Heterocycloalkyl compounds as CCR2 / CCR5 antagonists

Abstract

The invention relates to a series of compounds with heterocycloalkyl, or isomers or pharmaceutically acceptable salts thereof, and to a use thereof in manufacturing a medicine of treatment CCR2/CCR5 antagonist-related diseases, specifically to a compound of Formula (I), or an isomer or pharmaceutically acceptable salt thereof.

##STR00001##

Claims

1. A compound of the formula (I), or an isomer or pharmaceutically acceptable salt thereof, ##STR00181## wherein, N is selected from the group consisting of 1, 2, and 3; R.sub.1 is 4 to 6 membered heterocycloalkyl, which is optionally substituted by 1, 2 or 3 R.sub.a; R.sub.2 is C.sub.1-6 alkyl, which is optionally substituted by 1, 2 or 3 R.sub.b; R.sub.3 is C.sub.1-6 alkoxy, which is optionally substituted by 1, 2 or 3 R.sub.c; X.sub.1 is selected from the group consisting of O, S and —NH—; L.sub.1 is —(CRR).sub.m—; L.sub.2 is —CRR—; m is selected from the group consisting of 1, 2, 3, and 4; R.sub.a, R.sub.b and R.sub.c are independently selected from the group consisting of H, F, Cl, Br, I, OH, NH.sub.2, CN, and CH.sub.3; each R is independently selected from the group consisting of H, F, CL, BR, I, OH, NH.sub.2, CN, and CH; the 4 to 6-membered heterocycloalkyl comprises 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from the group consisting of —NH—, —O—S— and N; and the sulfur atom with “*” is a chiral sulfur atom, which exists as a (R) or (S) single enantiomer or is riched in one of the enantiomers.

2. The compound, or the isomer or pharmaceutically acceptable salt thereof according to claim 1, wherein R.sub.2 is C.sub.1-3 alkyl, which is optionally substituted by 1, 2 or 3 R.sub.b.

3. The compound, or the isomer or pharmaceutically acceptable salt thereof according to claim 2, wherein R.sub.2 is CH.sub.2CH.sub.3.

4. The compound, or the isomer or pharmaceutically acceptable salt thereof according to claim 1, wherein R.sub.3 is C.sub.4-6 alkoxy, which is optionally substituted by 1, 2 or 3 R.sub.c.

5. The compound, or the isomer or pharmaceutically acceptable salt thereof according to claim 4, wherein R.sub.3 is ##STR00182##

6. The compound, or the isomer or pharmaceutically acceptable salt thereof according to claim 1, wherein L.sub.1 is —CH.sub.2CH.sub.2—.

7. The compound, or the isomer or pharmaceutically acceptable salt thereof according to claim 6, wherein the structural unit ##STR00183## ##STR00184##

8. The compound, the isomer or pharmaceutically acceptable salt thereof according to claim 1, wherein L.sub.2 is —CH.sub.2—.

9. The compound, or the isomer or pharmaceutically acceptable salt thereof according to claim 8, wherein R.sub.1 is selected from the group consisting of oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, Hexapyridyl, morpholinyl and dioxanyl, which is optionally substituted by 1, 2 or 3 R.sub.a.

10. The compound, or the isomer or pharmaceutically acceptable salt thereof according to claim 9, wherein R.sub.1 is selected from the group consisting of ##STR00185## which is optionally substituted by 1, 2 or 3 R.sub.a.

11. The compound, or the isomer or pharmaceutically acceptable salt thereof according to claim 8, wherein the structural unit ##STR00186## is selected from the group consisting of ##STR00187##

12. The compound, or the isomer or pharmaceutically acceptable salt thereof according to claim 11, wherein the structural unit ##STR00188## is selected from the group consisting of ##STR00189##

13. The compound, or the isomer or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound, or the isomer or pharmaceutically acceptable salt thereof is selected from the group consisting of ##STR00190## wherein, R.sub.1, R.sub.2, R.sub.3, X.sub.1, L.sub.1, L.sub.2 are defined in claim 1.

14. A compounds, or an isomer or pharmaceutically acceptable salt thereof of the following formula of: ##STR00191## ##STR00192## ##STR00193## ##STR00194## ##STR00195## ##STR00196## ##STR00197##

15. The compound, or the isomer, or pharmaceutically acceptable salt thereof according to claim 14, wherein the compound, or the isomer or pharmaceutically acceptable salt thereof is selected from the group consisting of ##STR00198## ##STR00199## ##STR00200## ##STR00201## ##STR00202## ##STR00203## ##STR00204##

16. The compound of claim 15, or the isomer or pharmaceutically acceptable salt thereof, wherein the compound, or the isomer or pharmaceutically acceptable salt thereof is selected from the group consisting of ##STR00205## ##STR00206## ##STR00207## ##STR00208## ##STR00209## ##STR00210## ##STR00211## ##STR00212##

17. A pharmaceutical composition, comprising a therapeutically effective amount of the compound, or the isomer or pharmaceutically acceptable salt thereof according to claim 1 as an active ingredient, and a pharmaceutically acceptable carrier.

