Vinylarene derivative and application

Abstract

The present invention relates to a vinylarene deriv. which modulates or inhibits the enzymic activity of indoleamine 2,3-dioxygenase 1 (IDO-1), and the use thereof, and further relates to a vinylarene deriv. and the use thereof. The vinylarene deriv. and its stereoisomer, cis- or trans-isomer, or tautomer thereof and pharmaceutically acceptable salt thereof, has an IDO-1 enzyme inhibitory activity, and is expected to provide brand new therapeutic methods and schemes for related diseases caused by IDO enzymes. ##STR00001##

Claims

1. A vinylarene derivative having formula I, its stereoisomer, cis-trans isomer, tautomer and pharmaceutically acceptable salt thereof where formula I includes: ##STR00178## and wherein ##STR00179## W is NH; X is NH or CH.sub.2; Y is O; J is C; K is C; M is C; R.sup.1 and R.sup.2 is selected from COOH, ##STR00180## or COOCH.sub.2CH.sub.3; R.sup.3 is selected from CH.sub.3; R.sup.4 is selected from H; R.sup.5 is selected from H; R.sup.6 is selected from H; R.sup.7 and R.sup.8 are the same or different and selected from n-butyl or isobutyl; R.sup.9 is selected from 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl, 2,4-difluorophenyl, 2-fluoro-4-methylphenyl, 3-trifluoromethyl-4-chlorophenyl, phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2-fluorophenyl, 4-fluorophenyl, 3-fluorophenyl or 5-methylisoxazolyl.

2. A treatment method comprising administering to a subject with a cancer selected from colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, kidney cancer, head and neck cancer, lymphoma, leukemia or melanoma an effective amount of the vinylarene derivative described in claim 1.

3. A pharmaceutical composition comprising an effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier or diluent.

Description

THE DETAILED DESCRIPTION OF THE INVENTION

(1) The following examples are provided to assist in a comprehensive understanding of the claims and their equivalents, and are not intended to limit the present invention.

Example 1

(2) ##STR00103##

(3) To a 250 mL flask, 10.0 g of 3′-nitro-4′-chlorocetophenone and 100 mL of di-n-butylamine were added, and the mixture was heated at 100° C. for 20 hours. After reaction was completed by TLC monitoring, the reaction mixture was evaporated to dryness, and the residue was dissolved in ethyl acetate (300 mL) and washed with water (100 mL×3), and the organic phase was dried over anhydrous sodium sulfate for 12 hr. The solvent was removed in vacuo. purification of residues by silica gel column chromatography (eluents are ethyl acetate and petroleum ether (boiling range 60-90° C.), the volume ratio is 1:6)) to obtain the compound 1-(4-(dibutylamino)-3-nitrophenyl)ethan-1-one, 11.3 g yellow solid.

(4) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ (ppm): 0.89 (t, J=7.5 Hz, 6H), 1.23-1.35 (m, 4H), 1.52-1.62 (m, 4H), 2.51 (s, 3H), 3.23 (t, J=7.2 Hz, 4H), 7.08 (dd, J=14.4, 3.9 Hz, 1H), 7.96 (dd, J=9.0, 2.1 Hz, 1H), 8.31 (dd, J=2.1 Hz, 1H).

Example 2

(5) ##STR00104##

(6) To a 250 mL flask, 9.9 g of sodium t-butoxide and 150 mL of tetrahydrofuran were added, and 23.0 g of ethyl 2-(diethoxyphosphoryl)acetate was added dropwise with stirring at a temperature of 0 to 5° C. After the dropwise addition completely, the mixture was stirred at room temperature for 0.5 hour, and the compound 1-(4-(dibutylamino)-3-nitrophenyl)ethan-1-one dissolved in 50 mL of tetrahydrofuran was added dropwise with stirring at a temperature of 20-30° C. After the dropwise addition completely, the mixture was stirred at room temperature for 12 hours. After reaction was completed by TLC monitoring, the reaction mixture was washed with a saturated aqueous solution of ammonium chloride (100 mL×3), and the organic phase was dried over anhydrous sodium sulfate for 12 hours, the solvent was removed in vacuo. Purification of residues by silica gel column chromatography (eluents are ethyl acetate and petroleum ether (boiling range 60-90° C.), volume ratio 1:10) to obtain the compound ethyl (E)-3-(4-(dibutylamino)-3-nitrophenyl)but-2-enoate, 6.3 g yellow solid.

(7) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ (ppm): 0.87 (t, J=7.5 Hz, 6H), 1.17-1.34 (m, 7H), 1.48-1.62 (m, 4H), 2.51 (s, 3H), 3.16 (t, J=7.2 Hz, 4H), 4.18 (q, J=7.2 Hz, 2H), 6.14 (d, J=1.2 Hz, 1H), 7.53-7.54 (m, 2H), 7.87 (d, J=2.1 Hz, 1H).

Example 3

(8) ##STR00105##

(9) To a 250 mL flask, 2.7 g of compound ethyl (E)-3-(4-(dibutylamino)-3-nitrophenyl)but-2-enoate, 4.0 g of ammonium chloride, zinc powder 4.9 g, 100 mL of ethanol and 20 mL of water were added, the mixture was stirred at room temperature for 2 hours. After reaction was completed by TLC monitoring, the reaction mixture was filtered, and the solvent of filtrate was removed in vacuo. Purification of residues by silica gel column chromatography (eluent ethyl acetate and petroleum ether (boiling range: 60-90° C.), volume ratio: 1:10) to obtain the compound ethyl (E)-3-(3-amino-4-(dibutylamino)phenyl)but-2-enoate, 0.3 g reddish brown viscous liquid.

(10) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ (ppm): 0.87 (t, J=6.9 Hz, 6H), 1.10 (t, J=6.9 Hz, 3H), 1.23-1.30 (m, 4H), 1.33-1.43 (m, 4H), 2.16 (d, J=1.5 Hz, 3H), 2.86 (t, J=7.5 Mz, 4H), 4.03 (q, J=6.9 Hz, 2H), 6.08 (d, J=0.9 Hz, 1H), 6.56-6.60 (m, 2H), 6.96 (d, J=7.5 Hz, 1H).

Example 4

(11) ##STR00106##

(12) To a 100 mL flask, 0.3 g of compound ethyl (E)-3-(3-amino-4-(dibutylamino)phenyl)but-2-enoate and acetonitrile 50 mL were added, irradiated with UV light (wavelength: 365 nM) for 48 hours, the solvent was removed in vacuo. Purification of residues by silica gel column chromatography (eluents are ethyl acetate and petroleum ether (boiling range 60-90° C.), volume ratio 1:10) to obtain the compound ethyl (Z)-3-(3-amino-4-(dibutylamino)phenyl)but-2-enoate, 0.11 g reddish brown viscous liquid.

(13) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ (ppm): 0.87 (t, J=−6.9 Hz, 6H), 1.09 (t, J=6.9 Hz, 3H), 1.22-1.30 (m, 4H), 1.33-1.42 (m, 4H), 2.15 (d, J=1.5 Hz, 3H), 2.86 (t, J=7.5 Mz, 4H), 4.01 (q, J=6.9 Hz, 2H), 5.82 (d, J=0.9 Hz, 1H), 6.56-6.60 (m, 2H), 6.97 (d, J=7.5 Hz, 1H).

Example 5

(14) ##STR00107##

(15) To a 100 mL flask, 0.4 g of the compound ethyl (E)-3-(3-amino-4-(dibutylamino)phenyl)but-2-enoate, 0.16 g of p-toluene isocyanate and 30 mL of tetrahydrofuran were added. The mixture was stirred at room temperature for 8 hours. After reaction was completed by TLC monitoring, the solvent was removed in vacuo. Purification of residues by silica gel column chromatography (eluents are ethyl acetate and petroleum ether (boiling range: 60-90° C.), volume ratio: 1:5) to obtain the compound ethyl (E)-3-(4-(dibutylamino)-3-(3-(p-tolyl)ureido)phenyl)but-2-enoate (Compound 518), 0.12 g white solid.

(16) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ (ppm): 0.81 (t, J=6.9 Hz, 6H), 1.12-1.16 (m, 81), 1.30 (t, J=6.9 Hz, 3H), 2.35 (s, 3H), 2.72 (t, J=6.9 Hz, 4H), 4.18 (q, J=6.9 Hz, 2H), 6.18 (s, 1H), 6.45 (s, 1H), 7.08-7.26 (m, 5H), 8.22 (s, 1H), 8.45 (s, 1H).

Example 6

(17) ##STR00108##

(18) To a 100 mL flask, 0.3 g of the compound ethyl (E)-3-(4-(dibutylamino)-3-(3-(p-tolyl)ureido)phenyl)but-2-enoate and acetonitrile 50 mL were added, irradiated with UV light (wavelength: 365 nM) for 48 hours, the solvent was removed in vacuo. Purification of residues by silica gel column chromatography (eluents are ethyl acetate and petroleum ether (boiling range 60-90° C.), volume ratio 1:6) to obtain the compound ethyl (Z)-3-(4-(dibutylamino)-3-(3-(p-tolyl)ureido)phenyl)but-2-enoate (Compound 2), 0.10 g white solid.

