), 5.12 (1H, t), 6.36 (1H, t, J=6.8 Hz), 7.21 (1H, m), 7.39-7.48 (2H, m), 7.54 (1H, s), 7.79 (1H, s), 8.79 (1H, s), 15.04 (1H, s)

MS (ESI): M+476

Examples 1-3-1-102, 2-1-2-8, 3-1-3-86, 4-1-4-54

[0407] In the same manner as in Examples 1-1 and 1-2 and the above-mentioned Examples, the compounds of Examples 1-3-1-102, 2-1-2-8, 3-1-3-86 and 4-1-4-54 were obtained. The chemical structures thereof are shown in Tables 1, 2, 3 and 4.

EXPERIMENTAL EXAMPLES

[0408] The following explains evaluation methods of the HIV integrase inhibitory activity of the compound of the present invention.

(i) Construction of recombinant integrase gene expression system

[0409] The 185th phenylalanine of HIV integrase full length gene (J. Virol., 67, 425-437 (1993)) was substituted by histidine and inserted into the restriction enzyme Ndel and Xhol sites of plasmid pET21a(+) (Novagen), whereby an integrase expression vector pET21a-IN-F185H was constructed.

(ii) Production and purification of integrase protein

[0410] Escherichia coli recombinant BL21(DE3) transformed with plasmid pET21a-IN-F185H obtained in (i) was shake cultured at 30° C. in a liquid medium containing ampicillin. When the culture reached the logarithmic growth phase, isopropyl-β-D-thiogalactopyranoside was added to promote expression of integrase gene. The culture was continued for 3 hrs to promote accumulation of the integrase protein. The recombinant E. coli was collected in pellets by centrifugal separation and preserved at −80° C.

[0411] The E. coli was suspended in Lysis buffer (20 mM HEPES (pH 7.5), 5 mM DTT, 10 mM CHAPS, 10% glycerol) containing 1M sodium chloride and subjected to repeat pressurization and depressurization for rupture, and centrifugal separation at 4° C., 40,000xg, 60 min to recover a water-soluble fraction (supernatant). This was diluted 10-fold with Lysis buffer free of sodium chloride, mixed with SP-Sepharose (Pharmacia Corporation) and stirred at 4° C. for 60 min to allow adsorption of integrase protein to the resin. The resin was washed with Lysis buffer containing 100 mM sodium chloride and the integrase protein was eluted with Lysis buffer containing 1M sodium chloride.

[0412] The eluted integrase protein solution was applied to a Superdex 75 (Pharmacia Corporation) column for gel filtration. The protein was eluted with Lysis buffer containing 1M sodium chloride.

[0413] The obtained fractions of the integrase protein were collected and preserved at −80° C.

(iii) Preparation of DNA solution

[0414] The following DNA synthesized by Greiner was dissolved in TE buffer (10 mM Tris-hydrochloric acid (pH 8.0), 1 mM EDTA) and mixed with donor DNA, target DNA, each complementary strand (+ and − strands) to 1 M. The mixture was heated at 95° C. for 5 min, 80° C. for 10 min, 70° C. for 10 min, 60° C. for 10 min, 50° C. for 10 min and 40° C. for 10 min and preserved at 25° C. to give a double stranded DNA, which was used for the test.

Donor DNA (-strand having biotin attached to the 5′ terminal)

Donor+strand: 5′-Biotin-ACC CTT TTA GTC AGT GTG GAA AAT CTC TAG CA-3′ (SEQ ID NO:1)

[0415] Donor—strand: 5′-ACT GCT AGA GAT TTT CCA CAC TGA CTA AAA G-3′ (SEQ ID NO:2)
Target DNA (+,—strands both having digoxigenin added at 3′ terminal)

Target+strand: 5′-TGA CCA AGG GCT AAT TCA CT-Dig-3′ (SEQ ID NO:3)

[0416] Target—strand: 5′-AGT GAA TTA GCC CTT GGT CA-Dig-3′ (SEQ ID NO:4)
(iv) Determination of enzyme (HIV integrase) inhibitory activity

[0417] The donor DNA was diluted with TE buffer to 10 nM, of which 50 μl was added to each well of streptavidin-coated microtiter plate (Roche) and allowed to adsorb at 37° C. for 60 min. The DNA was washed with phosphate buffer (Dulbecco PBS, Sanko Junyaku Co., Ltd.) containing 0.1% Tween 20 and phosphate buffer. Then, a reaction mixture (70 μl) having the following composition, a test substance (10 μl) diluted with the reaction mixture and 100 μg/ml integrase protein (10 μl) were added to each well and reacted at 37° C. for 60 min.

[0418] Then, 50 nM target DNA (10 μl) was added, reacted at 37° C. for 10 min and washed with phosphate buffer containing 0.1% Tween 20 to stop the reaction.

[0419] Then, 100 mU/ml peroxidase labeled anti-digoxigenin antibody solution (Roche, 100 μl) was added, and the mixture was reacted at 37° C. for 60 min, followed by washing with phosphate buffer containing 0.1% Tween 20.

[0420] A peroxidase color solution (Bio Rad, 100 μl) was added and allowed to react at room temperature for 4 min. The color reaction was stopped by adding 1N sulfuric acid (100 μl). The absorbance at 450 nm was measured.

[0421] The HIV integrase inhibitory activity (IC.sub.50) of the compound of the present invention was calculated from the inhibition rate according to the following formula. The results are shown in Tables 5, 6 and 7.

inhibition rate (%)=[1−(Object-Blank)/(Control-Blank)]×100

[0422] Object; absorbance of well in the presence of test compound Control; absorbance of well in the absence of test compound Blank; absorbance of well in the absence of test compound, in the absence of integrase protein

Evaluation of Antiviral Activity

[0423] The effect of combined use of the compound of the present invention with known anti-HIV agents can be determined as shown below.

[0424] For example, the effect of two-drug use of an existing nucleoside reverse transcriptase inhibitor (Zidovudine, Lamivudine, Tenofovir), a non-nucleoside reverse transcriptase inhibitor (Efavirenz) or a protease inhibitor (Indinavir, Nelfinavir) and a test substance A, and the like are evaluated in an acute infection system using HIV-1 IIIB-infected CEM-SS cells by the XTT method.

[0425] In addition, the effect of three-drug use of test substance A, Zidovudine and Lamivudine, or test substance A, Tenofovir and Lamivudine and the like is evaluated.

[0426] Prior to the combined use test, IC.sub.50 and CC.sub.50 of each pharmaceutical agent alone are determined. The effect of two-drug use is evaluated based on the combination of five concentrations of pharmaceutical agent A and nine concentrations of pharmaceutical agent B, which have been determined based on the above results. For three-drug use, high concentrations of pharmaceutical agent B and pharmaceutical agent C are mixed and the obtained concentrations are combined with the concentrations of pharmaceutical agent A for evaluation.

[0427] The experimental data of the test substance and pharmaceutical agent to be combined in the case of single use and combined use are analyzed by the programs of Prichard and Shipman MacSynergy II version 2.01 and Delta graph version 1.5d. A three dimensional plot is created at a 95% (or 68%, 99%) confidence level, from the percent inhibition at the concentration of each combined pharmaceutical agent, which is obtained from triplicate experiments, and the effect of combined use is evaluated based on the numerical values of μM.sup.2% calculated therefrom. The evaluation criteria are shown in the following.

TABLE-US-00001 definition of interaction μM.sup.2% highly synergistic >100 slightly synergistic +51 to +100 additive +50 to −50  slightly antagonistic −51 to −100 highly antagonistic <−100  

TABLE-US-00002 TABLE 1 [00096] 1-1 [00097] 1-2 [00098] 1-3 [00099] 1-4 [00100] 1-5 [00101] 1-6 [00102] 1-7 [00103] 1-8 [00104] 1-9 [00105] 1-10 [00106] 1-11 [00107] 1-12 [00108] 1-13 [00109] 1-14 [00110] 1-15 [00111] 1-16 [00112] 1-17 [00113] 1-18 [00114] 1-19 [00115] 1-20 [00116] 1-21 [00117] 1-22 [00118] 1-23 [00119] 1-24 [00120] 1-25 [00121] 1-26 [00122] 1-27 [00123] 1-28 [00124] 1-29 [00125] 1-30 [00126] 1-31 [00127] 1-32 [00128] 1-33 [00129] 1-34 [00130] 1-35 [00131] 1-36 [00132] 1-37 [00133] 1-38 [00134] 1-39 [00135] 1-40 [00136] 1-41 [00137] 1-42 [00138] 1-43 [00139] 1-44 [00140] 1-45 [00141] 1-46 [00142] 1-47 [00143] 1-48 [00144] 1-49 [00145] 1-50 [00146] 1-51 [00147] 1-52 [00148] 1-53 [00149] 1-54 [00150] 1-55 [00151] 1-56 [00152] 1-57 [00153] 1-58 [00154] 1-59 [00155] 1-60 [00156] 1-61 [00157] 1-62 [00158] 1-63 [00159] 1-64 [00160] 1-65 [00161] 1-66 [00162] 1-67 [00163] 1-68 [00164] 1-69 [00165] 1-70 [00166] 1-71 [00167] 1-72 [00168] 1-73 [00169] 1-74 [00170] 1-75 [00171] 1-76 [00172] 1-77 [00173] 1-78 [00174] 1-79 [00175] 1-80 [00176] 1-81 [00177] 1-82 [00178] 1-83 [00179] 1-84 [00180] 1-85 [00181] 1-86 [00182] 1-87 [00183] 1-88 [00184] 1-89 [00185] 1-90 [00186] 1-91 [00187] 1-92 [00188] 1-93 [00189] 1-94 [00190] 1-95 [00191] 1-96 [00192] 1-97 [00193] 1-98 [00194] 1-99 [00195] 1-100 [00196] 1-101 [00197] 1-102

TABLE-US-00003 TABLE 2 [00198] 2-1 [00199] 2-2 [00200] 2-3 [00201] 2-4 [00202] 2-5 [00203] 2-6 [00204] 2-7 [00205] 2-8

TABLE-US-00004 TABLE 3 [00206] 3-1 [00207] 3-2 [00208] 3-3 [00209] 3-4 [00210] 3-5 [00211] 3-6 [00212] 3-7 [00213] 3-8 [00214] 3-9 [00215] 3-10 [00216] 3-11 [00217] 3-12 [00218] 3-13 [00219] 3-14 [00220] 3-15 [00221] 3-16 [00222] 3-17 [00223] 3-18 [00224] 3-19 [00225] 3-20 [00226] 3-21 [00227] 3-22 [00228] 3-23 [00229] 3-24 [00230] 3-25 [00231] 3-26 [00232] 3-27 [00233] 3-28 [00234] 3-29 [00235] 3-30 [00236] 3-31 [00237] 3-32 [00238] 3-33 [00239] 3-34 [00240] 3-35 [00241] 3-36 [00242] 3-37 [00243] 3-38 [00244] 3-39 [00245] 3-40 [00246] 3-41 [00247] 3-42 [00248] 3-43 [00249] 3-44 [00250] 3-45 [00251] 3-46 [00252] 3-47 [00253] 3-48 [00254] 3-49 [00255] 3-50 [00256] 3-51 [00257] 3-52 [00258] 3-53 [00259] 3-54 [00260] 3-55 [00261] 3-56 [00262] 3-57 [00263] 3-58 [00264] 3-59 [00265] 3-60 [00266] 3-61 [00267] 3-62 [00268] 3-63 [00269] 3-64 [00270] 3-65 [00271] 3-66 [00272] 3-67 [00273] 3-68 [00274] 3-69 [00275] 3-70 [00276] 3-71 [00277] 3-72 [00278] 3-73 [00279] 3-74 [00280] 3-75 [00281] 3-76 [00282] 3-77 [00283] 3-78 [00284] 3-79 [00285] 3-80 [00286] 3-81 [00287] 3-82 [00288] 3-83 [00289] 3-84 [00290] 3-85 [00291] 3-86

TABLE-US-00005 TABLE 4 [00292] 4-1 [00293] 4-2 [00294] 4-3 [00295] 4-4 [00296] 4-5 [00297] 4-6 [00298] 4-7 [00299] 4-8 [00300] 4-9 [00301] 4-10 [00302] 4-11 [00303] 4-12 [00304] 4-13 [00305] 4-14 [00306] 4-15 [00307] 4-16 [00308] 4-17 [00309] 4-18 [00310] 4-19 [00311] 4-20 [00312] 4-21 [00313] 4-22 [00314] 4-23 [00315] 4-24 [00316] 4-25 [00317] 4-26 [00318] 4-27 [00319] 4-28 [00320] 4-29 [00321] 4-30 [00322] 4-31 [00323] 4-32 [00324] 4-33 [00325] 4-34 [00326] 4-35 [00327] 4-36 [00328] 4-37 [00329] 4-38 [00330] 4-39 [00331] 4-40 [00332] 4-41 [00333] 4-42 [00334] 4-43 [00335] 4-44 [00336] 4-45 [00337] 4-46 [00338] 4-47 [00339] 4-48 [00340] 4-49 [00341] 4-50 [00342] 4-51 [00343] 4-52 [00344] 4-53 [00345] 4-54

TABLE-US-00006 TABLE 5 Enzyme activity Enzyme activity Ex. No. IC.sub.50 (μM) Ex. No. IC.sub.50 (μM) 1-1 0.029 1-2 0.033 1-3 0.36 1-4 0.24 1-6 0.14 1-7 0.067 1-8 0.046 1-9 0.017 1-10 0.072 1-11 0.18 1-12 0.71 1-13 0.14 1-14 0.075 1-15 0.23 1-16 0.032 1-17 0.084 1-18 0.12 1-19 0.081 1-20 0.69 1-21 0.074 1-22 0.11 1-23 0.19 1-24 0.29 1-25 0.16 1-26 0.18 1-27 0.076 1-28 0.059 1-29 0.24 1-30 0.14 1-31 0.17 1-32 0.068 1-33 0.14 1-34 0.35 1-36 0.18 1-37 0.11 1-38 0.17 1-39 0.18 1-40 0.11 1-41 0.21 1-42 0.13 1-43 0.024 1-44 0.051 1-45 0.21 1-46 0.42 1-47 0.098 1-48 0.38 1-49 0.053 1-50 0.11 1-51 0.18 1-63 0.02 1-64 0.056 1-65 0.12 1-66 0.049 1-67 0.79 1-68 0.049 1-69 0.074 1-70 0.082 1-71 0.013 1-72 0.025 1-73 0.031 1-74 0.098 1-75 0.016 1-76 0.028 1-77 0.063 1-78 0.59 1-79 0.077 1-80 0.35 1-86 0.15 1-87 0.14 1-88 0.45 1-92 0.28 1-93 0.37 1-96 0.23 1-97 0.13 2-1 0.17 2-2 0.18 2-3 0.11 2-4 0.018 2-5 0.30 2-6 0.092 2-7 0.079 2-8 0.085

TABLE-US-00007 TABLE 6 Enzyme activity Enzyme activity Ex. No. IC.sub.50 (μM) Ex. No. IC.sub.50 (μM) 3-1 0.47 3-2 0.2 3-3 0.19 3-4 0.011 3-5 0.024 3-6 0.011 3-8 0.34 3-9 0.084 3-10 0.018 3-12 0.016 3-13 0.029 3-14 0.014 3-17 0.013 3-20 0.01 3-21 0.03 3-22 0.79 3-23 0.0072 3-24 0.039 3-25 0.069 3-26 0.011 3-27 0.075 3-33 0.0087 3-34 0.011 3-35 0.011 3-36 0.051 3-37 0.011 3-38 0.015 3-39 0.049 3-42 0.72 3-43 0.018 3-44 0.0096 3-45 0.015 3-47 0.0086 3-48 0.021 3-49 0.0079 3-50 0.018 3-52 0.012 3-53 0.0079 3-54 0.0064 3-55 0.0087 3-56 0.012 3-57 0.015 3-58 0.008 3-59 0.008 3-60 0.0055 3-61 0.0076 3-62 0.027 3-63 0.017 3-64 0.018 3-65 0.015 3-66 0.048 3-67 0.0064 3-69 0.0043 3-72 0.0038 3-73 0.0033 3-74 0.0049 3-76 0.0085 3-77 0.0089 3-78 0.016 3-79 0.0067 3-80 0.0088 3-86 0.14

TABLE-US-00008 TABLE 7 Enzyme activity Enzyme activity Ex. No. IC.sub.50 (μM) Ex. No. IC.sub.50 (μM) 4-1 0.86 4-4 0.55 4-5 0.13 4-6 0.46 4-7 0.13 4-8 0.033 4-9 0.021 4-11 0.22 4-12 0.065 4-13 0.30 4-15 0.031 4-16 0.0071 4-17 0.0031 4-18 0.0020 4-19 0.0029 4-20 0.0017 4-21 0.0045 4-22 0.0029 4-23 0.0038 4-24 0.0025 4-25 0.0019 4-26 0.0015 4-27 0.0029 4-28 0.0027 4-29 0.0045 4-30 0.0029 4-31 0.0021 4-32 0.0029 4-33 0.0020 4-34 0.0039 4-35 0.0043 4-36 0.0037 4-37 0.0019 4-38 0.0033 4-39 0.0041 4-40 0.0043 4-41 0.0023 4-42 0.0023 4-43 0.0028 4-44 0.0024 4-45 0.0034 4-46 0.0050 4-47 0.0023 4-48 0.0030 4-49 0.0057 4-50 0.0031

[0428] The NMR and MS data of the Example compounds shown in the above-mentioned Table 1 to Table 4 are described in the following.