18-19. (canceled)

20. A pharmaceutical composition, comprising a therapeutically effective amount of the compound, or the isomer or pharmaceutically acceptable salt thereof according to claim 13 as an active ingredient, and a pharmaceutically acceptable carrier.

21. A method for treatment of CCR2/CCR5 antagonist-related diseases, comprising administrating to a subject the compound, or the isomer or pharmaceutically acceptable salt thereof according to claim 1.

22. A method for treatment of non-alcoholic fatty hepatitis, comprising administrating to a subject the compound, or the isomer or pharmaceutically acceptable salt thereof according to claim 1.

23. A method for treatment of CCR2/CCR5 antagonist-related diseases or non-alcoholic fatty hepatitis, comprising administrating to a subject the compound, or the isomer or pharmaceutically acceptable salt thereof according to claim 13.

24. A method for treatment of CCR2/CCR5 antagonist-related diseases or non-alcoholic fatty hepatitis, comprising administrating to a subject the pharmaceutical composition according to claim 17.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0079] FIG. 1 shows effect of WX001 on tumor volume of MC38 colon cancer tumor model of mice.

DETAILED DESCRIPTION

[0080] The invention will be described in detail below by examples, which is not intended to be inappropriate restrictions to the invention. The invention has been described in detail herein, in which embodiments of the invention are disclosed. It will be obvious to those skilled in the art that various changes and improvements can be made to the specific embodiments of the invention without departing from the spirit and scope of the invention.

Reference Example 1: Fragment BB-1A-7

[0081] ##STR00047## ##STR00048##

[0082] Step 1: Synthesis of Compound BB-1A-2

[0083] Tetrabutylammonium bromide (86.58 g, 302.63 mmol) and potassium hydroxide (339.6 g, 6.05 mol) were suspended in toluene (5000 mL) to form a mixture, after the mixture was refluxed for 16 hours, piperidine-2-ketone (500.00 g, 5.04 mol) and methoxy chloride (1.03 kg, 6.56 mol) was added thereto. The mixture was held at 100° C. for 24 hours, was cooled to room temperature, and washed three times with water (2000 mL×3). The organic phase was dried with anhydrous sodium sulfate, filtered and concentrated. The concentrated solution is separated by a chromatographic column to obtain the compound BB-1A-2.

[0084] Step 2: Synthesis of Compound BB-1A-4

[0085] A solution of compound BB-1A-2 (40 g) and sodium hydroxide (7.29 g) in water (200 mL) was stirred at 80° C. for 24 hours. The mixture was neutralized with concentrated hydrochloric acid (7.38 mL) at 0° C. to obtain a mixed solution of BB-1A-3. To this mixed solution were added sodium carbonate (65.66 g) and dimethyl sulfoxide (600 mL) at room temperature. Then 5-bromo-2-fluoro-benzaldehyde (46.11 g) was added dropwise to the mixture at 100° C. The reaction mixture was then refluxed at 100° C. for 48 hours and was adjusted to pH=7 with ammonium chloride (1 mol/L) aqueous solution under ice-cooling, and extracted with ethyl acetate (1 L×3). The organic layer was washed with water and brine, dried with anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate=200:1 to 1:1) to obtain the compound BB-1A-4.

[0086] Step 3: Synthesis of Compound BB-1A-5

[0087] To a mixture of compound BB-1A-4 (10 g) and sodium carbonate (12.61 g) in acetonitrile (100 mL) was added a solution of methyl iodide (22 g) in acetonitrile (50 mL). Under the atmosphere of nitrogen, the reaction mixture was stirred at 15-30° C. for 24 hours, was quenched with water (300 mL), and extracted with ethyl acetate (400 mL×2). The organic layer was washed with brine, dried with anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=50:1 to 20:1 to 10:1) to obtain the compound BB-1A-5.

[0088] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 10.31 (s, 1H) 7.89 (d, J=2.5 Hz, 1H) 7.54 (dd, J=9.0, 2.51 Hz, 1H) 7.04 (d, J=8.5 Hz, 2H) 6.97 (d, J=9.0 Hz, 1H) 6.80 (d, J=8.5 Hz, 2H) 4.21 (s, 2H) 3.77 (s, 3H) 3.63 (s, 3H) 3.07 (t, J=6.8 Hz, 2H) 2.25 (t, J=6.8 Hz, 2H) 1.46-1.58 (m, 4H).