Example 7

(19) ##STR00109##

(20) To a 100 mL flask, 100 g of compound ethyl (E)-3-(4-(dibutylamino)-3-(3-(p-tolyl)ureido) phenyl)but-2-enoate, ethanol 50 mL and 3.0 g of sodium hydroxide were added. The mixture was stirred at room temperature for 12 hours. After reaction was completed by TLC monitoring, the solvent was removed in vacuo, and the residue was dissolved in ethyl acetate (300 mL) and water (100 mL), and the mixture was adjusted to pH=3 with concentrated hydrochloric acid, and the organic phase was dried over anhydrous sodium sulfate for 12 hours, the solvent was removed in vacuo. Purification of residues by silica gel column chromatography (eluents are ethyl acetate and petroleum ether (boiling range 60-90° C.) in a volume ratio of 1:2) to obtain the compound (E)-3-(4-(dibutylamino)-3-(3-(p-tolyl)ureido)phenyl)but-2-enoic acid (Compound 525), 0.11 g white solid.

(21) .sup.1H-NMR (300 MHz, CDCl.sub.3) δ (ppm): 0.81 (t. J=6.9 Hz, 6H), 1.13-1.17 (m, 8H), 2.35 (s, 31-H), 2.73 (t, J=6.9 Hz, 4H), 6.17 (s, 1H), 6.46 (s, 1H), 7.07-7.25 (m, 5H), 8.23 (s, 1H), 8.46 (s, 1H), 12.05 (s, 1H). MS (ESI), m/z (%): 438.32 [M+H].sup.+.

Example 8

(22) ##STR00110##

(23) To a 100 mL flask, 0.3 g of compound (E)-3-(4-(dibutylamino)-3-(3-(p-tolyl)ureido)phenyl)but-2-enoic acid and 50 mL of acetonitrile were added, irradiated with UV light (wavelength: 365 nM) for 48 hours, the solvent was removed in vacuo. Purification of residues by silica gel column chromatography (eluents are ethyl acetate and petroleum ether (boiling range 60-90° C.), volume ratio 1:2) to obtain compound (Z)-3-(4-(dibutylamino)-3-(3-(p-tolyl)ureido)phenyl)but-2-enoic acid (Compound 9), 0.16 g white solid.

(24) .sup.1H-NMR (300 MHz, DMSO-d.sub.6) δ (ppm): 0.85 (t, J=6.9 Hz, 6H), 1.19-1.31 (m, 8H), 2.26 (s, 3H), 2.50 (s, 3H), 2.83-2.88 (m, 4H), 5.81 (s, 1H), 7.03-7.12 (m, 3H), 7.33-7.37 (m, 2H), 8.04 (s, 1H), 8.82-8.36 (m, 1H), 8.36 (s, 1H), 9.35 (s, 1H). MS (ESI), m/z (%): 438.32 [M+H].sup.+.

Example 9

(25) ##STR00111##

(26) To a 100 mL flask, 0.5 g of the compound ethyl (E)-3-(3-amino-4-(diisobutylamino)phenyl)but-2-enoate (preparation method is the same as in Example 1, Example 2 and Example 3), 3 g of 2,4-difluorophenyl isocyanate and 30 mL of tetrahydrofuran were added. The mixture was stirred at room temperature for 4 hours. After reaction was completed by TLC monitoring, the solvent was removed in vacuo. Purification of residues by silica gel column chromatography (eluents are ethyl acetate and petroleum ether (boiling range: 60-90° C.), volume ratio: 1:5) to obtain the compound ethyl (E)-3-(3-(3-(2,4-difluorophenyl)ureido)-4-(diisobutylamino)phenyl) but-2-enoate (Compound 564), 0.16 g white solid.

(27) .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ (ppm): 0.83 (d, J=6.0 Hz, 12H), 1.24 (t, J=6.0 Hz, 3H), 1.69-1.72 (m, 2H), 2.49 (s, 3H), 2.79 (d, J=12.0 Hz, 4H), 4.13 (q, J=6.0 Hz, 2H), 6.09 (s, 1H), 7.03-7.05 (m, 1H), 7.19-7.23 (m, 2H), 7.29-7.31 (t, J=6 Hz, 1H), 7.98-8.01 (m, 1H), 8.05 (d, J=6.0 Hz, 1H), 8.09 (s, 1H), 9.33 (s, 1H). MS (ESI), m/z (%): 488.32[M+H].sup.+.

Example 10

(28) ##STR00112##

(29) To a 100 mL flask, 0.3 g of the compound ethyl (E)-3-(3-(3-(2,4-difluorophenyl)ureido)-4-(diisobutylamino)phenyl) but-2-enoate, ethanol 50 mL and sodium hydroxide 3.0 g were added. The mixture was stirred at room temperature for 12 hours. After reaction was completed by TLC monitoring, the solvent was removed in vacuo, and the residue was dissolved in ethyl acetate (300 mL) and water (100 mL), and the mixture was adjusted to pH=3 with concentrated hydrochloric acid, and the organic phase was dried over anhydrous sodium sulfate for 12 hours, the solvent was removed in vacuo. Purification of residues by silica gel column chromatography (eluents are ethyl acetate and petroleum ether (boiling range 60-90° C.), volume ratio 1:2) to obtain the compound (E)-3-(3-(3-(2,4-difluorophenyl)ureido)-4-(diisobutylamino)phenyl)but-2-enoic acid (Compound 571), 0.15 g white solid.

(30) .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ (ppm): 9.31 (s, 1H), 8.08 (s, 1H), 8.05 (d, J=6.0 Hz, 1H), 7.98-8.03 (m, 1H), 7.29-7.31 (t, J=6 Hz, 1H), 7.19-7.24 (m, 2H), 7.01-7.06 (m, 1H), 6.05 (s, 1H), 2.86-2.90 (m, 4H), 2.48 (s, 3H), 1.69-1.72 (m, 2H), 0.82 (d, J=6.0 Hz, 12H). MS (ESI), m/z (%): 460.27[M+H].sup.+.

Example 11

(31) ##STR00113##

(32) To a 100 mL flask, 0.1 g of compound (E)-3-(3-(3-(2,4-difluorophenyl)ureido)-4-(diisobutylamino)phenyl)but-2-enoic acid and 50 mL of acetonitrile, irradiated with UV light (wavelength: 365 nM) for 48 hours, the solvent was removed in vacuo. Purification of residues by silica gel column chromatography (eluents are ethyl acetate and petroleum ether (boiling range 60-90° C.), volume ratio 1:2) to obtain the compound (Z)-3-(3-(3-(2,4-difluorophenyl)ureido)-4-(diisobutylamino)phenyl)but-2-enoic acid (Compound 55), 0.03 g white solid.

(33) .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ 11.88 (s, 1H), 9.28 (s, 1H), 8.05 (s, 1H), 7.94 (td, J=9.1, 6.5 Hz, 1H), 7.78 (d, J=1.7 Hz, 1H), 7.34-7.24 (m, 1H), 7.13 (d, J=8.3 Hz, 1H), 7.04 (t, J=8.0 Hz, 1H), 6.87 (dd, J=8.2, 1.6 Hz, 1H), 5.84 (s, 1H), 2.70 (d, J=6.8 Hz, 4H), 2.09 (s, 3H), 1.71-1.66 (m, 2H), 0.85 (d, J=6.0 Hz, 12H). MS (ESI), m/z (%): 460.28[M+H].sup.+.

(34) Partial Compound Nuclear Magnetic Resonance Data:

(35) ##STR00114##

(36) .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ (ppm): 0.85 (t, J=6.9 Hz, 6H), 1.45-1.17 (m, 8H), 2.50 (s, 3H), 2.87 (m, 4H), 5.86 (s, 1H), 6.85-7.32 (m, 4H), 8.05-8.00 (m, 1H), 8.25-8.32 (m, 1H), 8.66 (s, 1H), 9.40 (s, 1H). MS (ESI), m/z (%): 460.29 [M+H].sup.+. White solid.

(37) ##STR00115##

(38) .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ (ppm): 0.85 (t, J=6.0 Hz, 6H), 1.17-1.37 (m, 8H), 2.27 (s, 3H), 2.50 (s, 3H), 2.86-2.90 (m, 4H), 5.85 (s, 1H), 6.83 (d, J=0.6 Hz, 1H), 6.95 (d, J=0.6 Hz, 1H), 7.06 (d, J=1.2 Hz, 1H), 7.16 (dd, J=4.2, 1.2 Hz, 1H), 7.88-7.94 (m, 1H), 8.33 (s, 1H), 8.63 (s, 1H), 9.28 (s, 1H). MS (ESI), m/z (%): 456.32[M+H].sup.+. White solid.