Example 1-1

[0429] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 3.75 (2H, t, J=4.7 Hz), 4.36 (2H, s), 4.60 (2H, t, J=4.8 Hz), 4.98 (1H, brs), 7.37-7.39 (1H, m), 7.45 (1H, dd, J=1.4, 7.6 Hz), 7.57 (1H, dd, J=1.5, 8.0 Hz), 7.81 (1H, dd, J=2.1, 8.9 Hz), 8.02 (1H, d, J=8.8 Hz), 8.15 (1H, d, J=1.8 Hz), 8.86 (1H, s), 15.18 (1H, brs)

MS (ESI): M+392

Example 1-2

[0430] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 3.78 (2H, m), 4.35 (2H, s), 4.64 (2H, m), 5.00 (1H, m), 7.39 (2H, m), 7.47 (1H, m), 7.58 (1H, m), 8.00 (1H, m), 8.81 (1H, s), 14.80 (1H, s)

MS (ESI): M+409

Example 1-3

[0431] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 2.85 (3H, s), 3.41 (2H, m), 4.37 (2H, s), 4.63 (2H, t, J=5.6 Hz), 7.25-7.29 (1H, m), 7.39 (1H, dd, J=7.8, 7.8 Hz), 7.47 (1H, dd, J=1.5, 7.7 Hz), 7.58 (1H, dd, J=1.5, 7.8 Hz), 7.84 (1H, dd, J=2.0, 8.9 Hz), 8.00 (1H, d, J=8.9 Hz), 8.15 (1H, d, J=1.8 Hz), 8.91 (1H, s)

MS (ESI): M+469

Example 1-4

[0432] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 4.38 (2H, s), 4.46 (2H, t, J=5.9 Hz), 4.90 (2H, t, J=5.9 Hz), 6.84 (1H, s), 7.14 (1H, s), 7.37-7.47 (3H, m), 7.59 (1H, m), 7.82 (1H, m), 8.01 (1H, m), 8.15 (1H, s), 8.66 (1H, s), 14.99 (1H, s)

MS (ESI): M+441

Example 1-5

[0433] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 2.87 (3H, s), 3.12 (3H, s), 4.35 (2H, s), 5.59 (2H, s), 7.38-7.45 (2H, m), 7.57 (1H, m), 7.71-7.76 (2H, m), 8.12 (1H, s), 8.94 (1H, s)

MS (ESI): M+432

Example 1-6

[0434] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 2.64 (3H, d, J=4.4), 4.35 (2H, s), 5.24 (2H, s), 7.35-7.47 (2H, m), 7.56-7.65 (2H, m), 7.80 (1H, m), 8.13 (1H, s), 8.32 (1H, q, J=4.4 Hz), 9.00 (1H, s)

MS (ESI): M+418

Example 1-7

[0435] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 4.36 (2H, s), 5.23 (2H, s), 7.35-7.45 (2H, m), 7.54-7.65 (3H, m), 7.83-7.88 (2H, m), 8.13 (1H, s), 9.01 (1H, s)

MS (ESI): M+404

Example 1-8

[0436] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 1.57 (6H, d, J=6.5 Hz), 4.37 (2H, s), 5.24 (1H, m), 7.38 (1H, dd, J=7.7, 7.7 Hz) 7.46 (1H, dd, J=1.6, 7.7 Hz), 7.58 (1H, dd, J=1.6, 7.7 Hz), 7.85 (1H, dd, J=2.1, 8.9 Hz), 8.15-8.18 (2H, m), 8.86 (1H, s)

MS (ESI): M+389

Example 1-9

[0437] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 4.35 (2H, s), 5.98 (2H, s), 7.37-7.44 (4H, m), 7.57 (1H, m), 7.83 (1H, m), 8.10-8.12 (2H, m), 8.99 (1H, s)

MS (ESI): M+440

Example 1-10

[0438] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 2.85 (2H, m), 4.36 (2H, s), 4.74 (2H, m), 7.38-7.46 (2H, m), 7.58 (1H, m), 7.85 (1H, m), 8.00 (1H, m), 8.14 (1H, s), 9.00 (1H, s)

MS (ESI): M+419

Example 1-11

[0439] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 3.74 (2H, dt, J=4.8, 5.6 Hz), 4.59 (2H, t, J=4.9 Hz), 4.66 (2H, s), 4.98 (1H, t, J=5.6 Hz), 7.48-7.53 (4H, m), 7.85-8.08 (5H, m), 8.18 (1H, m), 8.83 (1H, s), 15.24 (1H, brs)

MS (ESI): M+373

Example 1-12

[0440] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 3.70 (2H, m), 3.72 (3H, s), 4.27 (2H, s), 4.38 (2H, m), 4.96 (1H, br), 7.32-7.41 (2H, m), 7.54 (1H, dd, J=1.8, 7.3 Hz), 7.61 (1H, dd, J=2.2, 8.8 Hz), 7.76 (1H, d, J=8.8 Hz), 8.00 (1H, d, J=2.2 Hz), 8.55 (1H, s)

MS (ESI): M+405

Example 1-13

[0441] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 2.67 (2H, m), 4.37 (2H, s), 4.73 (2H, m), 6.97 (1H, br), 7.38-7.48 (3H, m), 7.58 (1H, m), 7.87 (1H, m), 8.01 (1H, m), 8.15 (1H, s), 8.93 (1H, s)

MS (ESI): M+418

Example 1-14

[0442] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 2.30 (3H, s), 4.34 (2H, s), 5.62 (2H, s), 7.37 (1H, m), 7.44 (1H, m), 7.55 (1H, m), 7.72-7.78 (2H, m), 8.10 (1H, s), 8.90 (1H, s)

MS (ESI): M+403

Example 1-15

[0443] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 4.31 (2H, s), 5.84 (2H, s), 7.26-7.41 (7H, m), 7.55 (1H, m), 7.73 (1H, m), 7.83 (1H, m), 8.13 (1H, m), 9.23 (1H, s), 15.18 (1H, brs)

MS (ESI): M+437

Example 1-16

[0444] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 3.12 (2H, t, J=7.3 Hz), 4.38 (2H, s), 4.78 (2H, t, J=7.3 Hz), 7.20-7.28 (5H, m), 7.37-7.47 (3H, m), 7.58 (1H, m), 7.85 (1H, m), 8.09 (1H, m), 8.15 (1H, s), 8.79 (1H, s), 15.07 (1H, brs)

MS (ESI): M+451

Example 1-17

[0445] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 2.13 (2H, tt, J=7.3, 7.6 Hz), 2.70 (1H, t, J=7.6 Hz), 4.36 (2H, s), 4.58 (2H, t, J=7.3 Hz), 7.15-7.24 (5H, m), 7.38-7.44 (3H, m), 7.57 (1H, m), 7.82 (1H, m), 7.96 (1H, m), 8.13 (1H, s), 8.98 (1H, s), 15.14 (1H, brs)

MS (ESI): M+465

Example 1-18

[0446] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 0.89 (6H, d, J=6.7 Hz), 2.16 (1H, tq, J=6.7, 7.6 Hz), 4.37 (2H, s), 4.39 (2H, d, J=7.6 Hz), 7.38-7.47 (2H, m), 7.58 (1H, m), 7.83 (1H, dd, J=2.0, 8.9 Hz), 8.02 (1H, d, J=8.9 Hz), 8.14 (1H, d, J=2.0 Hz), 8.97 (1H, s), 15.15 (1H, brs)

MS (ESI): M+403

Example 1-19

[0447] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 1.61-1.64 (2H, m), 1.76-1.84 (2H, m), 2.60 (2H, t, J=7.5 Hz), 4.36 (2H, s), 4.56 (2H, t, J=7.2 Hz), 7.15-7.17 (3H, m), 7.22-7.24 (2H, m), 7.38-7.40 (1H, m), 7.44 (1H, m), 7.56-7.59 (1H, m), 7.82 (1H, d, J=2 Hz), 7.96 (1H, d, J=8.9 Hz), 8.14 (1H, d, J=1.8 Hz), 9.01 (1H, s), 15.15 (1H, brs)

MS (ESI): M+514

Example 1-20

[0448] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 4.28 (2H, s), 5.73 (2H, s), 7.02 (1H, d, J=7.6 Hz), 7.27-7.43 (11H, m), 7.55 (1H, d, J=7.6 Hz), 7.60-7.62 (1H, m), 8.08 (1H, d, J=1.6 Hz), 8.92 (1H, s), 14.97 (1H, brs)

MS (ESI): M+502

Example 1-21

[0449] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 1.45-1.49 (2H, m), 1.81-1.85 (2H, m), 3.42 (2H, t, J=6.3 Hz), 4.36 (2H, s), 4.56 (2H, t, J=7.4 Hz), 7.38 (1H, dd, J=7.7, 7.8 Hz), 7.44-7.46 (1H, m), 7.57 (1H, dd, J=1.4, 7.8 Hz), 7.83 (1H, dd, J=2.0, 8.8 Hz), 8.0 (1H, d, J=8.9 Hz), 8.14 (1H, d, J=1.8 Hz), 9.01 (1H, s), 15.18 (1H, brs)

MS (ESI): M+420

Example 1-22

[0450] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 4.32 (2H, s), 6.16 (2H, s), 7.32-7.42 (4H, m), 7.51-7.55 (2H, m), 7.77-7.89 (3H, m), 8.06-8.12 (2H, m), 9.31 (1H, s), 15.02 (1H, brs)

MS (ESI): M+494

Example 1-23

[0451] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 4.31 (2H, s), 5.83 (2H, s), 7.19-7.21 (1H, m), 7.33-7.43 (2H, m), 7.54-7.59 (2H, m), 7.68-7.79 (3H, m), 8.12 (1H, s), 9.25 (1H, s), 15.05 (1H, brs)

MS (ESI): M+508

Example 1-24

[0452] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 2.18 (6H, s), 2.64 (2H, br). 4.36 (2H, s), 4.63 (2H, br), 7.38-7.40 (1H, m), 7.45 (1H, d, J=1.3 Hz), 7.56-7.58 (1H, m), 7.84 (1H, m), 8.00 (1H, d, J=8.9 Hz), 8.14 (1H, d, J=1.7 Hz), 8.90 (1H, s), 15.15 (1H, brs)

MS (ESI): M+419

Example 1-25

[0453] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 1.93-1.98 (2H, m), 3.45 (2H, t, J=5.6 Hz), 4.36 (2H, s), 4.59 (2H, t, J=7.0 Hz), 4.68 (1H, br), 7.37 (1H, dd, J=7.7, 7.8 Hz), 7.44-7.468 (1H, m), 7.57 (1H, d, J=7.8 Hz), 7.83-7.99 (1H, m), 8.00 (1H, d, J=8.9 Hz), 8.14 (1H, s), 8.96 (1H, s), 15.16 (1H, brs)

MS (ESI): M+406

Example 1-26

[0454] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 3.21 (3H, s), 3.70 (2H, t, J=4.8 Hz), 4.36 (2H, s), 4.75 (2H, t, J=4.8 Hz), 7.38 (1H, dd, J=7.7, 7.7 Hz), 7.44-7.47 (1H, m), 7.58 (1H, dd, J=1.6, 7.8 Hz), 7.83 (1H, dd, J=2.1, 8.9 Hz), 8.04 (1H, d, J=8.9 Hz), 8.14 (1H, d, J=2.0 Hz), 8.89 (1H, s), 15.14 (1H, brs)

MS (ESI): M+406

Example 1-27

[0455] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 4.36 (2H, s), 5.68(2H, q, J=8.7 Hz), 7.38 (1H, dd, J=7.7, 7.7 Hz), 7.46 (1H, dd, J=1.7, 7.7 Hz), 7.89 (1H, dd, J=2.1, 8.9 Hz), 8.13-8.16 (2H, m), 9.11 (1H, s), 14.71 (1H, brs)

MS (ESI): M+430

Example 1-28

[0456] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 4.34 (2H, s), 4.78 (2H, s), 7.34-7.44 (2H, m), 7.55-7.57 (1H, m), 7.69 (1H, d, J=8.7 Hz), 7.76 (1H, d, J=9.0 Hz), 8.09 (1H, s), 8.85 (1H, s), 15.37 (1H, brs)

MS (ESI): M+406

Example 1-29

[0457] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 2.04 (3H, s), 3.27-3.38 (2H, m), 4.37 (2H, s), 4.78 (2H, t, J=6.8 Hz), 7.37-7.39 (1H, m), 7.45-7.47 (1H, m), 7.58-7.61 (1H, m), 7.85-7.87 (1H, m), 8.03-8.05 (1H, m), 8.15 (1H, s), 8.73 (1H, s), 8.81 (1H, s)

MS (ESI): M+473

Example 1-30

[0458] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 1.20 (3H, d, J=6.2 Hz), 3.96 (1H, br), 4.15-4.23 (1H, m), 4.36 (2H, s), 4.65-4.69 (1H, m), 5.02 (1H, br), 7.37 (1H, dd, J=7.7, 8.0 Hz), 7.45 (1H, d, J=6.6 Hz), 7.57 (1H, d, J=8.1 Hz), 7.81 (1H, d, J=8.8 Hz), 8.03 (1H, d, J=9.1 Hz), 8.13 (1H, s), 8.84 (1H, s)

MS (ESI): M+406

Example 1-31

[0459] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 3.75 (2H, m), 4.19 (2H, s), 4.61 (2H, m), 5.00 (1H, br), 7.27-7.40 (4H, m), 7.86 (1H, m), 8.02 (1H, m), 8.26 (1H, m), 8.86 (1H, s), 15.29 (1H, s)

MS (ESI): M+357

Example 1-32

[0460] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 2.10 (3H, s), 2.95 (2H, t, J=6.6 Hz), 4.37 (2H, s), 4.76 (2H, t, J=6.6 Hz), 7.38 (1H, dd, J=7.7, 7.8 Hz), 7.45-7.47 (1H, m), 7.58 (1H, dd, J=1.5, 7.9 Hz), 7.90 (1H, dd, J=2.0, 8.9 Hz), 8.00 (1H, d, J=8.9 Hz), 8.15 (1H, d, J=1.8 Hz), 9.02 (1H, s), 15.12 (1H, brs)

MS (ESI): M+422

Example 1-33

[0461] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 3.75 (2H, s), 4.33 (2H, s), 4.60 (2H, t, J=4.8 Hz), 4.98 (1H, br), 7.30-7.33 (1H, m), 7.39-7.42 (2H, m), 7.80 (1H, dd, J=1.7, 8.9 Hz), 8.02 (1H, d, J=8.9 Hz), 8.09 (1H, s), 8.85 (1H, s), 15,14(1H, brs)

MS (ESI): M+375

Example 1-34

[0462] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 1.33-1.44 (4H, m), 1.75-1.81 (2H, m), 3.36-3.38 (2H, m), 4.54 (2H, t, J=7.2 Hz), 7.38 (1H, dd, J=7.7, 7.7 Hz), 7.46 (1H, d, J=6.1 Hz), 7.57 (1H, d, J=7.8 Hz), 7.83 (1H, d, J=8.7 Hz), 8.00 (1H, d, J=8.9 Hz), 8.14 (1H, s), 9.01 (1H, s), 15.19 (1H, brs)