[0089] Step 4: Synthesis of Compound BB-1A-6

[0090] To a solution of compound BB-1A-5 (11 g) in dimethyl carbonate (42.8 g) was added sodium methoxide (6.84 g) to form a mixture. The mixture was heated to 60° C. and stirred at 60° C. for 35 hours, adjusted to pH (7-8) with ammonium chloride in aqueous solution (1 mol/L), and filtered. The filter cake was evaporated under reduced pressure to obtain the compound BB-1A-6.

[0091] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 7.74 (s, 1H) 7.26 (s, 1H) 7.05-7.11 (m, 3H) 6.88 (d, J=8.53 Hz, 2H) 6.53 (d, J=9.03 Hz, 1H) 4.39 (s, 2H) 3.80 (d, J=2.01 Hz, 6H) 3.48 (t, J=5.02 Hz, 2H) 2.58 (t, J=6.02 Hz, 2H) 1.47 (d, J=5.52 Hz, 2H).

[0092] Step 5: Synthesis of Compound BB-1A

[0093] To a solution of compound BB-1A-6 (10 g) in toluene (50 mL) was added trifluoroacetic acid (100 mL). The reaction mixture was heated to 60° C. and stirred at 60° C. for 8 hours, was neutralized to pH=7 with saturated sodium bicarbonate under ice cooling, and extracted with ethyl acetate (250 mL×2). The organic layer was washed with brine, dried with anhydrous sodium sulfate, and concentrated. The residue was purified by a silica gel column (petroleum ether/ethyl acetate=50:1 to 5:1) to obtain the compound BB-1A.

[0094] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 7.66 (s, 1H) 7.39-7.05 (m, 1H) 6.85 (d, J=8.8 Hz, 1H) 6.36 (d, J=8.8 Hz, 1H) 3.81 (s, 3H) 3.51 (t, J=5.2 Hz 2H) 2.75 (d, J=6.8 Hz, 2H) 1.49-1.40 (m, 2H).

[0095] Step 6: Synthesis of Compound BB-1A-7

[0096] At 25° C., BB-1A (7.5 g, 25.32 mmol, 1 eq) and BB-2 (8.92 g, 27.86 mmol, 1.1 eq) were dissolved in dimethyl sulfoxide (62.5 mL) and water (12.5 mL), and then Pd(dppf)Cl.sub.2 (926.50 mg, 1.27 mmol, 0.05 eq) and potassium carbonate (10.50 g, 75.97 mmol, 3 eq) were added thereto to form a reaction mixture. The reaction mixture was reacted at 80° C. under the atmosphere of nitrogen for 18 hours, and filtered. The filtrate was added with 100 mL of water, and then extracted three times with ethyl acetate (100 mL×3). The combined organic phases are washed once with saturated brine, dried with anhydrous sodium sulfate, and filtered and evaporated under reduced pressure to obtain a crude product. The crude product was separated by column chromatography (petroleum ether:ethyl acetate EA=20:1 to 8:1) to obtain the compound BB-1A-7 (8 g).

[0097] MS-ESI (m/z): 410.0 (M+1).sup.+

Reference Example 2: Fragment BB-1B

[0098] ##STR00049##

[0099] Synthetic Route:

##STR00050## ##STR00051##

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

[0101] To a solution of compound BB-1B-1 (45 g) in pyridine (450 mL) was added p-toluenesulfonyl chloride (55.94 g) at 25° C. and stirred at 55° C. for 5 hours to form a mixture. The mixture was added with water (200 mL) and extracted with ethyl acetate (100 mL×3). The combined organic layer was washed with saturated brine (200 mL), dried with anhydrous sodium sulfate, filtered and evaporated under reduced pressure to obtain a residue. The residue was purified by a silica gel column (petroleum ether/ethyl acetate=100:1 to 10:1) to obtain BB-1B-2.

