CXCR2 ANTAGONIST

Abstract

A compound as a CXCR2 antagonist and an application thereof in preparing a drug as a CXCR2 antagonist. In particular, the present invention relates to a compound represented by formula (II) or an isomer or pharmaceutically acceptable salt thereof.

##STR00001##

Claims

1. A compound of formula (II), a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, ##STR00224## wherein, T.sub.1 is selected from C(R.sub.2R.sub.3) and N(R.sub.4); ring A is selected from 5-6 membered heteroaryl and phenyl, wherein each of the 5-6 membered heteroaryl and phenyl is optionally substituted by one, two or three R.sub.a; R.sub.1 is selected from C.sub.1-6 alkyl, NH.sub.2(CO)C.sub.1-3 alkyl-, 5-10 membered heteroaryl-C.sub.1-3 alkyl-, C.sub.3-7 cycloalkyl, 5-9 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl and C.sub.1-6 alkyl-phenyl, wherein each of the C.sub.1-6 alkyl, NH.sub.2(CO)C.sub.1-3 alkyl-, 5-10 membered heteroaryl-C.sub.1-3 alkyl-, C.sub.3-7 cycloalkyl, 5-9 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl and C.sub.1-6 alkyl-phenyl is optionally substituted by one, two or three R; each of R.sub.2 and R.sub.3 is independently selected from H, F, Cl, Br, I, OH, NH.sub.2 and C.sub.1-3 alkyl optionally substituted by one, two or three R.sub.b; R.sub.4 is selected from H and C.sub.1-3 alkyl optionally substituted by one, two or three R.sub.c; each R.sub.a is independently selected from H, F, Cl, Br, I, OH, NH.sub.2 and C.sub.1-3 alkyl optionally substituted by one, two or three R; each of R.sub.b and R.sub.c is independently selected from H, F, Cl, Br, I, OH and NH.sub.2; each R is independently selected from H, F, Cl, Br, I, OH, NH.sub.2, C.sub.1-3 alkyl, C.sub.1-3 alkyl-(CO)NH, C.sub.1-3 alkyl-O(CO)NH, C.sub.3-6 cycloalkyl-(CO)NH and C.sub.1-6 alkyl-O(CO), wherein each of the C.sub.1-3 alkyl, C.sub.1-3 alkyl-(CO)NH, C.sub.3-6 cycloalkyl-(CO)NH and C.sub.1-6 alkyl-O(CO) is optionally substituted by one, two or three R; each R is independently selected from F, Cl, Br, I, OH and NH.sub.2; each of the 5-6 membered heteroaryl, 5-10 membered heteroaryl and 5-9 membered heterocycloalkyl independently contains one, two, three or four heteroatoms or heteroatomic groups independently selected from NH, C(O), O, S and N.

2. The compound, the tautomer or stereoisomer thereof, or the pharmaceutically acceptable salt thereof as defined in claim 1, wherein R is selected from F, Cl, Br, I, OH, NH.sub.2, Me, Et, ##STR00225## wherein each of the Me, Et, ##STR00226## is optionally substituted by one, two or three R; and/or, each R.sub.a is independently selected from H, F, Cl, Br, I, OH, NH.sub.2 and Me; and/or, each of R.sub.2 and R.sub.3 is independently selected from H, F, Cl, Br, I, OH, NH.sub.2 and Me; and/or, R.sub.4 is selected from H and Me.

3. The compound, the tautomer or stereoisomer thereof, or the pharmaceutically acceptable salt thereof as defined in claim 2, wherein R is selected from F, Cl, Br, I, OH, NH.sub.2, Me, ##STR00227##

4. (canceled)

5. The compound, the tautomer or stereoisomer thereof, or the pharmaceutically acceptable salt thereof as defined in claim 1, wherein R.sub.1 is selected from methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, NH.sub.2(CO)CH.sub.2, isoindoline-1,3-dione-(CH.sub.2).sub.2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, tetrahydropyranyl, tetrahydrofuranyl, 1,4-diazepanyl, C.sub.1-4 alkyl-phenyl, 2-azaspiro[3.3]heptyl and 7-azaspiro[3.5]nonanyl, wherein each of the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, NH.sub.2(CO)CH.sub.2, isoindoline-1,3-dione-(CH.sub.2).sub.2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, tetrahydropyranyl, tetrahydrofuranyl, 1,4-diazepanyl, C.sub.1-4 alkyl-phenyl, 2-azaspiro[3.3]heptanyl and 7-azaspiro[3.5]nonanyl is optionally substituted by one, two or three R.

6. The compound, the tautomer or stereoisomer thereof, or the pharmaceutically acceptable salt thereof as defined in claim 5, wherein R.sub.1 is selected from Me, Et, ##STR00228## wherein each of the Me, Et, ##STR00229## is optionally substituted by one, two or three R.

7. The compound, the tautomer or stereoisomer thereof, or the pharmaceutically acceptable salt thereof as defined in claim 6, wherein R.sub.1 is selected from Me, ##STR00230##

8-9. (canceled)

10. The compound, the tautomer or stereoisomer thereof, or the pharmaceutically acceptable salt thereof as defined in claim 1, wherein ring A is selected from furanyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, isothiazolyl, pyridyl and phenyl, wherein each of the furanyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, isothiazolyl, pyridyl and phenyl is optionally substituted by one, two or three R.sub.a.

11. The compound, the tautomer or stereoisomer thereof, or the pharmaceutically acceptable salt thereof as defined in claim 1, wherein ring A is selected from ##STR00231## wherein each of the ##STR00232## is optionally substituted by one, two or three R.sub.a.

12. The compound, the tautomer or stereoisomer thereof, or the pharmaceutically acceptable salt thereof as defined in claim 1, wherein ring A is selected from ##STR00233##

13. The compound, the tautomer or stereoisomer thereof, or the pharmaceutically acceptable salt thereof as defined in claim 1, wherein the moiety ##STR00234## is selected from ##STR00235##

14. The compound, the tautomer or stereoisomer thereof, or the pharmaceutically acceptable salt thereof as defined in claim 1, wherein the compound is selected from: ##STR00236## wherein, R.sub.1 is as defined in claim 1; R.sub.2 and R.sub.3 are as defined in claim 1; R.sub.4 is as defined in claim 1; ring A is as defined in claim 1; the carbon atom marked with * is a chiral carbon atom presented in the form of single (R) or (S) enantiomer or enriching in one enantiomer.

15. The compound, the tautomer or stereoisomer thereof, or the pharmaceutically acceptable salt thereof as defined in claim 1, wherein the compound is selected from: ##STR00237## ##STR00238## wherein, R.sub.1 is as defined in claim 1; R.sub.2 and R.sub.3 are as defined in claim 1, R.sub.4 is as defined in claim 1; the carbon atom marked with * is a chiral carbon atom presented in the form of single (R) or (S) enantiomer or enriching in one enantiomer.

16. The compound, the tautomer or stereoisomer thereof, or the pharmaceutically acceptable salt thereof as defined in claim 1, wherein the compound is selected from: ##STR00239## ##STR00240## wherein, m is 0, 1 or 2; n is 1 or 2; R is as defined in claim 1; R.sub.2 and R.sub.3 are as defined in claim 1, R.sub.4 is as defined in claim 1; R.sub.a is as defined in claim 1; the carbon atom marked with * is a chiral carbon atom presented in the form of single (R) or (S) enantiomer or enriching in one enantiomer of (R) or (S).

17. A compound, a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from ##STR00241## ##STR00242## ##STR00243## ##STR00244## ##STR00245## ##STR00246## ##STR00247##

18. The compound, the tautomer or stereoisomer thereof, or the pharmaceutically acceptable salt thereof as defined in claim 17, wherein the compound is selected from ##STR00248## ##STR00249##

19. The compound, the tautomer or stereoisomer thereof, or the pharmaceutically acceptable salt thereof as defined in claim 17, wherein the compound is selected from ##STR00250## ##STR00251## ##STR00252## ##STR00253## ##STR00254## ##STR00255## ##STR00256## ##STR00257## ##STR00258##

20. A pharmaceutical composition comprising a therapeutically effective amount of the compound, the tautomer or stereoisomer thereof or the pharmaceutically acceptable salt thereof as defined in claim 1 as an active ingredient, and a pharmaceutically acceptable carrier.

21-22. (canceled)

23. A method for treating a CXCR2 related disease in a subject in need thereof, comprising administering a therapeutically effective amount of the compound, the tautomer or stereoisomer thereof or the pharmaceutically acceptable salt thereof as defined in claim 1 to the subject.

24. A method for treating COPD in a subject in need thereof, comprising administering a therapeutically effective amount of the compound, the tautomer or stereoisomer or the pharmaceutically acceptable salt thereof as defined in claim 1 to the subject.

25. A method for antagonizing CXCR2 in a subject in need thereof, comprising administering a therapeutically effective amount of the compound, the tautomer or stereoisomer thereof or the pharmaceutically acceptable salt thereof as defined in claim 1 to the subject.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0086] FIG. 1 shows the relationship between the proportion of neutrophils in the lung tissue of the animal in each group and the compound dose.

[0087] FIG. 2 shows the relationship between the proportion of neutrophils in the alveolar lavage fluid of the animal in each group and the compound dose.

[0088] FIG. 3 shows the relationship between the proportion of monocytes in the alveolar lavage fluid of the animal in each group and the compound dose.

DETAILED DESCRIPTION OF THE EMBODIMENT

[0089] The following embodiments further illustrate the present disclosure, but the present disclosure is not limited thereto. The present disclosure has been described in detail herein, and specific embodiments thereof have also been disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present disclosure without departing from the spirit and scope of the present disclosure.

[0090] Fragment BB-1

##STR00053##

[0091] Synthetic Route:

##STR00054##

[0092] Step 1: Synthesis of Compound BB-1-2

[0093] Chloroacetaldehyde (40% aqueous solution, 21.89 mL) was dissolved in 250 mL of water, and NaHCO.sub.3 (11.8 g, 140.47 mmol) was added at 0 C., followed by addition of compound BB-1-1 (10 g, 89.19 mmol) in portions. The reaction was allowed to run at 30 C. for 40 hours. After the reaction was completed, the mixture was adjusted to pH of 1 with 40% H.sub.2SO.sub.4, diluted with ethyl acetate (100 mL), and then extracted with ethyl acetate (100 mL3). The obtained organic phases were combined, dried over anhydrous sodium sulfate and filtered, and the solvent was removed under reduced pressure to obtain a crude product, which was separated with a chromatography column (eluent: ethyl acetate/petroleum ether=0-40%) to obtain the target compound BB-1-2. .sup.1H NMR (400 MHz, CHLOROFORM-d) ppm 7.50 (d, J=1.5 Hz, 1H), 6.35 (d, J=1.5 Hz, 1H), 2.71 (t, J=6.0 Hz, 2H), 2.56-2.46 (m, 2H), 2.14-2.03 (m, 2H).

[0094] Step 2: Synthesis of Compound BB-1-3

[0095] Compound BB-1-2 (3.8 g, 27.91 mmol) was dissolved in 100 mL of methanol, followed by addition of anhydrous sodium acetate (2.78 g, 33.84 mmol) and hydroxylamine hydrochloride (2.92 g, 41.99 mmol), and the mixture was stirred overnight at room temperature. After the reaction was completed, the solvent was removed under reduced pressure. To the residue was added 80 mL of water, followed by extraction with ethyl acetate (50 mL3). The obtained organic phases were combined, and dried over anhydrous sodium sulfate. After the desiccant was removed by filtration, the solvent was removed under reduced pressure to obtain a crude product of the target compound BB-1-3, which was directly used in the next reaction.

[0096] Step 3: Synthesis of Compound BB-1

[0097] Compound BB-1-3 (3.0 g, 19.85 mmol) was dissolved in 120 mL of methanol, followed by addition of NiCl.sub.2.6H.sub.2O (5.21 g, 21.92 mmol) and NaBH.sub.4 (7.45 g, 196.86 mmol), and the mixture was stirred at 0 C. for 3 hours. After the reaction was completed, 10 mL of saturated NH.sub.4Cl solution was added, and the resulting mixture was diluted with 40 mL of ethyl acetate, and extracted with ethyl acetate (50 mL3). The obtained organic phases were combined, and dried over anhydrous sodium sulfate. After the desiccant was removed by filtration, the solvent was removed under reduced pressure to obtain the target compound BB-1. .sup.1H NMR (400 MHz, METHANOL-d.sub.4) ppm 7.39-7.32 (m, 1H), 6.23 (s, 1H), 3.97 (br s, 1H), 2.54-2.38 (m, 2H), 2.09 (br d, J=5.0 Hz, 1H), 1.96-1.87 (m, 1H), 1.77-1.65 (m, 2H).

[0098] Fragment BB-2

##STR00055##

[0099] Synthetic Route:

##STR00056##

[0100] Step 1: Synthesis of Compound BB-2-2

[0101] Compound BB-2-1 (50 g, 308.60 mmol) was dissolved in 300 mL of tert-butyl methyl ether, followed by addition of a solution of 12.34 g of sodium hydroxide in 25 mL of water. Under an ice bath, trimethylacetyl chloride (39.07 g, 324.03 mmol, 39.87 mL) was added dropwise, and the reaction mixture was maintained at a temperature not exceeding 35 C. After the reaction was completed, to the mixture was added 200 mL of ethyl acetate for dilution and the resulting mixture was extracted with 100 mL of ethyl acetate. The extracted organic phase was washed with saturated brine (100 mL2) and dried over anhydrous sodium sulfate, filtered and concentrated to obtain the target product BB-2-2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 9.45 (s, 1H), 8.04 (d, J=2.5 Hz, 1H), 7.65 (dd, J=2.5, 8.8 Hz, 1H), 7.55 (d, J=8.8 Hz, 1H), 1.22 (s, 9H).

[0102] Step 2: Synthesis of Compound BB-2

[0103] Compound BB-2-2 (7.08 g, 28.76 mmol) was dissolved in 150 mL of THF, and n-butyllithium (2.5 M, 29 mL) was added dropwise at 60 C. After the dropwise addition was completed, the reaction mixture was cooled to 0 C. and stirred. After 15 minutes, sulfur powder (1.84 g, 57.53 mmol) was added at 60 C. The reaction mixture was stirred at room temperature overnight. After the reaction was completed, 2 N HCl (40 mL) was added to quench the reaction, and the resulting mixture was diluted with 100 mL of ethyl acetate and extracted with ethyl acetate (100 mL3). The organic phases were combined, washed with saturated brine (80 mL2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product of BB-2, which was directly used in the subsequent reaction.

[0104] Fragment BB-3

##STR00057##

[0105] Synthetic Route:

##STR00058##

[0106] Step 1: Synthesis of Compound BB-3

[0107] Compound BB-3-1 (25 g, 124.22 mmol) was dissolved in 200 mL of DCM, and triethylamine (37.71 g, 372.65 mmol, 51.87 mL) was added dropwise at 0 C. Methanesulfonyl chloride (37.04 g, 323.35 mmol, 25.03 mL) was then added dropwise under an ice bath, and stirred at this temperature for 1 hour. After the reaction was completed, 100 mL of water was added to quench the reaction. The reaction mixture was diluted with 100 mL of DCM and extracted with DCM (100 mL2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was separated with a chromatography column (eluent: ethyl acetate/petroleum ether=0-30%) to obtain the target compound BB-3. .sup.1H NMR (400 MHz, CHLOROFORM-d) ppm 4.74 (br s, 1H), 3.71-3.59 (m, 2H), 3.51-3.30 (m, 2H), 3.17 (s, 1H), 3.07 (s, 3H), 2.04-1.90 (m, 2H), 1.84 (tdd, J=4.3, 8.6, 12.9 Hz, 1H), 1.49 (s, 9H).

[0108] Fragment BB-4

##STR00059##

[0109] Synthetic Route:

##STR00060##

[0110] Step 1: Synthesis of Compound BB-4-1

[0111] Compound BB-2 (12.57 g, 52.00 mmol) was dissolved in 200 mL of DMF, followed by addition of potassium carbonate (7.19 g, 52.00 mmol) and compound BB-3 (9.44 g, 33.80 mmol), and the reaction mixture was stirred at 80 C. overnight. After the reaction was completed, 150 mL of water was added to quench the reaction, and then the resulting mixture was diluted with 100 mL of ethyl acetate and extracted with ethyl acetate (100 mL3). The organic phases were combined, washed with saturated brine (100 mL3), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was separated with a chromatography column (eluent: ethyl acetate/petroleum ether=0-10%) to obtain compound BB-4-1. .sup.1H NMR (400 MHz, CHLOROFORM-d) ppm 7.55 (br d, J=8.5 Hz, 1H), 7.41 (br d, J=8.3 Hz, 1H), 3.85 (br d, J=12.5 Hz, 1H), 3.51 (br s, 1H), 2.91 (br s, 2H), 2.12 (br s, 1H), 1.83 (br s, 1H), 1.69-1.61 (m, 1H), 1.53 (s, 9H), 1.47 (s, 2H), 1.36 (br s, 9H).

[0112] Step 2: Synthesis of Compound BB-4

[0113] Compound BB-4-1 (6.10 g, 14.35 mmol) was dissolved in 150 mL of DCM, followed by addition of m-CPBA (85%, 17.48 g, 86.12 mmol) in portions at 10 C., and the resulting mixture was stirred at 10 C. for 5 hours. After the reaction was completed, 100 mL of saturated sodium sulfite solution and 100 mL of saturated sodium bicarbonate solution were added. The mixture was diluted with 100 mL of DCM, and extracted with DCM (100 mL3). The organic phases were combined, washed with saturated brine (50 mL2) and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the solvent was removed under reduced pressure to obtain a crude product, which was separated with a chromatography column (eluent: ethyl acetate/petroleum ether=0-25%) to obtain the target compound BB-4. .sup.1H NMR (400 MHz, CHLOROFORM-d) ppm 7.85 (d, J=8.5 Hz, 1H), 7.51 (d, J=8.3 Hz, 1H), 4.24 (br s, 1H), 4.07 (br s, 1H), 3.57 (br s, 1H), 3.07 (br s, 1H), 2.71 (br t, J=12.3 Hz, 1H), 2.25 (br s, 1H), 2.03-1.80 (m, 3H), 1.54 (s, 9H), 1.38 (br s, 9H).

[0114] Fragment BB-5

##STR00061##

[0115] Synthetic Route:

##STR00062##

[0116] Step 1: Synthesis of Compound BB-5-2

[0117] Chloroacetaldehyde (40% aqueous solution, 22.38 mL) and NaHCO.sub.3 (9 g, 107.13 mmol) were dissolved in 50 mL of water, followed by addition of compound BB-5-1 (10 g, 89.18 mmol) at 0 C., and the reaction mixture was stirred at 0-25 C. for 18 hours. After the reaction was completed, the mixture was adjusted to pH of 1 with 40% H.sub.2SO.sub.4 and extracted with ethyl acetate (100 mL3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was separated with a chromatography column (eluent: ethyl acetate/petroleum ether=0 to 30%) to obtain the target compound BB-5-2. .sup.1H NMR (400 MHz, CHLOROFORM-d) ppm 2.17-2.24 (m, 2H) 2.52 (dd, J=7.28, 5.77 Hz, 2H) 2.90 (t, J=6.27 Hz, 2H) 6.69 (d, J=2.01 Hz, 1H) 7.34 (d, J=2.01 Hz, 1H).

[0118] Step 2: Synthesis of Compound BB-5-3

[0119] Compound BB-5-2 (1 g, 7.34 mmol), anhydrous sodium acetate (0.8 g, 9.76 mmol) and hydroxylamine hydrochloride (698.78 mg, 10.06 mmol) were dissolved in 15 mL of methanol, and the reaction mixture was stirred at room temperature overnight. After the reaction was completed, the solvent was evaporated under reduced pressure, and 5 mL of ethyl acetate and 3 mL of water were added to the residue, which was then extracted with ethyl acetate (5 mL3). The organic phases were combined, washed with water (5 mL2) and saturated brine (5 mL), and dried over anhydrous sodium sulfate. After the desiccant was removed by filtration, the solvent was removed under reduced pressure to obtain a crude product of the target compound BB-5-3, which was directly used in the next reaction.

[0120] Step 3: Synthesis of Compound BB-5

[0121] Compound BB-5-3 (400 mg, 2.65 mmol) was dissolved in 5 mL of methanol, followed by addition of NiCl.sub.2.6H.sub.2O (628.98 mg, 2.65 mmol), and the temperature was lowered to 0 C. NaBH.sub.4 (1 g, 26.46 mmol) was added thereto in portions, and the resulting mixture was stirred at 0 C. for half an hour. After the reaction was completed, the solvent was evaporated under reduced pressure, and then the residue was diluted with 20 mL of ethyl acetate and 15 mL of water, and extracted with ethyl acetate (20 mL3). The organic phases were combined, washed with saturated brine (10 mL2) and dried over anhydrous sodium sulfate. After the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure to remove the solvent to obtain a crude product of the target compound BB-5, which was directly used in the subsequent reaction. .sup.1H NMR (400 MHz, CHLOROFORM-d) ppm 1.33-1.48 (m, 1H) 1.72-1.77 (m, 1H) 1.86-1.96 (m, 2H) 2.37-2.57 (m, 2H) 3.73-3.90 (m, 1H) 6.31 (d, J=1.76 Hz, 1H) 7.16-7.22 (m, 1H).