MS (ESI): M+434

Example 1-35

[0463] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 2.33-2.45 (4H, br), 2.64 (2H, t, J=6.2 Hz), 3.52 (2H, t, J=4.4 Hz), 4.27 (2H, s), 4.40 (2H, br), 7.34-7.42 (2H, m), 7.55-7.60 (2H, m), 7.71 (1H, d, J=8.6 Hz), 8.04 (1H, s), 8.57 (1H, s)

MS (ESI): M+461

Example 1-36

[0464] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 4.08 (3H, s), 4.37 (2H, s), 7.37 (1H, dd, J=7.7, 7.7 Hz), 7.44-7.46 (1H, m), 7.57 (1H, dd, J=1.7, 7.8 Hz), 7.84-7.87 (1H, m), 7.92 (1H, d, J=8.8 Hz), 8.12 (1H, s), 9.01 (1H, s), 15.20 (1H, brs)

MS (ESI): M+362

Example 1-37

[0465] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 1.41 (3H, t, J=7.1 Hz), 4.36 (2H, s), 4.58(2H, q, J=7.1 Hz), 7.38 (1H, dd, J=7.8, 7.7 Hz), 7.44-7.46 (1H, m), 7.57 (1H, dd, J=1.5, 7.9 Hz), 7.83 (1H, dd, J=2.1, 8.8 Hz), 8.01 (1H, d, J=8.8 Hz), 8.14 (1H, s), 9.02 (1H, s), 15.18 (1H, brs)

MS (ESI): M+376

Example 1-38

[0466] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 0.90 (3H, t, J=7.3 Hz), 1.77-1.85 (2H, m), 4.36 (2H, s), 4.51 (2H, t, J=7.3 Hz), 7.38 (1H, dd, J=7.8, 7.6 Hz), 7.44-7.46 (1H, m), 7.58 (1H, dd, J=1.7, 7.8 Hz), 7.83 (1H, dd, J=2.1, 8.8 Hz), 8.02 (1H, d, J=8.9 Hz), 8.14 (1H, d, J=2.0 Hz), 9.02 (1H, s), 15.18 (1H, brs)

MS (ESI): M+390

Example 1-39

[0467] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 0.90 (3H, t, J=7.3 Hz), 1.30-1.37 (2H, m), 1.74-1.79 (2H, m), 4.36 (2H, s), 4.54 (2H, t, J=7.3 Hz), 7.38 (1H, dd, J=7.6, 7.8 Hz), 7.46 (1H, dd, J=1.7, 7.6 Hz), 7.58 (1H, dd, J=1.7, 7.8 Hz), 7.83 (1H, dd, J=2.1, 8.9 Hz), 8.00 (1H, d, J=8.9 Hz), 8.14 (1H, d, J=2.0 Hz), 9.01 (1H, s), 15.18 (1H, brs)

MS (ESI): M+404

Example 1-40

[0468] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 1.27-1.29 (2H, m), 1.47-1.50 (2H, m), 1.59-1.66 (4H, m), 2.31-2.40 (1H, m), 4.36 (2H, s), 4.51 (2H, d, J=7.6 Hz), 7.38-7.47 (2H, m), 7.57 (1H, dd, J=1.5, 7.8 Hz), 7.82 (1H, dd, J=2.0, 8.8 Hz), 8.05 (1H, d, J=8.9 Hz), 8.14 (1H, d, J=1.8 Hz), 9.028 (1H, s), 15.16 (1H, brs)

MS (ESI): M+430

Example 1-41

[0469] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 3.11 (3H, s), 3.77 (2H, t), 4,37(2H, s), 4.99 (2H, t), 7.35-7.41 (1H, m), 7.47 (1H, d), 7.58 (1H, d, J=7.8 Hz), 7.83-7.92 (2H, m), 8.16 (1H, s), 9.05 (1H, s)

MS (ESI): M+454

Example 1-42

[0470] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 1.10 (4H, br), 1.54-1.65 (4H, br), 1.83 (1H, br), 4.36 (2H, s), 4.40 (2H, d, J=7.4 Hz), 7.38 (1H, dd, J=7.7, 7.8 Hz), 7.45-7.48 (1H, m), 7.58 (1H, dd, J=1.6, 7.8 Hz), 7.81-7.84 (1H, m), 8.02 (1H, d, J=8.9 Hz), 8.13 (1H, s), 8.93 (1H, s), 15.17 (1H, brs)

MS (ESI): M+444

Example 1-43

[0471] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 4.37 (2H, s), 4.49-4.56 (1H, m), 4.77-4.82 (1H, m), 4.91-4.97 (1H, m), 5.81 (1H, d, J=4.7 Hz), 7.30-760(8H, m), 7.81 (1H, d, J=11.0 Hz), 8.08 (1H, d, J=8.9 Hz), 8.17 (1H, d), 8.93 (1H, s), 15.19 (1H, brs)

MS (ESI): M+468

Example 1-44

[0472] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 4.37 (2H, s), 4.72-4.76 (1H, m), 4.92 (2H, t, J=4.6 Hz), 4.98-5.01 (1H, m), 7.38 (1H, dd, J=7.8, 8.1 Hz), 7.44-7.46 (1H, m), 7.58 (1H, dd, J=1.6, 7.9 Hz), 7.84 (1H, dd, J=2.1, 9.0 Hz), 8.03 (1H, d, J=9.3 Hz), 8.15 (1H, d, J=1.8 Hz), 8.78 (1H, s), 8.98 (1H, s)

MS (ESI): M+394

Example 1-45

[0473] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 3.21 (2H, br), 4.27 (2H, s), 4.65 (2H, br), 7.20-7.28 (2H, m), 7.33-7.41 (2H, m), 7.54-7.70 (5H, m), 7.77 (1H, d, J=8.7 Hz), 8.05 (1H, s), 8.50 (1H, s), 8.52 (1H, s)

MS (ESI): M+453

Example 1-46

[0474] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 2.93 (2H, t), 4.35 (2H, s), 4.48 (2H, s), 7.38 (1H, dd, J=7.7, 7.7 Hz), 7.45 (1H, d, J=6.2 Hz), 7.57 (1H, d, J=7.7 Hz), 7.82 (1H, d), 8.02 (1H, d, J=9.1 Hz), 8.13 (1H, s), 8.92 (1H, s)

MS (ESI): M+391

Example 1-47

[0475] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 1.13 (6H, s), 4.35 (2H, s), 4.50 (2H, s), 4.90 (1H, brs), 7.35-7.46 (2H, m), 7.57 (1H, d, J=7.7 Hz), 7.78 (1H, d, J=7.1 Hz), 8.10 (1H, s), 8.19 (1H, d, J=9.0 Hz), 8.88 (1H, s), 15.22 (1H, brs)

MS (ESI): M+420

Example 1-48

[0476] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 1.68 (3H, s), 3.46 (2H, br). 4.36 (2H, s), 4.56 (2H, br), 7.38-7.60 (3H, m), 7.81-8.13 (4H, m), 8.80 (1H, s)

MS (ESI): M+433

Example 1-49

[0477] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 1.00 (3H, t, J=7.0 Hz), 3.41 (2H, br), 3.82(2H, q), 4.36 (2H, s), 4.57 (2H, br), 7.24 (1H, m), 7.38 (1H, m), 7.46 (1H, m), 7.58 (1H, m), 7.83 (1H, m), 8.03 (1H, m), 8.13 (1H, s), 8.82 (1H, s)

MS (ESI): M+463

Example 1-50

[0478] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 3.75 (2H, m), 4.26 (2H, s), 4.61 (2H, t, J=4.8 Hz), 5.00 (1H, br), 7.17-7.36 (3H, m), 7.83 (1H, dd, J=2.0, 8.8 Hz), 8.03 (1H, d, J=8.9 Hz), 8.21 (1H, s), 8.87 (1H, s), 15.22 (1H, brs)

MS (ESI): M+360

Example 1-51

[0479] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 3.75 (2H, m), 4.28 (2H, s), 4.61 (2H, t, J=4.8 Hz), 5.00 (1H, br), 7.24-7.28 (1H, m), 7.44-7.55 (2H, m), 7.80 (1H, dd, J=2.1, 8.8 Hz), 8.02 (1H, d, J=8.9 Hz), 8.13 (1H, d, J=1.9 Hz), 8.86 (1H, s), 15.22 (1H, s)

MS (ESI): M+376

Example 1-52

[0480] .sup.1H NMR (CDCl.sub.3 300 MHz) (δ) ppm: 1.42 (3H, t, J=7.1 Hz), 4.05 (2H, s), 4.40(2H, q, J=7.1 Hz), 5.35 (2H, s), 7.13-7.28 (8H, m), 7.33-7.35 (2H, m), 8.41 (1H, d, J=2.0 Hz), 8.58 (1H, s)

MS (ESI): M+398

Example 1-53

[0481] .sup.1H NMR (CDCl.sub.3 300 MHz) (δ) ppm: 4.10 (2H, s), 5.48 (2H, s), 7.13-7.50 (12H, m), 8.41 (1H, d, J=1.9 Hz), 8.87 (1H, s), 14.96 (1H, brs)

MS (ESI): M+370

Example 1-54

[0482] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 4.16 (2H, s), 5.44 (2H, s), 7.19-7.34 (5H, m), 7.74 (1H, d, J=8.8 Hz), 7.83 (1H, dd, J=2.0, 8.9 Hz), 8.22 (1H, d, J=1.9 Hz), 9.08 (1H, s), 13.58 (1H, brs), 15.13 (1H, brs)

MS (ESI): M+338

Example 1-55

[0483] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 0.89 (3H, t, J=7.3 Hz), 1.25-1.35 (5H, m), 1.66-1.76 (2H, m), 4.09 (2H, s), 4.21(2H, q, J=7.1 Hz), 4.34 (2H, t, J=7.2 Hz), 7.20-7.33 (5H, m), 7.66 (1H, dd, J=2.1, 8.7 Hz), 7.74 (1H, d, J=8.7 Hz), 8.06 (1H, d, J=1.9 Hz), 8.64 (1H, s)

MS (ESI): M+364

Example 1-56

[0484] .sup.1H NMR (CDCl.sub.3 300 MHz) (δ) ppm: 0.99 (3H, t, J=7.3 Hz), 1.43 (2H, m), 1.84-1.94 (2H, m), 4.15 (2H, s), 4.28 (2H, t, J=7.4 Hz), 7.20-7.34 (5H, m), 7.52 (1H, d, J=8.8 Hz), 7.65 (1H, dd, J=2.1, 8.8 Hz), 8.42 (1H, d, J=1.9 Hz), 8.72 (1H, s), 15.04 (1H, brs)

MS (ESI): M+336

Example 1-57

[0485] .sup.1H NMR (CDCl.sub.3 300 MHz) (δ) ppm: 1.41 (3H, t, J=7.2 Hz), 3.85 (3H, s), 4.11 (2H, s), 4.39(2H, q, J=7.2 Hz), 7.17-7.35 (6H, m), 7.51 (1H, dd, J=2.4, 8.4 Hz), 8.42 (1H, d, J=1.8 Hz), 8.45 (1H, s)

MS (ESI): M+322

Example 1-58

[0486] .sup.1H NMR (CDCl.sub.3 300 MHz) (δ) ppm: 3.99 (3H, s), 4.16 (2H, s), 7.19-7.33 (5H, m), 7.52 (1H, d, J=8.7 Hz), 7.68 (1H, dd, J=2.0, 8.7 Hz), 8.41 (1H, s), 8.72 (1H, s)

MS (ESI): M+294

Example 1-59

[0487] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 2.08-2.15 (2H, m), 2.69 (2H, t, J=7.8 Hz), 4.16 (2H, s), 4.57 (2H, t, J=7.3 Hz), 7.15-7.31 (10H, m), 7.81 (1H, dd, J=2.0, 8.8 Hz), 7.92 (1H, d, J=8.8 Hz), 8.20 (1H, d, J=1.9 Hz), 8.96 (1H, s), 15.21 (1H, brs)

MS (ESI): M+398

Example 1-60

[0488] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 3.11 (2H, t, J=7.3 Hz), 4.18 (2H, s), 4.77 (2H, t, J=7.4 Hz), 7.19-7.35 (10H, m), 7.86 (1H, d, J=8.7 Hz), 8.06 (1H, d, J=8.8 Hz), 8.22 (1H, s), 8.76 (1H, s), 15.14 (1H, brs)

MS (ESI): M+384

Example 1-61

[0489] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 1.99-2.03 (2H, m), 2.37 (2H, t, J=7.1 Hz), 4.17 (2H, s), 4.54 (2H, t, J=7.3 Hz), 7.21-7.34 (5H, m), 7.87 (1H, dd, J=2.0, 8.8 Hz), 8.05 (1H, d, J=8.8 Hz), 8.21 (1H, d, J=1.9 Hz), 8.98 (1H, s), 12.01 (1H, brs), 15.28 (1H, brs)

MS (ESI): M+366

Example 1-62

[0490] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 4.15 (2H, s), 5.48 (2H, s), 7.06-7.10 (1H, m), 7.20-7.22 (1H, m), 7.28-7.34 (6H, m), 7.56-7.58 (2H, m), 7.74 (1H, d, J=8.8 Hz), 7.848.9 Hz), 8.23 (1H, s), 9.10 (1H, s), 10.63 (1H, brs), 15.18 (1H, brs)

MS (ESI): M+413

Example 1-63

[0491] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 3.72 (2H, m), 4.26 (2H, s), 4.35 (2H, m), 5.23 (1H, br), 7.32-7.41 (2H, m), 7.53-7.58 (2H, m), 7.72 (1H, m), 8.05 (1H, s), 8.63 (1H, s)

MS (ESI): M+391

Example 1-64

[0492] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 3.72 (2H, m), 4.23 (2H, s), 4.35 (2H, m), 5.24 (1H, br), 7.25-7.40 (3H, m), 7.57 (1H, m), 7.72 (1H, m), 8.03 (1H, s), 8.63 (1H, s)

MS (ESI): M+375

Example 1-65

[0493] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 3.12 (2H, t, J=7.3 Hz), 4.31 (2H, s), 4.78 (2H, t, J=7.3 Hz), 7.20-7.36 (7H, m), 7.46-7.48 (2H, m), 7.86 (1H, m), 8.09 (1H, m), 8.15 (1H, s), 8.78 (1H, s), 15.08 (1H, brs)

MS (ESI): M+417

Example 1-66

[0494] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 3.79 (2H, m), 4.39 (2H, s), 4.65 (2H, m), 5.04 (1H, m), 7.31-7.47 (3H, m), 7.88 (1H, m), 8.07 (1H, m), 8.19 (1H, m), 8.90 (1H, s), 15.25 (1H, s)

MS (ESI): M+375

Example 1-67

[0495] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 3.74 (2H, m), 4.35 (2H, s), 4.62 (2H, m), 5.00 (1H, br), 7.62 (1H, m), 7.81 (1H, m), 7.90 (1H, m), 8.02-8.13 (2H, m), 8.23 (1H, m), 8.32 (1H, m), 8.87 (1H, s)

MS (ESI): M+368

Example 1-68

[0496] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 2.09 (3H, s), 4.35 (2H, s), 5.75 (2H, s), 7.37 (1H, m), 7.44 (1H, m), 7.55 (1H, m), 7.83 (1H, m), 8.01 (1H, m), 8.12 (1H, m), 9.10 (1H, s)

MS (ESI): M+407

Example 1-69

[0497] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 3.20 (3H, s), 4.36 (2H, s), 6.22 (2H, s), 7.36-7.47 (2H, m), 7.58 (1H, m), 7.86 (1H, m), 8.12-8.15 (2H, m), 9.04 (1H, s)

MS (ESI): M+439

Example 1-70

[0498] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 1.22 (9H, s), 4.36 (2H, s), 5.99 (2H, s), 7.35-7.46 (3H, m), 7.58 (1H, m), 7.84 (1H, m), 8.08-8.11 (2H, m), 8.95 (1H, s), 14.75 (1H, br)