[0102] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 10.51 (s, 1H), 8.04 (d, J=2.3 Hz, 1H), 7.73 (d, J=8.5 Hz, 2H), 7.63-7.59 (m, 1H), 7.57-7.52 (m, 1H), 7.24 (d, J=8.0 Hz, 2H), 3.89 (s, 3H), 2.38 (s, 3H)

[0103] Step 2: Synthesis of Compound BB-1B-3

[0104] Sodium hydrogen (6.14 g, 60% purity) and DMF (50 mL) were added to a solution of BB-1B-2 (59 g) in DMF (200 mL) at 0° C., and then stirred at 25° C. under the atmosphere of nitrogen for 2 hours, sodium iodide (23.02 g) and ethyl 4-bromobutyrate (32.95 g) were added thereto at 0° C. and stirred at 80° C. under the atmosphere of nitrogen for 16 hours, and then sodium hydrogen (6.14 g, 60% purity) and DMF (50 mL) were added thereto at 0° C. and stirred at 80° C. under the atmosphere of nitrogen for 15 hours. The mixture was added with water (200 mL) and extracted with ethyl acetate (50 mL×3). The combined organic layer was washed with saturated brine (200 mL), dried with anhydrous sodium sulfate, and filtered and evaporated under reduced pressure to obtain a yellow oil. Concentrated sulfuric acid (100 mL, 98% purity) and acetic acid (157.5 g) were add to the yellow oil at 0° and stirred at 90° C. for 2.5 hours. The mixture was adjusted to pH=8 with 12 mol/L sodium hydroxide in aqueous solution and then extracted with ethyl acetate (300 mL×3), and washed with saturated brine (300 mL) to combine organic layers. The combined organic layer was dried with anhydrous sodium sulfate, and filtered and evaporated under reduced pressure to obtain a residue. The residue was purified with a silica gel column (petroleum ether/ethyl acetate=50:1 to 5:1) to obtain BB-1B-3.

[0105] Step 3: Synthesis of Compound BB-1B-4

[0106] The reactants BB-1B-3 (6 g) and Boc anhydride (15.16 g) were dissolved in tetrahydrofuran (100 mL), and N,N-lutidine (4.58 g) was added to form a mixture. The mixture was stirred at 70° C. for 4 hours, quenched with water (100 mL) and was extracted with ethyl acetate (100 mL×3). The combined organic layer was washed with saturated brine (100 mL), dried with anhydrous sodium sulfate, filtered and evaporated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=50:1 to 20:1) to obtain BB-1B-4.

[0107] MS-ESI (m/z): 283.9[M-55].sup.+

[0108] Step 4: Synthesis of Compound BB-1B-5

[0109] Sodium methoxide (2.13 g) was added to a solution of reactant BB-1B-4 (2.68 g) in dimethyl carbonate (50 mL) at 25° C., and stirred at 100° C. under the atmosphere of nitrogen for 2 hours. The mixture was quenched with water (50 mL) and extracted with ethyl acetate (100 mL×3). The combined organic layer was washed with saturated brine (100 mL), dried with anhydrous sodium sulfate, filtered and evaporated under reduced pressure to obtain a residue. The residue was purified by silica gel column (petroleum ether/ethyl acetate=50:1 to 5:1) to obtain compound BB-1B-5.

[0110] MS-ESI (m/z): 342.1[M-55].sup.+

[0111] Step 5: Synthesis of Compound BB-1B-6

[0112] Sodium borohydride (484.49 mg) was added to a solution of reactant BB-1B-5 (1.7 g) in tetrahydrofuran (20 mL) at −40° C. and methanol (10 mL) was added thereto. The mixture was stirred at −15° C. for 0.5 hour, quenched with water (50 mL), and extracted with ethyl acetate (100 mL×3). The combined organic layer was washed with saturated brine (100 mL), dried with anhydrous sodium sulfate, filtered and evaporated under reduced pressure to obtain the compound BB-1B-6.

[0113] Step 6: Synthesis of Compound BB-1B-7

[0114] The reactants BB-1B-6 (1.93 g) and triethylamine (1.56 mL) were dissolved in a tetrahydrofuran (20 mL) solution, and methanesulfonyl chloride (1.29 g) was added thereto at 0° C. The mixture was stirred at room temperature for 15 hours under the atmosphere of nitrogen, and then 1,8-diazacyclo[5,4,0]-undecene (1.14 g) was added thereto, and stirred at room temperature for 1 hour and quenched with water (50 mL) and extracted with ethyl acetate (100 mL×3). The combined organic layer was washed with saturated brine (100 mL), dried with anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=50:1 to 5:1) to obtain the compound BB-1B-7.

[0115] MS-ESI (m/z): 326.0[M-55].sup.+

[0116] Step 7: Synthesis of Compound BB-1B-8

[0117] Under the atmosphere of nitrogen, the reactants BB-1B-7 (0.35 g), BB-2 (351.86 mg) and potassium carbonate (379.64 mg) were added to a solution of dimethyl sulfoxide (10 mL) and water [1,1′-Bis(diphenylphosphine)ferrocene]dichloride palladium dichloromethane complex (74.77 mg), and then the mixture was stirred at 80° C. under nitrogen protection for 16 hours. Water (50 mL) was added to the mixture and extracted with ethyl acetate (50 mL×3). The combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was passed through Purification by preparative thin layer chromatography (PE:EA=5:1) gave compound BB-1B-8.