(39) ##STR00116##

(40) .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ 12.21 (s, 1H), 9.22 (s, 1H), 8.06 (s, 1H), 8.00 (s, 1H), 7.86 (t, J=8.5 Hz, 1H), 7.45 (d, J=15.8 Hz, 1H), 7.28 (d, J=9.6 Hz, 1H), 7.16 (d, J=8.4 Hz, 1H), 7.05 (d, J=12.2 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H), 5.89 (s, 1H), 2.80 (d, J=6.9 Hz, 4H), 2.45 (d, J=0.7 Hz, 3H), 2.21 (s, 3H), 1.71 (dt, J=13.3, 6.7 Hz, 2H), 0.82 (d, J=6.6 Hz, 12H). MS (ESI), m/z (%): 438.30[M+H].sup.+. White solid.

(41) ##STR00117##

(42) .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ 11.88 (s, OH), 9.28 (s, OH), 8.05 (s, 1H), 7.94 (td, J=9.1, 6.5 Hz, 1H), 7.78 (d, J=1.7 Hz, 1H), 7.34-7.24 (m, 1H), 7.13 (d, J=8.3 Hz, 1H), 7.04 (t, J=8.0 Hz, 1H), 6.87 (dd, J=8.2, 1.6 Hz, 1H), 5.84 (s, 1H), 2.70 (d, J=6.8 Hz, 4H), 2.09 (s, 3H), 1.71-1.66 (m, 2H), 0.85 (t, J=8.0 Hz, 12H). MS (ESI), m/z (%): 460.28[M+H].sup.+. White solid.

(43) ##STR00118##

(44) .sup.1H-NMR (300 MHz, DMSO-d.sub.6) δ (ppm): 9.28 (s, 1H), 8.63 (s, 1H), 8.33 (s, 1H), 7.88-7.94 (m, 1H), 7.16 (dd, J=4.2, 1.2 Hz, 1H), 7.06 (d, J=1.2 Hz, 1H), 6.95 (d, J=0.6 Hz, 1H), 6.83 (d, J=0.6 Hz, 1H), 5.85 (s, 1H), 2.86-2.90 (m, 4H), 2.48 (s, 3H), 2.10 (s, 3H), 1.63-1.71 (m, 2H), 0.82 (d, J=6.0 Hz, 12H). MS (ESI), m/z (%): 456.29[M+H].sup.+. White solid.

(45) ##STR00119##

(46) .sup.1H-NMR (300 MHz, DMSO-d.sub.6) δ (ppm): 0.85 (t, J=−6.9 Hz, 6H), 1.27-1.30 (m, 11H), 2.53 (s, 3H), 2.87-2.89 (m, 4H), 4.13 (q, J=6.9 Hz, 2H), 6.08 (s, 1H), 7.13-7.17 (m, 2H), 7.50 (d, J=9.3 Hz, 1H), 7.70 (d, J=9.3 Hz, 1H), 8.01 (s, 1H), 8.35 (s, 1H), 8.39 (s, 1H), 9.88 (s, 1H). MS (ESI), m/z (%): 488.55[M+H].sup.+. White solid.

(47) ##STR00120##

(48) .sup.1H-NMR (300 MHz, DMSO-d.sub.6) δ (ppm): 0.84 (t, J=6.9 Hz, 6H), 1.20-1.30 (m, 11H), 2.30 (s, 3H), 2.52 (s, 3H), 2.86-2.88 (m, 4H), 4.12 (q, J=6.9 Hz, 2H), 6.07 (s, 1H), 6.87-6.96 (m, 3H), 7.09 (s, 1H), 7.95-8.01 (m, 1H), 8.35 (s, 1H), 8.61 (s, 111), 9.21 (s, 1H). MS (ESI), m/z (%): 484.36[M+H].sup.+. White solid.

(49) ##STR00121##

(50) .sup.1H-NMR (300 MHz, DMSO-d.sub.6) δ (ppm): 0.85 (t, J=6.9 Hz, 6H), 1.19-1.34 (m, 8H), 2.49 (s, 3H), 2.86-2.91 (m, 4H), 6.05 (s, 1H), 6.91 (t, J=8.7 Hz, 3H), 7.00-7.12 (m, 3H), 8.10-8.19 (m, 1H), 8.32 (s, 1H), 8.26 (s, 1H), 8.63 (s, 1H), 9.32 (s, 1H). MS (ESI), m/z (%): 460.29[M+H].sup.+. White solid.

(51) ##STR00122##

(52) .sup.1H-NMR (300 MHz, DMSO-d.sub.6) δ (ppm): 0.85 (t, J=6.9 Hz, 6H), 1.20-1.30 (m, 8H), 1.80 (s, 3H), 2.43 (s, 3H), 2.84-2.89 (m, 4H), 6.05 (s, 1H), 6.86-6.94 (m, 2H), 7.03-7.11 (m, 2H), 7.95-8.00 (m, 1H), 8.29 (s, 1H), 8.59 (s, 1H), 9.19 (s, 1H). MS (ESI), m/z (%): 456.32 [M+H].sup.+. White solid.

(53) ##STR00123##

(54) .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ (ppm): 0.83 (d, J=6.0 Hz, 12H), 1.24 (t, J=6.0 Hz, 3H), 1.69-1.72 (m, 2H), 2.49 (s, 3H), 2.79 (d, J=12.0 Hz, 4H), 4.13 (q, J=6.0 Hz, 2H), 6.09 (s, 1H), 7.03-7.05 (m, 1H), 7.19-7.23 (m, 2H), 7.29-7.31 (t, =6 Hz, 1H), 7.98-8.01 (m, 1H), 8.05 (d, J=6.0 Hz, 1H), 8.09 (s, 1H), 9.33 (s, 1H). MS (ESI), m/z (%): 488.32[M+H].sup.+. White solid.

(55) ##STR00124##

(56) .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ (ppm): 9.31 (s, 1H), 8.08 (s, 1H), 8.05 (d, J=6.0 Hz, 1H), 7.98-8.03 (m, 1H), 7.29-7.31 (t, J=6 Hz, 1H), 7.19-7.24 (m, 2H), 7.01-7.06 (m, 1H), 6.05 (s, 1H), 2.86-2.90 (m, 4H), 2.48 (s, 3H), 1.69-1.72 (m, 2H), 0.82 (d, J=6.0 Hz, 12H). MS (ESI), m/z (%): 460.27[M+H].sup.+. White solid.

(57) ##STR00125##

(58) .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ (ppm): 12.11 (s, 1H), 9.23 (s, 1H), 8.07 (s, 1H), 8.02 (s, 11-), 7.86 (t, J=8.5 Hz, 1H), 7.19 (s, 2H), 7.06 (d, J=12.2 Hz, 1H), 6.95 (d, J=8.2 Hz, 1H), 6.06 (d, J=1.1 Hz, 11H), 2.77 (d, J=6.9 Hz, 4H), 2.46 (d, J=0.7 Hz, 3H), 2.27 (s, 3H), 1.70 (dt, J=13.4, 6.7 Hz, 2H), 0.83 (d, J=6.6 Hz, 12H). MS (ESI), m/z (%): 456.30[M+H].sup.+. White solid.

(59) ##STR00126##

(60) .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ (ppm): 0.80 (t, J=6.0 Hz, 6H), 1.14-1.25 (m, 11H), 2.48 (s, 3H), 2.73 (t, J=6.0 Hz, 4H), 3.83 (s, 2H), 4.13 (q, J=6.0 Hz, 2H), 6.08 (s, 1H), 7.22-7.25 (m, 4H), 7.37-7.40 (m, 1H), 7.46-7.48 (m, 1H), 8.40 (s, 1H), 8.90 (s, 1H). MS (ESI), m/z (%): 469.34 [M+H].sup.+. White solid.

(61) ##STR00127##

(62) .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ (ppm): 0.80 (t, J=6.0 Hz, 6H), 1.13-1.23 (m, 8H), 2.45 (s, 3H), 2.71 (t, J=6.0 Hz, 4H), 3.83 (s, 2H), 6.05 (s, 1H), 7.22-7.27 (m, 4H), 7.37-7.40 (m, 1H), 7.46-7.48 (m, 1H), 8.39 (s, 1H), 8.89 (s, 1H), 12.18 (s, 1H). MS (ESI), m/z (%): 441.15[M+H].sup.+. White solid.

(63) ##STR00128##

(64) .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 12.13 (s, 1H), 8.44 (s, 1H), 8.36 (s, 1H), 7.27-7.12 (m, 6H), 6.00 (s, 1H), 3.74 (s, 2H), 2.50 (s, 2H), 2.48 (s, 2H), 2.41 (s, 3H), 2.22 (s, 31-), 1.51 (dt, J=13.1, 6.4 Hz, 2H), 0.69 (d, J=6.5 Hz, 12H). MS (ESI), m/z (%): 437.31 [M+H].sup.+. White solid.