MS (ESI): M+496

Example 1-71

[0499] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 2.62 (3H, d, J=4.7 Hz), 4.36 (2H, s), 6.11 (2H, s), 7.36-7.47 (2H, m), 7.54-7.60 (2H, m), 7.84 (1H, m), 8.10-8.13 (2H, m), 8.98 (1H, s), 14.79 (1H, br)

MS (ESI): M+454

Example 1-72

[0500] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 2.77 (6H, s), 4.37 (2H, s), 6.20 (2H, s), 7.39 (1H, dd, J=7.8, 7.8 Hz), 7.47 (1H, dd, J=1.7, 7.8 Hz), 7.59 (1H, dd, J=1.7, 7.8 Hz), 7.89 (1H, m), 8.11-8.14 (2H, m), 9.04 (1H, s), 14.69 (1H, br)

MS (ESI): M+468

Example 1-73

[0501] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 3.75 (2H, br), 4.36 (2H, s), 4.60 (2H, m), 5.00 (1H, br), 7.39-7.49 (2H, m), 7.82 (1H, m), 8.04 (1H, m), 8.11 (1H, s), 8.87 (1H, s), 15.14 (1H, brs)

MS (ESI): M+393

Example 1-74

[0502] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 3.41 (1H, m), 3.51 (1H, m), 3.82 (1H, m), 4.26 (1H, m), 4.36 (2H, s), 4.79 (1H, m), 4.93 (1H, m), 5.19 (1H, m), 7.38 (1H, m), 7.46 (1H, m), 7.58 (1H, m), 7.84 (1H, m), 7.97 (1H, m), 8.15 (1H, m), 8.84 (1H, s)

MS (ESI): M+421

Example 1-75

[0503] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 4.32 (2H, s), 5.98 (2H, s), 7.31-7.43 (5H, m), 7.80 (1H, m), 8.06 (1H, m), 8.12 (1H, m), 8.99 (1H, m), 14.81 (1H, brs)

MS (ESI): M+424

Example 1-76

[0504] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 2.62 (3H, d, J=4.4 Hz), 4.32 (2H, s), 6.11 (2H, s), 7.30-7.43 (3H, m), 7.53 (1H, q, J=4.4 Hz), 7.84 (1H, m), 8.06 (1H, s), 8.12 (1H, m), 8.98 (1H, m), 14.74 (1H, s)

MS (ESI): M+438

Example 1-77

[0505] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 2.77 (6H, s), 4.33 (2H, s), 6.19 (2H, s), 7.27-7.44 (3H, m), 7.89 (1H, m), 8.06-8.14 (2H, m), 9.03 (1H, s), 14.64 (1H, s)

MS (ESI): M+452

Example 1-78

[0506] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 3.74 (2H, dt, J=4.8, 5.6 Hz), 4.17 (2H, s), 4.60 (2H, t, J=4.8 Hz), 4.99 (1H, t, J=5.6 Hz), 7.20-7.32 (5H, m), 7.82 (1H, m), 7.99 (1H, m), 8.21 (1H, m), 8.84 (1H, s), 15.27 (1H, s)

MS (ESI): M+323

Example 1-79

[0507] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 2.34 (3H, s), 3.75 (2H, br). 4.30 (2H, s), 4.61 (2H, t, J=4.7 Hz), 5.00 (1H, br), 7.21-7.31 (3H, m), 7.81 (1H, dd, J=2.0, 8.9 Hz), 8.01 (1H, d, J=8.9 Hz), 8.15 (1H, d, J=2.0 Hz), 8.86 (1H, s), 15.23 (1H, s)

MS (ESI): M+371

Example 1-80

[0508] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 3.76 (2H, m), 4.31 (2H, s), 4.61 (2H, m), 5.01 (1H, m), 7.23 (1H, m), 7.36-7.47 (2H, m), 7.65 (1H, m), 7.81 (1H, m), 8.02 (1H, m), 8.14 (1H, m), 8.86 (1H, s)

MS (ESI): M+401

Example 1-81

[0509] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 2.26 (3H, s), 3.75 (2H, m). 4.12 (2H, s), 4.60 (2H, m), 4.99 (1H, m), 7.10-7.18 (4H, m), 7.80 (1H, m), 7.99 (1H, m), 8.20 (1H, m), 8.85 (1H, s), 15.29 (1H, s)

MS (ESI): M+337

Example 1-82

[0510] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 3.73 (2H, dt, J=4.8, 5.2 Hz). 3.84 (3H, s), 4.28 (2H, s), 4.60 (2H, t, J=4.8 Hz), 5.00 (1H, t, J=5.2 Hz), 7.04-7.07 (2H, m), 7.30 (1H, m), 7.79 (1H, m), 8.00 (1H, m), 8.11 (1H, m), 8.84 (1H, s), 15.22 (1H, s)

MS (ESI): M+387

Example 1-83

[0511] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 3.75 (2H, m), 4.50 (2H, s), 4.62 (2H, m), 7.60-8.15 (5H, m), 8.35 (1H, s), 8.68 (1H, m), 8.87 (1H, s), 15.25 (1H, br)

MS (ESI): M+324

Example 1-84

[0512] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 3.75 (2H, m), 4.33 (2H, s), 4.62 (2H, m), 7.57 (2H, d, J=6.3 Hz), 7.89 (1H, dd, J=2.1, 8.7 Hz), 8.07 (1H, d, J=8.7 Hz), 8.32 (1H, d, J=2.1 Hz), 8.62 (1H, d, J=6.3 Hz), 8.88 (2H, s)

MS (ESI): M+324

Example 1-85

[0513] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 3.21 (3H, s), 3.77 (2H, m), 4.61 (2H, m), 4.66 (2H, s), 5.02 (1H, m), 7.38 (1H, m), 7.55 (1H, m), 7.68 (1H, m), 7.81 (1H, m), 8.00-8.05 (2H, m), 8.19 (1H, m), 8.87 (1H, s)

MS (ESI): M+401

Example 1-86

[0514] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 3.73 (2H, m), 4.15 (2H, s), 4.58 (2H, m), 5.00 (1H, m), 7.23-7.50 (10H, m), 7.88-7.92 (2H, m), 8.83 (1H, s)

MS (ESI): M+399

Example 1-87

[0515] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 3.75 (2H, m), 4.30 (2H, s), 4.61 (2H, m), 5.00 (1H, br), 7.26-7.38 (2H, m), 7.43-7.49 (2H, m), 7.82 (1H, m), 8.02 (1H, m), 8.14 (1H, m), 8.86 (1H, s), 15.32 (1H, s)

MS (ESI): M+357

Example 1-88

[0516] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 3.74 (2H, m), 4.25 (2H, s), 4.60 (2H, m), 4.98 (1H, br), 7.25-7.53 (6H, m), 7.59-7.66 (3H, m), 7.87 (1H, m), 8.10 (1H, m), 8.29 (1H, m), 8.85 (1H, s), 15.30 (1H, s)

MS (ESI): M+399

Example 1-89

[0517] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 3.79 (2H, m), 4.33 (2H, s), 4.64 (2H, m), 5.03 (1H, m), 7.57-7.65 (3H, m), 7.76 (1H, m), 7.91 (1H, m), 8.06 (1H, m), 8.32 (1H, m), 8.90 (1H, s), 15.31 (1H, s)

MS (ESI): M+391

Example 1-90

[0518] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 1.30 (3H, t, J=6.8 Hz), 3.74 (2H, m), 3.98 (2H, q, J=6.8 Hz), 4.12 (2H, s), 4.60 (2H, m), 5.01 (1H, m), 6.76 (1H, m), 6.82-6.84 (2H, m), 7.20 (1H, m), 7.82 (1H, m), 7.99 (1H, m), 8.22 (1H, m), 8.85 (1H, s)

MS (ESI): M+367

Example 1-91

[0519] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 3.75 (2H, m), 4.25 (2H, s), 4.61 (2H, m), 7.53 (1H, m), 7.66-7.71 (2H, m), 7.83-7.89 (2H, m), 8.02 (1H, m), 8.28 (1H, m), 8.87 (1H, s)

MS (ESI): M+348

Example 1-92

[0520] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 2.48 (3H, m), 3.74 (2H, m).sub.f 4.26 (2H, s), 4.61 (2H, m), 5.09 (1H, br), 7.19 (1H, m), 7.39 (2H, m), 7.82 (1H, m), 8.04 (1H, m), 8.13 (1H, s), 8.85 (1H, s), 15.22 (1H, s)

MS (ESI): M+403

Example 1-93

[0521] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 3.75 (2H, m), 4.24 (2H, s), 4.61 (2H, m), 5.02 (1H, br), 7.38-7.47 (4H, m), 7.80 (1H, m), 8.03 (1H, m), 8.16 (1H, m), 8.86 (1H, s), 15.23 (1H, s)

MS (ESI): M+407

Example 1-94

[0522] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 3.76 (2H, m), 3.99 (2H, s), 4.61 (2H, m), 5.01 (3H, m), 6.41 (3H, m), 6.93 (1H, m), 7.78 (1H, m), 8.00 (1H, m), 8.20 (1H, m), 8.86 (1H, s)

MS (ESI): M+338

Example 1-95

[0523] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 1.00 (3H, s), 3.76 (2H, m).sub.f 4.13 (2H, s), 4.61 (2H, m), 5.01 (1H, m), 6.98 (1H, m), 7.23 (1H, m), 7.43 (2H, m), 7.81 (1H, m), 8.01 (1H, m), 8.21 (1H, m), 8.86 (1H, s), 9.87 (1H, s)

MS (ESI): M+380

Example 1-96

[0524] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 3.73 (2H, m), 4.18 (2H, s), 4.59 (2H, m), 4.98 (1H, br), 7.26 (1H, s), 7.29 (1H, m), 7.39 (1H, m), 7.53 (1H, m), 7.99 (1H, s), 8.24 (1H, m), 8.85 (1H, s), 15.25 (1H, s)

MS (ESI): M+401

Example 1-97

[0525] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 2.28 (3H, s), 3.75 (2H, m), 4.25 (2H, s), 4.61 (2H, m), 5.04 (1H, br), 7.13 (1H, s), 7.29-7.36 (2H, m), 7.81 (1H, m), 8.03 (1H, m), 8.13 (1H, s), 8.86 (1H, s), 15.24 (1H, s)

MS (ESI): M+371

Example 1-98

[0526] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 2.59 (6H, s), 3.75 (2H, m), 4.33 (2H, s), 4.61 (2H, m), 5.00 (1H, m), 7.59-7.64 (3H, m), 7.73 (1H, m), 7.87 (1H, m), 8.03 (1H, m), 8.27 (1H, s), 8.86 (1H, s), 15.27 (1H, s)

MS (ESI): M+430

Example 1-99

[0527] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 3.75 (2H, m), 4.26 (2H, s), 4.61 (2H, m), 5.00 (1H, br), 7.21 (1H, m), 7.38-7.51 (2H, m), 7.83 (1H, m), 8.03 (1H, m), 8.22 (1H, s), 8.87 (1H, s)

MS (ESI): M+375

Example 1-100

[0528] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 3.76 (2H, m), 4.26 (2H, s), 4.61 (2H, m), 4.99 (1H, m), 7.25 (1H, m), 7.61 (1H, m), 7.81 (1H, m), 8.04 (1H, m), 8.16 (1H, m), 8.87 (1H, s), 15.16 (1H, s)

MS (ESI): M+393

Example 1-101

[0529] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 3.79 (2H, m), 4.01 (3H, s), 4.19 (2H, s), 4.64-4.65 (2H, m), 5.02 (1H, t, J=5.5 Hz), 7.25 (1H, d, J=1.6 Hz), 7.31-7.35 (2H, m), 7.56-7.58 (1H, m), 7.82 (1H, s), 8.78 (1H, s), 15.38 (1H, brs)

MS (ESI): M+422

Example 1-102

[0530] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 1.19 (2H, m), 1.30 (2H, m), 3.83 (1H, m), 4.37 (2H, s), 7.38 (1H, m), 7.46 (1H, m), 7.57 (1H, m), 7.89 (1H, m), 8.12 (1H, m), 8.24 (1H, m), 8.73 (1H, s), 15.05 (1H, s)

MS (ESI): M+387

Example 2-1

[0531] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 4.37 (2H, s), 6.88 (2H, brs), 7.35-7.47 (2H, m), 7.58 (1H, m), 7.87 (1H, dd, J=2.1, 8.9 Hz), 8.08 (1H, d, J=2.1 Hz), 8.16 (1H, d, J=8.9 Hz), 8.86 (1H, s), 15.24 (1H, brs)

MS (ESI): M+362

Example 2-2

[0532] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 3.75 (3H, brs), 4.36 (2H, s), 7.35 (1H, m), 7.42 (1H, m), 7.54 (1H, m), 7.72 (1H, m), 7.85 (1H, m), 8.10 (1H, s), 9.03 (1H, s), 11.61 (1H, brs)

MS (ESI): M+420

Example 2-3

[0533] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 2.16 (3H, s), 4.36 (2H, s), 7.35-7.45 (2H, m), 7.58 (1H, dd, J=1.8, 7.8 Hz), 7.76-7.85 (2H, m), 8.10 (1H, s), 8.96 (1H, s), 12.02 (1H, brs), 14.77 (1H, brs)

MS (ESI): M+405

Example 2-4

[0534] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 3.32 (3H, s), 4.37 (2H, s), 7.38 (1H, m), 7.46 (1H, m), 7.58 (1H, m), 7.86 (1H, m), 8.06-8.10 (2H, m), 8.82 (1H, s), 14.60 (1H, br)

MS (ESI): M+440

Example 2-5

[0535] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 3.46 (3H, s), 3.53 (3H, s), 4.37 (2H, s), 7.38 (1H, dd, J=7.8, 7.8 Hz), 7.47 (1H, dd, J=2.1, 7.8 Hz), 7.58 (1H, dd, J=2.1, 7.8 Hz), 7.88 (1H, dd, J=1.8, 8.7 Hz), 7.97 (1H, d, J=8.7 Hz), 8.12 (1H, d, J=1.8 Hz), 9.11 (1H, s), 15.54 (1H, brs)

MS (ESI): M+454

Example 2-6

[0536] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 2.96 (6H, s), 4.36 (2H, s), 7.38 (1H, dd, J=7.8, 7.8 Hz), 7.46 (1H, dd, J=2.0, 7.8 Hz), 7.57 (1H, dd, J=2.0, 7.8 Hz), 7.86 (1H, dd, J=2.2, 8.8 Hz), 8.12 (1H, d, J=2.2 Hz), 8.25 (1H, d, J=8.8 Hz), 9.25 (1H, s), 15.14 (1H, brs)

MS (ESI): M+390

Example 2-7

[0537] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 2.84 (3H, d), 4.35 (2H, s), 7.19 (1H, q), 7.38 (1H, m), 7.45 (1H, m), 7.55 (1H, m), 7.85 (1H, m), 8.09-8.11 (2H, m), 8.99 (1H, m)

MS (ESI): M+376

Example 2-8

[0538] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 1.09 (3H, t, J=7.1 Hz), 3.13 (2H, dq, J=6.1, 7.1 Hz), 4.36 (2H, s), 7.19 (1H, t, J=6.1 Hz), 7.38 (1H, dd, J=7.7, 7.7 Hz), 7.46 (1H, dd, J=1.7, 7.7 Hz), 7.58 (1H, dd, J=1.7, 7.8 Hz), 7.85 (1H, dd, J=2.1, 8.8 Hz), 8.10 (1H, d, J=2.1 Hz), 8.15 (1H, d, J=8.8 Hz), 8.99 (1H, s), 15.14 (1H, brs)

MS (ESI): M+390

Example 3-1

[0539] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 3.75 (2H, m), 3.79 (3H, s), 4.28 (2H, s), 4.57 (2H, m), 5.02 (1H, m), 7.17 (1H, m), 7.32 (1H, m), 7.57 (2H, m), 7.76 (1H, m), 8.83 (1H, m), 15.75 (1H, s)

MS (ESI): M+421

Example 3-2

[0540] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 2.24 (3H, s), 3.77 (2H, dd, J=5.2, 5.6 Hz), 4.27 (2H, s), 4.61 (2H, t, J=5.2 Hz), 5.05 (1H, t, J=5.6 Hz), 7.23 (2H, m), 7.34 (1H, m), 7.76 (1H, m), 8.03 (1H, m), 8.08 (1H, m), 8.86 (1H, s), 15.23 (1H, s)