[0122] Fragment BB-6

##STR00063##

[0123] Synthetic Route:

##STR00064##

[0124] Step 1: Synthesis of Compound BB-6-1

[0125] BB-2 (12.00 g, 49.64 mmol) and 2-bromoisopropane (9.17 g, 74.56 mmol, 7.00 mL) were dissolved in 120 mL of DMF, followed by addition of potassium carbonate (10 g, 72.35 mmol), and the mixture was stirred at 80 C. overnight. After the reaction was completed, to the mixture 150 mL of water was added, and the resulting mixture was extracted with ethyl acetate (150 mL3). The organic phases were combined, washed successively with water (80 mL3) and saturated brine (80 mL3), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was separated with a chromatography column (eluent: ethyl acetate/petroleum ether=0-20%) to obtain compound BB-6-1. .sup.1H NMR (400 MHz, CHLOROFORM-d) ppm 1.31 (d, J=6.78 Hz, 6H) 1.51 (s, 9H) 3.80 (spt, J=6.69 Hz, 1H) 7.39 (d, J=8.53 Hz, 1H) 7.51 (d, J=8.53 Hz, 1H).

[0126] Step 2: Synthesis of Compound BB-6

[0127] Compound BB-6-1 (10 g, 35.23 mmol) was dissolved in 150 mL of DCM, followed by addition of m-CPBA (30.00 g, 147.77 mmol) at 0 C., and the resulting mixture was stirred and reacted at 0 C. for 1 hour, and then warmed to 30 C. and reacted for 5 hours. After the reaction was completed, to the mixture was added saturated sodium sulfite solution at 0 C. until the potassium iodide starch test paper did not turn blue. Saturated sodium bicarbonate solution was added to obtain pH>7, and the mixture was stirred at room temperature for half an hour. The mixture was extracted with ethyl acetate (150 mL3). The organic phases were combined, washed with saturated brine (100 mL2) and dried over anhydrous sodium sulfate. After the desiccant was removed by filtration, the crude product obtained by concentration was separated with a chromatography column (eluent: ethyl acetate/petroleum ether=0 to 30%) to obtain the target compound BB-6. .sup.1H NMR (400 MHz, CHLOROFORM-d) ppm 1.40 (d, J=6.78 Hz, 6H) 1.54 (s, 9H) 3.68-3.78 (m, 1H) 7.50 (d, J=8.28 Hz, 1H) 7.84 (d, J=8.53 Hz, 1H).

[0128] Fragment BB-7

##STR00065##

[0129] Synthetic Route:

##STR00066##

[0130] Step 1: Synthesis of Compound BB-7

[0131] According to the steps 2 and 3 in the synthesis of BB-1, BB-7 was synthesized using BB-7-1.

[0132] Fragment BB-8

##STR00067##

[0133] Synthetic Route:

##STR00068##

[0134] Step 1: Synthesis of Compound BB-8

[0135] According to the step 1 in the synthesis of BB-3, BB-8 was synthesized using BB-8-1.

[0136] Fragment BB-9

##STR00069##

##STR00070##

[0137] Step 1: Synthesis of Compound BB-9

[0138] According to the step 1 in the synthesis of BB-3, BB-9 was synthesized using BB-9-1.

[0139] Fragment BB-10

##STR00071##

[0140] Synthetic Route:

##STR00072##

[0141] Step 1: Synthesis of Compound BB-10

[0142] According to the step 1 in the synthesis of BB-3, BB-10 was synthesized using BB-10-1.

[0143] Fragment BB-11

##STR00073##

[0144] Synthetic Route:

##STR00074##

[0145] Step 1: Synthesis of Compound BB-11

[0146] According to the steps 2 and 3 in the synthesis of BB-1, BB-11 was synthesized using BB-11-1. .sup.1H NMR (400 MHz, METHANOL-d.sub.4) ppm 7.14 (d, J=5.2 Hz, 1H), 7.05 (d, J=5.2 Hz, 1H), 3.93 (br d, J=5.6 Hz, 1H), 2.82-2.75 (m, 2H), 1.88-1.80 (m, 2H), 1.69-1.59 (m, 2H)

[0147] Fragment BB-12

##STR00075##

[0148] Synthetic Route:

##STR00076##

[0149] Step 1: Synthesis of Compound BB-12

[0150] According to the steps 2 and 3 in the synthesis of BB-1, BB-12 was synthesized using BB-12-1. .sup.1H NMR (400 MHz, METHANOL-d.sub.4) ppm 8.36-8.30 (m, 1H), 7.91 (d, J=7.6 Hz, 1H), 7.27 (t, J=6.4 Hz, 1H), 4.05-3.98 (m, 1H), 2.97-2.86 (m, 2H), 2.13-2.07 (m, 2H), 1.76-1.71 (m, 2H).

[0151] Fragment BB-13

##STR00077##

[0152] Synthetic Route:

##STR00078##

[0153] Step 1: Synthesis of Compound BB-13

[0154] According to the steps 2 and 3 in the synthesis of BB-1, BB-13 was synthesized using BB-13-1.

[0155] Fragment BB-14

##STR00079##

[0156] Synthetic Route:

##STR00080##

[0157] Step 1: Synthesis of Compound BB-14

[0158] Compound BB-14-1 (50 mg, 326.37 mol) was dissolved in 5 mL of methanol, followed by addition of ammonium acetate (251.57 mg, 3.26 mmol) and sodium cyanoborohydride (51.27 mg, 815.92 mol), and the reaction mixture was heated to 80 C. and stirred for 16 hours. After the reaction was completed, the reaction mixture was directly concentrated to dryness to obtain a crude product. The crude product was separated and purified with a thin layer chromatography preparative plate to obtain compound BB-14. .sup.1H NMR (400 MHz, METHANOL-d.sub.4) ppm 8.97 (s, 1H), 4.51 (t, J=5.6 Hz, 1H), 2.93-2.81 (m, 2H), 2.28-2.18 (m, 1H), 2.14-2.03 (m, 1H), 1.94 (br d, J=6.0 Hz, 2H)

[0159] Fragment BB-15

##STR00081##

[0160] Synthetic Route:

##STR00082##

[0161] Step 1: Synthesis of Compound BB-15-2

[0162] Cerium ammonium nitrate (195.57 g, 356.74 mmol) was dissolved in methanol (400 mL), and a solution of dimethoxypropene (38.58 g, 535.11 mmol) and compound BB-15-1 (20 g, 178.37 mmol) in methanol (400 mL) was slowly added dropwise at 35 C. under nitrogen atmosphere over 0.5 hour. The reaction mixture was further stirred at 35 C. for 0.5 hour. After the reaction was completed, 400 mL of water and 80 mL of saturated sodium thiosulfate solution were added to quench the reaction mixture. The mixture was concentrated under reduced pressure to remove methanol, and the residue was extracted with ethyl acetate (750 mL2). The organic phases were combined, washed with saturated brine (750 mL1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified with a flash preparative chromatography (eluent: ethyl acetate/petroleum ether=0-25%) to obtain compound BB-15-2. .sup.1H NMR (400 MHz, CHLOROFORM-d) ppm 6.18 (s, 1H), 3.70-3.64 (m, 2H), 2.55-2.50 (m, 2H), 2.40-2.35 (m, 2H), 2.21 (s, 3H), 2.03-1.97 (m, 2H).

[0163] Step 2: Synthesis of Compound BB-15-3

[0164] Compound BB-15-2 (9.90 g, 58.86 mmol) and sulfonated poly(divinylbenzene-co-styrene) (10 g) were dissolved in toluene (500 mL), and the reaction mixture was heated to 120 C. and stirred for 12 hours. After the reaction was completed, the reaction mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was separated and purified with a flash preparative chromatography (eluent: ethyl acetate/petroleum ether=0-20%) to obtain compound BB-15-3. .sup.1H NMR (400 MHz, CHLOROFORM-d) ppm 6.02 (s, 1H), 2.68 (t, J=6.2 Hz, 2H), 2.54-2.47 (m, 2H), 2.34 (s, 3H), 2.13-2.06 (m, 2H).

[0165] Step 3: Synthesis of Compound BB-15-4

[0166] Compound BB-15-3 (380 mg, 2.53 mmol) was dissolved in methanol (15 mL), followed by addition of sodium acetate (622.71 mg, 7.59 mmol) and hydroxylamine hydrochloride (351.67 mg, 5.06 mmol), and the reaction mixture was stirred at 50 C. for 3 hours. After the reaction was completed, the reaction mixture was concentrated to dryness, followed by addition of 80 mL of ethyl acetate and 30 mL of water. The resulting mixture was stirred thoroughly, and allowed to stand for liquid separation. The organic phase was washed with saturated brine (30 mL*1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product of the compound BB-15-4, which was directly used in the next step.

[0167] Step 4: Synthesis of Compound BB-15-5

[0168] Compound BB-15-4 (420 mg, 2.54 mmol) was dissolved in methanol (15 mL), followed by addition of nickel chloride hexahydrate (664.77 mg, 2.80 mmol) and sodium borohydride (961.85 mg, 25.43 mmol) at 25 C. The reaction mixture was heated to 80 C., and stirred at 80 C. for 0.5 hour. After the reaction was completed, the reaction mixture was concentrated to dryness, followed by addition of 80 mL of ethyl acetate and 50 mL of water. The resulting mixture was stirred thoroughly, filtered, and allowed to stand for liquid separation. The organic phase was washed with saturated brine (50 mL*1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound BB-15-5, which was directly used in the next step. .sup.1H NMR (400 MHz, CHLOROFORM-d) ppm 5.76 (s, 1H), 3.91 (br t, J=5.6 Hz, 1H), 2.46-2.31 (m, 2H), 2.25 (s, 3H), 2.07-2.01 (m, 1H), 1.88-1.77 (m, 1H), 1.74-1.66 (m, 2H), 1.62-1.51 (m, 2H)

[0169] Step 5: Synthesis of Compound BB-15

[0170] Compound BB-15-5 (735 mg, 4.86 mmol) was dissolved in dichloromethane (50 mL), followed by addition of sodium carbonate (618.25 mg, 5.83 mmol) and 4-nitrobenzyl chloroformate (1.08 g, 5.35 mmol). The mixture was stirred at 25 C. for 0.5 hour. After the reaction was completed, the reaction mixture was poured into water (50 mL) and extracted with dichloromethane (50 mL). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain the intermediate compound BB-15, which was directly used in the subsequent reaction without purification.

[0171] .sup.1H NMR (400 MHz, CHLOROFORM-d) ppm (d, J=9.2 Hz, 2H), 7.28 (d, J=9.2 Hz, 2H), 5.75 (s, 1H), 5.34 (br d, J=7.6 Hz, 1H), 4.84-4.73 (m, 1H), 2.43-2.27 (m, 2H), 2.20 (s, 3H), 2.04-1.95 (m, 1H), 1.92-1.83 (m, 1H), 1.78-1.67 (m, 2H).

[0172] Fragment BB-16

##STR00083##

##STR00084##

[0173] Step 1: Synthesis of Compound BB-16-2

[0174] Compound BB-16-1 (20.00 g, 146.90 mmol) was dissolved in 1,2-dichloroethane (300 mL), followed by addition of 1-trifluoromethyl-1,2-benzoiodoxol-3(H)-one (51.06 g, 161.59 mmol) and cuprous iodide (41.97 g, 220.35 mmol). The reaction mixture was stirred at 60 C. for 14 hours. After the reaction mixture was filtered, the filtrate was washed with saturated aqueous sodium bicarbonate solution (200 mL2), and then filtered. The filtrate was extracted with dichloromethane (100 mL2). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified with a silica gel chromatography column (eluent: petroleum ether/ethyl acetate, 100:1 to 5:1) to obtain compound BB-16-2. .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 6.80 (s, 1H), 2.83-2.79 (m, 2H), 2.65-2.61 (m, 2H), 2.24-2.17 (m, 2H).

[0175] Step 2: Synthesis of Compound BB-16-3

[0176] Compound BB-16-2 (8.50 g, 41.64 mmol) was dissolved in anhydrous toluene (150 mL), followed by addition of (R)-()-2-methyl-2-propanesulfinamide (7.57 g, 62.46 mmol) and tetraethyl titanate (28.49 g, 124.91 mmol). The reaction mixture was stirred at 90 C. for 3 hours. Water (100 mL) and ethyl acetate (100 mL) were added to the reaction mixture, which was then thoroughly stirred and filtered, and the filtrate was extracted with ethyl acetate (60 mL2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified with a silica gel chromatography column (eluent: petroleum ether/ethyl acetate, 10:1 to 1:1) to obtain compound BB-16-3.

[0177] Step 3: Synthesis of Compound BB-16-4

[0178] Compound BB-16-3 (8.30 g, 27.01 mmol) was dissolved in tetrahydrofuran (150 mL), and diisobutylaluminum hydride solution (1 M solution in toluene, 41 mL, 40.5 mmol) was slowly added dropwise at 0 C. under nitrogen atmosphere. The reaction mixture was stirred at 0 C. for 1 hour. Water (200 mL) was added to the reaction mixture to quench the reaction. The resulting mixture was thoroughly stirred and filtered, and the filtrate was extracted with ethyl acetate (100 mL2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified with a silica gel chromatography column (eluent: petroleum ether/ethyl acetate, 10:1 to 1:1) to obtain compound BB-16-4.

[0179] Step 4: Synthesis of Compound BB-16-5

[0180] Compound BB-16-4 (6.20 g, 20.04 mmol) was dissolved in anhydrous tetrahydrofuran (60 mL), and concentrated hydrochloric acid (8 mL, 12 N) was added dropwise at 0 C. The reaction mixture was stirred at 0 C. for 1 hour. The reaction mixture was adjusted to pH of 8-9 with sodium carbonate aqueous solution and filtered, and the filtrate was concentrated under reduced pressure. To the residue was added water (30 mL) and the mixture was extracted with dichloromethane (40 mL2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified with a silica gel chromatography column (eluent: dichloromethane/methanol, 100:1 to 10:1) to obtain compound BB-16-5. .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 6.58 (s, 1H), 3.40-3.98 (m, 1H), 2.47-2.41 (m, 2H), 2.15-2.11 (m, 1H), 1.89-1.86 (m, 1H), 1.74-1.65 (m, 2H)

[0181] Two enantiomers with a retention time of 1.785 min and 2.006 min and a ratio of 88.3:11.7 were detected by supercritical fluid chromatography analysis.

[0182] Analytical conditions: column: ChiralPak IC-3 1504.6 mm I.D., 3 m; mobile phase, A: carbon dioxide, B: ethanol (0.05% diethylamine); gradient, from 5% to 40% of B in 5.5 min, then 5% of B for 1.5 min; flow rate: 2.5 mL/min; column temperature: 40 C.; detection wavelength: 220 nm

[0183] Step 5: Synthesis of Compound BB-16

[0184] Compound BB-16-5 (300 mg, 1.46 mmol) was dissolved in dichloromethane (10 mL), followed by addition of sodium carbonate (232.46 mg, 2.19 mmol) and 4-nitrobenzyl chloroformate (265.25 mg, 1.32 mmol). The mixture was stirred at 20 C. for 1 hour. After the reaction was completed, the reaction mixture was diluted with dichloromethane (40 mL) and washed with water (50 mL). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was separated and purified with a flash preparative chromatography (eluent: ethyl acetate/petroleum ether=0-20%) to obtain the intermediate compound BB-16.

[0185] Fragment BB-17

##STR00085##

[0186] Synthetic Route:

##STR00086##

[0187] Step 1: Synthesis of Compound BB-17-1

[0188] According to the method for synthesizing the fragment BB-16-3, compound BB-17-1 was synthesized using compound BB-16-2. .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 6.76 (s, 1H), 3.27-3.21 (m, 1H), 3.12-3.06 (m, 1H), 2.72-2.69 (m, 2H), 2.09-2.03 (m, 2H), 1.32 (s, 9H).

[0189] Step 2: Synthesis of Compound BB-17-2

[0190] Compound BB-17-1 (0.35 g, 1.14 mmol) was dissolved in tetrahydrofuran (2 mL), and sodium borohydride (86.2 mg, 2.28 mmol) was added at 0 C. under nitrogen atmosphere. The reaction mixture was stirred at 26 C. for 1 hour. Saturated brine (30 mL) was added to the reaction mixture to quench the reaction, and the resulting mixture was extracted with dichloromethane (50 mL3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product of compound BB-17-2, which was directly used in the next step.

[0191] Step 3: Synthesis of Compound BB-17-3.

[0192] According to the method for synthesizing the fragment BB-16-5, compound BB-17-3 was synthesized using compound BB-17-2.

[0193] Step 4: Synthesis of Compound BB-17.

[0194] According to the method for synthesizing the fragment BB-16, compound BB-17 was synthesized using compound BB-17-3.

[0195] Fragment BB-18

##STR00087##

[0196] Synthetic Route:

##STR00088##

[0197] Step 1: Synthesis of Compound BB-18-2

[0198] Compound BB-18-1 (1.10 g, 2.41 mmol) was dissolved in toluene (10 mL), then concentrated hydrochloric acid (12 M, 4.01 mL) was added to the reaction mixture, and the mixture was heated to 80 C. and stirred for 12 hours. After completion of the reaction as indicated by thin layer chromatography and liquid chromatography, the reaction mixture was concentrated to obtain a crude product of BB-18-2 as a brown solid.

[0199] Step 2: Synthesis of Compound BB-18

[0200] The above compound BB-18-2 (0.70 g, 2.41 mmol) was dissolved in dichloromethane (10 mL), followed by addition of saturated NaHCO.sub.3 solution to obtain pH>7, and FmocCl (465.81 mg, 1.44 mmol) was added at 0 C. The mixture was stirred at 25 C. for 1 hour. After completion of the reaction as indicated by thin layer chromatography and liquid chromatography, the reaction mixture was separated into layers, and the aqueous phase was extracted three times with ethyl acetate (20 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (SiO.sub.2, petroleum ether/ethyl acetate=3/1) to obtain BB-18. .sup.1H NMR (400 MHz, CHLOROFORM-d) ppm 10.47 (br s, 1H), 7.77 (d, J=7.2 Hz, 2H), 7.55 (br d, J=7.2 Hz, 2H), 7.44-7.38 (m, 2H), 7.37-7.29 (m, 2H), 6.87 (br d, J=8.0 Hz, 1H), 6.78 (br s, 1H), 4.43 (br s, 2H), 4.21 (br s, 1H), 4.02 (br s, 2H), 3.73 (br s, 1H), 3.37-2.99 (m, 1H), 2.88-2.77 (m, 1H), 2.15 (br s, 1H), 1.99-1.78 (m, 2H), 1.32-1.19 (m, 1H)

[0201] Fragment BB-19

##STR00089##

[0202] Synthetic Route:

##STR00090##

[0203] Step 1: Synthesis of Compound BB-19-2

[0204] Compound BB-19-1 (0.6 g, 4.08 mmol) was dissolved in methanol (20 mL), followed by addition of sodium acetate (1.00 g, 12.23 mmol) and hydroxylamine hydrochloride (424.95 mg, 6.12 mmol), and the reaction mixture was stirred at 20 C. for 1 hour. After the reaction was completed, the reaction mixture was quenched by adding 20 mL of saturated sodium bicarbonate solution, concentrated under reduced pressure to remove methanol, and extracted with dichloromethane (30 mL*2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to dryness to obtain a crude product of the compound BB-19-2, which was directly used in the next step.

[0205] Step 2: Synthesis of Compound BB-19

[0206] Compound BB-19-2 (440 mg, 2.71 mmol) was dissolved in methanol (35 mL), followed by addition of wet palladium on carbon (50 mg, 10% purity). The reaction mixture was stirred at 25 C. for 16 hours under hydrogen (50 psi) atmosphere. After the reaction was completed, the reaction mixture was filtered through diatomite, and the filtrate was concentrated under reduced pressure to dryness to obtain a crude product of the compound BB-19, which was directly used in the next step.

[0207] .sup.1H NMR (400 MHz, METHANOL-d.sub.4) ppm 8.32 (br d, J=4.4 Hz, 1H), 7.50 (br d, J=7.6 Hz, 1H), 7.16 (m, 1H), 4.02-3.89 (m, 1H), 2.84-2.74 (m, 2H), 2.11-1.91 (m, 2H), 1.82-1.67 (m, 2H).

[0208] Fragment BB-20

##STR00091##

[0209] Synthetic Route:

##STR00092##

[0210] Step 1: Synthesis of Compound BB-20-2

[0211] At room temperature, BB-20-1 (2.00 g, 18.00 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL), followed by addition of pyridine (2.85 g, 35.99 mmol) and acetyl chloride (2.83 g, 35.99 mmol). The reaction mixture was heated to 60 C. and stirred for 2 hours. After the reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate=0:1, then dichloromethane/methanol=20:1) to obtain compound BB-20-2. .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.82 (br.s, 1H), 6.59 (s, 1H), 2.60-2.56 (m, 2H), 2.39-2.35 (m, 2H), 2.15 (s, 3H), 2.07-2.02 (m, 2H).