(65) ##STR00129##

(66) .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 8.59 (s, 1H), 8.07 (d, J=1.9 Hz, 1H), 7.74 (s, 1H), 7.28 (d, J=8.0 Hz, 1H), 7.13 (dt, J=8.5, 5.3 Hz, 2H), 6.98 (s, 1H), 6.93 (d, J 8.4 Hz, 1H), 6.00 (s, 1H), 2.64 (d, J=6.9 Hz, 4H), 2.42 (s, 3H), 2.21 (s, 3H), 2.15 (s, 3H), 1.60 (dd, J=13.0, 6.4 Hz, 2H), 0.78 (d, J=6.6 Hz, 12H). MS (ESI), m/z (%): 452.32 [M+H].sup.+. White solid.

(67) ##STR00130##

(68) .sup.1H-NMR (500 MHz, DMSO-d.sub.6) δ 12.17 (s, 1H), 8.80 (d, J=15.8 Hz, 1H), 8.33 (s, 1H), 7.43 (t, J=7.4 I-Hz, 1H), 7.36 (dd, J=13.4, 6.2 Hz, 1H), 7.28 (s, 2H), 7.20 (dd, J=12.6, 5.3 Hz, 2H), 6.05 (s, 1H), 3.85-3.77 (m, 2H), 2.61 (t, J=12.7 Hz, 4H), 2.45 (s, 3H), 1.62 (dt, J=12.0, 6.0 Hz, 2H), 0.79 (d, J=6.6 Hz, 12H). MS (ESI), m/z (%): 441.27 [M+H].sup.+. White solid.

(69) ##STR00131##

(70) .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ 12.16 (s, 1H), 8.72 (d, J=21.6 Hz, 1H), 8.30 (s, 1H), 7.38 (s, 2H), 7.31-7.13 (m, 4H), 6.04 (s, 1H), 3.74 (d, J=18.0 Hz, 2H), 2.59 (t, J=13.6 Hz, 4H), 2.45 (s, 3H), 1.59 (d, J=5.8 Hz, 2H), 0.77 (d, J=5.9 Hz, 12H). MS (ESI), m/z (%): 441.27 [M+H].sup.+. White solid.

(71) ##STR00132##

(72) .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 12.12 (s, 1H), 9.42 (s, 1H), 8.20 (d, J=2.1 Hz, 1H), 7.86 (s, 1H), 7.33 (d, J=8.4 Hz, 2H), 7.13 (dt, J=8.4, 5.3 Hz, 2H), 7.06 (d, J=8.3 Hz, 2H), 6.03 (d, J=1.2 Hz, 11H), 2.77 (d, J=5.3 Hz, 2H), 2.53 (t, J=10.7 Hz, 1H), 2.44 (d, J=1.0 Hz, 3H), 2.21 (s, 3H), 1.89-1.79 (m, 2H), 1.64 (d, J=11.7 Hz, 2H), 1.46 (d, J=10.7 Hz, 1H), 1.31 (ddd, J=22.4, 14.4, 7.9 Hz, 2H), 1.14 (ddd, J=30.5, 21.7, 12.0 Hz, 4H), 0.78 (d, J=6.6 Hz, 6H). MS (ESI), m/z (%): 464.33 [M+H].sup.+. White solid.

(73) ##STR00133##

(74) .sup.1H-NMR (300 MHz, DMSO-d.sub.6) δ (ppm): 0.86 (t, J=6.9 Hz, 61H), 1.19-1.37 (m, 11H), 2.53 (s, 3H), 2.89 (t, J=6.6 Hz, 4H), 4.14 (q, J=6.9 Hz, 2H), 6.09 (d, J=1.2 Hz, 1H), 6.90-6.94 (m, 1H), 7.07-7.15 (m, 2H), 7.19-7.28 (m, 2H), 7.72 (d, J=1.8 Hz, 1H), 8.33 (s, 1H), 8.37 (d, J=1.5 Hz, 1H), 9.57 (s, 1H). MS (ESI), m/z (%): 487.30[M+H].sup.−. White solid.

(75) ##STR00134##

(76) Compound 1022: R.sup.2 is an ethyl ester group, and the olefinic bond is trans, and the specific structure is as follows:

(77) .sup.1H-NMR (300 MHz, DMSO-d.sub.6) δ (ppm): 0.85 (t, J=6.9 Hz, 6H), 1.25-1.35 (m, 11H), 2.50 (s, 3H), 2.89 (m, 4H), 4.09-4.16 (m, 2H), 6.06 (s, 1H), 6.98-7.03 (m, 3H), 7.22-7.27 (m, 1H), 7.35-7.37 (m, 1H), 8.00 (d, J=8.1 Hz, 1H), 8.26 (s, 1H), 8.68 (s, 1H), 8.96 (s, 1H). MS (ESI), m/z (%): 487.29[M+H].sup.+. White solid.

(78) ##STR00135##

(79) .sup.1H-NMR (300 MHz, DMSO-d.sub.6) δ (ppm): 0.85 (t, J=6.9 Hz, 6H), 1.18-1.33 (m, 11H), 2.53 (s, 3H), 2.86-2.92 (m, 4H), 4.13 (q, J=6.9 Hz, 2H), 7.07-7.15 (m, 2H), 7.23 (d, J=−9.0 Hz, 2H), 7.50 (d, J=9.0 Hz, 2H), 8.32 (s, 1H), 8.38 (s, 1H), 9.53 (s, 1H). MS (ESI), m/z (%): 487.29[M+H].sup.+. White solid.

(80) ##STR00136##

(81) Compound 1024: R.sup.2 is an ethyl ester group, and the olefinic bond is trans, and the specific structure is as follows:

(82) .sup.1H-NMR (300 MHz, DMSO-d.sub.6) δ (ppm): 0.85 (t, J=6.9 Hz, 6H), 1.18-1.32 (m, 11H), 2.51 (s, 3H), 2.87-2.89 (m, 4H), 4.12 (q, J=6.9 Hz, 2H), 6.07 (s, 1H), 6.91-6.93 (m, 1H), 7.07-7.17 (m, 311), 8.12-8.14 (m, 1H), 8.33 (s, 1H), 8.36 (s, 1H), 9.31 (s, 1H). MS (ESI), m/z (%): 555.34[M+H].sup.+. White solid.

(83) ##STR00137##

(84) R.sup.2 is an ethyl ester group, and the olefinic bond is trans, and the specific structure is as follows:

(85) .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ (ppm): 0.79 (t, J=6.0 Hz, 6H), 1.15 (q, J=6.0 Hz, 4H), 1.23-1.27 (m, 7H), 2.50 (s, 3H), 2.82 (t, J=6.0 Hz, 4H), 3.83 (s, 2H), 4.14 (q, J=6.0, 2H), 6.08 (s, 1H), 7.16 (d, J=12 Hz, 1H), 7.22 (t, J=12 Hz, 1H), 7.34 (d, J=6.0 Hz, 1H), 7.39 (dd, J=12.0, 6.0 Hz, 2H), 7.48 (d, J=6.0 Hz, 2H), 8.45 (s, 1H), 8.97 (s, 1H), 10.37 (s, 1H). MS (ESI), m/z (%): 468.31 [M+H].sup.+. White solid.

(86) ##STR00138##

(87) R.sup.2 is an ethyl ester group, and the olefinic bond is trans, and the specific structure is as follows:

(88) .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ (ppm): 0.81 (t, J=6.0 Hz, 6H), 1.21-1.29 (m, 11H), 2.29 (s, 3H), 2.51 (s, 3H), 2.90 (t, J=6.0 Hz, 41-), 4.15 (q, J=6.0 Hz, 4H), 6.11 (s, 1H), 6.80 (d, J=6.0 Hz, 1H), 7.15-7.25 (m, 4H), 7.36 (s, 1H), 8.35 (s, 1H), 8.39 (d, J=6.0 Hz 1H), 9.49 (s, 1H). MS (ESI), m/z (%): 466.36[M+H].sup.+. White solid.

(89) ##STR00139##

(90) .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ (ppm): 0.83 (t, J=6.0 Hz, 6H), 1.13-1.33 (m, 8H), 2.50 (s, 3H), 2.86-2.92 (m, 4H), 6.10 (s, 1H), 7.07-7.09 (m, 1H), 7.13-7.22 (m, 1H), 7.29-7.32 (m, 2H), 7.47 (d, J=12 Hz, 1H), 7.97 (s, 1H), 8.21 (s, 1H), 8.75 (s, 1H), 9.18 (s, 1H). MS (ESI), m/z (%): 459.27 [M+H].sup.+. White solid.