MS (ESI): M+371

Example 3-3

[0541] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 3.73 (5H, s), 4.21 (2H, s), 4.61 (2H, t, J=4.8 Hz), 5.01 (1H, t, J=5.2 Hz), 5.02 (1H, m), 7.12 (1H, m), 7.25 (1H, m), 7.37 (1H, m), 7.81 (1H, m), 8.01 (1H, m), 8.19 (1H, m), 8.86 (1H, s), 15.26 (1H, s)

MS (ESI): M+387

Example 3-4

[0542] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 3.80 (2H, m), 4.01 (3H, s), 4.12 (2H, s), 4.65 (2H, m), 5.02 (1H, m), 7.17-7.50 (4H, m), 8.03 (1H, s), 8.81 (1H, s), 15.45 (1H, s)

MS (ESI): M+405

Example 3-5

[0543] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 3.74 (2H, t), 4.17 (2H, s), 4.56 (2H, t), 5.02 (1H, br), 7.20 (1H, m), 7.31 (1H, m), 7.38 (1H, m), 7.52-7.56 (2H, m), 8.86 (1H, s), 13.63 (1H, s)

MS (ESI): M+407

Example 3-6

[0544] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 3.78 (2H, t), 4.18 (2H, s), 4.44-4.49 (2H, m), 5.08 (1H, t), 7.20-7.25 (2H, m), 7.34-7.40 (1H, m), 7.56 (1H, d), 7.82 (1H, s), 8.77 (1H, s), 11.10-11.30 (1H, br), 15.49 (1H, s)

MS (ESI): M+408

Example 3-7

[0545] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 2.68 (3H, d, J=4.4 Hz), 3.74 (2H, t, J=4.8 Hz), 4.04 (2H, s), 4.60 (2H, t, J=4.8 Hz), 5.01 (1H, t), 5.27 (1H, q, J=5.2 Hz), 6.51-6.56 (2H, m), 6.95 (1H, d), 7.07-7.09 (1H, m), 7.78 (1H, d, J=9.2 Hz), 7.98 (1H, d, J=8.8 Hz), 8.21 (1H, s), 8.84 (1H, s), 15.33 (1H, s)

MS (ESI): M+353

Example 3-8

[0546] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 2.62 (6H, s), 3.74 (2H, t), 4.24 (2H, s), 4.60 (2H, t, J=4.8 Hz), 5.01 (1H, t), 6.97-7.05 (2H, m), 7.21 (2H, m), 7.77 (1H, d, J=11.2 Hz), 7.97 (1H, d), 8.16 (1H, s), 8.85 (1H, s), 15.29 (1H, s)

MS (ESI): M+367

Example 3-9

[0547] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 4.35 (2H, s), 7.11 (1H, d, J=8.8 Hz), 7.37-7.40 (1H, m), 7.44 (1H, d), 7.56 (1H, d), 7.69-7.74 (6H, m), 8.19 (1H, s), 8.68 (1H, s), 14.99 (1H, s)

MS (ESI): M+424

Example 3-10

[0548] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 3.84-3.95 (4H, m), 4.36 (2H, s), 5.11-5.19 (3H, m), 7.38 (1H, m), 7.45 (1H, d), 7.57 (1H, d), 7.82 (1H, d, J=9.2 Hz), 8.15 (1H, d, J=8.8 Hz), 8.90 (1H, s), 15.21 (1H, s)

MS (ESI): M+422

Example 3-11

[0549] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 3.76 (2H, t), 4.05 (2H, s), 4.59 (2H, t), 5.00 (1H, t), 6.61 (1H, d), 6.64 (1H, s), 6.70 (1H, d, J=8.0 Hz), 7.09-7.11 (1H, m), 7.81 (1H, d, J=8.8 Hz), 8.00 (1H, d, J=8.8 Hz), 8.21 (1H, s), 8.86 (1H, s), 9.30 (1H, s), 15.30 (1H, s)

MS (ESI): M+340

Example 3-12

[0550] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 1.80-1.90 (2H, m), 2.45-2.50 (2H, m), 2.60-2.70 (2H, m), 4.36 (2H, s), 5.11-5.16 (1H, m), 7.38-7.40 (1H, m), 7.45 (1H, d), 7.57 (1H, d), 7.81 (1H, d, J=8.8 Hz), 7.93 (1H, d), 8.14 (1H, s), 8.68 (1H, s), 15.16 (1H, s)

MS (ESI): M+402

Example 3-13

[0551] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 1.70-1.90 (4H, m), 1.91-2.00 (2H, m), 2.20-2.30 (2H, m), 4.37 (2H, s), 5.20-5.30 (1H, m), 7.38-7.40 (1H, m), 7.45 (1H, d), 7.57 (1H, d), 7.86 (1H, d), 8.16 (1H, d), 8.19 (1H, s), 8.75 (1H, s), 15.16 (1H, s)

MS (ESI): M+416

Example 3-14

[0552] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 3.70-3.80 (2H, m), 3.96 (3H, s), 4.32 (2H, s), 4.81 (2H, t), 4.90 (1H, t), 7.35-7.43 (2H, m), 7.54-7.59 (2H, m), 7.69 (1H, s), 8.69 (1H, s), 15.16 (1H, s)

MS (ESI): M+422

Example 3-15

[0553] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 2.88 (3H, s), 2.95 (3H, s), 3.70-3.80 (2H, m), 4.21 (2H, s), 4.61 (2H, t), 4.99 (1H, t), 7.20-7.23 (1H, m), 7.33 (1H, s), 7.37-7.38 (2H, dx2), 7.86 (1H, d), 8.02 (1H, d, J=8.8 Hz), 8.26 (1H, s), 8.86 (1H, s), 15.30 (1H, s)

MS (ESI): M+395

Example 3-16

[0554] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 2.71 (6H, s), 3.70-3.76 (2H, m), 4.58 (2H, s), 4.60 (2H, t, J=5.2 Hz), 5.02 (1H, t), 7.42 (1H, d), 7.51 (1H, m), 7.64 (1H, m), 7.80 (1H, d), 7.84 (1H, d), 8.01 (1H, d, J=8.8 Hz), 8.11 (1H, s), 8.86 (1H, s), 15.25 (1H, s)

MS (ESI): M+431

Example 3-17

[0555] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 3.73-3.75 (2H, m), 4.24 (2H, s), 4.61 (2H, t), 5.00 (1H, t, J=5.6 Hz), 7.31 (1H, m), 7.48-7.51 (1H, m), 7.84 (1H, d), 8.02 (1H, d), 8.21 (1H, s), 8.87 (1H, s), 15.22 (1H, s)

MS (ESI): M+394

Example 3-18

[0556] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 3.70-3.80 (2H, m), 4.56 (2H, s), 4.60 (2H, t), 5.00 (1H, t), 7.38-7.43 (2H, m), 7.52-7.54 (1H, m), 7.78 (1H, d), 7.87 (1H, d, J=7.8 Hz), 7.98 (1H, d, J=8.9 Hz), 8.11 (1H, s), 8.84 (1H, s), 12.60-13.00 (1H, br), 15.29 (1H, s)

MS (ESI): M+368

Example 3-19

[0557] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 3.74-3.77 (2H, m), 4.58 (2H, s), 4.61 (2H, t), 5.02 (1H, t, J=5.6 Hz), 7.29 (1H, d), 7.46 (1H, m), 7.56 (1H, m), 7.70 (1H, m), 7.81 (1H, d), 7.87 (1H, d), 8.01 (1H, s), 8.18 (1H, s), 8.86 (1H, s), 15.27 (1H, s)

MS (ESI): M+417

Example 3-20

[0558] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 1.37 (3H, t, J=6.9 Hz), 3.70-3.80 (2H, m), 4.22 (2H, s), 4.28 (2H, q, J=6.9 Hz), 4.65 (2H, t), 5.00 (1H, t), 7.30-7.34 (3H, m), 7.60 (1H, d), 7.92 (1H, s), 8.80 (1H, s), 15.44 (1H, s)

MS (ESI): M+436

Example 3-21

[0559] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 3.76 (2H, m), 4.40 (2H, s), 4.63 (2H, t, J=5.1 Hz), 5.02 (1H, t, J=5.6 Hz), 7.20 (1H, d, J=6.3 Hz), 7.35-7.39 (1H, m), 7.62 (1H, d, J=6.3 Hz), 8.00 (1H, s), 8.32 (1H, s), 8.89 (1H, s), 15.87 (1H, s)

MS (ESI): M+426

Example 3-22

[0560] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 3.80 (2H, t, J=5.3 Hz), 4.48 (2H, s), 4.75 (2H, t, J=4.6 Hz), 5.06 (1H, t, J=5.6 Hz), 7.24 (1H, d, J=6.3 Hz), 7.39-7.42 (1H, m), 7.65 (1H, d, J=6.7 Hz), 7.95 (1H, s), 8.40 (1H, s), 9.00 (1H, s), 14.62 (1H, s)

MS (ESI): M+460

Example 3-23

[0561] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 1.53 (3H, d, J=6.4 Hz), 3.76-3.83 (2H, m), 4.26 (2H, s), 5.19-5.23 (2H, m), 7.20-7.22 (1H, m), 7.41-7.49 (2H, m), 7.86 (1H, d), 8.17 (1H, d, J=8.8 Hz), 8.24 (1H, s), 8.88 (1H, s)

MS (ESI): M+390

Example 3-24

[0562] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 1.53 (3H, d, J=6.8 Hz), 3.76-3.82 (2H, m), 4.26 (2H, s), 5.19-5.23 (2H, m), 7.22-7.24 (1H, m), 7.41-7.49 (2H, m), 7.86 (1H, d), 8.17 (1H, d, J=9.2 Hz), 8.24 (1H, s), 8.88 (1H, s)

MS (ESI): M+390

Example 3-25

[0563] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 3.40-3.50 (2H, m), 4.34 (2H, s), 4.57 (2H, t), 4.89 (1H, t), 7.24-7.27 (1H, m), 7.45-7.51 (2H, m), 8.35 (1H, s), 8.45 (1H, s), 9.00 (1H, s), 14.30-14.40 (1H, br)

MS (ESI): M+444

Example 3-26

[0564] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 3.84-3.96 (4H, m), 4.26 (2H, s), 5.13-5.18 (3H, m), 7.19-7.21 (1H, m), 7.40-7.48 (2H, m), 7.84 (1H, d, J=9.2 Hz), 8.15 (1H, d, J=8.8 Hz), 8.23 (1H, s), 8.90 (1H, s), 15.24 (1H, s)

MS (ESI): M+406

Example 3-27

[0565] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 3.77 (2H, t, J=5.2 Hz), 4.53 (2H, s), 4.68 (2H, t, J=4.8 Hz), 5.01 (1H, t, J=5.6 Hz), 7.32 (1H, d, J=6.0 Hz), 7.39-7.43 (1H, m), 7.64 (1H, d, J=6.4 Hz), 8.07 (1H, s), 8.79 (1H, s), 8.96 (1H, s), 14.61 (1H, s)

MS (ESI): M+417

Example 3-28

[0566] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 0.97 (3H, t, J=7.2 Hz), 2.58 (3H, s), 2.84 (2H, q, J=7.2 Hz), 3.77 (2H, t), 4.21 (2H, s), 4.60 (2H, t), 5.00 (1H, t), 7.00-7.02 (1H, m), 7.12 (1H, d), 7.20-7.24 (2H, m), 7.78 (1H, d, J=8.8 Hz), 7.98 (1H, d, J=8.8 Hz), 8.17 (1H, s), 8.84 (1H, s), 15.31 (1H, s)

MS (ESI): M+381

Example 3-29

[0567] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 0.78 (3H, t, J=7.2 Hz), 1.42 (2H, m), 2.56 (3H, s), 2.76 (2H, t, J=6.8 Hz), 3.74 (2H, t), 4.23 (2H, s), 4.60 (2H, t, J=4.8 Hz), 5.02 (1H, t, J=5.6 Hz), 7.00-7.03 (1H, m), 7.09 (1H, d), 7.20-7.21 (2H, m), 7.77 (1H, d, J=9.2 Hz), 7.99 (1H, d, J=8.8 Hz), 8.15 (1H, s), 8.85 (1H, s), 15.30 (1H, s)

MS (ESI): M+395

Example 3-30

[0568] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 2.52 (3H, s), 3.77 (2H, t, J=4.8 Hz), 4.01 (2H, s), 4.30 (2H, s), 4.61 (2H, t), 4.90-5.10 (1H, br), 7.03-7.09 (2H, m), 7.20-7.26 (7H, m), 7.76 (1H, d), 7.98 (1H, d), 8.17 (1H, s), 8.85 (1H, s), 15.30 (1H, s)

MS (ESI): M+443

Example 3-31

[0569] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 2.94 (3H, s), 3.09 (3H, s), 3.75 (2H, m), 4.13-4.18 (1H, m), 4.44-4.48 (1H, m), 4.61 (2H, t), 5.02 (1H, t, J=5.6 Hz), 7.33-7.37 (3H, m), 7.52 (1H, d, J=9.2 Hz), 7.81 (1H, d), 8.01 (1H, d, J=8.8 Hz), 8.15 (1H, s), 8.86 (1H, s), 15.27 (1H, s)

MS (ESI): M+431

Example 3-32

[0570] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 1.01 (6H, d), 2.52 (3H, s), 3.12-3.19 (1H, m), 3.73-3.75 (2H, m), 4.20 (2H, s), 4.60 (2H, t), 5.02 (1H, t), 7.00-7.02 (1H, m), 7.11 (1H, d), 7.19-7.22 (2H, m), 7.77 (1H, d, J=8.8 Hz), 7.98 (1H, d, J=9.2 Hz), 8.18 (1H, s), 8.84 (1H, s), 15.31 (1H, s)

MS (ESI): M+395

Example 3-33

[0571] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 1.86 (9H, s), 4.26 (2H, s), 7.22-7.24 (1H, m), 7.42-7.49 (2H, m), 7.79 (1H, d, J=9.2 Hz), 8.28 (1H, s), 8.39 (1H, d, J=8.8 Hz), 8.98 (1H, s), 15.16 (1H, s)

MS (ESI): M+388

Example 3-34

[0572] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 3.71 (2H, m), 3.96 (3H, s), 4.21 (2H, s), 4.81 (2H, t), 4.89 (1H, t), 7.19-7.24 (1H, m), 7.40-7.52 (3H, m), 7.77 (1H, s), 8.68 (1H, s), 15.17 (1H, s)

MS (ESI): M+406

Example 3-35

[0573] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 3.75 (2H, m), 4.09 (2H, s), 4.83 (2H, t), 5.33 (1H, t), 5.81 (2H, s), 7.15 (1H, s), 7.15-7.24 (1H, m), 7.36 (1H, m), 7.48 (1H, m), 7.57 (1H, s), 8.77 (1H, s), 15.37 (1H, s)

MS (ESI): M+391

Example 3-36

[0574] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 3.79 (2H, t), 4.60 (2H, s), 4.68 (2H, t), 5.05 (1H, t), 7.11 (1H, d, J=6.0 Hz), 7.30-7.34 (1H, m), 7.57 (1H, d, J=6.8 Hz), 8.02 (1H, s), 8.38 (1H, s), 8.95 (1H, s), 13.60-14.00 (1H, br), 14.88 (1H, s)

MS (ESI): M+436

Example 3-37

[0575] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 3.70-3.72 (2H, m), 4.98 (3H, s), 4.23 (2H, s), 4.81 (2H, t), 4.89 (1H, t), 7.20-7.26 (1H, m), 7.50 (1H, s), 7.62-7.67 (2H, m), 8.68 (1H, s), 15.10 (1H, s)

MS (ESI): M+424

Example 3-38

[0576] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 2.67 (6H, s), 3.39 (2H, m), 4.21 (2H, s), 4.72 (1H, t), 4.97 (2H, t), 7.20-7.22 (1H, m), 7.40-7.50 (2H, m), 7.65 (1H, s), 7.84 (1H, s), 15.10 (1H, s)

MS (ESI): M+419

Example 3-39

[0577] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 2.10 (3H, s), 4.50-4.60 (2H, m), 4.23 (2H, s), 4.65 (2H, t), 5.00 (1H, t), 7.20-7.30 (1H, m), 7.40-7.50 (2H, m), 7.65 (1H, s), 8.20 (1H, s), 8.83 (1H, s), 10.20 (1H, s), 15.00 (1H, s)