[0212] Step 2: Synthesis of Compound BB-20-3

[0213] At 0 C., compound BB-20-2 (1.00 g, 6.53 mmol) was dissolved in anhydrous N,N-dimethylformamide (15 mL), followed by addition of N-bromosuccinimide (1.39 g, 7.83 mmol). The reaction mixture was heated to 25 C. and stirred for 4 hours. The reaction mixture was added to water (30 mL) to quench the reaction, and extracted with ethyl acetate (40 mL2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 3:1 to 1:1) to obtain compound BB-20-3. .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.95 (s, 1H), 3.27-3.23 (m, 2H), 2.61-2.57 (m, 2H), 2.23 (s, 3H), 2.07-2.00 (m, 2H).

[0214] Step 3: Synthesis of Compound BB-20-4

[0215] Compound BB-20-3 (1.20 g, 5.17 mmol) was dissolved in anhydrous dioxane (15 mL), followed by addition of cesium carbonate (3.54 g, 10.86 mmol), cuprous iodide (196 mg, 1.03 mmol) and dimethylglycine hydrochloride (433 mg, 3.10 mmol). The reaction mixture was heated to 90 C. and stirred for 3 hours. The reaction mixture was filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (dichloromethane/methanol, 100:1 to 40:1) to obtain compound BB-20-4. .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 2.85-2.82 (m, 2H), 2.61-2.54 (m, 5H), 2.22-2.15 (m, 2H).

[0216] Step 4: Synthesis of Compound BB-20-5

[0217] Compound BB-20-4 (540 mg, 3.57 mmol) was dissolved in anhydrous toluene (10 mL), followed by addition of 2-methyl-2-propanesulfinamide (563 mg, 4.64 mmol) and tetraethyl titanate (2.44 g, 10.72 mmol). The reaction mixture was stirred at 100 C. for 3 hours. Water (30 mL) and ethyl acetate (30 mL) were added to the reaction mixture, and the resulting mixture was thoroughly stirred and filtered, and the filtrate was extracted with ethyl acetate (20 mL2). The organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (dichloromethane/methanol, 100:1 to 40:1) to obtain compound BB-20-5.

[0218] Step 5: Synthesis of Compound BB-20-6

[0219] Compound BB-20-5 (570 mg, 2.24 mmol) was dissolved in anhydrous methanol (10 mL), followed by addition of sodium borohydride (84 mg, 2.24 mmol) at 0 C. The reaction mixture was stirred at 40 C. for 1 hour. Water (2 mL) was added to the reaction mixture to quench the reaction, and the resulting mixture was concentrated under reduced pressure to obtain a crude product of the compound BB-20-6.

[0220] Step 6: Synthesis of Compound BB-20

[0221] Compound BB-20-6 (580 mg, 2.26 mmol) was dissolved in methanol (5 mL), followed by addition of concentrated hydrochloric acid (1 mL, 12 N). The reaction mixture was stirred at 25 C. for 0.5 hour. The reaction mixture was adjusted to pH of 8-9 with sodium carbonate solid, and filtered. The filtrate was concentrated under reduced pressure. To the residue was added dichloromethane/methanol=10:1 (30 mL), and the mixture was stirred for 3 minutes, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (dichloromethane/methanol, 50:1 to 20:1) to obtain compound BB-20. .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 4.00-3.97 (m, 1H), 2.50-2.41 (m, 5H), 2.11-2.08 (m, 1H), 1.87-1.84 (m, 1H), 1.75-1.72 (m, 1H), 1.63-1.56 (m, 3H).

[0222] Fragment BB-21

##STR00093##

[0223] Synthetic Route:

##STR00094##

[0224] Step 1: Synthesis of Compound BB-21-2

[0225] Compound BB-21-1 (10 g, 89.19 mmol) was dissolved in dichloromethane (200 mL), and a solution of liquid bromine (14.25 g, 89.19 mmol, 4.60 mL) in dichloromethane (150 mL) was slowly added dropwise at 0 C. over half an hour. After the dropwise addition was completed, the reaction mixture was stirred at 25 C. for 1 hour. After the reaction was completed, the reaction mixture was concentrated to dryness to obtain a crude product, which was separated and purified with a flash preparative chromatography (eluent: ethyl acetate/petroleum ether=0-20%) to obtain compound BB-21-2. .sup.1H NMR (400 MHz, CHLOROFORM-d) ppm 6.41 (s, 1H), 2.88 (t, J=6.0 Hz, 2H), 2.61-2.54 (m, 2H), 2.13-2.02 (m, 2H)

[0226] Step 2: Synthesis of Compound BB-21-3

[0227] A solution of compound BB-21-2 (1 g, 5.23 mmol) and thioacetamide (393.32 mg, 5.23 mmol) in ethanol (30 mL) was heated to 90 C. and stirred for 12 hours. After the reaction was completed, the reaction mixture was concentrated to dryness to obtain a crude product, which was separated and purified with a flash preparative chromatography (eluent: ethyl acetate/petroleum ether=0-40%) to obtain compound BB-21-3. .sup.1H NMR (400 MHz, CHLOROFORM-d) ppm 3.05 (t, J=6.0 Hz, 2H), 2.70 (s, 3H), 2.67-2.61 (m, 2H), 2.28-2.20 (m, 2H).

[0228] Step 3: Synthesis of Compound BB-21

[0229] Compound BB-21-3 (170 mg, 1.02 mmol) was dissolved in methanol (20 mL), followed by addition of ammonium acetate (783.58 mg, 10.17 mmol) and sodium cyanoborohydride (319.41 mg, 5.08 mmol). The reaction mixture was heated to 80 C. and stirred for 12 hours. After the reaction was completed, the reaction mixture was concentrated to dryness to obtain a crude product, which was separated and purified with a flash preparative chromatography (eluent: methanol/dichloromethane=0-10%) to obtain compound BB-21. .sup.1H NMR (400 MHz, METHANOL-d.sub.4) ppm 4.43-4.35 (m, 1H), 3.35 (s, 3H), 2.86-2.79 (m, 2H), 2.33-2.23 (m, 1H), 2.13-2.04 (m, 1H), 1.92-1.82 (m, 2H)

[0230] Fragment BB-22

##STR00095##

##STR00096##

[0231] Step 1: Synthesis of Compound BB-22-2

[0232] At 25 C., sodium hydroxide (5.14 g, 128.41 mmol) was dissolved in water (150.00 mL), followed by addition of compound BB-22-1 (18 g, 128.41 mmol), and the reaction was allowed to run at 100 C. for 2 hours. The reaction mixture was extracted with ethyl acetate (200 mL2). The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was separated and purified by flash silica gel column chromatography (petroleum ether/ethyl acetate 100-75%) to obtain compound BB-22-2.

[0233] Step 2: Synthesis of Compound BB-22-3

[0234] At 25 C., sulfuric acid (3.18 g, 32.42 mmol) was dissolved in water (150.00 mL), followed by addition of a solution of compound BB-22-2 (5.00 g, 32.42 mmol) in tetrahydrofuran (50.00 mL), and the reaction was allowed to run for 48 hours at 100 C. The reaction mixture was extracted with ethyl acetate (50 mL2). The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was separated and purified by flash silica gel column chromatography (petroleum ether/ethyl acetate 100-83%) to obtain compound BB-22-3. .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 6.00 (m, 1H), 5.90 (s, 1H), 2.40 (s, 2H), 2.30 (m, 2H), 1.09 (s, 6H)

[0235] Step 3: Synthesis of Compound BB-22-4

[0236] At 25 C., chloroacetaldehyde (1.79 g, 9.12 mmol) and sodium bicarbonate (0.72 g, 8.56 mmol) were dissolved in water (20.00 mL), followed by addition of a solution of compound BB-22-3 (1.00 g, 7.13 mmol) in methanol (10.00 mL) at 0 C. The reaction was allowed to run for 60 hours at 25 C. The reaction mixture was diluted with ethyl acetate (10 mL), adjusted to pH of 1 with 10% sulfuric acid aqueous solution, and extracted with ethyl acetate (10 mL2). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, was and the residue was separated and purified with a thin layer chromatography silica gel plate (petroleum ether/ethyl acetate=80%) to obtain compound BB-22-4.

[0237] Step 4: Synthesis of Compound BB-22-5

[0238] At 25 C., BB-22-4 (733 mg, 4.46 mmol) and tert-butylsulfinamide (0.65 g, 5.36 mmol) were dissolved in toluene (10.00 mL), followed by addition of tetraethyl titanate (5.09 g, 22.32 mmol). The reaction was allowed to run for 16 hours at 110 C. Water (10 mL) was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (10 mL2). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by flash silica gel column chromatography (petroleum ether/ethyl acetate 100-75%) to obtain compound BB-22-5.

[0239] Step 5: Synthesis of Compound BB-22-6

[0240] According to the method for synthesizing the fragment BB-20-6, compound BB-22-6 was synthesized using compound BB-22-5.

[0241] Step 6: Synthesis of Compound BB-22

[0242] According to the method for synthesizing the fragment BB-20, compound BB-22 was synthesized using compound BB-22-6. .sup.1H NMR (400 MHz, CDCl.sub.3) ppm (d, J=1.2 Hz, 1H), 6.17 (d, J=1.6 Hz, 1H), 3.89 (m, 1H), 2.34 (m, 1H), 2.22-2.13 (m, 1H), 1.88 (m, 1H), 1.37 (m, 1H), 1.09 (s, 3H), 0.93 (s, 3H).

[0243] Fragment BB-23

##STR00097##

##STR00098##

[0244] Step 1: Synthesis of Compound BB-23-2

[0245] Compound BB-23-1 (9 g, 64.22 mmol) was dissolved in tetrachloromethane (400 mL), followed by addition of N-bromosuccinimide (11.43 g, 64.22 mmol) and 2,2-azobis(2-methylpropionitrile) (1.05 g, 6.42 mmol), and then the reaction system was purged with nitrogen three times. The reaction mixture was reacted at 75 C. for three hours. After completion of the reaction as indicated by thin layer chromatography, dichloromethane (300 mL) and deionized water (300 mL) were added to the reaction mixture. The organic phase was isolated, washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain BB-23-2, which was directly used in the next step.

[0246] Step 2: Synthesis of Compound BB-23-3

[0247] Compound BB-23-2 (13 g, 59.35 mmol) was dissolved in N,N-dimethylformamide (200 mL), followed by addition of ethyl 2-(methylamino)acetate hydrochloride (9.12 g, 59.35 mmol) and potassium carbonate (24.61 g, 178.06 mmol). The reaction mixture was reacted at 25 C. for 2 hours. After completion of the reaction as indicated by thin layer chromatography, to the reaction mixture were added ethyl acetate (500 mL) and deionized water (500 mL). The organic phase was isolated, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5:1 to 1:1) to obtain BB-23-3. .sup.1H NMR (400 MHz, CHLOROFORM-d) ppm 7.50 (d, J=2.0 Hz 1H), 6.66 (d, J=1.6 Hz 1H), 4.19 (q, J=14.4 Hz, 2H), 3.93 (s, 2H), 3.90 (s, 3H), 3.28 (s, 2H), 2.41 (s, 3H), 1.28 (t, J=7.2 Hz, 3H).

[0248] Step 3: Synthesis of Compound BB-23-4

[0249] Compound BB-23-3 (10 g, 39.17 mmol) was dissolved in tetrahydrofuran (300 mL). The mixture was cooled to 78 C., and a solution of potassium tert-butoxide (8.79 g, 78.35 mmol) in tetrahydrofuran (100 mL) was slowly added dropwise to the above reaction mixture. The reaction was allowed to run for 14 hours at 78 C. After completion of the reaction as indicated by thin layer chromatography, to the reaction mixture were added dilute hydrochloric acid (1 M, 78 mL), saturated ammonium chloride (200 mL) and ethyl acetate (500 mL). The organic phase was isolated, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain BB-23-4.

[0250] Step 4: Synthesis of Compound BB-23-5

[0251] Compound BB-23-4 (4 g, 17.92 mmol) was added to dilute hydrochloric acid (1 M, 100 mL), and the reaction mixture was heated to 100 C. and reacted for 6 hours. After completion of the reaction as indicated by thin layer chromatography, to the reaction mixture were added saturated sodium carbonate (20 mL) and dichloromethane (100 mL). The organic phase was isolated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain BB-23-5. .sup.1H NMR (400 MHz, CHLOROFORM-d) ppm 7.62 (d, J=1.6 Hz 1H), 6.44 (d, J=1.6 Hz 1H), 3.70 (s, 2H), 3.30 (s, 2H), 2.52 (s, 3H).

[0252] Step 5: Synthesis of Compound BB-23-6

[0253] Compound BB-23-5 (1 g, 6.62 mmol) was dissolved in ethanol (30 mL), followed by addition of sodium acetate (1.09 g, 13.23 mmol). The reaction mixture was reacted at 80 C. for 12 hours. After completion of the reaction as indicated by thin layer chromatography, to the reaction mixture were added dichloromethane (100 mL) and deionized water (50 mL). The organic phase was isolated, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain BB-23-6. .sup.1H NMR (400 MHz, CD.sub.3OD) ppm 7.55 (d, J=2.0 Hz 1H), 6.47 (d, J=2.0 Hz, 1H), 3.69 (s, 2H), 3.60 (s, 2H), 2.53 (s, 3H).

[0254] Step 5: Synthesis of Compound BB-23

[0255] Compound BB-23-6 (0.25 g, 1.50 mmol) was dissolved in tetrahydrofuran (30 mL), followed by addition of lithium aluminum hydride (285.50 mg, 7.52 mmol). The reaction mixture was then heated to 80 C. and reacted for 2 hours. After completion of the reaction as indicated by thin layer chromatography, to the reaction mixture were added deionized water (10 mL) and tetrahydrofuran (10 mL). The mixture was filtered through diatomite, and concentrated to obtain a crude product. The crude product was purified by column chromatography to obtain BB-23. .sup.1H NMR (400 MHz, CHLOROFORM-d) ppm 7.28 (d, J=1.2 Hz 1H), 6.18 (d, J=1.6 Hz 1H), 3.96 (s, 1H), 3.46-3.42 (m, 1H), 3.21-3.17 (m, 1H). 2.82-2.78 (m, 1H), 2.63-2.59 (m, 1H), 2.46 (s, 3H).

[0256] Fragment BB-24

##STR00099##

[0257] Synthetic Route:

##STR00100##

[0258] Step 1: Synthesis of Compound BB-24-3

[0259] Compound BB-24-2 (10.00 g, 45.90 mmol) was dissolved in toluene (400 mL), and then compound BB-24-1 (11.03 g, 45.90 mmol) and triethylamine (19.16 mL, 137.69 mmol) were added into the reaction mixture. The mixture was heated to 120 C. and stirred for 12 hours. After completion of the reaction as indicated by thin layer chromatography, the reaction mixture was concentrated, followed by addition of water (30 mL) and ethyl acetate (30 mL). The aqueous phase was extracted three times with ethyl acetate (30 mL3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was purified by column chromatography (dichloromethane/methanol=20/1) to obtain BB-24-3. .sup.1H NMR (400 MHz, CHLOROFORM-d) ppm 7.36-7.26 (m, 10H), 3.85-3.77 (m, 1H), 3.75-3.62 (m, 4H), 2.94-2.80 (m, 4H), 2.79-2.68 (m, 2H), 2.53-2.41 (m, 2H)

[0260] Step 2: Synthesis of Compound BB-24-4

[0261] Compound BB-24-3 (8.10 g, 27.33 mmol) was dissolved in methanol (300 mL), and then palladium hydroxide on carbon (2.00 g) was added to the reaction mixture. The mixture was stirred at room temperature for 3 hours under hydrogen atmosphere (15 psi). After completion of the reaction as indicated by thin layer chromatography, the reaction mixture was filtered through diatomite at room temperature to remove the catalyst, and the filtrate was rotary-evaporated to obtain a crude product of the compound BB-24-4.

[0262] Step 3: Synthesis of Compound BB-24-5

[0263] Compound BB-24-4 (2.60 g, 22.38 mmol) was dissolved in methanol (26 mL), followed by addition of triethylamine (7.48 mL, 53.72 mmol) and Boc.sub.2O (9.77 g, 44.77 mmol), and the mixture was stirred at 25 C. for 1 hour. After completion of the reaction as indicated by thin layer chromatography and liquid chromatography, the reaction mixture was concentrated at room temperature and quenched with water (20 mL), and then extracted with dichloromethane (20 mL3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=1:1) to obtain BB-24-5. .sup.1H NMR (400 MHz, CHLOROFORM-d) ppm 4.31-4.08 (m, 1H), 4.03-3.86 (m, 3H), 3.86-3.54 (m, 1H), 3.54-3.27 (m, 2H), 3.12-3.11 (m, 1H), 3.03 (m, 1H), 2.78 (m, 1H), 1.48 (s, 9H), 1.47 (s, 9H).

[0264] Step 4: Synthesis of Compound BB-24

[0265] Compound BB-24-5 (1.00 g, 3.16 mmol) was dissolved in dichloromethane (10 mL), followed by addition of triethylamine (1.10 mL, 3.90 mmol), DMAP (193.06 mg, 1.58 mmol) and p-toluenesulfonyl chloride (1.21 g, 6.32 mmol) to the reaction mixture at 0 C. The mixture was heated to 40 C. and stirred for 1 hour. After completion of the reaction as indicated by thin layer chromatography, the reaction mixture was quenched with water (20 mL) at room temperature, and extracted with dichloromethane (20 mL3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=7:3) to obtain compound BB-24. .sup.1H NMR (400 MHz, CHLOROFORM-d) =7.88-7.75 (m, 2H), 7.36 (br d, J=7.2 Hz, 2H), 4.79-4.57 (m, 1H), 3.88-3.27 (m, 8H), 2.46 (s, 3H), 1.52-1.38 (m, 18H).

[0266] Fragment BB-25

##STR00101##

[0267] Synthetic Route:

##STR00102##

[0268] Compound WX001-1 (0.70 g, 2.41 mmol) was dissolved in dichloromethane (10 mL), and saturated NaHCO.sub.3 solution was added to obtain pH>7, followed by addition of FmocCl (465.81 mg, 1.44 mmol) at 0 C. The mixture was stirred at 25 C. for 1 hour. After completion of the reaction as indicated by thin layer chromatography and liquid chromatography, the reaction mixture was separated into layers, and the aqueous phase was extracted three times with ethyl acetate (20 mL3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (SiO.sub.2, petroleum ether/ethyl acetate=3/1) to obtain BB-25. .sup.1H NMR (400 MHz, CHLOROFORM-d) ppm 10.47 (br s, 1H), 7.77 (d, J=7.2 Hz, 2H), 7.55 (br d, J=7.2 Hz, 2H), 7.44-7.38 (m, 2H), 7.37-7.29 (m, 2H), 6.87 (br d, J=8.0 Hz, 1H), 6.78 (br s, 1H), 4.43 (br s, 2H), 4.21 (br s, 1H), 4.02 (br s, 2H), 3.73 (br s, 1H), 3.37-2.99 (m, 1H), 2.88-2.77 (m, 1H), 2.15 (br s, 1H), 1.99-1.78 (m, 2H), 1.32-1.19 (m, 1H).

[0269] Fragment BB-26

##STR00103##

##STR00104##

[0270] Step 1: Synthesis of Compound BB-26-1

[0271] At 25 C., compound BB-2-2 (50.00 g, 203.14 mmol) was dissolved in tetrahydrofuran (500.00 mL). The mixture was cooled to 25 C., followed by dropwise addition of n-butyllithium (2.5 M, 138.14 mL, 345.34 mmol) under nitrogen atmosphere while maintaining the internal temperature below 10 C. After the dropwise addition was completed, the reaction was allowed to run for 5 minutes at 10 C., followed by dropwise addition of a solution of iodine (103.12 g, 406.29 mmol) in tetrahydrofuran (250.00 mL) while maintaining the internal temperature below 5 C. After the dropwise addition was completed, the reaction was allowed to run for 8 minutes at 5 C. The mixture was quenched with saturated aqueous solution of sodium thiosulfate (200 mL), and extracted with ethyl acetate (200 mL2). The organic phase was washed with saturated aqueous solution of sodium thiosulfate (200 mL) and saturated brine (200 mL2), dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was separated and purified by flash silica gel column chromatography (petroleum ether/ethyl acetate 100-96%) to obtain compound BB-26-1.

[0272] Step 2: Synthesis of Compound BB-26

[0273] At 25 C., compound BB-26-1 (10.00 g, 29.80 mmol), cuprous iodide (1.14 g, 5.96 mmol), 1,10-phenanthroline (1.07 g, 5.96 mmol) and potassium thioacetate (6.81 g, 59.60 mmol) were dissolved in toluene (100.00 mL) and reacted at 90 C. for 20 hours under nitrogen atmosphere. After cooling to room temperature, the mixture was quenched with water (100 mL), diluted with ethyl acetate (100 mL), filtered, and extracted with ethyl acetate (200 mL2). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was separated and purified by flash silica gel column chromatography (petroleum ether/ethyl acetate 100-94%) to obtain compound BB-26.