(91) ##STR00140##

(92) .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ (ppm): 0.85 (t, J=6.0 Hz, 6H), 1.21-1.31 (m, 8H), 2.50 (s, 3H), 2.92 (m, 4H), 4.09-4.16 (m, 2H), 6.10 (s, 1H), 7.02-7.03 (m, 1H), 7.27-7.33 (m, 3H), 7.76 (m, 1H), 8.01 (d, J=7.8 Hz, 1H), 8.32 (s, 1H), 8.47 (s, 1H), 9.84 (s, 1H). MS (ESI), m/z (%): 459.29[M+H].sup.+. White solid.

(93) ##STR00141##

(94) .sup.1H-NMR (300 MHz, DMSO-d.sub.6) δ (ppm): 0.85 (t, J=6.9 Hz, 6H), 1.24-1.30 (m, 8H), 2.56 (s, 3H), 2.87-2.90 (m, 4H), 6.05 (s, 1H), 7.12-7.16 (m, 2H), 7.46-7.50 (m, 1H), 7.71 (d, J=8.1 Hz, 1H), 8.35-8.38 (m, 2H), 9.85 (s, 1H). MS (ESI), m/z (%): 527.29[M+H].sup.+. White solid.

(95) ##STR00142##

(96) The olefinic bond is trans, Y is S substituted, and R is hydrogen. The specific structure is as follows:

(97) .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ (ppm): 0.80 (t, J=6.0 Hz, 6H), 1.16 (q, J=6.0 Hz, 4H), 1.22-1.28 (m, 4H), 2.51 (s, 3H), 2.80 (t, J=6.0 Hz, 4H), 3.85 (s, 2H), 6.09 (s, —1H), 7.17 (d, J-=12 Hz, 1H), 7.23 (t, J=12 Hz, 1H), 7.33 (d, J=6.0 Hz, 1H), 7.39 (dd, J=12.0, 6.0 Hz, 2H), 7.47 (d, J=6.0 Hz, 2H), 8.46 (s, 1H), 8.97 (s, 1H), 8.97 (s, 1H), 10.37 (s, 1H), 12.03 (s, 1H). MS (ESI), m/z (%): 440.27[M+H].sup.+. White solid.

(98) ##STR00143##

(99) .sup.1H-NMR (600 MHz, CDCl.sub.3) δ (ppm): 8.37 (d, J=1.8 Hz, 1H), 8.13 (s, 1H), 7.60 (d, J=2.4 Hz, 1H), 7.38 (d, J=8.7 Hz, 1H), 7.27 (dd, J=9.5, 3.1 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H), 7.12 (dd, J=8.3, 2.0 Hz, 1H), 6.48 (s, 1H), 5.64 (s, 1H), 2.62 (d, J=7.2 Hz, 4H), 2.46 (s, 3H), 1.73 (dp, J=13.4, 6.7 Hz, 2H), 0.90 (d, J=6.6 Hz, 12H). MS (ESI), m/z (%): 474.31[M+H].sup.+. White solid.

(100) ##STR00144##

(101) .sup.1H-NMR (600 MHz, CDCl.sub.3) δ (ppm): 8.39 (d, J=1.8 Hz, 1H), 8.15 (s, 1H), 7.66 (d, J=9.8 Hz, 2H), 7.46 (t, J=7.8 Hz, 1H), 7.36 (d, J=7.7 Hz, 1H), 7.19 (d, J=8.3 Hz, 1H), 7.12 (dd, J=8.3, 2.0 Hz, 1H), 6.54 (s, 1H), 5.65 (s, 1H), 2.62 (d, J=7.2 Hz, 4H), 2.46 (s, 3H), 1.83-1.65 (m, 2H), 0.90 (d, J=6.6 Hz, 12H). MS (ESI), m/z (%): 473.29[M+H].sup.+. White solid.

(102) ##STR00145##

(103) .sup.1H-NMR (600 MHz, CDCl.sub.3) δ (ppm): 8.38 (d, J=1.7 Hz, 1H), 8.17 (s, 1H), 7.66-7.48 (m, 4H), 7.19 (d, J 8.4 Hz, 1H), 7.13 (dd, J=8.3, 1.8 Hz, 1H), 6.67 (s, 1H), 5.65 (s, 1H), 2.63 (d, J=7.2 Hz, 4H), 2.46 (s, 2H), 1.75 (dd, J=13.4, 6.7 Hz, 2H), 0.91 (d, J=6.5 Hz, 12H). MS (ESI), m/z (%): 473.23 [M+H].sup.+. White solid.

(104) ##STR00146##

(105) .sup.1H-NMR (600 MHz, CDCl.sub.3) δ (ppm): 8.43 (s, 1H), 8.03 (s, 1H), 7.29-7.17 (m, 2H), 7.14 (d, J=8.5 Hz, 2H), 7.09 (d, J=8.3 Hz, 1H), 6.97 (d, J=7.5 Hz, 1H), 6.40 (s, 1H), 5.64 (s, 1H), 2.57 (d, J=7.2 Hz, 4H), 2.46 (s, 3H), 2.35 (s, 3H), 1.68 (m, 2H), 0.83 (d, J=6.6 Hz, 12H). MS (ESI), m/z (%): 419.35[M+H].sup.+. White solid.

(106) ##STR00147##

(107) .sup.1H-NMR (600 MHz, CDCl.sub.3) δ (ppm): 8.39 (d, J=1.8 Hz, 1H), 8.12 (s, 1H), 7.46 (s, 1H), 7.27 (d, J=5.6 Hz, 2H), 7.17 (d, J=8.3 Hz, 1H), 7.11 (d, J=7.8 Hz, 2H), 6.41 (s, 1H), 5.64 (s, 1H), 2.60 (d, J=7.2 Hz, 4H), 2.46 (s, 3H), 1.72 (m, 2H), 0.88 (d, J=6.6 Hz, 12H). MS (ESI), m/z (%): 440.27[M+H].sup.+. White solid.

(108) ##STR00148##

(109) .sup.1H-NMR (600 MHz, CDCl.sub.3) δ (ppm): 8.39 (s, 1H), 8.09 (s, 1H), 7.32 (dd, J=25.8, 8.0 Hz, 4H), 7.17 (d, J=8.3 Hz, 1H), 7.11 (d, J=8.3 Hz, 1H), 6.40 (s, 1H), 5.64 (s, 1H), 2.59 (d, J=6.9 Hz, 4H), 2.46 (s, 3H), 1.81-1.64 (m, 2H), 0.88 (d, J=6.3 Hz, 12H). MS (ESI), m/z (%): 440.27[M+H].sup.+. White solid.

(110) ##STR00149##

(111) .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ (ppm): 12.13 (s, 1H), 9.42 (s, 1H), 8.16 (d, J=1.9 Hz, 1H), 7.80 (s, 1H), 7.35 (s, 1H), 7.21 (ddd, J=22.3, 20.0, 7.9 Hz, 4H), 6.80 (d, J=7.4 Hz, 1H), 6.07 (s, 1H), 2.74 (d, J=6.9 Hz, 4H), 2.48 (s, 3H), 2.29 (s, 3H), 1.68 m, 2H), 0.90-0.78 (m, 12H). MS (ESI), m/z (%): 438.30[M+H].sup.+. White solid.

(112) ##STR00150##

(113) .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 8.66 (s, 1H), 8.24 (s, 1H), 7.33 (dd, J=8.3, 5.7 Hz, 2H), 7.24-7.18 (m, 2H), 7.13 (t, J=8.9 Hz, 2H), 5.91 (d, J=1.1 Hz, 1H), 3.71 (s, 2H), 2.54 (t, J=10.5 Hz, 4H), 2.39 (d, J=0.9 Hz, 3H), 1.55 (dt, J=13.2, 6.4 Hz, 2H), 1.42 (s, 9H), 0.73 (t, J=6.6 Hz, 12H). MS (ESI), m/z (%): 497.39 [M+H].sup.+. White solid.

(114) ##STR00151##

(115) .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ 8.71 (d, J=34.7 Hz, 1H), 8.31 (s, 1H), 7.38-7.31 (m, 4H), 7.28 (t, J=6.4 Hz, 1H), 7.24 (d, J=8.3 Hz, 2H), 5.95 (d, J=1.2 Hz, 1H), 3.73 (d, J=22.4 Hz, 2H), 2.64-2.53 (m, 4H), 2.43 (d, J=1.0 Hz, 3H), 1.58 (dt, J=13.3, 6.5 Hz, 2H), 1.46 (s, 9H), 0.76 (d, J=6.6 Hz, 12H). MS (ESI), m/z (%): 479.37 [M+H].sup.+. White solid.

(116) ##STR00152##

(117) .sup.1H-NMR (600 MHz, DMSO-d.sub.6) 8.79 (d, J=17.0 Hz, 1H), 8.30 (s, 1H), 7.43 (t, J=7.5 Hz, 1H), 7.35 (dd, J=13.8, 7.1 Hz, 1H), 7.27 (s, 2H), 7.20 (dd, J=12.8, 5.9 Hz, 2H), 5.95 (d, J=1.2 Hz, 1H), 3.78 (d, J=25.1 Hz, 2H), 2.59 (dd, J=35.8, 6.6 Hz, 4H), 2.44 (d, J=1.1 Hz, 3H), 1.65-1.56 (nm, 2H), 1.46 (s, 9H), 0.80 (t, J=6.2 Hz, 12H). MS (ESI), m/z (%): 497.39 [M+H].sup.+. White solid.