MS (ESI): M+433

Example 3-40

[0578] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 3.74-3.75 (2H, m), 4.55 (2H, s), 4.65 (2H, t), 5.00 (1H, t), 7.17 (1H, d, J=6.3 Hz), 7.34-7.39 (1H, m), 7.62 (1H, d, J=6.6 Hz), 7.73 (1H, d, J=9.3 Hz), 8.34 (1H, d, J=9.3 Hz), 8.97 (1H, s), 14.62 (1H, s)

MS (ESI): M+417

Example 3-41

[0579] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 1.45 (3H, s), 2.97 (3H, s), 3.74-3.76 (2H, m), 4.12 (2H, s), 4.61 (2H, m), 5.03 (1H, t, J=5.6 Hz), 7.24-7.30 (1H, m), 7.30-7.39 (3H, m), 7.76 (1H, d), 8.01 (1H, d, J=8.8 Hz), 8.13 (1H, s), 8.87 (1H, s), 15.23 (1H, s)

MS (ESI): M+395

Example 3-42

[0580] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 0.88 (6H, t, J=7.2 Hz), 2.91 (4H, q, J=6.8 Hz), 3.75 (2H, m), 4.23 (2H, s), 4.60 (2H, t), 5.02 (1H, t, J=5.6 Hz), 7.00-7.06 (1H, m), 7.14-7.25 (3H, m), 7.77 (1H, d), 7.98 (1H, d, J=8.8 Hz), 8.16 (1H, s), 8.84 (1H, s), 15.32 (1H, s)

MS (ESI): M+395

Example 3-43

[0581] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 1.78 (6H, s), 3.99 (2H, s), 4.25 (2H, s), 4.23 (2H, s), 5.52 (1H, br), 7.20-7.22 (1H, m), 7.42-7.49 (2H, m), 7.76 (1H, d, J=9.2 Hz), 8.27 (1H, s), 8.34 (1H, d, J=9.2 Hz), 9.05 (1H, s)

MS (ESI): M+404

Example 3-44

[0582] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 1.36 (3H, t, J=6.9 Hz), 3.70-3.80 (2H, m), 4.12 (2H, s), 4.24 (2H, q, J=7.0 Hz), 4.62 (2H, t), 5.00 (1H, t), 7.16-7.27 (3H, m), 7.40-7.50 (1H, m), 8.12 (1H, s), 8.80 (1H, s), 15.50 (1H, s)

MS (ESI): M+420

Example 3-45

[0583] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 3.70-3.80 (2H, m), 3.84 (3H, s), 3.85 (3H,$), 4.19 (2H, s), 4.75 (2H, t), 4.92 (1H, t, J=5.6 Hz), 7.21-7.28 (2H, m), 7.45-7.50 (1H, m), 7.95 (1H, s), 8.75 (1H, s), 15.09 (1H, s)

MS (ESI): M+436

Example 3-46

[0584] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 2.62 (3H, s), 3.74 (2H, m), 4.02 (2H, s), 4.61 (2H, t), 5.01 (1H, t), 5.50-5.60 (1H, m), 6.30-6.43 (3H, m), 6.95-7.01 (1H, m), 7.82 (1H, d), 7.99 (1H, d, J=8.8 Hz), 8.21 (1H, s), 8.85 (1H, s), 15.33 (1H, s)

MS (ESI): M+353

Example 3-47

[0585] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 1.42 (3H, t, J=6.8 Hz), 3.70-3.80 (2H, m), 4.20-4.23 (4H, m), 4.84-5.00 (3H, m), 7.20-7.30 (1H, m), 7.40-7.49 (3H, m), 7.77 (1H, s), 8.67 (1H, s)

MS (ESI): M+420

Example 3-48

[0586] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 2.78 (3H, s), 3.60-3.70 (2H, m), 4.16 (2H, s), 4.75-4.79 (2H, m), 5.38 (1H, t), 6.20-6.27 (1H, m), 7.07 (1H, s), 7.20-7.23 (1H, m), 7.39-7.49 (3H, m), 8.80 (1H, s), 15.32 (1H, s)

MS (ESI): M+405

Example 3-49

[0587] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 0.94 (3H, t, J=7.2 Hz), 1.72-1.78 (2H, m), 3.77 (2H, m), 4.13-4.14 (4H, m), 4.62 (2H, t), 5.00 (1H, br), 7.12-7.18 (2H, m), 7.26 (1H, s), 7.44-7.46 (1H, m), 8.13 (1H, s), 8.79 (1H, s), 15.49 (1H, s)

MS (ESI): M+434

Example 3-50

[0588] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 3.00 (3H, s), 3.08 (3H, s), 3.75-3.77 (2H, m), 4.16 (2H, s), 4.57 (2H, t), 5.00 (1H, t, J=5.6 Hz), 7.09-7.18 (2H, m), 7.24 (1H, s), 7.40-7.41 (1H, m), 7.85 (1H, s), 8.01 (1H, s), 8.72 (1H, s), 15.67 (1H, s)

MS (ESI): M+446

Example 3-51

[0589] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 3.72 (3H, s), 3.72-3.80 (2H, m), 3.95 (3H, s), 4.06 (2H, s), 4.40-4.50 (2H, m), 5.00 (1H, t), 7.12 (1H, s), 7.15-7.19 (2H, m), 7.40-7.45 (1H, m), 7.88 (1H, s), 8.51 (1H, s)

MS (ESI): M+420

Example 3-52

[0590] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 3.77 (2H, m), 4.17 (2H, s), 4.72 (2H, t, J=4.8 Hz), 4.97 (1H, t, J=5.6 Hz), 7.08 (2H, d, J=7.6 Hz), 7.09-7.25 (2H, m), 7.31-7.36 (2H, m), 7.43-7.49 (3H, m), 8.04 (1H, s), 7.76 (1H, s), 15.02 (1H, s)

MS (ESI): M+468

Example 3-53

[0591] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 1.24 (6H, d, J=7.2 Hz), 3.75 (2H, t), 4.08 (2H, s), 4.61 (2H, t), 4.99-5.04 (2H, m), 7.11-7.20 (2H, m), 7.28 (1H, s), 7.43-7.45 (1H, m), 8.17 (1H, s), 8.79 (1H, s), 15.52 (1H, s)

MS (ESI): M+434

Example 3-54

[0592] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 0.99 (3H, t, J=7.3 Hz), 1.60-1.70 (2H, m), 3.00-3.10 (2H, m), 3.70-3.80 (2H, m), 4.15 (2H, s), 4.82 (2H, t), 5.50 (1H, t), 6.20 (1H, t), 7.08 (1H, s), 7.10-7.20 (1H, m), 7.40-7.51 (3H, m), 8.78 (1H, s), 15.30-15.40 (1H, br)

MS (ESI): M+433

Example 3-55

[0593] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 1.24 (3H, t, J=6.9 Hz), 3.08 (2H, m), 3.71-3.80 (2H, m), 4.15 (2H, s), 4.83 (2H, t), 5.43 (1H, t), 6.21 (1H, t), 7.10 (1H, s), 7.17-7.23 (1H, m), 7.36-7.52 (3H, m), 8.78 (1H, s)

MS (ESI): M+419

Example 3-56

[0594] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 1.53 (3H, d, J=6.8 Hz), 3.72 (2H, m), 3.99 (3H, s), 4.21 (2H, s), 5.12 (1H, t), 5.70-5.90 (1H, m), 7.20-7.21 (1H, m), 7.40-7.55 (3H, m), 7.76 (1H, s), 8.85 (1H, s), 15.00-15.20 (1H, br)

MS (ESI): M+420

Example 3-57

[0595] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 1.52 (3H, d, J=6.8 Hz), 3.71 (2H, t), 4.00 (3H, s), 4.23 (2H, s), 5.10 (1H, t), 5.80-5.90 (1H, m), 7.20-7.30 (1H, m), 7.51 (1H, s), 7.60-7.67 (2H, m), 8.85 (1H, s), 14.90-15.10 (1H, br)

MS (ESI): M+438

Example 3-58

[0596] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 1.03 (3H, d, J=8.4 Hz), 1.78-1.87 (2H, m), 3.73-3.75 (2H, m), 4.12 (2H, t), 4.20 (2H, s), 4.85 (2H, t), 4.92 (1H, t), 7.20 (1H, m), 7.39-7.51 (3H, m), 7.76 (1H, s), 8.68 (1H, s), 15.17 (1H, s)

MS (ESI): M+434

Example 3-59

[0597] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 1.35 (6H, s), 3.72-3.75 (2H, m), 4.20 (2H, s), 4.83-4.91 (4H, m), 7.20 (1H, m), 7.39-7.49 (3H, m), 7.74 (1H, s), 8.66 (1H, s), 15.18 (1H, s)

MS (ESI): M+434

Example 3-60

[0598] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 0.86 (3H, t, J=7.3 Hz), 1.80-2.10 (2H, m), 3.70-3.90 (2H, m), 4.26 (2H, s), 5.00-5.10 (1H, m), 5.17 (1H, t, J=5.4 Hz), 7.19-7.24 (1H, m), 7.39-7.51 (2H, m), 7.84 (1H, d, J=8.8 Hz), 8.20 (1H, d, J=8.8 Hz), 8.23 (1H, s), 8.86 (1H, s), 15.24 (1H, s)

MS (ESI): M+404

Example 3-61

[0599] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 1.36 (3H, t, J=6.9 Hz), 1.52 (3H, d, J=6.6 Hz), 3.78-3.80 (2H, m), 4.12 (2H, s), 4.26 (2H, q, J=7.0 Hz), 5.21-5.30 (2H, m), 7.16-7.24 (2H, m), 7.40-7.46 (2H, m), 8.14 (1H, s), 8.81 (1H, s), 15.40-15.60 (1H, br)

MS (ESI): M+434

Example 3-62

[0600] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 2.88 (6H, s), 3.70-3.80 (2H, m), 4.22 (2H, s), 4.60-4.70 (2H, m), 5.05 (1H, t), 7.20-7.31 (3H, m), 7.50-7.60 (1H, m), 7.80 (1H, s), 8.78 (1H, s), 15.30-15.40 (1H, br)

MS (ESI): M+419

Example 3-63

[0601] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 0.90-1.29 (5H, m), 1.62-1.80 (6H, m), 3.75-3.78 (2H, m), 3.96 (2H, d, J=10.8 Hz), 4.13 (2H, s), 4.60-4.62 (2H, m), 5.02 (1H, t), 7.06-7.24 (2H, m), 7.14 (1H, s), 7.42-7.44 (1H, m), 8.16 (1H, s), 8.79 (1H, s)

MS (ESI): M+488

Example 3-64

[0602] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 0.85-0.89 (6H, m), 2.96-3.00 (2H, m), 3.10-3.20 (2H, m), 3.33-3.40 (2H, m), 4.22 (2H, s), 4.74 (1H, t), 5.09-5.10 (2H, m), 7.20 (1H, m), 7.38-7.47 (2H, m), 7.59 (1H, s), 7.89 (1H, s), 8.72 (1H, s), 15.08 (1H, s)

MS (ESI): M+447

Example 3-65

[0603] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 2.91 (3H, d, J=4.7 Hz), 3.75-3.81 (2H, m), 4.01 (2H, s), 4.50-4.55 (2H, m), 5.04 (1H, t, J=5.5 Hz), 6.59 (1H, s), 6.60-6.68 (1H, m), 7.15-7.24 (2H, m), 7.51-7.55 (1H, m), 7.63 (1H, s), 8.65 (1H, s), 15.90 (1H, s)

MS (ESI): M+405

Example 3-66

[0604] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 1.91-2.00 (4H, m), 3.40-3.50 (4H, m), 3.70-3.81, (2H, m), 4.30 (2H, s), 4.50-4.55 (2H, m), 5.05 (1H, t), 6.87 (1H, s), 7.10-7.12 (1H, m), 7.18-7.21 (1H, m), 7.49-7.52 (1H, m), 7.72 (1H, s), 8.69 (1H, s), 15.65 (1H, s)

MS (ESI): M+445

Example 3-67

[0605] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 1.44 (3H, t), 1.55 (3H, d), 3.70-3.77, (2H, m), 4.19 (2H, s), 4.28 (2H, q, J=8.8 Hz), 5.14 (1H, t), 5.83-5.90 (1H, m), 7.20 (1H, m), 7.39-7.40 (1H, m), 7.48-7.50 (2H, m), 7.75 (1H, s), 8.86 (1H, s), 15.13 (1H, s)

MS (ESI): M+434

Example 3-68

[0606] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 0.86 (3H, t, J=7.3 Hz), 1.37 (3H, t, J=6.9 Hz), 1.80-2.00, (2H, m), 3.70-3.90 (2H, m), 4.12 (2H, s), 4.20-4.28 (2H, m), 5.00-5.17 (2H, m), 7.14-7.30 (2H, m), 7.42-7.49 (2H, m), 8.14 (1H, s), 8.78 (1H, s), 15.50 (1H, s)

MS (ESI): M+448

Example 3-69

[0607] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 1.09-1.27 (5H, m), 1.68-1.82 (6H, m), 3.71-3.73 (2H, m), 3.99 (2H, d, J=5.6 Hz), 4.20 (2H, s), 4.80-4.85 (2H, m), 4.92 (1H, t, J=5.6 Hz), 7.20 (1H, m), 7.38-7.40 (1H, m), 7.40-7.53 (2H, m), 7.75 (1H, s), 8.68 (1H, s), 15.16 (1H, s)

MS (ESI): M+488

Example 3-70

[0608] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 0.70 (3H, d, J=6.4 Hz), 1.12 (3H, d, J=6.4 Hz), 2.30-2.40 (1H, m), 3.75-3.78 (1H, m), 3.95-4.00 (1H, m), 4.25 (2H, s), 4.80-4.85 (1H, m), 5.18 (1H, t), 7.20-7.21 (1H, m), 7.41-7.48 (2H, m), 7.84 (1H, d), 8.21 (1H, s), 8.25 (1H, d, J=9.2 Hz), 8.92 (1H, s), 15.21 (1H, s)

MS (ESI): M+418

Example 3-71

[0609] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 0.85 (3H, d), 0.90 (3H, d), 1.40-1.50 (1H, m), 1.80-1.91 (2H, m), 3.71-3.80 (2H, m), 4.25 (2H, s), 5.15-5.20 (2H, m), 7.20-7.21 (1H, m), 7.41-7.48 (2H, m), 7.84 (1H, d, J=8.8 Hz), 8.22 (1H, s), 8.24 (1H, d, J=8.8 Hz), 8.83 (1H, s), 15.20 (1H, s)

MS (ESI): M+432

Example 3-72

[0610] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 0.86 (3H, t, J=7.3 Hz), 1.23 (6H, m), 1.80-2.00 (2H, m), 3.70-3.90 (2H, m), 4.09 (2H, s), 5.00-5.18 (3H, m), 7.12-7.21 (2H, m), 7.44-7.47 (2H, m), 8.20 (1H, s), 8.79 (1H, s), 15.54 (1H, s)

MS (ESI): M+462

Example 3-73

[0611] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 0.87 (3H, t, J=7.3 Hz), 1.80-2.10 (2H, m), 3.70-3.90 (2H, m), 4.02 (3H, s), 4.11 (2H, s), 5.00-5.19 (2H, m), 7.16-7.24 (2H, m), 7.44-7.48 (2H, m), 8.04 (1H, s), 8.78 (1H, s), 15.44 (1H, s)

MS (ESI): M+434

Example 3-74

[0612] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 1.23 (6H, dx2), 1.51 (3H, d, J=6.6 Hz), 3.77 (2H, t), 4.09 (2H, s), 4.90-5.10 (1H, m), 5.19-/o 5.30 (2H, m), 7.12-7.21 (2H, m), 7.41-7.47 (2H, m), 8.20 (1H, s), 8.81 (1H, s), 15.55 (1H, s)

MS (ESI): M+448

Example 3-75

[0613] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 1.00 (9H, s), 4.07-4.12 (2H, m), 4.30 (2H, s), 5.12-5.14 (2H, m), 7.20-7.25 (1H, m), 7.40-7.45 (1H, m), 7.51-7.53 (1H, m), 7.87 (1H, d), 8.25 (1H, s), 8.41 (1H, d, J=9.2 Hz), 8.85 (1H, s), 15.20-15.21 (1H, br)