[0274] Fragment BB-27

##STR00105##

[0275] Synthetic Route:

##STR00106## ##STR00107##

[0276] Step 1: Synthesis of Compound BB-27-2

[0277] Compound BB-27-1 (83.79 g, 429.57 mmol) was dissolved in ethanol (500 mL), followed by addition of potassium carbonate (69.66 g, 504.00 mmol), potassium iodide (836.65 mg, 5.04 mmol) and benzylamine (54.00 g, 504.00 mmol). The mixture was heated to 85 C. and stirred for 16 hours. After the reaction was completed, the precipitated solid was removed by filtration under reduced pressure, and the filtrate was collected. The filtrate was concentrated to dryness under reduced pressure, and the residue was separated and purified with a flash preparative chromatography (eluent: ethyl acetate/petroleum ether=0-20%) to obtain compound BB-27-2. .sup.1H NMR (400 MHz, CHLOROFORM-d) ppm 7.38-7.26 (m, 5H), 4.20 (q, J=7.2 Hz, 2H), 3.62 (s, 2H), 1.37 (s, 6H), 1.31 (t, J=7.2 Hz, 3H).

[0278] Step 2: Synthesis of Compound BB-27-3

[0279] A mixture of compound BB-27-2 (25.3 g, 114.33 mmol), ethyl bromobutyrate (23.41 g, 120.04 mmol) and potassium iodide (948.93 mg, 5.72 mmol) was heated to 120 C. and stirred for 24 hours. After the reaction was completed, the reaction mixture was diluted by adding ethyl acetate (250 mL). The precipitated solid was removed by filtration under reduced pressure, and the filtrate was collected. The filtrate was concentrated to dryness under reduced pressure, and the residue was separated and purified with a flash preparative chromatography (eluent: ethyl acetate/petroleum ether=0-10%) to obtain compound BB-27-3. .sup.1H NMR (400 MHz, CHLOROFORM-d) ppm 7.40-7.26 (m, 4H), 7.22-7.16 (m, 1H), 4.20-4.14 (m, 2H), 4.10-4.01 (m, 2H), 3.82 (s, 2H), 2.70-2.61 (m, 2H), 2.17 (t, J=7.2 Hz, 2H), 1.56-1.48 (m, 2H), 1.36 (s, 6H), 1.29 (t, J=7.2 Hz, 3H), 1.20 (t, J=7.2 Hz, 3H).

[0280] Step 3: Synthesis of Compound BB-27-4

[0281] Compound BB-27-3 (8.5 g, 25.34 mmol) was dissolved in tetrahydrofuran (250 mL), followed by addition of sodium hydride (3.04 g, 76.02 mmol, 60% purity), and the mixture was heated to 80 C. and stirred for 4 hours. After the reaction was completed, the reaction mixture was concentrated to dryness under reduced pressure, followed by addition of 100 mL of water and adjusting the pH to 5 with dilute hydrochloric acid, during which the temperature was kept below 10 C. with an ice bath. The mixture was neutralized with sodium bicarbonate solid to obtain a neutral pH, and extracted with ethyl acetate (250 mL2). The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain compound BB-27-4, which was directly used in the next step without purification. .sup.1H NMR (400 MHz, CHLOROFORM-d) ppm 12.41 (s, 1H), 7.40-7.29 (m, 5H), 4.23-4.18 (m, 2H), 3.61 (s, 2H), 2.51 (t, J=5.6 Hz, 2H), 2.16 (t, J=5.6 Hz, 2H), 1.39 (s, 6H), 1.28 (t, J=7.2 Hz, 3H)

[0282] Step 4: Synthesis of Compound BB-27-5

[0283] Compound BB-27-4 (7.1 g, 24.54 mmol) was dissolved in 6 M hydrochloric acid (177.50 mL), and the reaction mixture was heated to 110 C. and stirred for 3 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, adjusted to pH 8 by addition of sodium hydroxide solid, and extracted with ethyl acetate (250 mL2). The organic phases were combined, washed with saturated brine (250 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain compound BB-27-5, which was directly used in the next step without purification. .sup.1H NMR (400 MHz, CHLOROFORM-d) ppm 7.39-7.24 (m, 5H), 3.62 (s, 2H), 2.65 (t, J=6.0 Hz, 2H), 2.49 (t, J=7.2 Hz, 2H), 1.87-1.77 (m, 2H), 1.30 (s, 6H).

[0284] Step 5: Synthesis of Compound BB-27-6

[0285] Compound BB-27-5 (2.5 g, 11.50 mmol) was dissolved in methanol (10 mL), followed by addition of wet palladium on carbon (100 mg, 10% purity), and the reaction mixture was stirred at 25 C. for 3 hours under hydrogen atmosphere (30 psi). After the reaction was completed, the reaction mixture was filtered through diatomite, and the filtrate was concentrated to dryness under reduced pressure to obtain compound BB-27-6, which was directly used in the next step. .sup.1H NMR (400 MHz, CHLOROFORM-d) ppm 3.08-2.99 (m, 2H), 2.49 (t, J=6.8 Hz, 2H), 2.08-1.98 (m, 2H), 1.25 (s, 6H).

[0286] Step 6: Synthesis of Compound BB-27-7

[0287] Compound BB-27-6 (1.25 g, 9.83 mmol) was dissolved in dichloromethane (35 mL), followed by addition of 35 mL of aqueous sodium bicarbonate solution (2.48 g, 29.48 mmol) and FmocCl (2.54 g, 9.83 mmol). The reaction mixture was stirred at 25 C. for 2 hours. After the reaction was completed, the reaction mixture was extracted with dichloromethane (30 mL2). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure, and the residue was separated and purified with a flash preparative chromatography (eluent: ethyl acetate/petroleum ether=0-30%) to obtain compound BB-27-7.

[0288] Step 7: Synthesis of Compound BB-27-8

[0289] Compound BB-27-7 (497 mg, 1.42 mmol) was dissolved in methanol (10 mL), followed by addition of sodium borohydride (53.81 mg, 1.42 mmol) at 0 C., and the reaction mixture was warmed to 25 C. and stirred for 1 hour. After the reaction was completed, 10 mL of acetone was added to quench the reaction, and the reaction mixture was concentrated to dryness under reduced pressure, followed by addition of 10 mL of water and extraction with dichloromethane (25 mL2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure, and the residue was separated and purified with a flash preparative chromatography (eluent: ethyl acetate/petroleum ether=0-35%) to obtain compound BB-27-8.

[0290] Step 8: Synthesis of Compound BB-27-9

[0291] Compound BB-27-8 (790 mg, 2.25 mmol) was dissolved in dichloromethane (80 mL), followed by addition of triethylamine (568.66 mg, 5.62 mmol), 4-dimethylaminopyridine (274.63 mg, 2.25 mmol) and p-toluenesulfonyl chloride (642.85 mg, 3.37 mmol). The reaction mixture was stirred at 40 C. for 12 hours. After the reaction was completed, the reaction mixture was directly concentrated to dryness, and the residue was separated and purified with a flash preparative chromatograph (eluent: ethyl acetate/petroleum ether=0-20%) to obtain compound BB-27-9.

[0292] Step 9: Synthesis of Compound BB-27-10

[0293] Compound BB-26 (285 mg, 1.00 mmol) was dissolved in methanol (15 mL), followed by addition of potassium carbonate (347.01 mg, 2.51 mmol), and the reaction mixture was heated to 60 C. and stirred for 0.5 hour. The reaction mixture was concentrated to dryness under reduced pressure, and dissolved in dimethylformamide (35 mL), followed by addition of potassium carbonate (340.18 mg, 2.46 mmol) and compound BB-27-9 (497.81 mg, 984.54 mol). The reaction mixture was heated to 60 C. and stirred for 1 hour. After the reaction was completed, the reaction mixture was poured into 150 mL of water to quench the reaction, and the resulting mixture was extracted with ethyl acetate (50 mL3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure, and the residue was separated and purified with a flash preparative chromatography (eluent: methanol/dichloromethane=0-20%) to obtain compound BB-27-10.

[0294] Step 10: Synthesis of Compound BB-27-11

[0295] Compound BB-27-10 (20 mg, 56.67 mol) was dissolved in dichloromethane (5 mL), followed by addition of 2 mL of an aqueous solution of sodium bicarbonate (14.28 mg, 170.01 mol) and FmocCl (14.66 mg, 56.67 mol). The reaction mixture was stirred at 25 C. for 2 hours. After the reaction was completed, the reaction mixture was poured into 10 mL of water, and extracted with dichloromethane (10 mL2). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and dried under reduced pressure to obtain compound BB-27-11, which was directly used in the next step.

[0296] Step 11: Synthesis of Compound BB-27-12

[0297] Compound BB-27-11 (35 mg, 60.85 mol) was dissolved in dichloromethane (5 mL), and m-chloroperoxybenzoic acid (98.83 mg, 486.82 mol, 85% purity) was added in portions. The reaction mixture was stirred at 25 C. for 16 hours. After the reaction was completed, 2 mL of saturated sodium thiosulfate solution and 5 mL of saturated sodium bicarbonate solution were added to quench the reaction, and the resulting mixture was extracted with dichloromethane (10 mL2). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure to obtain compound BB-27-12, which was directly used in the next step.

[0298] Step 12: Synthesis of Compound BB-27

[0299] Compound BB-27-12 (35 mg, 57.65 mol) was dissolved in ethanol (5 mL), followed by addition of concentrated hydrochloric acid (12 M, 480.38 L). The reaction mixture was heated to 85 C. and stirred for 16 hours. After the reaction was completed, the reaction mixture was concentrated to dryness under reduced pressure, dissolved in 30 mL of ethyl acetate, washed with saturated sodium bicarbonate solution (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure to obtain compound BB-27, which was directly used in the next step.

Embodiment 1: WX001, WX001A, WX001B

[0300] ##STR00108##

[0301] Synthetic Route:

##STR00109## ##STR00110##

[0302] Step 1: Synthesis of Compound WX001-1

[0303] Compound BB-4 (3.25 g, 7.11 mmol) was dissolved in 15 mL of ethanol, followed by addition of concentrated hydrochloric acid (12 M, 9.5 mL), and the resulting mixture was heated to 80 C. and stirred overnight. After the reaction was completed, the solvent was removed under reduced pressure, and the pH value was adjusted to 12 with 2 M NaOH to obtain a crude product solution, which was directly used in the next reaction.

[0304] Step 2: Synthesis of Compound WX001-2

[0305] To the above crude product solution were added 10 mL of ethyl acetate and Boc.sub.2O (1.55 g, 7.12 mmol, 1.64 mL), and the reaction was allowed to run for 1.5 hours at 0 C. After the reaction was completed, the mixture was diluted with 20 mL of ethyl acetate and extracted with ethyl acetate (20 mL3). The organic phases were combined, washed with saturated brine (15 mL3), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was separated by a chromatography column (eluent: ethyl acetate/petroleum ether=0-25%) to obtain the target compound WX001-2. .sup.1H NMR (400 MHz, CHLOROFORM-d) ppm 10.47 (br s, 1H), 6.92-6.86 (m, 1H), 6.81 (d, J=8.2 Hz, 1H), 4.26 (br s, 1H), 4.04 (br s, 3H), 3.76-3.66 (m, 1H), 3.08 (br s, 1H), 2.76 (br t, J=12.6 Hz, 1H), 2.21 (br d, J=10.4 Hz, 1H), 1.98-1.84 (m, 2H), 1.58 (s, 1H), 1.42 (s, 9H).

[0306] Step 3: Synthesis of Compound WX001-3

[0307] Triphosgene (158 mg, 532.43 mol) was dissolved in 5 mL of DCM, followed by addition of BB-5 (220 mg, 1.60 mmol) and triethylamine (54.36 mg, 537.25 mol, 74.47 L). After stirring at room temperature for 30 minutes, the reaction mixture was concentrated. The obtained crude product was dissolved in 5 mL of DCM, followed by addition of WX001-2 (200 mg, 511.67 mol) and triethylamine (117.01 mg, 1.16 mmol, 160.29 L), and the resulting mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was concentrated to obtain a crude product of WX001-3, which was directly used in the next reaction.

[0308] Step 4: Synthesis of Compound WX001

[0309] Compound WX001-3 (300.00 mg, 541.47 mol) was dissolved in 5 mL of ethyl acetate, followed by addition of HCl/EtOAc (4 M, 4.00 mL), and the reaction mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was concentrated to obtain a crude product, which was separated by high performance liquid chromatography to obtain the target compound WX001. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.57-1.75 (m, 2H) 1.74-1.93 (m, 7H) 1.96 (br d, J=13.2 Hz, 2H) 2.89 (br s, 2H) 3.11 (br t, J=11.6 Hz, 1H) 3.24 (br d, J=12.0 Hz, 1H) 3.42-3.46 (m, 1H) 4.16 (br t, J=11.4 Hz, 1H) 4.63-4.71 (m, 1H) 6.37 (s, 1H) 7.17 (d, J=9.0 Hz, 1H) 7.36-7.49 (m, 2H) 8.22 (d, J=8.8 Hz, 1H) 8.56 (s, 1H) 8.82-9.59 (m, 2H) 10.92 (br s, 1H).

[0310] Step 5: Synthesis of Compounds WX001A and WX001B

[0311] Compound WX001 was resolved by supercritical fluid chromatography (separation conditions: column, Chiralpak AD-3 1004.6 mm ID., 3 m; mobile phase, A: carbon dioxide, B: methanol (0.05% diethylamine); flow rate: 2.8 mL/min; column temperature: 40 C.; detection wavelength: 220 nm) to obtain the chiral isomers WX001A and WX001B with a retention time of 4.883 min and 5.875 min, respectively, and a ratio of 1:1.

Embodiment 2: WX002, WX002A, WX002B

[0312] ##STR00111##

[0313] Synthetic Route:

##STR00112##

[0314] Step 1: Synthesis of Compound WX002-1

[0315] Compound BB-6 (10.80 g, 34.20 mmol) was dissolved in 60 mL of ethanol, followed by addition of concentrated hydrochloric acid (12 M, 20 mL), and the resulting mixture was heated to 80 C. and reacted with stirring overnight. After the reaction was completed, the solvent was evaporated under reduced pressure. The residue was adjusted to pH of 7 with 1 M NaOH, and extracted with ethyl acetate (40 mL3). The organic phases were combined, washed with saturated brine (30 mL3), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was then separated with a chromatography column (eluent: ethyl acetate/petroleum ether=0-30%) to obtain the target compound WX002-1. .sup.1H NMR (400 MHz, CHLOROFORM-d) ppm 1.40 (d, J=7.0 Hz, 6H) 3.89 (spt, J=6.8 Hz, 1H) 6.78-6.83 (m, 1H) 6.85-6.91 (m, 1H) 10.62 (s, 1H).

[0316] Step 2: Synthesis of Compound WX002

[0317] BB-5 (219.74. mg, 1.60 mmol) was dissolved in 5 mL of DCM, followed by addition of triphosgene (156.87 mg, 528.61 mol) and triethylamine (81.05 mg, 800.93 mol, 111.03 L). After the reaction mixture was stirred at room temperature for 30 minutes, the reaction mixture was concentrated. The obtained crude product was dissolved in 5 mL of DCM, followed by addition of WX002-1 (200 mg, 800.93 mol) and triethylamine (162.09 mg, 1.60 mmol, 222.04 L), and the resulting mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was concentrated, and the obtained crude product was separated by high-performance liquid chromatography to obtain the target compound WX002.

[0318] Step 3: Synthesis of Compounds WX002A and WX002B.

[0319] Compound WX002 was resolved by supercritical fluid chromatography (separation conditions: column, Chiralpak AD (250 mm30 mm, 5 m); mobile phase, A: carbon dioxide, B: methanol (0.1% ammonium hydroxide)) to obtain the chiral isomers WX002A and WX002B, with a retention time of 4.803 min and 5.672 min, respectively, and a ratio of 1:1.

[0320] According to the steps 1 to 3 in the synthesis of Embodiment 2, the embodiments in Table 1 were synthesized using BB-1 in the step 2. The structures in the table also represent their potential isomers.

TABLE-US-00001 TABLE 1 Embodiment Fragment in the step 2 Structure Compound 3 [00113] [00114] WX003 WX003A WX003B [00115] [00116]

Embodiment 4: WX004, WX004A, WX004B

[0321] ##STR00117##

[0322] Synthetic Route:

##STR00118##

[0323] Step 1: Synthesis of Compound WX004

[0324] BB-1 (105.28 mg, 767.50 mol) was dissolved in 5 mL of DCM, followed by addition of triphosgene (75.16 mg, 253.28 mol) and triethylamine (77.66 mg, 767.50 mol, 106.83 L). After stirring at room temperature for 30 minutes, the reaction mixture was concentrated. The obtained crude product was dissolved in 5 mL of DCM, followed by addition of WX001-2 (150.00 mg, 383.75 mol) and triethylamine (38.83 mg, 383.75 mol, 53.41 L), and the resulting mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was concentrated, and the obtained crude product was separated by high performance liquid chromatography to obtain the target compound WX004.

[0325] Step 2: Synthesis of Compounds WX004A and WX004B

[0326] Compound WX004 was resolved by supercritical fluid chromatography (separation conditions: column, ChiralCel OD-H 1504.6 mm I.D., 5 m; mobile phase, A: carbon dioxide, B: ethanol (0.05% diethylamine); flow rate: 2.5 mL/min; column temperature: 40 C.; detection wavelength: 220 nm) to obtain the chiral isomers WX004A and WX004B with a retention time of 4.499 min and 5.163 min, respectively, and a ratio of 1:1.

Embodiment 5: WX005, WX005A, WX005B

[0327] ##STR00119##

[0328] Synthetic Route:

##STR00120##

[0329] Step 1: Synthesis of Compound WX005-1

[0330] Compound BB-6 (1 g, 3.17 mmol) was dissolved in 30 mL of THF, and LiHMDS (1 M, 6.33 mL) was added dropwise at 70 C. After stirring at 70 C. for 0.5 hour, iodomethane (3.7 g, 26.07 mmol, 1.62 mL) was added and the reaction was allowed to run for 3 hours. After the reaction was completed, 20 mL of saturated ammonium chloride solution was added to quench the reaction. The mixture was diluted with 25 mL of ethyl acetate, and then extracted with ethyl acetate (25 mL3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was then separated with a chromatography column (eluent: ethyl acetate/petroleum ether=0-25%) to obtain the target compound WX005-1. .sup.1H NMR (400 MHz, CHLOROFORM-d) ppm 7.66 (dd, J=1.1, 8.4 Hz, 1H), 7.36-7.31 (m, 1H), 1.35 (s, 9H), 1.29 (s, 9H).

[0331] Step 2: Synthesis of Compound WX005-2

[0332] Compound WX005-1 (0.447 g, 1.36 mmol) was dissolved in 10 mL of ethanol, followed by addition of concentrated hydrochloric acid (12 M, 2 mL). The reaction mixture was heated to 80 C. and reacted under stirring overnight. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was adjusted to pH of 12 with 2 M NaOH, and extracted with ethyl acetate (10 mL3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was then separated with a chromatography column (eluent: ethyl acetate/petroleum ether=0-25%) to obtain the target compound WX005-2. .sup.1H NMR (400 MHz, CHLOROFORM-d) ppm 10.36 (s, 1H), 6.93-6.87 (m, 1H), 6.83 (d, J=8.0 Hz, 1H), 1.47 (s, 9H).

[0333] Step 3: Synthesis of Compound WX005

[0334] Compound BB-1 (208.05 mg, 1.52 mmol) was dissolved in 5 mL of DCM, followed by addition of triphosgene (148.52 mg, 500.49 mol) and triethylamine (153.47 mg, 1.52 mmol, 211.10 L). The reaction mixture was stirred at room temperature for 30 minutes, and then concentrated. The obtained crude product was dissolved in 5 mL of DCM, followed by addition of compound WX005-2 (200.00 mg, 758.32 mol) and triethylamine (76.73 mg, 758.32 mol, 105.55 L), and the reaction mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was concentrated, and the obtained crude product was separated by high performance liquid chromatography to obtain the target compound WX005.

[0335] Step 4: Synthesis of WX005A and WX005B.

[0336] Compound WX005 was resolved by supercritical fluid chromatography (separation conditions: column, ChiralCel OD-H 1504.6 mm 5 m; mobile phase, A: carbon dioxide, B: ethanol (0.05% diethylamine); flow rate: 2.5 mL/min; column temperature: 40 C.; detection wavelength: 220 nm) to obtain the chiral isomers WX005A and WX005B with a retention time of 4.205 min and 5.142 min, respectively, and a ratio of 1:1.