(118) ##STR00153##

(119) .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ 8.48 (s, 1H), 8.38 (s, 1H), 7.32-7.08 (m, 6H), 5.96 (s, 1H), 3.76 (d, J=21.2 Hz, 2H), 2.53 (t, J=9.0 Hz, 4H), 2.44 (s, 3H), 2.25 (d, J=12.5 Hz, 3H), 1.56 (td, J=13.1, 6.5 Hz, 2H), 1.46 (s, 9H), 0.73 (d, J=6.6 Hz, 12H). MS (ESI), m/z (%): 493.41 [M+H].sup.+. White solid.

(120) ##STR00154##

(121) .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ 12.14 (s, 1H), 8.71 (d, J=28.8 Hz, 1H), 8.33 (s, 1H), 7.39-7.18 (m, 7H), 6.04 (s, 1H), 3.73 (d, J=19.9 Hz, 2H), 2.56 (dd, J=29.0, 6.8 Hz, 4H), 2.45 (s, 3H), 1.67-1.48 (m, 2H), 0.77 (t, J=9.6 Hz, 12H). MS (ESI), m/z (%): 423.28 [M+H].sup.+. White solid.

(122) ##STR00155##

(123) .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 9.69 (s, 1H), 8.06 (d, J=1.7 Hz, 1H), 7.82 (s, 1H), 7.48 (d, J=12.0 Hz, 1H), 7.28 (dd, J=15.2, 8.1 Hz, 1H), 7.15 (ddd, J=16.2, 14.1, 8.2 Hz, 3H), 6.80-6.72 (m, 1H), 5.94 (s, 1H), 2.69 (t, J=10.2 Hz, 4H), 2.42 (s, 3H), 1.64 (dt, J=13.2, 6.5 Hz, 2H), 1.43 (s, 9H), 0.80 (d, J=6.6 Hz, 12H). MS (ESI), m/z (%): 498.37 [M+H].sup.+. White solid.

(124) ##STR00156##

(125) .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 8.57 (d, J=22.5 Hz, 1H), 8.06 (d, J=2.0 Hz, 1H), 7.72 (d, J=18.3 Hz, 1H), 7.31 (dd, J=28.4, 9.0 Hz, 1H), 7.12 (dt, J=8.4, 5.3 Hz, 2H), 6.98 (s, 1H), 6.93 (d, J=8.1 Hz, 1H), 5.92 (d, J=1.2 Hz, 1H), 2.70-2.56 (m, 4H), 2.43-2.34 (m, 3H), 2.20 (d, J=8.3 Hz, 3H), 2.16 (d, J=8.7 Hz, 3H), 1.60 (td, J=13.2, 6.5 Hz, 2H), 1.47-1.33 (m, 9H), 0.85-0.71 (m, 12H). MS (ESI), m/z (%): 508.41 [M+H].sup.+. White solid.

(126) ##STR00157##

(127) .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 9.72 (s, 1H), 8.08 (d, J=2.0 Hz, 1H), 7.84 (s, 1H), 7.49 (d, J=12.0 Hz, 1H), 7.29-7.24 (m, 1H), 7.21-7.15 (m, 2H), 7.11 (d, J=7.9 Hz, 1H), 6.77-6.72 (m, 1H), 6.03 (d, J=1.1 Hz, 1H), 2.71 (d, J=6.9 Hz, 4H), 2.43 (s, 3H), 1.64 (dd, J=11.9, 5.4 Hz, 2H), 0.81 (t, J=6.2 Hz, 12H). MS (ESI), m/z (%): 442.29 [M+H].sup.+. White solid.

(128) ##STR00158##

(129) .sup.1H-NMR (500 MHz, DMSO-d.sub.6) δ 9.45 (s, 1H), 8.22 (d, J=2.2 Hz, 1H), 7.91 (s, 1H), 7.36 (dd, J=10.7, 5.5 Hz, 2H), 7.19 (d, J=8.4 Hz, 1H), 7.15 (dd, J=8.3, 2.2 Hz, 1H), 7.10 (d, J=8.3 Hz, 2H), 5.99 (d, J=1.2 Hz, 1H), 2.81 (d, J=5.0 Hz, 2H), 2.58 (dd, =23.5, 11.8 Hz, 1H), 2.47 (d, J=1.0 Hz, 3H), 2.25 (s, 3H), 1.87 (d, J=11.1 Hz, 2H), 1.69 (d, J=12.5 Hz, 2H), 1.51 (d, J=8.4 Hz, 1H), 1.48 (s, 9H), 1.33 (ddd, J=25.1, 12.5, 5.5 Hz, 2H), 1.29-1.21 (m, 4H), 0.83 (d, J=6.6 Hz, 6H). MS (ESI), m/z (%): 520.40 [M+H].sup.+. White solid.

(130) ##STR00159##

(131) .sup.1H-NMR (500 MHz, DMSO-d.sub.6) δ 8.89 (s, 2H), 8.04 (td, J=9.1, 6.3 Hz, 1H), 7.68 (d, J=2.2 Hz, 1H), 7.36-7.19 (m, 2H), 7.02 (dd, J=11.4, 4.8 Hz, 1H), 6.87 (d, J=8.5 Hz, 1H), 5.95 (s, 1H), 3.19 (q, J=7.1 Hz, 2H), 2.43 (s, 3H), 1.44 (s, 9H), 1.22 (dd, J=9.1, 5.1 Hz, 3H). MS (ESI), m/z (%): 432.22 [M+H].sup.+. White solid.

(132) ##STR00160##

(133) .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ 9.40 (s, 1H), 8.71 (s, 11H), 8.53 (s, 1H), 8.20-8.07 (m, 1H), 7.46 (dd, J=15.3, 8.8 Hz, 1H), 7.27 (s, 1H), 7.08-6.96 (m, 2H), 6.05 (s, 1H), 3.28 (d, J=57.3 Hz, 2H), 2.50 (s, 3H), 1.48 (s, 9H), 1.04 (t, J=6.9 Hz, 3H) MS (ESI), m/z (%): 432.23 [M+H].sup.+. White solid.

(134) ##STR00161##

(135) .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ 11.88 (s, 1H), 8.63 (s, 1H), 8.21-8.03 (m, 2H), 7.61 (s, 1H), 7.38-7.22 (m, 2H), 7.00 (dt, J=10.3, 5.5 Hz, 1H), 6.66 (d, J=8.6 Hz, 1H), 6.01 (s, 1H), 3.14 (t, J=12.4 Hz, 2H), 2.46 (s, 3H), 1.22 (t, J=7.1 Hz, 3H). MS (ESI), m/z (%): 376.16 [M+H].sup.+. White solid.

(136) ##STR00162##

(137) .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ 12.26 (s, 1H), 9.40 (s, 1H), 8.72 (s, 1H), 8.57 (s, 1H), 8.21-8.10 (m, 1H), 7.54 (d, J=16.3 Hz, 1H), 7.46 (dd, J=15.6, 7.7 Hz, 1H), 7.25-7.17 (m, 1H), 7.01 (ddd, J=22.5, 16.5, 9.2 Hz, 2H), 6.14 (s, 1H), 3.93 (s, 1H), 3.23 (s, 1H), 2.53-2.51 (m, 3H), 1.05 (t, J=7.1 Hz, 3H). MS (ESI), m/z (%): 376.16 [M+H].sup.+. White solid.

(138) ##STR00163##

(139) .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 9.37 (s, 1H), 8.66 (s, 1H), 8.49 (d, J=1.6 Hz, 1H), 8.11 (dd, J=9.2, 3.1 Hz, 1H), 7.50 (s, 1H), 7.40 (dd, J=9.0, 2.7 Hz, 1H), 7.23 (d, J=1.4 Hz, 1H), 7.03 (d, J=9.1 Hz, 1H), 6.95 (d, J=7.7 Hz, 1H), 6.00 (d, J=1.2 Hz, 1H), 3.81 (s, 2H), 3.04 (s, 2H), 2.46 (s, 3H), 1.44 (s, 9H), 0.79 (t, J=7.4 Hz, 3H). MS (ESI), m/z (%): 446.23 [M+H].sup.+. White solid.

(140) ##STR00164##

(141) .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ 9.33 (s, 1H), 8.72 (s, 1H), 8.47 (d, J=2.0 Hz, 1H), 8.12 (td, J=9.3, 6.1 Hz, 11H), 7.69 (s, 1H), 7.27 (s, 1H), 7.03 (d, J=9.2 Hz, 1H), 6.95 (d, J=9.0 Hz, 1H), 6.00 (d, J=1.2 Hz, 1H), 3.07 (s, 3H), 2.45 (d, J=1.1 Hz, 3H), 1.44 (s, 9H). MS (ESI), m/z (%): 418.22 [M+H].sup.+. White solid.