MS (ESI): M+432

Example 3-76

[0614] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 3.70-3.81 (4H, m), 4.15 (2H, s), 4.24 (2H, t, J=5.0 Hz), 4.60-4.62 (2H, m), 5.00-5.02 (2H, m), 7.15-7.20 (1H, m), 7.32-7.34 (2H, m), 7.44-7.49 (1H, m), 8.06 (1H, s), 8.79 (1H, s), 15.48 (1H, s)

MS (ESI): M+436

Example 3-77

[0615] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 1.90-1.92 (2H, m), 3.53-3.54 (2H, m), 3.70-3.80 (2H, m), 4.12 (2H, s), 4.20-4.30 (2H, m), 4.60-4.70 (3H, m), 5.02 (1H, t), 7.16-7.22 (2H, m), 7.30 (1H, s), 7.40-7.50 (1H, m), 8.11 (1H, s), 8.80 (1H, s)

MS (ESI): M+450

Example 3-78

[0616] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 3.10-3.20 (2H, m), 3.60-3.80 (4H, m), 4.15 (2H, s), 4.78-4.85 (3H, m), 5.30-5.40 (1H, m), 6.10-6.20 (1H, m), 7.15-7.20 (2H, m), 7.30-7.52 (3H, m), 8.77 (1H, s), 15.33 (1H, s)

MS (ESI): M+435

Example 3-79

[0617] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 0.89 (3H, t, J=7.4 Hz), 1.90-2.00 (2H, m), 3.70-3.80 (2H, m), 3.99 (3H, s), 4.22 (2H, s), 5.15 (1H, t, J=5.4 Hz), 5.70-5.80 (1H, m), 7.19-7.24 (1H, m), 7.38-7.52 (2H, m), 7.55 (1H, s), 7.77 (1H, s), 8.86 (1H, s), 15.12 (1H, s)

MS (ESI): M+434

Example 3-80

[0618] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 1.59 (3H, d, J=7.2 Hz), 2.61 (3H, s), 2.80 (3H, s), 4.20 (2H, s), 4.96 (1H, t, J=5.6 Hz), 6.50-6.60 (1H, m), 7.19-7.23 (1H, m), 7.40-7.49 (2H, m), 7.60 (1H, s), 7.80 (1H, s), 8.81 (1H, s), 15.06 (1H, s)

MS (ESI): M+433

Example 3-81

[0619] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 4.10-4.40 (4H, m), 5.50-5.60 (1H, m), 6.20-6.30 (1H, m), 7.19-7.22 (1H, m), 7.30-7.40 (6H, m), 7.40-7.50 (1H, m), 7.77 (1H, d), 8.00 (1H, d), 8.21 (1H, s), 9.03 (1H, s), 15.11 (1H, s)

MS (ESI): M+452

Example 3-82

[0620] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 0.86 (3H, t), 1.18-1.34 (2H, m), 1.87-1.98 (2H, m), 3.73-3.84 (2H, m), 4.25 (2H, s), 5.13-5.17 (2H, m), 7.21 (1H, m), 7.41-7.48 (2H, m), 7.83 (1H, d, J=8.0 Hz), 8.19 (1H, d), 8.22 (1H, s), 8.85 (1H, s), 15.22 (1H, s)

MS (ESI): M+418

Example 3-83

[0621] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 0.72 (3H, t, J=7.3 Hz), 0.90-1.20 (5H, m), 2.10-2.30 (1H, m), 3.70-3.80 (1H, m), 3.90-4.10 (1H, m), 4.26 (2H, s), 4.90-5.00 (1H, m), 5.10-5.20 (1H, m), 7.20-7.25 (1H, m), 7.40-7.52 (2H, m), 7.84 (1H, d, J=7.8 Hz), 8.23 (1H, s), 8.26 (1H, d), 8.92 (1H, s), 15.22 (1H, s)

MS (ESI): M+432

Example 3-84

[0622] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 1.54 (3H, d, J=6.6 Hz), 3.81-3.82 (2H, m), 4.02 (3H, s), 4.12 (2H, s), 5.22 (1H, t, J=5.4 Hz), 5.23-5.40 (1H, m), 7.15-7.26 (2H, m), 7.44-7.50 (2H, m), 8.05 (1H, s), 8.82 (1H, s), 15.46 (1H, s)

MS (ESI): M-418

Example 3-85

[0623] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 3.25-3.38 (2H, m), 3.82-3.89 (2H, m), 4.21 (2H, s), 5.27 (1H, t), 5.40-5.50 (1H, m), 7.10-7.21 (6H, m), 7.30-7.40 (1H, m), 7.40-7.50 (1H, m), 7.77 (1H, d), 8.14 (1H, d), 8.14 (1H, s), 8.96 (1H, s), 15.15 (1H, s)

MS (ESI): M+466

Example 3-86

[0624] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 3.70-3.80 (2H, m), 4.42 (2H, s), 4.69 (2H, t), 4.95 (1H, t), 7.37-7.42 (1H, m), 7.51 (1H, d, J=6.2 Hz), 7.59 (1H, d, J=7.9 Hz), 8.48 (1H, s), 8.99 (1H, s), 9.04 (1H, s), 14.68 (1H, s)

MS (ESI): M+393

Example 4-1

[0625] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 3.26 (3H, s), 3.74 (2H, m), 4.42 (2H, s), 4.61 (2H, m), 5.09 (1H, br), 7.78 (1H, m), 7.84 (2H, m), 8.04-8.07 (2H, m), 8.18 (1H, m), 8.86 (1H, s), 15.19 (1H, s)

MS (ESI): M+435

Example 4-2

[0626] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 3.73 (2H, m), 4.23 (2H, s), 4.59 (2H, m), 4.99 (1H, br), 7.20 (1H, m), 7.31-7.34 (2H, m), 7.44 (1H, m), 7.85 (1H, m), 8.01 (1H, s), 8.26 (1H, m), 8.85 (1H, s), 15.27 (1H, s)

MS (ESI): M+407

Example 4-3

[0627] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 1.15 (3H, t, J=7.6 Hz), 2.57 (2H, q, J=7.6 Hz), 3.73 (2H, m), 4.13 (2H, s), 4.59 (2H, m), 4.99 (1H, m), 7.05 (2H, m), 7.13 (1H, m), 7.20 (1H, m), 7.81 (1H, m), 7.98 (1H, m), 8.21 (1H, s), 8.84 (1H, s), 15.28 (1H, s)

MS (ESI): M+351

Example 4-4

[0628] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 1.07 (3H, t, J=7.53 Hz), 2.58 (2H, q, J=7.53 Hz), 3.76 (2H, m), 4.22 (2H, s), 4.61 (2H, m), 5.02 (1H, m), 7.19-7.23 (4H, m), 7.76 (1H, m), 8.01 (1H, m), 8.09 (1H, s), 8.86 (1H, s), 15.26 (1H, s)

MS (ESI): M+351

Example 4-5

[0629] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 2.28 (3H, s), 3.75 (2H, m), 4.24 (2H, s), 4.61 (2H, m), 5.04 (1H, br), 7.13 (1H, d, J=8.1 Hz), 7.28-7.36 (2H, m), 7.81 (1H, d, J=6.7 Hz), 8.03 (1H, d, J=8.9 Hz), 8.13 (1H, s), 8.86 (1H, s), 15.24 (1H, brs)

MS (ESI): M+372

Example 4-6

[0630] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 3.75 (2H, m), 4.29 (2H, s), 4.62 (2H, m), 5.07 (1H, m), 7.19 (1H, m), 7.40 (1H, m), 7.52 (1H, m), 7.84 (1H, m), 8.05 (1H, m), 8.19 (1H, s), 8.87 (1H, s), 15.20 (1H, s)

MS (ESI): M+375

Example 4-7

[0631] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 3.75 (2H, m), 4.29 (2H, s), 4.61 (2H, t, J=5.0 Hz), 5.01 (2H, t, J=5.4 Hz), 7.45 (1H, d), 7.51 (1H, d, J=11.2 Hz), 7.74 (1H, d), 7.84 (1H, dd), 8.01 (1H, d), 8.15 (1H, s), 8.86 (1H, s), 15.21 (1H, brs)

MS (ESI): M+436

Example 4-8

Example 4-9

[0632] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 3.76 (2H, m), 4.34 (2H, s), 4.59 (2H, m), 5.01 (1H, m), 7.37 (2H, m), 7.62 (1H, m), 8.07 (2H, m), 8.88 (1H, s), 14.99 (1H, s)

MS (ESI): M+409

Example 4-10

[0633] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 3.20 (3H, s), 3.74 (2H, m), 4.31 (2H, s), 4.61 (2H, t), 5.00 (1H, t), 7.55-7.66 (2H, m), 7.78 (1H, d), 7.84-7.89 (2H, m), 8.03 (1H, d, J=8.9 Hz), 8.30 (1H, s), 8.86 (1H, s), 15.27 (1H, brs)

MS (ESI): M+402

Example 4-11

[0634] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 3.75 (2H, m), 4.18 (2H, s), 4.61 (2H, m), 5.02 (1H, m), 6.69 (1H, m), 6.77 (1H, m), 7.23 (1H, m), 7.80 (1H, m), 8.02 (1H, m), 8.15 (1H, s), 8.86 (1H, s), 9.66 (1H, s), 15.24 (1H, s)

MS (ESI): M+373

Example 4-12

[0635] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 3.75 (2H, m), 4.29 (2H, s), 4.58 (2H, m), 5.00 (1H, s), 7.31 (1H, m), 7.35 (1H, m), 7.58 (1H, m), 7.71 (1H, m), 7.82 (1H, m), 8.86 (1H, s)

MS (ESI): M+409

Example 4-13

[0636] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 1.34 (3H, t, J=6.8 Hz), 3.73 (2H, m), 4.00 (2H, q, J=6.8 Hz), 4.09 (2H, s), 4.59 (2H, m), 5.00 (1H, m), 6.89 (1H, m), 6.95 (1H, m), 7.19 (1H, m), 7.27 (1H, m), 7.83 (1H, m), 7.97 (1H, m), 8.24 (1H, s), 8.84 (1H, s), 15.33 (1H, s)

MS (ESI): M+367

Example 4-14

[0637] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 3.73 (2H, m), 4.06 (2H, s), 4.60 (2H, m), 5.05 (1H, m), 6.74 (1H, m), 6.85 (1H, m), 7.05 (1H, m), 7.14 (1H, m), 7.82 (1H, m), 7.99 (1H, m), 8.19 (1H, s), 8.84 (1H, s), 9.55 (1H, s), 15.34 (1H, s)

MS (ESI): M+339

Example 4-15

[0638] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 2.49 (3H, s), 3.77 (2H, m), 4.27 (2H, s), 4.60 (2H, m), 5.01 (1H, s), 7.17 (1H, m), 7.35 (1H, m), 7.59 (1H, m), 7.78 (1H, s), 7.95 (1H, s), 8.81 (1H, s), 15.22 (1H, s)

MS (ESI): M+406

Example 4-16

[0639] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 1.35 (3H, d), 1.40 (3H, d), 1.54 (3H, d, J=6.8 Hz), 3.72 (2H, m), 4.20 (2H, s), 4.86-4.92 (1H, m), 5.12 (1H, t, J=5.2 Hz), 5.80-5.90 (1H, m), 7.20 (1H, m), 7.39-7.52 (3H, m), 7.74 (1H, s), 8.84 (1H, s), 15.13 (1H, s)

MS (ESI): M+448

Example 4-17

[0640] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 0.89 (3H, t, J=7.2 Hz), 1.35-1.37 (6H, d), 1.88-2.06 (2H, m), 3.73-3.79 (2H, m), 4.20 (2H, s), 4.80-5.00 (1H, m), 5.16 (1H, t), 5.81-5.84 (1H, m), 7.20 (1H, m), 7.40-7.53 (3H, m), 7.75 (1H, s), 8.83 (1H, s), 15.09 (1H, s)

MS (ESI): M+462

Example 4-18

[0641] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 0.80-1.40 (6H, m), 1.40-1.60 (2H, m), 1.70-1.80 (1H, m), 1.80-2.10 (2H, m), 3.70-3.80 (1H, m), 3.90-4.00 (1H, m), 4.26 (2H, s), 4.80-5.00 (1H, m), 5.19 (1H, t), 7.22-7.25 (1H, m), 7.42-7.49 (2H, m), 7.85 (1H, d), 8.22 (1H, s), 8.26 (1H, d, J=9.1 Hz), 8.95 (1H, s)

MS (ESI): M+458

Example 4-19

[0642] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 0.70 (3H, d, J=6.6 Hz), 1.14 (3H, d, J=6.4 Hz), 1.21-1.24 (6H, m), 2.20-2.40 (1H, m), 3.70-3.80 (1H, m), 3.90-4.00 (1H, m), 4.09 (2H, s), 4.80-4.90 (1H, m), 5.00-5.20 (2H, m), 7.12-7.22 (2H, m), 7.43-7.47 (2H, m), 8.19 (1H, s), 8.87 (1H, s), 15.51 (1H, s)

MS (ESI): M+476

Example 4-20

[0643] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 0.97 (9H, s), 1.18 (3H, d, J=5.9 Hz), 1.26 (3H, d, J=6.0 Hz), 4.04-4.09 (4H, m), 5.09-5.13 (3H, m), 7.12-7.21 (2H, m), 7.43-7.51 (2H, m), 8.19 (1H, s), 8.78 (1H, s), 15.46 (1H, s)

MS (ESI): M+490

Example 4-21

[0644] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 0.89 (3H, t, J=7.6 Hz), 1.44 (3H, t), 1.92-2.06 (2H, m), 3.78 (2H, m), 4.19 (2H, s), 4.25 (2H, q), 5.17 (1H, t, 5.6 Hz), 5.78-5.83 (1H, m), 7.20 (1H, m), 7.39-7.51 (3H, m), 7.76 (1H, s), 8.85 (1H, s), 15.11 (1H, s)

MS (ESI): M+448

Example 4-22

[0645] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 0.80-1.30 (6H, m), 1.50-1.80 (5H, m), 1.80-1.90 (2H, m), 3.60-3.80 (2H, m), 4.26 (2H, s), 5.10-5.20 (2H, m), 7.22 (1H, m), 7.30-7.50 (2H, m), 7.85 (1H, d), 8.23 (1H, d), 8.23 (1H, s), 8.84 (1H, s), 15.20 (1H, s)

MS (ESI): M+472

Example 4-23

[0646] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 0.85 (3H, d), 0.91 (3H, d), 1.24-1.27 (6H, m), 1.35-1.43 (1H, m), 1.70-1.80 (1H, m), 1.91-1.95 (1H, m), 3.75-3.80 (2H, m), 4.08 (2H, s), 5.00-5.10 (1H, m), 5.16-5.19 (2H, m), 7.14-7.21 (2H, m), 7.43-7.44 (2H, m), 8.18 (1H, s), 8.79 (1H, s)

MS (ESI): M+490

Example 4-24

[0647] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 0.72 (3H, d), 1.09 (3H, d), 1.37-1.40 (6H, m), 2.35-2.38 (1H, m), 3.77-3.79 (1H, m), 3.91-3.94 (1H, m), 4.20 (2H, s), 4.92-4.96 (1H, m), 5.23 (1H, t), 5.74-5.76 (1H, m), 7.21 (1H, m), 7.40-7.53 (3H, m), 7.75 (1H,$), 8.88 (1H, s), 15.08 (1H, s)

MS (ESI): M+476

Example 4-25

[0648] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 0.84 (3H, d, J=6.8 Hz), 0.87 (3H, d, J=6.4 Hz), 1.37 (3H, d, J=11.2 Hz), 1.42 (3H, d, J=10.8 Hz), 1.83-1.87 (2H, m), 3.79-3.80 (2H, m), 4.20 (2H, s), 4.90-4.96 (1H, m), 5.20 (1H, t), 6.08-6.10 (1H, m), 7.21 (1H, m), 7.39-7.55 (3H, m), 7.75 (1H,$), 8.78 (1H, s), 15.08 (1H, s)