Embodiment 6: WX006, WX006A, WX006B

[0337] ##STR00121##

##STR00122## ##STR00123##

[0338] Step 1: Synthesis of Compound WX006-1

[0339] The crude compound BB-2 (6.95 g, 28.75 mmol) was dissolved in 120 mL of DMF, followed by addition of potassium carbonate (3.98 g, 28.80 mmol) and 1-bromo-3-chloropropane (5.44 g, 34.55 mmol), and the reaction mixture was stirred at 80 C. for 16 hours. After the reaction was completed, the solvent was evaporated under reduced pressure. To the residue was added 100 mL of water, followed by extraction with ethyl acetate (80 mL3). The obtained organic phases were combined and dried over anhydrous sodium sulfate. After the desiccant was removed by filtration, the crude product obtained after concentration was separated with a chromatography column (eluent: ethyl acetate/petroleum ether=0-10%) to obtain the target compound WX006-1. .sup.1H NMR (400 MHz, CHLOROFORM-d) ppm 7.53 (d, J=8.4 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 3.72 (t, J=6.2 Hz, 2H), 3.29 (t, J=6.8 Hz, 2H), 2.13-1.93 (m, 2H), 1.53 (s, 9H).

[0340] Step 1: Synthesis of Compound WX006-2

[0341] Compound WX006-1 (3.28 g, 10.31 mmol) was dissolved in 100 mL of DCM, followed by addition of m-CPBA (12.55 g, 61.84 mmol) at 10 C., and the reaction mixture was stirred at 10 C. for 5 hours. After the reaction was completed, 50 mL of saturated sodium sulfite solution, 50 mL of saturated sodium bicarbonate solution and 50 mL of DCM were added. The aqueous phase was extracted with DCM (50 mL3), and the organic phases were combined and dried over anhydrous sodium sulfate. After the desiccant was removed by filtration, the crude product obtained after concentration was separated with a chromatography column (eluent: ethyl acetate/petroleum ether=0-15%) to obtain the target compound WX006-2. .sup.1H NMR (400 MHz, CHLOROFORM-d) ppm 7.85 (d, J=8.4 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 3.74-3.64 (m, 4H), 2.44-2.28 (m, 2H), 1.54 (s, 9H).

[0342] Step 3: Synthesis of Compound WX006-3

[0343] The compound WX006-2 (2.61 g, 7.45 mmol) was dissolved in 60 mL of tetrahydrofuran, and cooled to 70 C., followed by addition of KHMDS (1.64 g, 8.20 mmol). The reaction mixture was stirred at 70 C. for 1 hour. After the reaction was completed, 20 mL of water was added to quench the reaction, and the mixture was diluted with 30 mL of ethyl acetate. The aqueous phase was extracted with ethyl acetate (30 mL3). The organic phases are combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was then separated with a chromatography column (developing solvent: ethyl acetate/petroleum ether=0-15%) to obtain the target compound WX006-3. .sup.1H NMR (400 MHz, CHLOROFORM-d) ppm 7.81 (d, J=8.4 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 3.09 (tt, J=4.6, 8.0 Hz, 1H), 1.53 (s, 9H), 1.51-1.48 (m, 2H), 1.15-1.09 (m, 2H).

[0344] Step 4: Synthesis of Compound WX006-4

[0345] Compound WX006-3 (2.05 g, 6.53 mmol) was dissolved in 40 mL of ethanol, followed by addition of concentrated hydrochloric acid (12 M, 9 mL). The mixture was heated to 80 C. and reacted with stirring overnight. After the reaction was completed, the solvent was removed under reduced pressure, and the residue was adjusted to pH of 9 by addition of saturated sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate (50 mL3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was then separated with a chromatography column (developing solvent: ethyl acetate/petroleum ether=0-25%) to obtain the target compound WX006-4. .sup.1H NMR (400 MHz, CHLOROFORM-d) ppm 10.34 (s, 1H), 6.90-6.86 (m, 1H), 6.79 (d, J=8.3 Hz, 1H), 4.09-3.93 (m, 2H), 3.22 (tt, J=4.6, 8.0 Hz, 1H), 1.46-1.39 (m, 2H), 1.18-1.10 (m, 2H).

[0346] Step 5: Synthesis of Compound WX006

[0347] Compound BB-1 (0.84 g, 6.12 mmol) was dissolved in 20 mL of DCM, followed by addition of triphosgene (0.55 g, 1.85 mmol) and triethylamine (620.95 mg, 6.14 mmol). The reaction mixture was stirred at room temperature for 30 minutes, and then concentrated. The obtained crude product was dissolved in 20 mL of DCM, followed by addition of compound WX006-4 (0.76 g, 3.07 mmol) and triethylamine (310.48 g, 3.07 mmol), and the reaction mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was concentrated, and the obtained crude product was separated by high performance liquid chromatography, and then further separated with a chromatography column (eluent: ethyl acetate/petroleum ether=0-40%) to obtain the target compound WX006.

[0348] Step 6: Synthesis of Compounds WX006A and WX006B

[0349] Compound WX006 was resolved by supercritical fluid chromatography (separation conditions: column, Chiralpak AD-3 1504.6 mm 3 m; mobile phase, A: carbon dioxide, B: methanol (0.05% diethylamine); flow rate: 2.5 mL/min; column temperature: 40 C.; detection wavelength: 220 nm) to obtain the chiral isomers WX006A and WX006B with a retention time of 6.531 min and 7.085 min, respectively, and a ratio of 1:1.

Embodiment 7: WX007, WX007A, WX007B

[0350] ##STR00124##

[0351] Synthetic Route:

##STR00125## ##STR00126##

[0352] Step 1: Synthesis of Compound WX007-1

[0353] Compound BB-2 (1.5 g, 6.21 mmol) was dissolved in 30 mL of DMF, followed by addition of potassium carbonate (1 g, 7.24 mmol) and bromoethane (730 mg, 6.70 mmol, 0.5 mL), and the reaction mixture was stirred at 80 C. overnight. After the reaction was completed, the solvent was evaporated under reduced pressure. To the residue was added 50 mL of water, and the mixture was extracted with ethyl acetate (30 mL3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was then separated with a chromatography column (eluent: ethyl acetate/petroleum ether=0-5%) to obtain compound WX007-1. .sup.1H NMR (400 MHz, CHLOROFORM-d) ppm 7.50 (d, J=8.4 Hz, 1H), 7.38 (d, J=8.4 Hz, 1H), 3.20 (q, J=7.4 Hz, 2H), 1.53 (s, 9H), 1.33-1.29 (m, 3H).

[0354] Step 2: Synthesis of Compound WX007-2

[0355] Compound WX007-1 (0.84 g, 3.11 mmol) was dissolved in 20 mL of DCM, followed by addition of m-CPBA (3.79 g, 18.68 mmol), and the reaction mixture was stirred at 10 C. for 5 hours. After the reaction was completed, 40 mL of saturated sodium sulfite solution, 40 mL of saturated sodium bicarbonate solution and 30 mL of DCM were added. The mixed solution was extracted with DCM (30 mL3), and the obtained organic phases were combined and dried over anhydrous sodium sulfate. After the desiccant was removed by filtration, the filtrate was evaporated under reduced pressure to remove the solvent, and the obtained crude product was separated with a chromatography column (eluent: ethyl acetate/petroleum ether=0-25%) to obtain the target compound WX007-2. .sup.1H NMR (400 MHz, CHLOROFORM-d) ppm 7.83 (d, J=8.4 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H), 3.50 (q, J=7.4 Hz, 2H), 1.53 (s, 9H), 1.37 (t, J=7.4 Hz, 3H).

[0356] Step 3: Synthesis of Compound WX007-3

[0357] Compound WX007-2 (0.82 g, 2.72 mmol) was dissolved in 10 mL of ethanol, followed by addition of concentrated hydrochloric acid (12 M, 3 mL). The mixture was heated to 80 C. and reacted with stirring overnight. After the reaction was completed, the solvent was evaporated under reduced pressure, followed by addition of saturated sodium bicarbonate solution to obtain a pH of 9, and the mixture was extracted with ethyl acetate (30 mL3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was then separated with a chromatography column (eluent: ethyl acetate/petroleum ether=0-35%) to obtain the target compound WX007-3. .sup.1H NMR (400 MHz, CHLOROFORM-d) ppm 10.60 (s, 1H), 6.89-6.84 (m, 1H), 6.84-6.79 (m, 1H), 3.54 (q, J=7.4 Hz, 2H), 1.36 (t, J=7.4 Hz, 3H).

[0358] Step 4: Synthesis of Compound WX007

[0359] Compound BB-1 (93.13 mg, 678.86 mol) was dissolved in 5 mL of DCM, followed by addition of triphosgene (60.44 mg, 203.66 mol) and triethylamine (68.69 mg, 678.86 mol, 94.49 L). The reaction mixture was stirred at room temperature for 30 minutes, and then concentrated. The obtained crude product was dissolved in 5 mL of DCM, followed by addition of compound WX007-3 (0.08 g, 339.43 mol) and triethylamine (34.35 mg, 339.43 mol, 47.24 L), and the reaction mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was concentrated, and the obtained crude product was separated by high performance liquid chromatography to obtain the target compound WX007.

[0360] Step 5: Synthesis of Compounds WX007A and WX007B

[0361] Compound WX007 was resolved by supercritical fluid chromatography (separation conditions: column, column, AD (250 mm30 mm, 5 m); mobile phase, isopropanol (0.1% ammonium hydroxide)) to obtain the chiral isomers WX007A and WX007B with a retention time of 5.048 min and 5.605 min, respectively, and a ratio of 1:1.

[0362] According to the steps 1 to 5 in the synthesis of Embodiment 7, the embodiments in Table 2 were synthesized using different fragments in the step 1. The structures in the table also represent their potential isomers.

TABLE-US-00002 TABLE 2 Embodiment Fragment in the step 1 Structure Compound 8 [00127] [00128] WX008 WX008A WX008B [00129] [00130] 9 [00131] [00132] WX009 10 [00133] [00134] WX010 WX010A WX010B [00135] [00136] 11 [00137] [00138] WX011 WX011A WX011B [00139] [00140] 12 [00141] [00142] WX012 WX012A WX012B [00143] [00144]

Embodiment 13: WX013, WX013A, WX013B

[0363] ##STR00145##

[0364] Synthetic Route:

##STR00146## ##STR00147##

[0365] Step 1: Synthesis of Compound WX013-1

[0366] Compound BB-4 (0.58 g, 1.27 mmol) was dissolved in 10 mL of ethanol, followed by addition of concentrated hydrochloric acid (12 M, 1.5 mL). The mixture was heated to 80 C. and reacted with stirring overnight. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was adjusted to pH of 9 with saturated sodium bicarbonate solution, and extracted with ethyl acetate (30 mL3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was then separated with a chromatography column (eluent: methanol/dichloromethane=0-5%) to obtain compound WX013-1. .sup.1H NMR (400 MHz, METHANOL-d.sub.4) ppm 6.92-6.85 (m, 2H), 4.60 (br s, 2H), 3.89-3.79 (m, 1H), 3.27 (br s, 1H), 3.01 (br d, J=11.8 Hz, 1H), 2.91 (dd, J=10.6, 12.4 Hz, 1H), 2.65-2.55 (m, 1H), 2.11-2.03 (m, 1H), 1.90-1.80 (m, 2H), 1.55 (br d, J=14.6 Hz, 1H).

[0367] Step 2: Synthesis of Compound WX013-2

[0368] Compound WX013-1 (0.2 g, 687.84 mol) was dissolved in 3 mL of water, followed by addition of a solution of triethylamine (174.48 mg, 1.72 mmol, 240 L) and N-[2-(trimethylsilyl)ethoxycarbonyloxy]succinimide (0.17 g, 655.53 mol) in dioxane (3 mL), and the reaction mixture was stirred at room temperature overnight. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was diluted with 10 mL of water and extracted with ethyl acetate (10 mL3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was then separated with a chromatography column (eluent: ethyl acetate/petroleum ether=0-30%) to obtain the target compound WX013-2. .sup.1H NMR (400 MHz, CHLOROFORM-d) ppm 10.41 (s, 1H), 6.86-6.81 (m, 1H), 6.81-6.76 (m, 1H), 4.36 (br d, J=12.4 Hz, 1H), 4.10-4.06 (m, 1H), 4.00 (br s, 2H), 3.73-3.63 (m, 1H), 3.09 (br s, 1H), 2.81-2.71 (m, 1H), 2.13 (br d, J=12.8 Hz, 1H), 1.93-1.79 (m, 2H), 1.51-1.43 (m, 1H), 0.94 (t, J=8.4 Hz, 2H), 0.00 (s, 9H).

[0369] Step 3: Synthesis of Compound WX013-3.

[0370] Compound BB-5 (0.35 g, 2.55 mmol) was dissolved in 10 mL of DCM, followed by addition of triphosgene (0.23 g, 775.07 mol) and triethylamine (259.13 mg, 2.56 mmol, 356.44 L). The reaction mixture was stirred at room temperature for 30 minutes, and then concentrated. The obtained crude product was dissolved in 10 mL of DCM, followed by addition of compound WX013-2 (0.557 g, 1.28 mmol) and triethylamine (129.57 mg, 1.28 mmol, 178.22 L), and the reaction mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was concentrated, and the obtained crude product of WX013-3 was directly used in the next reaction.

[0371] Step 4: Synthesis of Compound WX013.

[0372] Compound WX013-3 (0.765 g, 1.28 mmol) was dissolved in 15 mL of THF, and the reaction system was purged with nitrogen three times, followed by addition of TBAF (1 M, 5 mL). The reaction mixture was stirred at 50 C. for 48 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and the residue was diluted with 20 mL of water and extracted with ethyl acetate (15 mL3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was then separated by high performance liquid chromatography to obtain compound WX013.

[0373] Step 5: Synthesis of Compounds WX013A and WX013B

[0374] The compound WX013 was resolved by supercritical fluid chromatography (separation conditions: column, AD (250 mm30 mm, 10 m); mobile phase, ethanol (0.1% ammonium hydroxide) C.) to obtain the chiral isomers WX013A and WX013B with a retention time of 3.126 min and 5.932 min, respectively, and a ratio of 1:1.

Embodiment 14: WX014

[0375] ##STR00148##

[0376] Synthetic Route:

##STR00149##

[0377] Step 1: Synthesis of Compound WX014-1

[0378] The crude product of compound BB-2 (5 g, 20.68 mmol) and potassium carbonate (2.86 g, 20.68 mmol) were dissolved in 100 mL of DMF, followed by addition of N-(2-bromoethyl)phthalimide (5.25 g, 20.68 mmol), and the reaction mixture was stirred at 80 C. for 18 hours. After the reaction was completed, the solvent was evaporated under reduced pressure. To the residue were added 50 mL of water and 50 mL of ethyl acetate, and the mixture was extracted with ethyl acetate (40 mL3). The obtained organic phases were combined, washed with water (20 mL3) and 30 mL of saturated brine sequentially, and dried over anhydrous sodium sulfate. After removing the desiccant by filtration, the filtrate was distilled under reduced pressure to remove the solvent, and the obtained crude product was separated with a chromatography column (eluent: ethyl acetate/petroleum ether=0-20%) to obtain the target compound WX014-1. .sup.1H NMR (400 MHz, CHLOROFORM-d) ppm 1.45 (s, 9H) 3.47 (t, J=6.6 Hz, 2H) 3.85 (t, J=6.6 Hz, 2H) 7.13 (d, J=8.4 Hz, 1H) 7.27 (d, J=8.4 Hz, 1H) 7.57-7.62 (m, 2H) 7.63-7.68 (m, 2H).

[0379] Step 2: Synthesis of Compound WX014-2

[0380] Compound WX014-1 (2 g, 4.82 mmol) was dissolved in 50 mL of DCM, followed by addition of m-CPBA (5.87 g, 28.92 mmol) in portions at 10 C., and the reaction mixture was stirred at 10 C. to 20 C. for 20 hours. After the reaction was completed, 40 mL of saturated sodium sulfite solution, 40 mL of saturated sodium bicarbonate solution and 50 mL of ethyl acetate were added, followed by extraction with ethyl acetate (30 mL3). The organic phases were combined, washed with saturated brine (30 mL2), and dried over anhydrous sodium sulfate. After the desiccant was removed by filtration, the filtrate was evaporated under reduced pressure to remove the solvent, and slurried with a mixed solvent (PE:EA=20:1) to obtain the target compound WX014-2. .sup.1H NMR (400 MHz, CHLOROFORM-d) ppm 1.57 (s, 9H) 4.00-4.12 (m, 2H) 4.17 (t, J=6.2 Hz, 2H) 7.26 (s, 1H) 7.59 (d, J=8.6 Hz, 1H) 7.70 (s, 4H).

[0381] Step 3: Synthesis of Compound WX014-3

[0382] Compound WX014-2 (2 g, 4.48 mmol) was dissolved in 10 mL of ethanol, followed by addition of concentrated hydrochloric acid (12 M, 10 mL). The mixture was heated to 80 C. and reacted with stirring overnight. After the reaction was completed, the solvent was evaporated under reduced pressure, and saturated sodium bicarbonate solution was added to the residue to adjust pH to 7, followed by extraction with ethyl acetate (20 mL3). The obtained organic phases were combined, washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was then separated with a chromatography column (eluent: ethyl acetate/petroleum ether=20/1 to 2/1) to obtain the target compound WX014-3. .sup.1H NMR (400 MHz, CHLOROFORM-d) ppm 4.05-4.09 (m, 2H) 4.11 (br d, J=6.8 Hz, 2H) 4.15 (d, J=7.2 Hz, 2H) 6.58 (d, J=8.4 Hz, 1H) 6.66-6.72 (m, 1H) 7.75-7.78 (m, 2H) 7.80-7.84 (m, 2H) 10.40 (s, 1H).

[0383] Step 4: Synthesis of Compound WX014

[0384] Compound BB-1 (111.31 mg, 811.44 mol) was dissolved in 5 mL of DCM, followed by addition of triphosgene (79.49 mg, 267.86 mol) and triethylamine (159.44 mg, 1.58 mmol, 219.31 L). The reaction mixture was stirred at room temperature for 30 minutes, and then concentrated. The obtained crude product was dissolved in 5 mL of DCM, followed by addition of compound WX014-3 (0.3 g, 787.81 mol) and triethylamine (79.72 mg, 787.81 mol, 109.65 L), and the reaction mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was concentrated, and the obtained crude product was separated by high performance liquid chromatography to obtain the target compound WX014. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 10.54 (br s, 1H), 8.03 (br s, 1H), 7.89 (br s, 1H), 7.74 (br d, J=9.2 Hz, 4H), 7.57 (br s, 1H), 7.41 (br d, J=7.0 Hz, 1H), 6.86 (br s, 1H), 6.35 (br s, 1H), 4.80 (br s, 1H), 4.20 (br s, 2H), 4.02 (br s, 2H), 3.17 (br s, 1H), 2.39 (br s, 1H), 1.94 (br s, 1H), 1.76 (br s, 3H).

Embodiment 15: WX015

[0385] ##STR00150##

[0386] Synthetic Route:

##STR00151##

[0387] Step 1: Synthesis of Compound WX015

[0388] Compound WX014 (0.428 g, 786.80 mol) was added to 5 mL of ethanol, followed by addition of hydrazine hydrate (2.06 g, 34.98 mmol, 2 mL), and the reaction mixture was stirred at 80 C. for half an hour. After the reaction was completed, the solvent was evaporated under reduced pressure, and the crude product was separated by high performance liquid chromatography to obtain the target product WX015. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.64-1.82 (m, 4H) 1.88 (br s, 1H), 2.41 (br s, 1H), 3.08 (br s, 2H), 3.64 (br t, J=5.8 Hz, 2H), 4.81 (br s, 1H), 6.08 (d, J=8.4 Hz, 1H), 6.30 (s, 1H), 7.37 (br d, J=8.4 Hz, 1H), 7.50 (s, 1H), 7.78 (d, J=8.4 Hz, 1H), 8.17 (s, 1H).

Embodiment 16: WX016, WX016A, WX016B

[0389] ##STR00152##

[0390] Synthetic Route:

##STR00153##

[0391] Step 1: Synthesis of Compound WX016

[0392] Compound WX015 (0.080 g, 193.30 mol) and cyclopropylformyl chloride (60.62 mg, 579.89 mol, 52.71 L) were added to 5 mL of DCM, followed by addition of triethylamine (58.68 mg, 579.89 mol, 80.71 L). The reaction mixture was stirred at room temperature overnight. After the reaction was completed, the solvent was evaporated under reduced pressure, and the obtained crude product was separated by high performance liquid chromatography to obtain the product WX016.

[0393] Step 2: Synthesis of Compounds WX016A and WX016B.

[0394] Compound WX016 was resolved by supercritical fluid chromatography (separation conditions: column, ChiralPak AD-3 1504.6 mm I.D., 3 m; mobile phase, A: carbon dioxide, B: ethanol (0.05% diethylamine); flow rate: 2.5 mL/min; column temperature: 40 C.; detection wavelength: 220 nm) to obtain the chiral isomers WX006A and WX006B with a retention time of 7.007 min and 7.668 min, respectively, and a ratio of 1:1.

Embodiment 17: WX017, WX017A, WX017B

[0395] ##STR00154##

##STR00155##

[0396] Step 1: Synthesis of Compound WX017

[0397] Compound WX015 (0.04 g, 96.65 mol) and methyl chloroformate (1.3 g, 13.76 mmol, 1.07 mL) were added to 2 mL of DCM, followed by addition of triethylamine (29.34 mg, 289.94 mol, 40.36 L). The reaction mixture was stirred at room temperature overnight. After the reaction was completed, the solvent was evaporated under reduced pressure, and the crude product was separated by high-performance liquid chromatography to obtain the product WX017.