(142) ##STR00165##

(143) .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ 12.63-11.42 (m, 1H), 9.24 (s, 1H), 8.83-8.55 (m, 2H), 8.36-8.14 (m, 1H), 7.98 (s, 1H), 7.25 (dd, J=33.2, 25.4 Hz, 2H), 6.88-6.81 (m, 2H), 6.21 (s, 1H), 4.02 (s, 1H), 3.20 (s, 1H), 2.65-2.59 (m, 3H), 1.64 (s, 2H), 0.92 (dd, J=14.9, 7.4 Hz, 3H). MS (ESI), m/z (%): 390.21 [M+H].sup.+. White solid.

(144) ##STR00166##

(145) .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ 9.17-9.02 (m, 1H), 8.70 (d, J=46.5 Hz, 2H), 8.22 (dd, J=15.1, 9.1 Hz, 1H), 7.96 (s, 1H), 7.30 (s, 2H), 6.86-6.80 (m, 2H), 6.21 (s, 1H), 3.27 (d, J=5.4 Hz, 3H), 2.58 (s, 3H). MS (ESI), m/z (%): 362.26 [M+H].sup.+. White solid.

(146) ##STR00167##

(147) .sup.1H-NMR (400 MHz, CDCl.sub.3) δ 8.45 (s, 1H), 7.96 (s, 1H), 7.63 (d, J=16.0 Hz, 1H), 7.21 (s, 1H), 7.14 (s, 1H), 7.11 (s, 3H), 6.41 (d, J=16.0 Hz, 1H), 4.22 (q, J=7.1 Hz, 2H), 2.53 (d, J=7.2 Hz, 4H), 2.32 (s, 3H), 1.65 (dt, J=13.5, 6.7 Hz, 2H), 1.31 (t, J=7.1 Hz, 3H), 0.79 (d, J=6.6 Hz, 12H). MS(ESI), m/z (%): 452.34 [M+H].sup.+. White solid.

(148) ##STR00168##

(149) .sup.1H-NMR (400 MHz, CDCl.sub.3) δ 8.41 (s, 1H), 8.18 (s, 1H), 7.99 (td, J=9.2, 6.0 Hz, 1H), 7.63 (d, J=16.0 Hz, 1H), 7.14 (s, 2H), 6.90-6.81 (m, 2H), 6.39 (s, 1H), 4.23 (q, J=7.1 Hz, 2H), 2.59 (d, J=7.3 Hz, 4H), 1.72 (dt, J=13.5, 6.8 Hz, 2H), 1.31 (t, J=7.1 Hz, 3H), 0.88 (d, J=6.6 Hz, 12H). MS(ESI), m/z (%): 474.33 [M+H].sup.+. White solid.

(150) ##STR00169##

(151) .sup.1H-NMR (400 MHz, CDCl.sub.3) δ 8.43 (s, 1H), 8.14 (s, 1H), 7.86 (t, J=8.4 Hz, 1H), 7.63 (d, J=16.0 Hz, 1H), 7.13 (s, 2H), 6.91 (dd, J=13.5, 10.4 Hz, 2H), 6.42 (d, J=16.0 Hz, 1H), 4.22 (q, J=7.1 Hz, 2H), 2.58 (d, J=7.2 Hz, 4H), 2.30 (s, 3H), 1.71 (dt, J=13.5, 6.8 Hz, 2H), 1.31 (t, J=7.1 Hz, 3H), 0.87 (d, J=6.6 Hz, 12H). MS(ESI), m/z (%): 470.31 [M+H].sup.+. White solid.

(152) ##STR00170##

(153) .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ 12.28 (s, 1H), 9.33 (s, 1H), 8.05 (d, J=15.7 Hz, 3H), 7.49 (d, J=15.8 Hz, 1H), 7.30 (d, J=8.3 Hz, 2H), 7.20 (s, 1H), 7.05 (s, 1H), 6.34-6.26 (m, 1H), 2.81 (d, J=6.3 Hz, 4H), 1.77-1.65 (m, 2H), 0.83 (d, J=6.1 Hz, 12H). MS(ESI), m/z (%): 446.23 [M+H].sup.+. White solid.

(154) ##STR00171##

(155) .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ 12.30 (s, 1H), 9.22 (s, 1H), 8.06 (s, 1H), 8.01 (s, 11H), 7.88 (t, J=8.5 Hz, 1H), 7.47 (d, J=15.8 Hz, 1H), 7.28 (d, J=9.6 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H), 7.07 (d, J=12.2 Hz, 1H), 6.95 (d, J=8.0 Hz, 1H), 6.30 (d, J=15.9 Hz, 1H), 2.80 (d, J=6.9 Hz, 4H), 2.27 (s, 3H), 1.71 (dt, J=13.3, 6.7 Hz, 2H), 0.82 (d, J=6.6 Hz, 12H). MS(ESI), m/z (%): 442.25 [M+H].sup.+. White solid.

(156) ##STR00172##

(157) .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ 8.81 (s, 1H), 8.24 (s, 1H), 7.73 (s, 1H), 7.66 (s, 1H), 7.59 (s, 1H), 7.56 (s, 1H), 7.51 (s, 11H), 7.26 (d, J=2.1 Hz, 1H), 7.24 (s, 1H), 5.97 (s, 1H), 3.91 (s, 2H), 2.61 (d, J=7.1 Hz, 4H), 2.44 (s, 3H), 1.60 (dd, J=13.4, 6.7 Hz, 2H), 1.46 (s, 9H), 0.77 (d, J=6.6 Hz, 12H). MS(ESI), m/z (%): 547.38 [M+H].sup.+. White solid.

(158) ##STR00173##

(159) .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ 8.77 (s, 1H), 8.24 (s, 1H), 7.73 (d, J=1.5 Hz, 1H), 7.66 (s, 2H), 7.51 (d, J=2.7 Hz, 1H), 7.42 (s, 2H), 5.95 (s, 1H), 3.89 (s, 2H), 2.60 (d, J=7.1 Hz, 4H), 2.44 (s, 3H), 1.59 (dd, J=13.3, 6.6 Hz, 2H), 1.46 (s, 9H), 0.76 (d, J=6.6 Hz, 12H). MS(ESI), m/z (%): 547.38 [M+H].sup.+. White solid.

(160) ##STR00174##

(161) .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ 12.04 (s, 1H), 8.73 (s, 1H), 8.27 (s, 1H), 7.44 (s, 1H), 7.38 (s, 1H), 7.36 (s, 1H), 7.27 (d, J=1.9 Hz, 1H), 7.25 (s, 1H), 6.04 (s, 1H), 3.79 (s, 2H), 2.61 (d, J=7.1 Hz, 4H), 2.45 (s, 3H), 1.60 (dd, J=12.4, 5.8 Hz, 2H), 0.77 (d, J=6.6 Hz, 12H). MS(ESI), m/z (%): 457.26 [M+H].sup.+. White solid.

(162) ##STR00175##

(163) .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ 12.06 (s, 1H), 8.73 (s, 1H), 8.33 (s, 1H), 7.64 (s, 1H), 7.52 (d, J=8.5 Hz, 1H), 7.46 (s, 1H), 7.28 (s, 2H), 6.04 (s, 1H), 3.92 (s, 2H), 2.64 (d, J=7.1 Hz, 4H), 2.45 (s, 3H), 1.64-1.61 (m, 2H), 0.81 (d, J=6.6 Hz, 12H). MS(ESI), m/z (%): 491.22 [M+H].sup.+. White solid.

(164) ##STR00176##

(165) .sup.1H-NMR (600 MHz, DMSO-d.sub.6) δ 12.02 (s, 1H), 8.80 (s, 1H), 8.23 (s, 1H), 7.73 (d, J=3.1 Hz, 1H), 7.68-7.66 (m, 1H), 7.27 (d, J=2.0 Hz, 1H), 7.25 (s, 1H), 7.21 (d, J=8.3 Hz, 1H), 6.93 (d, J=6.7 Hz, 1H), 6.04 (s, 1H), 3.90 (s, 2H), 2.62 (d, J=7.0 Hz, 4H), 2.45 (s, 3H), 1.59 (d, J=4.2 Hz, 2H), 0.76 (d, J=6.6 Hz, 12H). MS(ESI), m/z (%): 491.21 [M+H].sup.+. White solid.

(166) Test Method and Results of Inhibition Rate of IDO1 Enzyme in Hela Cells:

(167) Human cervical cancer cell line Hela (obtained from Chinese academy of sciences cell bank) was cultured in logarithmic growth phase and counted after routine digestion. RPMI 1640 complete medium (Corning, USA, containing 10% FBS) was used to adjust the concentration to Ix 10′/ml, inoculated into 96-well plates, 100 ul/well, incubated for 24 hours.