MS (ESI): M+490

Example 4-26

[0649] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 0.91 (9H, s), 1.35 (3H, d), 1.44 (3H, d), 4.02-4.03 (2H, m), 4.20 (2H, s), 4.92-4.95 (1H, m), 5.15 (1H, t), 6.43 (1H, t), 7.19-7.21 (1H, m), 7.39-7.48 (2H, m), 7.55 (1H, s), 7.79 (1H,$), 8.80 (1H, s), 15.05 (1H, s)

MS (ESI): M+490

Example 4-27

[0650] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 0.76 (3H, t), 0.97-1.03 (2H, m), 1.12 (3H, d), 2.10-2.20 (1H, m), 3.75-3.80 (1H, m), 3.98-4.02 (1H, m), 4.02 (3H, s), 4.11 (2H, s), 4.92-4.95 (1H, m), 5.19 (1H, t), 7.16-7.25 (2H, m), 7.44-7.50 (2H, m), 8.02 (1H, s), 8.87 (1H, s), 15.40 (1H, s)

MS (ESI): M+462

Example 4-28

[0651] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 0.74 (3H, t, J=7.6 Hz), 0.99-1.03 (2H, m), 1.11 (3H, d), 1.37 (3H, t, J=6.8 Hz), 2.10-2.20 (1H, m), 3.70-3.80 (1H, m), 3.96-4.00 (1H, m), 4.11 (2H, s), 4.26 (2H, q, J=7.2 Hz), 4.92-5.00 (1H, m), 5.18 (1H, t), 7.14-7.18 (1H, m), 7.24-7.25 (1H, m), 7.40 (1H, s), 7.44-7.46 (1H, m), 8.12 (1H, s), 8.86 (1H, s), 15.46 (1H, s)

MS (ESI): M+476

Example 4-29

[0652] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 0.89 (3H, t, J=7.3 Hz), 1.98-2.01 (2H, m), 2.70 (3H, s), 3.80-3.90 (2H, m), 4.21 (2H, s), 5.10-5.21 (2H, m), 7.15-7.22 (2H, m), 7.49-7.51 (1H, m), 7.65 (1H, s), 8.04 (1H, s), 8.84 (1H, s), 15.25 (1H, s)

MS (ESI): M+450

Example 4-30

[0653] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 0.70 (3H, d, J=6.5 Hz), 1.15 (3H, d, J=6.5 Hz), 1.37 (3H, t, J=6.9 Hz), 2.30-2.40 (1H, m), 3.70-3.80 (1H, m), 3.90-4.00 (1H, m), 4.11 (2H, s), 4.20-4.30 (2H, m), 4.80-4.90 (1H, m), 5.18 (1H, t), 7.14-7.20 (1H, m), 7.24-/o 7.26 (1H, m), 7.43-7.49 (2H, m), 8.13 (1H, s), 8.87 (1H, s), 15.49 (1H, s)

MS (ESI): M+462

Example 4-31

[0654] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 0.97 (9H, s), 1.37 (3H, t, J=6.9 Hz), 4.02-4.11 (4H, m), 4.25-4.31 (2H, m), 5.10-5.20 (2H, m), 7.14-7.26 (2H, m), 7.44-7.49 (2H, m), 8.12 (1H, s), 8.78 (1H, s), 15.43 (1H, s)

MS (ESI): M+476

Example 4-32

[0655] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 0.72 (3H, d, J=6.5 Hz), 1.16 (3H, d, J=6.5 Hz), 2.30-2.50 (1H, m), 3.70-3.90 (1H, m), 3.90-4.00 (1H, m), 4.03 (3H, s), 4.12 (2H, s), 4.80-4.90 (1H, m), 5.19 (1H, t), 7.19-7.25 (2H, m), 7.46-7.51 (2H, m), 8.04 (1H, s), 8.88 (1H, s), 15.44 (1H, s)

MS (ESI): M+448

Example 4-33

[0656] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 0.99 (9H, s), 3.99-4.11 (7H, m), 5.11-5.20 (2H, m), 7.19-7.25 (2H, m), 7.49-7.52 (2H, m), 8.03 (1H, s), 8.78 (1H, s), 15.39 (1H, s)

MS (ESI): M+462

Example 4-34

[0657] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 0.93 (9H, s), 3.90-4.03 (5H, m), 4.22 (2H, s), 5.10 (1H, t), 6.20 (1H, t), 7.20-7.30 (1H, m), 7.40-7.57 (2H, m), 7.60 (1H, s), 7.79 (1H, s), 8.78 (1H, s), 15.05 (1H, s)

MS (ESI): M+462

Example 4-35

[0658] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 0.86 (3H, t, J=7.2 Hz), 1.19-1.29 (8H, m), 1.90-1.93 (2H, m), 3.72-3.80 (2H, m), 4.08 (2H, s), 5.02-5.04 (1H, m), 5.10-5.20 (2H, m), 7.11-7.22 (2H, m), 7.43-7.46 (2H, m), 8.18 (1H, s), 8.78 (1H, s), 15.51 (1H, s)

MS (ESI): M+476

Example 4-36

[0659] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 0.88 (3H, t, J=7.2 Hz), 1.20-1.35 (2H, m), 1.36 (3H, t, J=6.8 Hz), 1.80-2.00 (2H, m), 3.70-3.80 (2H, m), 4.11 (2H, s), 4.25 (2H, q, J=7.2 Hz), 5.17 (1H, t, J=5.6 Hz), 7.14-7.18 (1H, m), 7.24-7.26 (1H, m), 7.41 (1H, s), 7.41-7.45 (1H, m), 8.13 (1H, s), 8.78 (1H, s), 15.48 (1H, s)

MS (ESI): M+462

Example 4-37

[0660] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 0.93 (9H, s), 1.49 (3H, t), 4.00 (2H, t, J=6.4 Hz), 4.20 (2H, s), 4.22-4.33 (2H, m), 5.12 (1H, t), 6.36 (1H, t, J=6.8 Hz), 7.21 (1H, m), 7.39-7.48 (2H, m), 7.54 (1H, s), 7.79 (1H, s), 8.79 (1H, s), 15.04 (1H, s)

MS (ESI): M+476

Example 4-38

[0661] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 0.89 (3H, t, J=8.0 Hz), 1.23-1.40 (2H, m), 1.80-2.00 (2H, m), 3.75-3.90 (2H, m), 4.02 (3H, s), 4.11 (2H, s), 5.10-5.21 (2H, m), 7.16-7.24 (2H, m), 7.44-7.49 (2H, m), 8.03 (1H, s), 8.80 (1H, s), 15.44 (1H, br)

MS (ESI): M+448

Example 4-39

[0662] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 0.74 (3H, t, J=7.1 Hz), 0.84-1.24 (11H, m), 2.10-2.30 (1H, m), 3.70-3.80 (1H, m), 3.90-4.00 (1H, m), 4.09 (2H, s), 4.80-5.17 (3H, m), 7.15-7.22 (2H, m), 7.40-7.50 (2H, m), 8.19 (1H, s), 8.87 (1H, s), 15.51 (1H, s)

MS (ESI): M+490

Example 4-40

[0663] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 0.80-0.89 (1H, m), 1.04-1.30 (11H, m), 1.50-1.60 (2H, m), 1.70-1.80 (1H, m), 1.93-2.01 (2H, m), 3.73-3.76 (1H, m), 3.96-4.00 (1H, m), 4.07 (2H, s), 4.80-4.89 (1H, m), 5.00-5.17 (2H, m), 7.12-7.21 (2H, m), 7.40-7.42 (2H, m), 8.17 (1H, s), 8.87 (1H, s)

MS (ESI): M+516

Example 4-41

[0664] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 0.80-1.30 (6H, m), 1.46 (3H, t, J=6.9 Hz), 1.50-1.70 (2H, m), 1.70-1.80 (1H, m), 1.90-2.10 (2H, m), 3.70-3.81 (1H, m), 3.92-4.00 (1H, m), 4.20 (3H, s), 4.23 (2H, q, J=6.6 Hz), 5.20 (1H, t, J=4.8 Hz), 5.70-5.81 (1H, m), 7.19-7.24 (1H, m), 7.38-7.51 (3H, m), 7.77 (1H, s), 8.91 (1H, s), 15.11 (1H, s)

MS (ESI): M+502

Example 4-42

[0665] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 0.84-1.30 (6H, m), 1.50-1.70 (2H, m), 1.70-1.90 (1H, m), 1.94-2.10 (2H, m), 3.70-3.79 (1H, m), 3.90-4.00 (1H, m), 4.03 (3H, s), 4.10 (2H, s), 4.80-5.00 (1H, m), 5.19 (1H, m), 7.19-7.30 (2H, m), 7.43-7.48 (2H, m), 8.02 (1H, s), 8.87 (1H, s), 15.45 (1H, s)

MS (ESI): M+488

Example 4-43

[0666] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 0.80-1.00 (1H, m), 1.14-1.28 (5H, m), 1.37 (3H, t, J=6.9 Hz), 1.50-1.70 (2H, m), 1.70-1.80 (1H, m), 1.90-2.10 (2H, m), 3.70-3.80 (1H, m), 3.90-4.00 (1H, m), 4.11 (2H, s), 4.25(2H, q), 4.80-5.00 (1H, m), 5.18 (1H, m), 7.17-7.26 (2H, m), 7.41-7.47 (2H, m), 8.13 (1H, s), 8.89 (1H, s)

MS (ESI): M+502

Example 4-44

[0667] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 0.80-1.00 (1H, m), 1.00-1.40 (5H, m), 1.50-1.70 (2H, m), 1.70-1.80 (1H, m), 1.90-2.10 (2H, m), 3.70-3.80 (1H, m), 3.90-4.00 (1H, m), 3.98 (3H, s), 4.21 (2H, s), 5.20 (1H, m), 5.60-5.70 (1H, m), 7.19-7.25 (1H, m), 7.39-7.54 (3H, m), 7.77 (1H, s), 8.92 (1H, s)

MS (ESI): M+488

Example 4-45

[0668] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 0.74 (3H, d, J=4.0 Hz), 1.08 (3H, d, J=8.0 Hz), 1.45 (3H, t, J=8.0 Hz), 2.36-2.40 (2H, m), 3.70-3.80 (1H, m), 3.89-3.93 (1H, m), 4.19 (2H, s), 4.26(2H, q, J=8.0 Hz), 5.20 (1H, t, J=8.0 Hz), 5.69-5.73 (1H, m), 7.17-7.20 (1H, m), 7.39 (1H, m), 7.48-7.51 (2H, m), 7.76 (1H, s), 8.89 (1H, s)

MS (ESI): M+462

Example 4-46

[0669] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 0.73 (3H, d, J=6.8 Hz), 1.08 (3H, d, J=6.8 Hz), 2.20-2.40 (2H, m), 3.81-3.91 (1H, m), 3.91-3.99 (1H, m), 3.99 (3H, s), 4.22 (2H, s), 5.20 (1H, m), 5.55-5.58 (1H, m), 7.10-7.22 (1H, m), 7.41-7.55 (3H, m), 7.77 (1H, s), 8.91 (1H, s), 15.09 (1H, s)

MS (ESI): M+448

Example 4-47

[0670] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 0.85 (3H, d, J=7.3 Hz), 1.10-1.34 (2H, m), 1.33 (6H, d, J=6.0 Hz), 1.70-2.00 (2H, m), 3.75 (2H, m), 4.17 (2H, s), 4.80-4.90 (1H, m), 5.14 (1H, m), 5.80-6.00 (1H, m), 7.10-7.20 (1H, m), 7.30-7.50 (3H, m), 7.72 (1H, s), 8.80 (1H, s)

MS (ESI): M+476

Example 4-48

[0671] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 0.89 (3H, t), 1.20-1.40 (2H, m), 1.44 (3H, t), 1.80-2.00 (2H, m), 3.78 (2H, m), 4.20 (2H, s), 4.23 (2H, q, J=6.8 Hz), 5.16 (1H, t, J=5.6 Hz), 5.90-5.92 (1H, m), 7.15-7.21 (1H, m), 7.39-7.52 (3H, m), 7.76 (1H, s), 8.84 (1H, s), 15.10 (1H, s)

MS (ESI): M+462

Example 4-49

[0672] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 0.89 (3H, t), 1.23-1.35 (2H, m), 1.87-1.96 (2H, m), 3.72-3.79 (2H, m), 3.98 (3H, s), 4.21 (2H, s), 5.15 (1H, t, J=5.2 Hz), 5.85-5.88 (1H, m), 7.15-7.21 (1H, m), 7.39-7.48 (2H, m), 7.54 (1H, s), 7.76 (1H, s), 8.85 (1H, s), 15.10 (1H, s)

MS (ESI): M+448

Example 4-50

[0673] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 0.80-1.00 (1H, m), 1.11-1.20 (4H, m), 1.20-1.30 (1H, m), 1.35 (3H, d), 1.40 (3H, d), 1.55-1.70 (2H, m), 1.72-1.80 (1H, m), 1.95-2.10 (2H, m), 3.77-3.79 (1H, m), 3.95-3.98 (1H, m), 4.20 (2H, s), 4.91-4.94 (1H, m), 5.24 (1H, t), 5.81-5.83 (1H, m), 7.15-7.21 (1H, m), 7.39-7.50 (2H, m), 7.53 (1H, s), 7.74 (1H, s), 8.89 (1H, s), 15.09 (1H, s)

MS (ESI): M+516

Example 4-51

[0674] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 0.91 (9H, s), 1.48 (3H, t, J=6.9 Hz), 3.90-4.00 (2H, m), 4.13 (2H, s), 4.22(2H, q, J=7.0 Hz), 4.90-5.00 (1H, m), 6.10-6.20 (1H, m), 7.17-7.22 (1H, m), 7.34-7.36 (2H, m), 7.45-7.50 (1H, m), 7.77 (1H, s), 8.75 (1H, s)

MS (ESI): M+476

Example 4-52

[0675] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 0.93 (9H, s), 3.90-4.02 (2H, m), 4.15 (2H, s), 4.80-4.81 (1H, m), 5.05 (1H, m), 7.19-7.21 (1H, m), 7.35-7.40 (1H, m), 7.43-7.45 (1H, m), 7.57 (1H, d), 8.01-8.03 (1H, d, J=8.8 Hz), 8.12 (1H, s), 8.76 (1H, s)

MS (ESI): M+432

Example 4-53

[0676] .sup.1H NMR (DMSO-d.sub.6 400 MHz) (δ) ppm: 0.81 (3H, d), 1.20 (3H, d), 2.28-2.41 (1H, m), 3.98 (3H, s), 4.00-4.05 (2H, m), 4.08 (2H, s), 4.51-4.60 (1H, m), 7.02-7.08 (2H, m), 7.19 (1H, s), 7.28-7.30 (1H, m), 8.15 (1H, s), 8.60 (1H, s)

MS (ESI): M+448

Example 4-54

[0677] .sup.1H NMR (DMSO-d.sub.6 300 MHz) (δ) ppm: 0.95 (9H, s), 3.96 (3H, s), 3.96-4.03 (4H, m), 4.83 (1H, m), 5.17 (1H, m), 7.13-7.23 (2H, m), 7.28 (1H, s), 7.42-7.47 (1H, m), 7.80 (1H, s), 8.73 (1H, s)

MS (ESI): M+462

Sequence Listing Free Text

[0678] SEQ ID NO:1: Donor+chain for HIV integrase activity determination [0679] SEQ ID NO:2: Donor—chain for HIV integrase activity determination [0680] SEQ ID NO:3: Target+chain for HIV integrase activity determination [0681] SEQ ID NO:4: Target—chain for HIV integrase activity determination

Industrial Field of Utilization

[0682] As is clear from the above results, the compounds of the present invention has high HIV integrase inhibitory activity.

[0683] Therefore, the compounds can be useful pharmaceutical agents for the prophylaxis or therapy of AIDS, as anti-HIV agents having HIV integrase inhibitory activity. Moreover, by a combined use with other anti-HIV agents such as protease inhibitors, reverse transcriptase inhibitors and the like, the compounds can become more effective anti-HIV agents. Since the compounds have high inhibitory activity specific for integrases, they can provide safe pharmaceutical agents for human with a fewer side effects.

[0684] This application is based on patent application Nos. 2002-336843, 2003-65807 and 2003-139616 filed in Japan, the contents of which are all hereby incorporated by reference.