[0398] Step 2: Synthesis of Compounds WX017A and WX017B.

[0399] Compound WX017 was resolved by supercritical fluid chromatography (separation conditions: column, ChiralPak AS-3 1504.6 mm I.D., 3 m; mobile phase, A: carbon dioxide, B: ethanol (0.05% diethylamine); flow rate: 2.5 mL/min; column temperature: 40 C.; detection wavelength: 220 nm) to obtain the chiral isomers WX017A and WX017B with a retention time of 4.776 min and 5.215 min, respectively, and a ratio of 1:1.

Embodiment 18: WX018, WX018A, WX018B

[0400] ##STR00156##

##STR00157## ##STR00158##

[0401] Step 1: Synthesis of Compound WX018-2

[0402] Compound WX018-1 (1.26 g, 12.72 mmol, 1 mL) was dissolved in 20 mL of DCM, followed by addition of triethylamine (1.45 g, 14.37 mmol, 2 mL) and chloroacetyl chloride (2.13 g, 18.86 mmol, 1.5 mL). The reaction mixture was stirred at 0 C. for 2 hours. After the reaction was completed, 50 mL of water was added to quench the reaction, and the mixture was diluted with 50 mL of DCM and extracted with DCM (50 mL3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound WX018-2. .sup.1H NMR (400 MHz, CHLOROFORM-d) ppm 6.83 (br s, 1H), 4.10-4.00 (m, 2H), 3.96-3.84 (m, 2H).

[0403] Step 2: Synthesis of Compound WX018-3

[0404] Compound BB-2 (2.47 g, 10.22 mmol) was dissolved in 50 mL of DMF, followed by addition of potassium carbonate (1.5 g, 10.85 mmol), potassium iodide (1 g, 6.02 mmol) and WX018-2 (1.84 g, 10.49 mmol). The reaction mixture was stirred at 80 C. for 2 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, followed by addition of 50 mL of water and extraction with ethyl acetate (40 mL3). The organic phases were combined, washed with saturated brine (50 mL2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was then separated with a chromatography column (eluent: ethyl acetate/petroleum ether=0-20%) to obtain compound WX018-3. .sup.1H NMR (400 MHz, CHLOROFORM-d) ppm 7.57 (d, J=8.4 Hz, 1H), 7.41 (d, J=8.4 Hz, 1H), 7.30 (br s, 1H), 3.94 (s, 2H), 3.86 (dq, J=6.8, 9.0 Hz, 2H), 1.52 (s, 9H).

[0405] Step 3: Synthesis of Compound WX018-4

[0406] Compound WX018-3 (0.788 g, 2.07 mmol) was dissolved in 20 mL of DCM, followed by addition of m-CPBA (2.52 g, 12.42 mmol) in portions, and the reaction mixture was stirred at 10 C. for 5 hours. After the reaction was completed, 20 mL of saturated sodium sulfite solution, 20 mL of saturated sodium bicarbonate solution and 20 mL of DCM were added, followed by extraction with DCM (20 mL3). The obtained organic phases were combined and dried over anhydrous sodium sulfate. After filtering to remove the desiccant, the filtrate was distilled under reduced pressure to remove the solvent, and the crude product was separated with a chromatography column (eluent: ethyl acetate/petroleum ether=0-30%) to obtain compound WX018-4. .sup.1H NMR (400 MHz, CHLOROFORM-d) ppm 7.89 (d, J=8.4 Hz, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.11 (br s, 1H), 4.51 (s, 2H), 3.92-3.83 (m, 2H), 1.54 (s, 9H).

[0407] Step 4: Synthesis of Compound WX018-5

[0408] Compound WX018-4 (0.61 g, 1.48 mmol) was dissolved in 10 mL of ethanol, followed by addition of concentrated hydrochloric acid (12 M, 5 mL). The mixture was heated to 80 C. and stirred with stirring overnight. After the reaction was completed, the solvent was evaporated under reduced pressure, followed by addition of 30 mL of saturated sodium bicarbonate solution and extraction with ethyl acetate (15 mL2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was then separated with a chromatography column (eluent: ethyl acetate/petroleum ether=0-50%) to obtain compound WX018-5. .sup.1H NMR (400 MHz, CHLOROFORM-d) ppm 10.29 (s, 1H), 6.92-6.87 (m, 1H), 6.85-6.81 (m, 1H), 4.51 (s, 2H), 4.19 (q, J=7.2 Hz, 2H), 1.20 (t, J=7.2 Hz, 3H).

[0409] Step 5: Synthesis of Compound WX018-6

[0410] Triphosgene (235.40 mg, 793.26 mol) was dissolved in 10 mL of DCM, followed by addition of compound BB-1 (326.46 mg, 2.38 mmol) and triethylamine (240.81 mg, 2.38 mmol, 331.24 L). The reaction mixture was stirred at room temperature for 30 minutes, and then concentrated. The obtained crude product was dissolved in 10 mL of DCM, followed by addition of compound WX018-5 (0.233 g, 793.26 mol) and triethylamine (80.27 mg, 793.26 mol, 110.41 L), and the mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was concentrated to obtain a crude product of compound WX018-6, which was directly used in the next reaction.

[0411] Step 6: Synthesis of Compound WX018-7

[0412] Compound WX018-6 (0.362 g, 792.30 mol) was dissolved in 5 mL of THF, 5 mL of ethanol and 1 mL of water, followed by addition of LiOH.H.sub.2O (166.24 mg, 3.96 mmol), and the reaction mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was concentrated, followed by addition of 20 mL of water and 30 mL of ethyl acetate for liquid separation. The aqueous phase was adjusted to pH of 2 with 2 N hydrochloric acid, and then extracted with ethyl acetate (30 mL3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product of compound WX018-7, which was directly used in the next reaction.

[0413] Step 7: Synthesis of Compound WX018

[0414] Compound WX018-7 (0.27 g, 629.60 mol) was dissolved in 5 mL of DMF, followed by addition of 2,2,2-trifluoroethylamine (74.84 mg, 755.52 mol, 59.40 L), HATU (0.36 g, 946.80 mol) and triethylamine (127.42 mg, 1.26 mmol, 175.27 L), and the reaction mixture was stirred at 40 C. overnight. After the reaction was completed, the solvent was evaporated under reduced pressure, followed by addition of 40 mL of water and extraction with ethyl acetate (30 mL2). The organic phases were combined, washed with saturated brine (30 mL2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude compound, which was then separated with a chromatography column (eluent: ethyl acetate/petroleum ether=0-50%) to obtain the target compound WX018.

[0415] Step 8: Synthesis of Compounds WX018A and WX018B.

[0416] Compound WX018 was resolved by supercritical fluid chromatography (separation conditions: column, DAICEL CHIRALPAK AS-H (250 mm30 mm, 5 m); mobile phase, ethanol (0.1% ammonium hydroxide)) to obtain the chiral isomers WX018A and WX018B, with a retention time of 4.070 min and 4.755 min, respectively, and a ratio of 1:1.

[0417] Table 3. NMR and MS Data of Each Embodiment

[0418] According to the steps 3 to 4 in the synthesis of Embodiment 1, the embodiment in Table 3 was synthesized using BB-7 in the step 3. The structures in the table also represent their potential isomers.

TABLE-US-00003 TABLE 3 Embodiment Fragment in the step 2 Structure Compound 19 [00159] [00160] WX019

[0419] WX019 .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.54 (s, 1H), 8.22 (d, J=8.8 Hz, 1H), 7.58 (br d, J=8.4 Hz, 1H), 7.29-7.24 (m, 1H), 7.20-7.15 (m, 2H), 7.14-7.08 (m, 2H), 4.91-4.81 (m, 1H), 4.18 (br t, J=11.6 Hz, 1H), 3.24 (br d, J=12.4 Hz, 1H), 3.11 (br t, J=12.0 Hz, 1H), 2.94-2.70 (m, 6H), 2.04-1.66 (m, 10H)

[0420] [M+H].sup.+: 464.0

[0421] According to the steps 1 to 4 in the synthesis of Embodiment 5, the embodiments in Table 4 were synthesized using benzyl bromide in the step 1. The structures in the table also represent their potential isomers.

TABLE-US-00004 TABLE 4 Embodiment Fragment in the step 1 Structure Compound 20 [00161] [00162] WX020 WX020A WX020B [00163] [00164]

[0422] Compound WX020 was resolved by supercritical fluid chromatography (separation conditions: column, DAICEL CHIRALPAK AY 250 mm30 mm, 20 m; mobile phase, A: carbon dioxide, B: ethanol (0.1% ammonium hydroxide); gradient, B %: 50%-50%) to obtain the chiral isomers WX020A and WX020B with a retention time of 2.214 min, 4.890 min, respectively, and a ratio of 1:1.

[0423] Analytical conditions: column: Lux Cellulose-2 1504.6 mm I.D., 3 m; mobile phase, A: carbon dioxide, B: ethanol (0.05% diethylamine); gradient, 40% of B; flow rate: 2.5 mL/min; column temperature: 40 C.; detection wavelength: 220 nm.

[0424] WX020A .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 10.41 (br s, 1H), 8.43 (br d, J=8.4 Hz, 1H), 8.19 (s, 1H), 7.54-7.45 (m, 2H), 7.36-7.22 (m, 5H), 7.15 (br s, 1H), 6.32 (d, J=1.6 Hz, 1H), 4.82 (br d, J=7.6 Hz, 1H), 3.06 (s, 2H), 2.47-2.41 (m, 1H), 2.37 (br d, J=6.8 Hz, 1H), 1.91 (m, 1H), 1.79-1.67 (m, 3H), 1.22 (s, 6H)

[0425] [M+H].sup.+: 503.1

[0426] WX020B .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 10.40 (br s, 1H), 8.44 (br d, J=8.8 Hz, 1H), 8.19 (s, 1H), 7.54-7.44 (m, 2H), 7.36-7.23 (m, 5H), 7.17 (br d, J=8.8 Hz, 1H), 6.32 (d, J=1.6 Hz, 1H), 4.88-4.78 (m, 1H), 3.06 (s, 2H), 2.43 (br s, 1H), 2.39-2.30 (m, 1H), 1.98-1.87 (m, 1H), 1.79-1.66 (m, 3H), 1.22 (s, 6H)

[0427] [M+H].sup.+: 503.1

Embodiment 21: WX021, WX021A, WX021B

[0428] ##STR00165##

[0429] Synthetic Route:

##STR00166## ##STR00167##

[0430] Step 1: Synthesis of Compound WX021-1

[0431] According to the steps 1 to 2 in the synthesis of BB-4, the target compound WX021-1 was synthesized using BB-8 in the step 1. .sup.1H NMR (400 MHz, CHLOROFORM-d) ppm 7.83 (d, J=8.4 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H), 4.26-4.18 (m, 1H), 4.03 (s, 2H), 3.94 (s, 2H), 2.82 (m, 2H), 2.51 (m, 2H), 1.55 (s, 9H), 1.45 (s, 9H).

[0432] Step 2: Synthesis of Compound WX021-2

[0433] Compound WX021-1 (0.29 g, 0.62 mmol) was dissolved in 5 mL of ethanol, followed by addition of 5 mL of hydrochloric acid (12 M). The reaction mixture was stirred at 85 C. for 14 hours. The reaction mixture was concentrated to dryness under reduced pressure, and dissolved in 5 mL of dichloromethane, followed by addition of 5 mL of saturated aqueous sodium bicarbonate solution and FmocCl (0.141 g, 0.55 mmol). The reaction mixture was stirred at 0 C. for 15 minutes. After the reaction was completed, the reaction mixture was diluted by adding 10 mL of dichloromethane, followed by liquid separation, and the organic phase was retained. The aqueous phase was extracted with dichloromethane (20 mL3).

[0434] The organic phases were combined, washed with saturated brine (15 mL2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was then separated with a chromatography column (eluent: ethyl acetate/petroleum ether=0-40%) to obtain compound WX021-2. .sup.1H NMR (400 MHz, CHLOROFORM-d) ppm 10.47 (s, 1H), 7.70 (d, J=7.6 Hz, 2H), 7.50 (d, J=7.6 Hz, 2H), 7.36-7.30 (m, 2H), 7.28-7.22 (m, 2H), 6.81-6.76 (m, 1H), 6.75-6.70 (m, 1H), 4.35-4.25 (m, 3H), 4.16-4.10 (m, 1H), 3.99 (s, 2H), 3.94 (s, 2H), 2.68 (m, 2H), 2.53-2.41 (m, 2H).

[0435] Step 3: Synthesis of Compound WX021-3

[0436] Triphosgene (93.83 mg, 316.18 mol) was dissolved in 5 mL of dichloromethane, followed by addition of compound BB-1 (130.12 mg, 948.54 mol) and triethylamine (72.70 mg, 718.45 mol, 0.1 mL). The reaction mixture was stirred at room temperature (18 C.) for 30 minutes, and then concentrated. The obtained crude product was dissolved in 5 mL of dichloromethane, followed by addition of compound WX021-2 (166 mg, 316.18 mol) and triethylamine (145.40 mg, 1.44 mmol, 0.2 mL), and the mixture was stirred at room temperature (18 C.) for 3.5 hours. After completion of the reaction, the reaction mixture was directly concentrated to dryness to obtain a crude product. The crude product of WX021-3 was directly used in the next reaction.

[0437] Step 4: Synthesis of Compound WX021

[0438] Compound WX021-3 (0.2 g, 290.62 mol) was dissolved in 10 mL of dichloromethane, followed by addition of diethylamine (7.10 g, 97.08 mmol), and the reaction mixture was stirred at 15 C. for 1 hour. After the reaction was completed, the reaction mixture was directly concentrated to dryness to obtain a crude product. The crude product was separated by high performance liquid chromatography to obtain the target compound WX021.

[0439] Step 5: Synthesis of Compounds WX021A and WX021B

[0440] Compound WX021 was resolved by supercritical fluid chromatography (separation conditions: column, DAICEL CHIRALPAK IC 250 mm30 mm, 10 m; mobile phase, A: carbon dioxide, B: isopropanol (0.1% ammonium hydroxide); gradient, B %: 50%-50%) to obtain the chiral isomers WX021A and WX021B with a retention time of 7.251 min and 10.541 min, respectively, and a ratio of 1:1.

[0441] Analytical conditions: Column: ChiralPak IC-3 1504.6 mm I.D., 3 um; mobile phase, A: carbon dioxide, B: isopropanol (0.1% ethanolamine); gradient, B %: 40%; flow rate: 2.5 mL/min; column temperature: 40 C.; detection wavelength: 220 nm.

[0442] WX021A .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.47 (br s, 1H), 8.18 (s, 1H), 7.72 (br s, 1H), 7.49 (d, J=1.6 Hz, 1H), 7.36 (br d, J=8.4 Hz, 1H), 6.30 (d, J=1.6 Hz, 1H), 6.05 (br s, 1H), 4.80 (br d, J=4.1 Hz, 1H), 4.75-4.61 (m, 1H), 3.93 (br d, J=6.4 Hz, 4H), 2.44 (br d, J=5.6 Hz, 2H), 1.93-1.84 (m, 1H), 1.80-1.66 (m, 3H), 1.51 (br s, 2H), 0.87-0.83 (m, 2H)

[0443] [M+H].sup.+: 466.0

[0444] WX021B .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.48 (br s, 1H), 8.18 (s, 1H), 7.75 (br s, 1H), 7.50 (d, J=1.6 Hz, 1H), 7.37 (br d, J=8.0 Hz, 1H), 6.30 (d, J=1.6 Hz, 1H), 4.81 (br s, 1H), 4.73-4.63 (m, 1H), 3.97-3.90 (m, 4H), 2.44 (br s, 2H), 1.89 (br d, J=4.8 Hz, 1H), 1.77-1.67 (m, 3H), 1.51 (br s, 2H), 0.87-0.84 (m, 2H)

[0445] [M+H].sup.+: 466.0

[0446] According to the steps 1 to 4 in the synthesis of Embodiment 21, the embodiments in Table 5 were synthesized using different fragments in the step 1. The structures in the table also represent their potential isomers.

TABLE-US-00005 TABLE 5 Embodiment Fragment in the step 1 Structure Compound 22 [00168] [00169] WX022 WX022A WX022B [00170] [00171] 23 [00172] [00173] WX023 WX023A WX023B [00174] [00175]

[0447] Compound WX022 was resolved by supercritical fluid chromatography (separation conditions: column, DAICEL CHIRALPAK AD 250 mm30 mm, 10 m; mobile phase, A: carbon dioxide, B: isopropanol (0.1% ammonium hydroxide); gradient, B %: 40%-40%) to obtain the chiral isomers WX022A and WX022B with a retention time of 6.755 min and 8.006 min, respectively, and a ratio of 1:1.

[0448] Analytical conditions: column: ChiralPak AD-3 1504.6 mm I.D., 3 um; mobile phase, A: carbon dioxide, B: isopropanol (0.1% ethanolamine); gradient, mobile phase B from 5% to 40% within 5.5 minutes, then 40% for 3 min, then 5% for 1.5 minutes; flow rate: 2.5 mL/min; column temperature: 40 C.; detection wavelength: 220 nm.

[0449] WX022A .sup.1H NMR (400 MHz, METHANOL-d.sub.4) ppm 7.94 (d, J=8.4 Hz, 1H), 7.37 (d, J=1.6 Hz, 1H), 6.52 (br d, J=7.6 Hz, 1H), 6.26 (d, J=1.6 Hz, 1H), 4.81-4.69 (m, 1H), 4.63 (s, 1H), 3.13-3.02 (m, 4H), 2.57-2.49 (m, 1H), 2.47-2.40 (m, 1H), 2.39-2.30 (m, 2H), 2.13 (br t, J=10.0 Hz, 2H), 2.01 (br s, 1H), 1.93-1.89 (m, 1H), 1.84-1.77 (m, 2H), 1.37-1.33 (m, 3H), 1.12 (br s, 1H)

[0450] [M+H].sup.+: 494.0

[0451] WX022B .sup.1H NMR (400 MHz, METHANOL-d.sub.4) ppm 7.94 (br d, J=8.8 Hz, 1H), 7.37 (s, 1H), 6.53 (br s, 1H), 6.26 (s, 1H), 4.75 (s, 1H), 3.06 (br s, 4H), 2.51 (s, 1H), 2.44 (br d, J=7.6 Hz, 1H), 2.35 (br s, 2H), 2.12 (br s, 2H), 2.01 (br s, 1H), 1.94-1.90 (m, 1H), 1.84-1.77 (m, 2H), 1.39-1.35 (m, 2H), 1.14 (br s, 2H)

[0452] [M+H].sup.+: 494.0

[0453] Compound WX023 was resolved by supercritical fluid chromatography (separation conditions: column, DAICEL CHIRALPAK AS-H 250 mm30 mm, 5 m; mobile phase, A: carbon dioxide, B: isopropanol (0.1% ammonium hydroxide); gradient, B %: 50%-50%) to obtain the chiral isomers WX023A and WX023B with a retention time of 2.129 min and 3.461 min, respectively, and a ratio of 1:1.

[0454] Analytical conditions: column: ChiralPak AS-3 1504.6 mm I.D., 3 um; mobile phase, A: carbon dioxide, B: isopropanol (0.05% diethylamine); gradient, mobile phase B was 40%; flow rate: 2.5 mL/min; column temperature: 40 C.; detection wavelength: 220 nm

[0455] WX023A .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.40 (br s, 1H), 8.13 (s, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.51-7.47 (m, 1H), 7.37 (br d, J=8.4 Hz, 1H), 6.30 (d, J=1.6 Hz, 1H), 5.99 (d, J=8.4 Hz, 1H), 4.81 (br d, J=4.4 Hz, 1H), 4.35 (br s, 1H), 2.84 (br t, J=10.8 Hz, 2H), 2.47-2.29 (m, 3H), 1.96-1.66 (m, 9H).

[0456] [M+H].sup.+: 453.9

[0457] WX023B .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.50 (br s, 1H), 8.14 (s, 1H), 7.78 (br d, J=8.4 Hz, 1H), 7.50 (d, J=1.6 Hz, 1H), 7.38 (d, J=8.4 Hz, 1H), 6.30 (d, J=1.6 Hz, 1H), 6.09 (br s, 1H), 4.82 (br s, 1H), 4.33 (br s, 1H), 2.92-2.82 (m, 2H), 2.46-2.38 (m, 1H), 2.48-2.29 (m, 2H), 2.00-1.62 (m, 9H).

[0458] [M+H].sup.+: 453.9

Embodiment 24: WX024, WX024A, WX024B

[0459] ##STR00176##

[0460] Synthetic Route:

##STR00177## ##STR00178##

[0461] Step 1: Synthesis of Compound WX024-1

[0462] According to the step 2 in the synthesis of Embodiment 21, the target compound WX024-1 was synthesized.

[0463] Step 2: Synthesis of Compound WX024-2

[0464] According to the step 5 in the synthesis of Embodiment 6, the target compound WX024-1 was synthesized using BB-11.