(168) Stimulant solution configuration: Human recombinant IFN-γ(Shanghai Sangon Biotech) was subpacked according to the instructions, the concentration was adjusted twice as high as the final concentration by RPMI1640 complete medium, that is 100 ng/ml.

(169) Compounds solution configuration: DMSO was used to dissolve the drug, and then RPMI 1640 was used to dilute the drug to twice the detection concentration.

(170) The old culture medium were discarded from 96-well plates, and added 100 ul stimulation solution and 100 ul compounds solution to each hole; set up interferon growth control group, each group had three multiple holes; incubated 48 hours.

(171) 180 uL medium from 96-well plate were collected and mixed with 45 μL of 30% (W/V) trichloroacetic acid. Plate was centrifuged for 5 min at 8000 rpm. The supernatant was added with fresh 4-dimethylaminobenzaldehyde (2%, W/V). After full shock, measured at 480 nm using a ElISA reader.

(172) TABLE-US-00007 TABLE 7 Inhibition rate of compounds on IDO1 activity enzyme in Hela cells Inhibition rate (%) Compound Number 10 μmol 100 nmol Compound 9 100 100 Compound 13 100 100 Compound 14 100 100 Compound 396 100 69.2 Compound 397 100 75.5 Compound 403 100 76.4 Compound 404 100 73.2 Compound 518 100 76.8 Compound 525 100 75.1 Compound 564 100 72.2 Compound 772 100 74.2 Compound 779 100 77.1 Compound 1021 100 42.1 Compound 1022 53.7 21.2 Compound 1023 100 35.1 Compound 1024 58.2 29.5 Compound 1025 68.8 24.6 Compound 1026 54.3 21.0 Compound 1027 100 71.1 Compound 1028 100 41.5 Compound 1030 100 23.8 Compound 1031 72.7 29.6

(173) The compounds described in the above table have certain inhibitory effects, Compounds 9, 13 and 14 can inhibit IDO-1 activity 100% at 100 nmol concentration.

(174) TABLE-US-00008 TABLE 8 IC.sub.50 Value (nmol/L) of compounds on IDO1 enzyme activity in Hela cells Inhibition rate IC.sub.50 Compound Number (nmol/L) Compound 13 3.69 Compound 14 0.18 Compound 51 3.69 Compound 55 0.09 Compound 56 0.13 Compound 525 1.36 Compound 530 8.26 INCB024360 3.78 IN-4 1.56

(175) As shown in the table above, the IC.sub.50 of the compounds is lower than 100 nmol/L, and the activities of the compounds 525, 13, 14, 56, 55 and 51 can reach or exceed those of the positive control drugs INCB024360 and IN-4, indicating that these compounds have good IDO1 enzyme inhibitory activities.

(176) As shown in Table 7 and Table 8 above, these compounds have potential therapeutic effects on colorectal cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, renal cancer, head and neck cancer, lymphoma, leukemia or melanoma with high expression of IDO1. It has potential therapeutic effects on other diseases such as viral infection, depression, organ transplant rejection or autoimmunity caused by high expression of IDO1.

(177) INCB024360 control sample was purchased from Beijing Innochem Technology Co., Ltd. with batch number WG0292821-160526001. IN-4 was purchased from Medchem Express Biotechnology Company, USA, with batch number Lot #19346.

(178) ##STR00177##
Pharmacokinetic Test and Results of Compound 55:

(179) 12 Male Sprague-Dawley rats were grouped random. The final concentration of compound 55 was 1.5 mg/ml. The drug was dissolved in a solvent system of 10% DMSO, 10% hydrogenated castor oil and 90% normal saline (compounds were dissolved by DMSO, hydrogenated castor oil and saline in turn by vortex or ultrasound), and the drug solution was given orally (30 mg/kg). The rats were fasted overnight but had free access to water, feeding resumed 4 hours after administration. Blood samples (0.3-0.4 mL) were collected into heparinized tubes by Retinal vein plexus at 0, 0.17, 0.33, 0.67, 1, 2, 4, 7, 10 and 24 hours after administration orally. Tubes were anticoagulated with heparin sodium (5% heparin sodium solution filled EP tube, poured out, dried). 100 uL plasma was obtained by centrifugation (10000 rpm, 3 min) and stored at −20° C. before analysis.

(180) TABLE-US-00009 TABLE 9 Oral pharmacokinetic data of compound 55 Testing Compound Unit Compound 55 Dosage mg/kg 30 mg/kg AUC ng .Math. h/mL 43655.98 T1/2 h 5.0 Cmax ng/mL 16760.13

(181) The results showed that compound 55 had good pharmacokinetic parameters.

(182) Pharmacodynamics of Some Compounds In Vivo (Intraperitoneal Injection):

(183) The anti-colon cancer CT26 activity of these compounds was tested in vivo. 1×10.sup.6 CT26 cells were inoculated subcutaneously in the right axillary of BALB/c mice by cell suspension inoculation. When the growth of tumors were clearly observed, 42 moderately tumor size animals were selected and randomly divided into test group, solvent control group and positive drug group, with 6 animals in each group. The positive drug group was given 1-methyl-D-tryptophan 300 mg/kg daily by oral, and the INCB024360 group was given compound INCB024360 50 mg/kg daily by intraperitoneal injection. The compound groups were intraperitoneally injected with 50 mg/kg of the compound every day, while the solvent control group was given the same dosage with the same volume of mixed solvent. The weight of the mice and the length and short diameter of the transplanted tumors were measured three times a week during the administration. The tumor volume (VT), relative volume (RVT) and tumor proliferation rate (T/C %) were calculated. After two weeks of administration, nude mice bearing tumors in each experimental group were executed by neck-lifting method. Solid tumour tissues were completely dissected. The weight of tumors in each experimental group was measured and the growth inhibition rate (%) was calculated.

(184) TABLE-US-00010 TABLE 10 Statistical table of tumor weight and inhibition rate of tumor weight Number of Tumor Inhibition animals weight rate Group (n) (mg) (%) Vehicle 6 3368.00 ± 557.96 0.0 1-MT 6 2509.17 ± 352.16 25.5 INCB024360 6 3026.17 ± 409.75 10.23 Compound 14 6 2727.33 ± 404.42 19.02 Compound 55 6 2121.17 ± 343.15 37.02

(185) At the end of the experiment, the I-MT activity of the positive drug was better than that of INCB024360, and compound 55 was equivalent to that of 1-MT, which was better than that of INCB024360.

(186) Pharmacodynamic of Some Compounds In Vivo (Oral Administration):

(187) The anti-colon cancer CT26 activity of these compounds was tested in vivo. 1×10.sup.6 CT26 cells were inoculated subcutaneously in the right axillary of BALB/c mice by cell suspension inoculation. When the growth of tumors were clearly observed, 56 moderately tumor size animals were selected and randomly divided into test group, solvent control group and positive drug group, with 8 animals in each group. In the positive drug group, INCB024360 was given 50 mg/kg each time, compound 14 was given 50 mg/kg each time, compound 55 low dose group, compound 55 middle dose group and compound 55 high dose group were given 20 mg/kg, 50 mg/kg and 100 mg/kg respectively, compound 55 intraperitoneal injection group was given 50 mg/kg each time. The solvent control group was given the same volume of mixed solvents by oral. The above groups were administered twice a day. The weight of the mice and the length and short diameter of the transplanted tumors were measured three times a week during the administration. The tumor volume (VT), relative volume (RVT) and tumor proliferation rate (T/C %) were calculated. After two weeks of administration, nude mice bearing tumors in each experimental group were executed by neck-lifting method. Solid tumour tissues were completely dissected. The weight of tumors in each experimental group was measured and the growth inhibition rate (%) was calculated.

(188) TABLE-US-00011 TABLE 11 Statistical table of tumor weight and inhibition rate of tumor weight Number of Tumor Inhibition Dose animals weight rate Group (mg/kg) (n) (mg) (%) Solvent control — 8 1267.13 ± 331.64  INCB024360 50 8 840.63 ± 144.34 33.66 Compound 55 20 8 1109.75 ± 191.47  12.42 Compound 55 50 8 924.25 ± 150.35 27.06 Compound 55 100 8 847.00 ± 305.01 33.16 Compound 14 50 8 793.38 ± 246.34 37.39 Compound 55 (IP) 50 8 824.00 ± 161.64 34.97

(189) At the end of the experiment, the activity of compound 55, high dose group and compound 14 was similar to that of positive drug INCB024360.

(190) Combining with the previous intraperitoneal injection in vivo pharmacodynamics experiments, compound 55 has better pharmacodynamics than INCB024360 under the condition of single administration per day, and is equivalent to INCB024360 under the condition of twice administration per day. The T1/2 data of INCB024360 reported in the literature were 2.3 hours and that of compound 55 was 5.0 hours. Combining animal pharmacodynamics experiment and pharmacokinetics experiment data, compound 55 has better pharmacokinetic properties than INCB024360, and can achieve considerable pharmacodynamics with fewer times of administration.