[0465] Step 3: Synthesis of Compound WX024

[0466] According to the step 4 in the synthesis of Embodiment 21, the target compound WX024 was synthesized.

[0467] Step 4: Synthesis of Compounds WX024A and WX024B

[0468] Compound WX024 was resolved by supercritical fluid chromatography (separation conditions: column, DAICEL CHIRALCEL OD-H 250 mm30 mm, 5 m; mobile phase, A: carbon dioxide, B: ethanol (0.1% ammonium hydroxide); gradient, B %: 45%-45%) to obtain the chiral isomers WX024A and WX024B with a retention time of 4.376 min and 4.794 min, respectively, and a ratio of 1:1.

[0469] Analytical conditions: column: Chiralcel OD-3 1504.6 mm I.D., 3 um; mobile phase, A: carbon dioxide, B: ethanol (0.1% ethanolamine); gradient, mobile phase B from 5% to 40% within 4.5 minutes, then maintained at 40% for 2.5 minutes, then maintained at 5% for 1 minute; flow rate: 2.8 mL/min; column temperature: 40 C.; detection wavelength: 220 nm

[0470] WX024A .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 7.88-7.75 (m, 2H), 7.39 (br d, J=8.4 Hz, 1H), 7.22 (d, J=5.2 Hz, 1H), 6.85 (d, J=5.2 Hz, 1H), 6.16 (br d, J=8.4 Hz, 1H), 4.75 (br s, 1H), 4.48 (br s, 1H), 3.12-2.98 (m, 2H), 2.78 (br d, J=13.2 Hz, 2H), 2.74-2.66 (m, 2H), 1.88 (br s, 2H), 1.78 (br s, 4H), 1.73-1.67 (m, 1H), 1.64-1.55 (m, 1H)

[0471] [M+H].sup.+: 470.0

[0472] WX024B .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.01 (br s, 1H), 7.82-7.72 (m, 1H), 7.41-7.28 (m, 1H), 7.22 (br d, J=5.2 Hz, 1H), 6.86 (br d, J=5.2 Hz, 1H), 6.07 (br d, J=8.0 Hz, 1H), 4.75 (br s, 1H), 4.40 (br s, 1H), 3.08-2.86 (m, 2H), 2.69 (br d, J=11.2 Hz, 4H), 1.90 (br d, J=8.4 Hz, 2H), 1.84-1.71 (m, 4H), 1.63 (br s, 2H)

[0473] [M+H].sup.+: 470.0

[0474] According to the steps 5 to 6 in the synthesis of Embodiment 6, the embodiments in Table 6 were synthesized using different fragments in the step 5. The structures in the table also represent their potential isomers.

TABLE-US-00006 TABLE 6 Embodiment Fragment in the step 1 Structure Compound 25 [00179] [00180] WX025 WX025A WX025B [00181] [00182] 26 [00183] [00184] WX026 WX026A WX026B [00185] [00186] 27 [00187] [00188] WX027 WX027A WX027B [00189] [00190] 28 [00191] [00192] WX028

[0475] Compound WX025 was resolved by supercritical fluid chromatography (separation conditions: column, DAICEL CHIRALCEL OJ-H 250 mm30 mm, 5 m; mobile phase, A: carbon dioxide, B: ethanol (0.1% ammonium hydroxide); gradient, B %: 40%-40%) to obtain the chiral isomers WX025A and WX025B with a retention time of 3.994 min and 4.753 min, respectively, and a ratio of 1:1.

[0476] Analytical conditions: column: Chiralcel OJ-3 1004.6 mm I.D., 3 um; mobile phase, A: carbon dioxide, B: ethanol (0.05% diethylamine); gradient, mobile phase B from 5% to 40 within 4.5 minutes, then maintained at 40% for 2.5 minutes, then maintained at 5% for 1 minute; flow rate: 2.8 mL/min; column temperature: 40 C.; detection wavelength: 220 nm

[0477] WX025A .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.26-8.17 (m, 2H), 7.40 (d, J=8.4 Hz, 1H), 7.27 (d, J=5.2 Hz, 1H), 6.90 (d, J=5.2 Hz, 2H), 4.82-4.74 (m, 1H), 3.47 (br s, 1H), 2.84-2.64 (m, 2H), 1.98-1.78 (m, 3H), 1.73-1.62 (m, 1H), 1.18 (br d, J=3.6 Hz, 2H), 1.15-1.05 (m, 2H)

[0478] [M+H].sup.+: 427.0

[0479] WX025B .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.28-8.16 (m, 2H), 7.40 (br d, J=8.0 Hz, 1H), 7.27 (d, J=5.4 Hz, 1H), 6.90 (d, J=5.2 Hz, 2H), 4.78 (br d, J=5.6 Hz, 1H), 3.46 (br d, J=4.4 Hz, 1H), 2.85-2.61 (m, 2H), 1.98-1.76 (m, 3H), 1.75-1.61 (m, 1H), 1.21-1.07 (m, 4H)

[0480] [M+H].sup.+: 427.0

[0481] Compound WX026 was resolved by supercritical fluid chromatography (separation conditions: column, DAICEL CHIRALCEL OD 250 mm30 mm, 10 m; mobile phase, A: carbon dioxide, B: methanol (0.1% ammonium hydroxide); gradient, B %: 35%-35%) to obtain the chiral isomers WX026A and WX026B with a retention time of 3.351 min and 4.422 min, respectively, and a ratio of 1:1.

[0482] Analytical conditions: column: Chiralcel OD-3 1004.6 mm I.D., 3 um; mobile phase, A: carbon dioxide, B: methanol (0.05% diethylamine); gradient, mobile phase B from 5% to 40% within 4.5 minutes, then maintained at 40% for 2.5 minutes, then maintained at 5% for 1 minute; flow rate: 2.8 mL/min; column temperature: 40 C.; detection wavelength: 220 nm

[0483] WX026A .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.38 (d, J=3.6 Hz, 1H), 8.30 (d, J=8.8 Hz, 1H), 8.22 (s, 1H), 7.65 (d, J=7.6 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.21 (m, 1H), 7.06 (br d, J=8.8 Hz, 1H), 4.95-4.86 (m, 1H), 2.93-2.81 (m, 2H), 2.01-1.81 (m, 4H), 1.78-1.69 (m, 1H), 1.22 (br d, J=4.4 Hz, 2H), 1.16 (br d, J=7.6 Hz, 2H)

[0484] [M+H].sup.+: 422.0

[0485] WX026B .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.38 (br d, J=3.6 Hz, 1H), 8.30 (br d, J=8.8 Hz, 1H), 8.22 (s, 1H), 7.65 (br d, J=7.6 Hz, 1H), 7.50 (br d, J=8.4 Hz, 1H), 7.21 (dd, J=4.8, 7.6 Hz, 1H), 7.05 (br d, J=8.8 Hz, 1H), 4.95-4.86 (m, 1H), 2.93-2.79 (m, 2H), 2.04-1.79 (m, 4H), 1.78-1.68 (m, 1H), 1.22 (br d, J=4.0 Hz, 2H), 1.16 (br d, J=7.6 Hz, 2H)

[0486] [M+H].sup.+: 422.0

[0487] Compound WX027 was resolved by supercritical fluid chromatography (separation conditions: column, DAICEL CHIRALCEL OD-H 250 mm30 mm, 5 m; mobile phase, A: carbon dioxide, B: methanol (0.1% ammonium hydroxide); gradient, B %: 40%-40%) to obtain the chiral isomers WX027A and WX027B with a retention time of 2.212 min and 3.034 min, respectively, and a ratio of 1:1.

[0488] Analytical conditions: Column: Chiralcel OD-3 1504.6 mm I.D., 3 um; mobile phase, A: carbon dioxide, B: methanol (0.05% diethylamine); gradient, 40% mobile phase B; flow rate: 2.5 mL/min; column temperature: 35 C.; detection wavelength: 220 nm

[0489] WX027A .sup.1H NMR (400 MHz, METHANOL-d.sub.4) ppm 8.30 (d, J=8.8 Hz, 1H), 7.22 (d, J=5.2 Hz, 1H), 7.07 (br d, J=8.8 Hz, 1H), 6.76 (d, J=5.2 Hz, 1H), 5.08-5.00 (m, 1H), 4.62 (s, 2H), 3.37-3.32 (m, 1H), 2.74-2.56 (m, 2H), 2.17-2.06 (m, 1H), 1.98-1.79 (m, 3H), 1.36-1.30 (m, 2H), 1.18 (br d, J=5.6 Hz, 2H)

[0490] [M+H].sup.+: 427.0

[0491] WX027B .sup.1H NMR (400 MHz, METHANOL-d.sub.4) ppm 8.31 (d, J=8.8 Hz, 1H), 7.22 (d, J=5.2 Hz, 1H), 7.09 (d, J=8.8 Hz, 1H), 6.76 (d, J=5.2 Hz, 1H), 5.08-5.00 (m, 1H), 4.62 (br s, 2H), 3.35-3.32 (m, 1H), 2.73-2.57 (m, 2H), 2.11 (dt, J=5.2, 9.3 Hz, 1H), 1.99-1.78 (m, 3H), 1.38-1.30 (m, 2H), 1.19 (m, 2H)

[0492] [M+H].sup.+: 427.0

[0493] WX028 .sup.1H NMR (400 MHz, METHANOL-d.sub.4) ppm 8.86 (s, 1H), 8.29 (d, J=8.8 Hz, 1H), 7.07 (br d, J=8.8 Hz, 1H), 5.11 (m, 1H), 4.61 (s, 3H), 2.87-2.78 (m, 2H), 2.23-1.79 (m, 5H), 1.32 (br s, 2H), 1.18 (br d, J=5.6 Hz, 2H)

[0494] [M+H].sup.+: 428.0

Embodiment 29: WX029, WX029A, WX029B

[0495] ##STR00193##

[0496] Synthetic Route:

##STR00194## ##STR00195##

[0497] Step 1: Synthesis of Compound WX029-1

[0498] Compound BB-18 (750 mg, 1.46 mmol) was dissolved in dichloromethane (60 mL), followed by addition of triethylamine (369.84 mg, 3.65 mmol) and the intermediate compound BB-15 (1.62 g, 5.12 mmol). The mixture was stirred at 40 C. for 16 hours. After completion of the reaction, the reaction mixture was diluted with dichloromethane (100 mL) and washed with water (100 mL). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure to obtain a crude product, which was then separated and purified with a flash preparative chromatography (eluent: ethyl acetate/petroleum ether=0-30%) to obtain compound WX029-1.

[0499] Step 2: Synthesis of Compound WX029

[0500] Compound WX029-1 (40 mg, 57.95 mol) was dissolved in dichloromethane (5 mL), followed by addition of diethylamine (355.00 mg, 4.85 mmol, 0.5 mL), and the reaction mixture was stirred at 25 C. for 1 hour. After the reaction was completed, the reaction mixture was diluted with 20 mL of dichloromethane, washed with 20 mL of water and 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by high performance liquid chromatography (neutral condition) to obtain WX029. .sup.1H NMR (400 MHz, METHANOL-d.sub.4) ppm 8.07-7.96 (m, 1H), 6.63 (br d, J=8.4 Hz, 1H), 5.81 (s, 1H), 4.15 (br s, 1H), 3.47 (m, 1H), 3.16-3.07 (m, 2H), 2.85-2.73 (m, 1H), 2.48-2.32 (m, 2H), 2.21 (s, 3H), 2.04 (m, 1H), 1.99-1.63 (m, 8H)

[0501] Step 3: Synthesis of Compounds WX029A and WX029B

[0502] Compound WX029 (58 mg, 123.94 mol) was resolved by supercritical fluid chromatography (separation conditions: column, DAICEL CHIRALPAK AD-H 250 mm30 mm, 5 m; mobile phase, A: carbon dioxide, B: ethanol (0.1% ammonium hydroxide); gradient, B %: 40%-40%) to obtain the chiral isomers WX029A and WX029B with a retention time of 5.922 min and 7.134 min, respectively, and a ratio of 1:1.

Embodiment 30: WX030, WX030A, WX030B

[0503] ##STR00196##

##STR00197## ##STR00198##

[0504] Step 1: Synthesis of Compound WX030-1

[0505] According to the synthesis method for WX029-1 in Embodiment 29, the target compound WX030-1 was synthesized.

[0506] Step 2: Synthesis of Compound WX030

[0507] According to the synthesis method for WX029 in Embodiment 29, the target compound WX030 was synthesized using WX030-1. .sup.1H NMR (400 MHz, METHANOL-d.sub.4) ppm 7.99-7.93 (m, 1H), 6.79 (s, 1H), 6.60-6.56 (m, 1H), 4.96 (s, 1H), 4.27 (br s, 1H), 3.58-3.54 (m, 1H), 3.16-3.08 (m, 2H), 2.82-2.79 (m, 1H), 2.54-2.46 (m, 2H), 2.03 (br s, 2H), 1.94-1.85 (m, 6H)

[0508] [M+H].sup.+:522.1

[0509] Step 3: Synthesis of Compounds WX030A and WX030B

[0510] Compound WX029 (70 mg, 134.12 mol) was resolved by supercritical fluid chromatography (separation conditions: column, DAICEL CHIRALPAK AS-H 250 mm30 mm, 5 m; mobile phase, A: carbon dioxide, B: ethanol (0.1% ammonium hydroxide); gradient, B %: 30%-30%) to obtain the chiral isomers WX030A and WX030B with a retention time of 3.548 min and 3.847 min, respectively, and a ratio of 1:1.

Embodiment 31: WX031

[0511] ##STR00199##

[0512] Synthetic Route:

##STR00200##

[0513] Step 1: Synthesis of Compound WX031-1

[0514] Compound WX006-4 (50 mg, 201.86 mol) was dissolved in dichloromethane (5 mL), followed by addition of triethylamine (51.07 mg, 504.65 mol) and p-nitrophenyl chloroformate (48.82 mg, 242.23 mol) at 0 C. The reaction mixture was stirred at 25 C. for 2 hours. After the reaction was completed, the reaction mixture was directly concentrated to dryness to obtain a crude product of compound WX031-1, which was directly used in the next step.

[0515] Step 2: Synthesis of Compound WX031

[0516] Compound WX031-1 (80 mg, 193.80 mol) was dissolved in tetrahydrofuran (10 mL), followed by addition of triethylamine (39.22 mg, 387.60 mol) and compound BB-19 (43.08 mg, 290.70 mol). The reaction mixture was heated to 60 C. and stirred for 14 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain a crude product. The crude product was separated by high performance liquid chromatography (neutral condition) to obtain WX031.

Embodiment 32: WX032

[0517] ##STR00201##

##STR00202##

[0518] Step 1: Synthesis of Compound WX032

[0519] Compound WX006-4 (100 mg, 403.72 mol) was dissolved in dichloromethane (10 mL), followed by addition of triethylamine (122.56 mg, 1.21 mmol) and the intermediate compound BB-16 (194.33 mg, 524.83 mol). The mixture was stirred at 5-20 C. for 16 hours. After the reaction was completed, the reaction mixture was diluted with dichloromethane (40 mL) and washed with water (50 mL). The organic phase was washed with saturated brine (50 mL2), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was separated and purified with a thin layer chromatography plate (eluent: dichloromethane/methanol=20:1) to obtain compound WX032. The structure also represents its potential isomers.

[0520] According to the step 1 in the synthesis of Embodiment 32, the embodiment in Table 7 was synthesized using BB-15 in the step 1. The structure in the table also represents its potential isomers.

TABLE-US-00007 TABLE 7 Embodiment Fragment in the step 1 Structure Compound 33 [00203] [00204] WX033

[0521] According to the step 1 in the synthesis of Embodiment 32, the embodiments in Table 8 were synthesized using WX002-1 in the step 1. The structures in the table also represent their potential isomers.

TABLE-US-00008 TABLE 8 Embodiment Fragment in the step 1 Structure Compound 34 [00205] [00206] WX034 35 [00207] WX035

Embodiment 36: WX036

[0522] ##STR00208##

[0523] Synthetic Route:

##STR00209##

[0524] Step 1: Synthesis of Compound WX036-1

[0525] According to the step 5 in the synthesis of fragment BB-15, the intermediate compound WX036-1 was synthesized using fragment BB-1.

[0526] Step 2: Synthesis of Compound WX036-2

[0527] Compound BB-27 (130 mg, 240.27 mol) was dissolved in dichloromethane (10 mL), followed by addition of triethylamine (72.94 mg, 720.81 mol) and the intermediate compound WX036-1 (145.26 mg, 480.54 mol). The mixture was stirred at 20 C. for 15 hours. After the reaction was completed, the reaction mixture was diluted with dichloromethane (50 mL) and washed with water (50 mL). The organic phase was washed with saturated brine (50 mL2), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was separated and purified with thin-layer chromatography plates twice (eluent: dichloromethane/methanol=20:1 and petroleum ether/ethyl acetate=2:1) to obtain compound WX036-2.

[0528] Step 2: Synthesis of Compound WX036

[0529] Compound WX036-2 (86 mg, 122.12 mol) was dissolved in dichloromethane (4 mL), followed by addition of diethylamine (446.59 mg, 6.11 mmol), and the reaction mixture was stirred at 20 C. for 12 hours. After the reaction was completed, the reaction mixture was diluted with dichloromethane (20 mL) and washed with water (20 mL). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was separated by high performance liquid chromatography (neutral condition) to obtain WX036. The structure also represents its potential isomers.

[0530] According to the steps 2 to 3 in the synthesis of Embodiment 36, Embodiment 37 in Table 9 was synthesized using BB-16 in the step 2. The structure in the table also represents its potential isomers.

TABLE-US-00009 TABLE 9 Embodiment Fragment in the step 2 Structure Compound 37 [00210] [00211] WX037

Embodiment 38: WX038

[0531] ##STR00212##

[0532] Synthetic Route:

##STR00213## ##STR00214##

[0533] Step 1: Synthesis of Compound WX038-1

[0534] According to the step 1 in the synthesis of fragment BB-4, the target compound WX038-1 was synthesized using BB-24 and BB-2. .sup.1H NMR (400 MHz, CHLOROFORM-d) ppm (br d, J=8.4 Hz, 1H), 7.40 (br d, J=8.4 Hz, 1H), 4.01-3.78 (m, 2H), 3.77-3.58 (m, 2H), 3.44-3.30 (m, 1H), 3.27-3.03 (m, 2H), 3.01-2.87 (m, 1H), 1.61 (br s, 1H), 1.57-1.40 (m, 18H), 1.34 (s, 5H), 1.24 (m, 4H).

[0535] Step 2: Synthesis of Compound WX038-2

[0536] According to the step 2 in the synthesis of fragment BB-4, the target compound WX038-2 was synthesized using WX038-1. .sup.1H NMR (400 MHz, CHLOROFORM-d) ppm 7.82 (m, 1H), 7.53-7.44 (m, 1H), 4.18 (m, 1H), 4.07-3.88 (m, 2H), 3.82 (m, 2H), 3.61 (m, 1H), 3.40-3.22 (m, 1H), 3.20-2.98 (m, 1H), 1.61-1.60 (m, 1H), 1.53 (s, 9H), 1.50-1.33 (m, 18H).

[0537] Step 3: Synthesis of Compound WX038-3

[0538] Compound WX038-2 (0.85 g, 1.49 mmol) was added to a mixed solvent of dichloromethane (9 mL) and trifluoroacetic acid (3 mL), and the mixture was stirred at 25 C. for 1 hour. After completion of the reaction as indicated by liquid chromatography, the reaction mixture was rotary-evaporated to dryness to obtain a crude product of WX038-3, which was directly used in the next step.

[0539] Step 4: Synthesis of Compound WX038-4

[0540] Compound WX038-3 (0.55 g, 1.48 mmol) was dissolved in dichloromethane (20 mL), and saturated aqueous NaHCO.sub.3 solution was added to obtain pH>7, followed by the addition of 9-fluorenylmethyl chloroformate (0.77 g, 2.97 mmol). The mixture was stirred at 25 C. for 1 hour. After completion of the reaction as indicated by thin layer chromatography and liquid chromatography, the reaction mixture was extracted with dichloromethane (10 mL3) at 25 C. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=3:1) to obtain compound WX038-4. .sup.1H NMR (400 MHz, CHLOROFORM-d) ppm 7.89-7.66 (m, 5H), 7.60-7.44 (m, 4H), 7.44-7.34 (m, 5H), 7.34-7.28 (m, 3H), 7.23 (m, 1H), 4.57-4.47 (m, 1H), 4.47-4.30 (m, 2H), 4.29-4.14 (m, 4H), 4.06 (br s, 2H), 4.01-3.91 (m, 1H), 3.89-3.68 (m, 1H), 3.64-3.43 (m, 2H), 3.39-3.25 (m, 1H), 3.23-3.11 (m, 1H), 1.51 (s, 9H).

[0541] Step 5: Synthesis of Compound WX038-5

[0542] Compound WX038-4 (1.20 g, 1.47 mmol) was dissolved in ethanol (20 mL), followed by addition of concentrated hydrochloric acid (7.35 mL). The mixture was then stirred at 90 C. for 24 hours. After completion of the reaction as indicated by thin layer chromatography and liquid chromatography, the reaction mixture was concentrated with a rotary evaporator, followed by the addition of saturated NaHCO.sub.3 solution (30 mL) and ethyl acetate (30 mL). The mixture was extracted with ethyl acetate (30 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain WX038-5. .sup.1H NMR (400 MHz, CHLOROFORM-d) ppm 7.77 (m, 4H), 7.59-7.46 (m, 4H), 7.41 (m, 4H), 7.34 (m, 5H), 6.81 (br s, 1H), 4.59 (br s, 2H), 4.46-4.16 (m, 5H), 3.94 (m, 3H), 3.75-3.37 (m, 3H), 3.30-3.11 (m, 1H), 2.92 (br s, 1H), 2.13-2.08 (m, 2H).

[0543] Step 6: Synthesis of Compound WX038-6

[0544] According to the step 1 in the synthesis of Embodiment 29, the target compound WX038-6 was synthesized using WX036-1 and WX038-5 in step 1.

[0545] Step 7: Synthesis of Compound WX038

[0546] According to the step 2 in the synthesis of Embodiment 29, the target compound WX038 was synthesized using WX038-6 in step 1.

[0547] According to the steps 1 to 2 in the synthesis of Embodiment 29, the embodiments in Table 10 were synthesized using different fragments in the step 1. The structures in the table also represent their potential isomers.

TABLE-US-00010 TABLE 10 Fragment in Embodiment the step 1 Structure Compound 39 [00215] [00216] WX039 40 [00217] WX040 41 [00218] [00219] WX041 42 [00220] [00221] WX042 43 [00222] [00223] WX043

TABLE-US-00011 TABLE 11 NMR and MS data of each embodiment Embodiment Compound NMR MS m/z: 29 WX029 SFC detection method: column, 468.0 WX029A Chiralpak AD-3 150 4.6 mm I.D., (M + H).sup.+ WX029B 3 m; mobile phase, A: carbon dioxide, B: ethanol (0.05% diethylamine); flow rate: 2.5 mL/min; column temperature: 35 C.; detection wavelength: 220 nm. The retention time of chiral isomers WX029A and WX029B was 5.922 min and 7.134 min, respectively, and the ratio was 1:1. WX029A: .sup.1H NMR (400 MHz, METHANOL-d.sub.4) ppm 7.93 (br d, J = 8.4 Hz, 1H), 6.54 (br d, J = 8.4 Hz, 1H), 5.80 (s, 1H), 4.34 (br s, 1H), 3.65 (br s, 1H), 3.19-3.02 (m, 2H), 2.78 (br t, J = 10.4 Hz, 1H), 2.47-2.28 (m, 2H), 2.21 (s, 3H), 2.03-1.68 (m, 9H) WX029B: .sup.1H NMR (400 MHz, METHANOL-d.sub.4) Shift = 7.91 (d, J = 8.4 Hz, 1H), 6.54 (d, J = 8.4 Hz, 1H), 5.80 (s, 1H), 4.33 (br s, 1H), 3.63 (br d, J = 12.4 Hz, 1H), 3.18-3.03 (m, 2H), 2.78 (br t, J = 10.4 Hz, 1H), 2.46-2.29 (m, 2H), 2.19 (s, 3H), 2.02-1.71 (m, 9H). 30 WX030 SFC detection method: column, 522.0 WX030A Chiralpak AS-3 (150 mm 4.6 mm, (M + H).sup.+ WX030B 3 m); mobile phase, A: carbon dioxide, B: ethanol (0.05% diethylamine). The retention time of chiral isomers WX030A and WX030B was 3.548 min and 3.847 min, respectively, and the ratio was 1:1. WX030A: .sup.1H NMR (400 MHz, METHANOL-d.sub.4) ppm 8.01 (d, J = 8.8 Hz, 1H), 6.80 (s, 1H), 6.64 (d, J = 8.8 Hz, 1H), 4.96 (s, 1H), 4.15 (br s, 1H), 3.46-3.43 (m, 1H), 3.15-3.09 (m, 2H), 2.82-2.80 (m, 1H), 2.55-2.47 (m, 2H), 2.07 (br s, 2H), 1.96-1.85 (m, 6H). WX030B: .sup.1H NMR (400 MHz, METHANOL-d.sub.4) ppm 8.03 (d, J = 8.0 Hz, 1H), 6.80 (s, 1H), 6.65(d, J = 8.4 Hz, 1H), 4.96 (s, 1H), 4.08 (br s, 1H), 3.48-3.41 (m, 1H), 3.14-3.09 (m, 2H), 2.84-2.79 (m, 1H), 2.58-2.47 (m, 2H), 2.06 (br s, 2H), 1.93-1.86 (m, 6H). 31 WX031 .sup.1H NMR (400 MHz, METHANOL- 422.1 d.sub.4) ppm 8.38-8.34 (m, 1H), 8.32 (M + H).sup.+ (d, J = 8.8 Hz, 1H), 7.60 (d, J = 7.2 Hz, 1H), 7.25 (m, 1H), 7.07 (d, J = 8.8 Hz, 1H), 4.93 (t, J = 5.6 Hz, 1H), 2.86 (m, 2H), 2.23-2.10 (m, 1H), 2.01 (m, 1H), 1.95-1.84 (m, 2H), 1.36-1.27 (m, 3H), 1.23-1.15 (m, 2H) 32 WX032 1H NMR (400 MHz, METHANOL- 479.0 d.sub.4) ppm 8.26 (d, J = 8.8 Hz, 1H), (M + H).sup.+ 7.02 (d, J = 8.8 Hz, 1H), 6.80 (s, 1H), 4.97 (m, 1H), 3.39-3.33 (m, 1H), 2.59-2.44 (m, 2H), 2.14-2.02 (m, 1H), 1.93-1.82 (m, 3H), 1.32 (m, 2H), 1.16 (m, 2H) 33 WX033 .sup.1H NMR (400 MHz, METHANOL- 447.0 d.sub.4) ppm 8.27 (d, J = 8.0 Hz, 1H), (M + Na).sup.+ 7.04 (d, J = 7.6 Hz, 1H), 5.82 (s, 1H), 5.08-4.93 (m, 1H), 3.47- 3.32 (m, 1H), 2.44-2.28 (m, 2H), 2.21 (s, 3H), 2.09-1.66 (m, 4H), 1.32-1.17 (m, 4H) 34 WX034 .sup.1H NMR (400 MHz, METHANOL- 481.0 d.sub.4) ppm 8.35 (d, J = 8.8 Hz, 1H), (M + H).sup.+ 7.09 (d, J = 8.8 Hz, 1H), 6.80 (s, 1H), 4.98-4.96 (m, 1H), 3.97-3.88 (m, 1H), 2.55-2.48 (m, 2H), 2.09- 2.07 (m, 1H), 1.90-1.83 (m, 3H), 1.34-1.32 (m, 6H). 35 WX035 .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 449.0 10.87 (s, 1H), 8.42 (d, J = 8.8 Hz, (M + H).sup.+ 1H), 7.04-7.01 (m, 2H), 5.80 (s, 1H), 5.03-4.95 (m, 2H), 3.92-3.85 (m, 1H), 2.44-2.34 (m, 2H), 2.25 (s, 3H), 2.06-2.01 (m, 1H), 1.94-1.89 (m, 1H), 1.80-1.74 (m, 2H),1.38- 1.36 (m, 6H). 36 WX036 .sup.1H NMR (400 MHz, METHANOL- 482.1 d.sub.4) ppm 8.02 (d, J = 8.4 Hz, 1H), (M + H).sup.+ 7.34 (s, 1H), 6.63 (d, J = 7.2 Hz, 1H), 6.23 (s, 1H), 4.07 (br d, J = 9.4 Hz, 1H), 3.01 (m, 2H), 2.57- 2.36 (m, 2H), 2.14 (m, 1H), 1.92 (m, 4H), 1.81 (m, 2H), 1.61 (br s, 2H), 1.59 (br s, 3H), 1.54 (br s, 3H) 37 WX037 1H NMR (400 MHz, METHANOL- 550.1 d.sub.4) ppm 7.97 (t, J = 8.8 Hz, 1H), (M + H).sup.+ 7.91 (s, 1H), 6.79 (s, 1H), 6.56 (t, J = 8.4 Hz, 1H), 5.49 (s, 1H), 4.96 (m, 1H), 4.09 (br d, J = 8.4 Hz, 1H), 3.00 (m, 2H), 2.60-2.42 (m, 2H), 2.18-2.02 (m, 2H), 1.99-1.78 (m, 4H), 1.65-1.51 (m, 6H)

TABLE-US-00012 Test example 1: In vitro activity evaluation 38 WX038 .sup.1H NMR (400 MHz, METHANOL-d.sub.4) 469.1 ppm 8.26 (d, J = 7.2 Hz, 1H), 7.37 (br s, (M + H).sup.+ 1H), 7.17 (d, J = 7.2 Hz, 1H), 6.26 (br s, 1H), 5.52-5.13 (m, 1H), 3.93 (m, 1H), 3.55- 3.35 (m, 4H), 3.12 (m, 4H), 2.60-2.37 (m, 2H), 2.03 (m, 1H), 1.84 (m, 3H) 39 WX039 .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 9.28 485.0 (br d, J = 9.6 Hz, 1H), 8.92 (br d, J = 10.4 (M + H).sup.+ Hz, 1H), 8.41 (s, 1H), 8.28 (d, J = 8.8 Hz, 1H), 7.58 (br d, J = 8.0 Hz, 1H), 7.17 (d, J = 8.8 Hz, 1H), 4.90-4.74 (m, 1H), 4.05- 3.98 (m, 1H), 3.36 (br d, J = 12.0 Hz, 2H), 2.97 (br d,J = 11.2 Hz, 2H), 2.84-2.64 (m, 2H), 2.60 (s, 3H), 2.02-1.87 (m, 5H), 1.85- 1.72 (m, 3H) 40 WX040 .sup.1H NMR (400 MHz, METHANOL-d.sub.4) 485.0 ppm 8.34 (br d, J = 8.4 Hz, 1H), 7.15 (d, (M + H).sup.+ J = 8.8 Hz, 1H), 4.96 (br s, 1H), 4.15 (m, 1H), 3.65 (m, 1H), 3.42-3.33 (m, 2H), 3.05 (m,1H), 2.90-2.80 (m, 1H), 2.79-2.69 (m, 1H), 2.65 (s, 3H), 2.12 (m, 2H), 2.06-1.68 (m, 6H) 41 WX041 .sup.1H NMR (400 MHz, METHANOL-d.sub.4) 482.0 ppm 8.06-7.95 (m, 1H), 7.35 (s, 1H), 6.62 (M + H).sup.+ (br d, J = 8.0 Hz, 1H), 6.21 (s, 1H), 4.60 (br s, 1H), 4.23 (br s, 1H), 3.56 (m, 1H), 3.16- 3.04 (m, 2H), 2.80 (m, 1H), 2.42-2.16 (m, 2H), 2.06-1.86 (m, 4H), 1.75 (br s, 1H), 1.57-1.49 (m, 1H), 1.09 (s, 3H), 0.99 (s, 3H) 42 WX042 .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 469.0 8.01(s, 1H), 7.76-7.73 (m, 1H), 7.44-7.38 (M + H).sup.+ (m, 1H), 6.12-6.11 (m, 1H), 4.87-4.84 (m, 1H), 4.46-4.43 (m, 1H), 3.11-3.07 (m, 3H), 2.85-2.82 (m, 1H), 2.68-2.66 (m, 1H), 2.36- 2.32 (m, 4H), 1.77-1.69 (m, 8H). 43 WX043 .sup.1H NMR (400 MHz, METHANOL-d.sub.4) 469.1 ppm 7.98-7.91(m, 1 H), 7.42 (s, 1 H), 6.59- (M + H).sup.+ 6.56 (m, 1 H), 6.30 (s, 1 H), 4.98 (m, 1 H),4.36-4.34 (m, 1 H),3.56-3.53(m, 2 H), 3.17-2.77(m, 6 H), 2.50(s, 3 H), 1.98- 1.87(m, 4H).

[0548] Experimental Purpose:

[0549] The IC.sub.50 values were determined to evaluate the antagonistic activity of the test compounds against CXCR2.

[0550] Experimental Method:

[0551] PathHunter CXCR2 -arrestin cells (DiscoverX) were grown under normal conditions and seeded on a white-walled 384-microwell plate at 20 L/well. Before testing, the cells were incubated at 37 C. for an appropriate time. The test compounds were serially diluted in DMSO at a three-fold dilution factor to obtain 8 serially diluted test compounds. Shortly before the test, the above serially diluted test compounds were further diluted with test buffer to 5 times the test concentration. 5 L of the further diluted test compounds was added to the cells and then the cells were incubated at 37 C. for 30 minutes. The vehicle concentration was 1%. 5 L of 6EC80 agonist (CXCL8) buffer was added to the cells and then the cells were incubated at 37 C. for 90 minutes. 15 L (50% v/v) of PathHunter detection reagent mixture was added in one portion, followed by one-hour incubation to generate the test signal. The microplates were read on a PerkinElmer Envision instrument for chemiluminescence signal. The biological activity of the test compounds was analyzed by CBIS data analysis suite (ChemInnovation, CA) and shown as IC.sub.50 values. The experimental results are shown in Table 12:

TABLE-US-00013 TABLE 12 Test results of in vitro activity of the compounds of the present disclosure CXCR2 Compound IC.sub.50 (nM) WX001A 152 WX002A 45 WX003A 17 WX004A 43 WX005A 14 WX006A 22 WX007A 42 WX008A 122 WX009 177 WX010A 61 WX011A 70 WX012A 17 WX013A 14 WX014 232 WX015 186 WX016A 134 WX017A 72 WX018A 133 WX020A 177 WX021A 720 WX022A 366 WX023A 36 WX024A 525 WX024B 667 WX025B 139 WX027A 269 WX028 472 WX029 15 WX029A 2 WX029B 245 WX030B 22 WX032 144 WX033 6 WX034 55 WX036 23

[0552] Conclusion: The compounds of the present disclosure have a strong antagonistic effect on CXCR2.

Test Example 2: Pharmacokinetic Evaluation of the Compounds

[0553] Experimental Purpose:

[0554] The pharmacokinetic parameters of the compounds in C57BL/6 mice were investigated.

[0555] Experimental Materials:

[0556] C57BL/6 mice (male, 18-30 g, 7-9 weeks old, Shanghai Lingchang Biotechnology Co., Ltd.)

[0557] Experimental Procedure:

[0558] Formulations containing an aqueous solution of 1% DMSO/10% hydroxypropyl--cyclodextrin as the vehicle were administered by intravenous injection (1 mpk), formulations containing an aqueous solution of 1% DMSO/1% hydroxypropyl methylcellulose/0.2% Tween 80 as the vehicle were administered by gavage (5 mpk). Before the animal experiment, all animals were fasted, and fed 4 hours after administration; all animals were free to drink water. The time points of blood collection: intravenous injection administration group: 0.083, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours; gavage administration group: 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours.

[0559] Whole blood samples (0.03 mL) were collected through the saphenous vein (or other suitable blood collection sites) at the prescribed time points, and all blood samples were added to labeled plastic centrifuge tubes containing K2-EDTA anticoagulant. After the blood samples were collected, the plasma was isolated by centrifugation, immediately placed in dry ice and stored at low temperature. All samples were analyzed by LC-MS/MS with a minimum detection limit of 2 nM. The non-compartmental model of WinNonlin Version 6.3 (Pharsight, Mountain View, Calif.) pharmacokinetic software was used to process the mean plasma concentration, and the linear-log trapezoid method was used to calculate the pharmacokinetic parameters.

[0560] The experimental results are shown in Table 13:

TABLE-US-00014 TABLE 13 Pharmacokinetic test results Sample to be Area under tested (compound the drug prepared in each concentration Bioavailability embodiment) Clearance Half-life time curve (F) (nM .Math. hr) (mL/min/kg) T.sub.1/2 (h) (AUC) (%) Danirixin 42.5 7.43 1580 34.3 WX003A 11.2 2.22 12689 70.3 WX006A 8.3 3.09 20091 83.8 WX012A 15.8 0.94 9392 82.5 WX013A 30.8 2.21 4438 75.5

[0561] Conclusion: The compounds of the present disclosure can significantly improve single or partial pharmacokinetic indices in mice.

Test Example 3: Evaluation of Pharmacokinetic and Tissue Distribution of the Compounds

[0562] Experimental Purpose:

[0563] The pharmacokinetic and tissue distribution of the compounds in Lewis rats was tested.

[0564] Experimental Materials:

[0565] Lewis rats (male, 202-239 g, 7-9 weeks old, Beijing Viton Lihua)

[0566] Experimental Procedure:

[0567] Formulations containing an aqueous solution of 1% hydroxypropyl methylcellulose/0.2% Tween 80 as the vehicle were administered by gavage (5 mpk). Before the animal experiment, all animals were fasted overnight, and fed 4 hours after administration; all animals were free to drink water. The time points of blood collection: danirixin administration group: 0.25, 1, 8 hours; gavage administration group: 0.5, 1, 4 hours.

[0568] Whole blood samples (0.2 mL) were collected through the saphenous vein (or other suitable blood collection sites) at the prescribed time points, and all blood samples were added to labeled plastic centrifuge tubes containing K2-EDTA anticoagulant. After the blood samples were collected, the plasma was separated by centrifugation, immediately placed in dry ice and stored at low temperature. All samples were analyzed by LC-MS/MS with a minimum detection limit of 2 nM. The non-compartmental model of WinNonlin Version 6.3 (Pharsight, Mountain View, Calif.) pharmacokinetic software was used to process the mean plasma concentration, and the log-linear trapezoid method was used to calculate the pharmacokinetic parameters.

[0569] The experimental results are shown in Table 14:

TABLE-US-00015 TABLE 14 Pharmacokinetic test results Positive control and the compound of the present disclosure Danirixin WX030B Ratio in lung blood 1.57 2.17

[0570] Conclusion: The compound of the present disclosure significantly improves the distribution ratio in lung tissue of rats.

Test Example 4: Therapeutic Effect of the Compounds on PPE-Induced COPD Model

[0571] Experimental Purpose:

[0572] The therapeutic effect of the compounds on PPE-induced COPD model in C57BL/6 mice was tested.

[0573] Experimental Materials:

[0574] Animals: C57BL/6 mice (female, 17.5-18.5 g, 6-8 weeks old)

[0575] Drugs: Porcine pancreas elastase (PPE) (sigma, 0.068 U/L); compound 1 in FIG. 1, FIG. 2 and FIG. 3 is danirixin; compound 2 is WX006A.

[0576] Grouping: (1) COPD model group (porcine pancreatic elastase model group) [0577] (2) PPE+ danirixin (40 mpk) [0578] (3) PPE+ danirixin (120 mpk) [0579] (4) PPE+WX006A (4 mpk) [0580] (5) PPE+WX006A (12 mpk)

[0581] Experimental Procedure:

[0582] 1. Modeling method: PPE was administered through by drip transfusion at the back of the tongue.

[0583] 2. Administration method: an aqueous solution of 1% DMSO/1% hydroxypropyl methylcellulose/0.2% Tween 80 was used as the vehicle; the animals were daily administered with a volume of 200 L/animal by gavage for 4 weeks.

[0584] 3. End point of the experiment: On the 29.sup.th day, the mice were euthanized, samples were collected, and flow cytometry was performed.

[0585] Flow Cytometry

[0586] The blood, alveolar lavage fluid and lung tissue of the mice were collected after 4 weeks of administration to determine the percentage of inflammatory cells.

[0587] 1) Alveolar lavage cells: the mice were euthanized. The neck was dissected, and the trachea was exposed and intubated, followed by lavage with 1 mL of sulphate buffer precooled at 4 C. for three times. The lavage fluids were combined, and centrifuged at 1200 rpm for 5 minutes. The supernatant was discarded and the cell suspension was collected.

[0588] 2) The blood and lung tissue of the mice were collected. The blood was subjected to erythrocyte lysis and washed to prepare a cell suspension; the lung tissue was cut into small pieces, and then digested with type I collagenase at 37 C. for 1.5 hours, filtered and subjected to erythrocyte lysis to prepare a cell suspension.

[0589] 3) The cells were counted and the cell suspensions were transferred into flow cytometry tubes.

[0590] 4) After dividing into flow cytometry tubes, CD45, Lytic, Ly6g, and CD11b fluorescent antibodies for flow cytometry were used for marking.

[0591] 5) After washing the cells, the percentage of neutrophils and monocytes in CD45.sup.+ cells was determined using a flow cytometer.

[0592] The experimental results are shown in FIG. 1, FIG. 2 and FIG. 3. It is concluded that in the PPE-induced mouse COPD model, the compound of the present disclosure significantly reduces the proportion of neutrophils in lung tissue, which is superior to the positive control danirixin. The compound of the present disclosure and danirixin both have a significant effect of reducing the proportions of neutrophils and monocytes in the alveolar lavage fluid at a high dose (120 mpk), and exhibit a good inhibitory effect on inflammation. Moreover, the compound of the present disclosure can achieve a comparable anti-inflammatory effect at a low dose (4 mpk).