[0118] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 7.74 (s, 1H), 7.58 (s, 1H), 7.51 (br d, J=8.8 Hz, 3H), 7.48 (br s, 1H), 7.01 (d, J=8.8 Hz, 2H), 4.20-4.16 (m, 2H), 3.85-3.80 (m, 5H), 3.56 (t, J=6.7 Hz, 2H), 2.92 (s, 2H), 2.05 (s, 1H), 1.66-1.58 (m, 2H), 1.56 (s, 9H), 1.45-1.35 (m, 4H), 0.94 (t, J=7.4 Hz, 3H).

[0119] Step 8: Synthesis of Compound BB-1B

[0120] To a solution of compound BB-1B-8 (0.23 g) in ethyl acetate (10 mL) was added a solution of 4M hydrochloric acid ethyl acetate (10 mL), and stirred at room temperature for 1 hour. The reaction solution was adjusted to pH 8 with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate (100 mL×3). The combined organic layer was washed with saturated brine (100 mL), dried with anhydrous sodium sulfate, filtered and evaporated under reduced pressure, to obtain the compound BB-1B.

[0121] MS-ESI (m/z): 396.3[M+1].sup.+

Reference Example 3: Fragment BB-1C

[0122] ##STR00052##

[0123] Step 1: Synthesis of Compound BB-1C-2

[0124] To 1M NaOH aqueous solution (381.18 mL) were added methanol (600 mL), 6-aminocaproic acid (50 g) and 4-methoxybenzaldehyde (52 g), and palladium on carbon (4.5 g, 10% purity) was added thereto. The reaction mixture was stirred at room temperature under the atmosphere of hydrogen (20-30 psi) for 24 hours, and filtered and evaporated under reduced pressure, acetone (300 mL). The residue was added with acetone (50 mL) and stirred at room temperature for 30 minutes, filtered and washed with acetone. The filter cake was vacuum dried to obtain the compound BB-1C-2.

[0125] MS-ESI m/z: 252.3 [M+H].sup.+

[0126] Step 2: Synthesis of Compound BB-1C-3

[0127] BB-1C-2 (86 g, 342.19 mmol, 1 equivalent) and 5-bromo-2-fluoro-benzaldehyde (55.57 g) were dissolved in dimethyl sulfoxide (350 mL), and sodium carbonate (90.67 g)) and water (175 mL) were added thereto. The reaction solution was stirred at 100° C. for 12 hours, and was poured into water (1200 mL) and adjusted to pH=3-4 with concentrated hydrochloric acid, and extracted with ethyl acetate (500 mL×2), The combined organic layer was washed with saturated brine (500 mL) and dried with anhydrous sulfuric acid sodium, and filtered and concentrated. The residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate=10/1 to 1/1) to obtain the compound BB-1C-3.

[0128] MS-ESI m/z: 434.2 [M+H].sup.+

[0129] Step 3: Synthesis of Compound BB-1C-4

[0130] To the N,N-dimethylformamide (300 mL) solution of BB-1C-3 (58 g) was added methyl iodide (15.49 mL) and potassium carbonate (36.91 g). The reaction solution was stirred at 25° C. for 4 hours and poured into water (1000 mL), and extracted with ethyl acetate (500 mL×2), the combined organic layer was washed with saturated brine (500 mL), dried with anhydrous sodium sulfate, and filtered and concentrated. The residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate=10/1 to 7/3) to obtain the compound BB-1C-4.

[0131] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 10.31 (s, 1H), 7.90 (d, J=2.4 Hz, 1H), 7.54 (dd, J=8.8, 2.4 Hz, 1H), 7.06 (d, J=8.8 Hz, 2H), 6.98 (d, J=8.8 Hz, 1H), 6.81 (d, J=8.8 Hz, 2H), 4.22 (s, 2H), 3.79 (s, 3H), 3.65 (s, 3H), 3.06 (t, J=7.6 Hz, 2H), 2.25 (t, J=7.6 Hz, 2H), 1.58-1.51 (m, 4H), 1.27-1.25 (m, 2H).

[0132] MS-ESI m/z: 448.2 [M+H].sup.+

[0133] Step 4: Synthesis of Compound BB-1C-5

[0134] Sodium methoxide (6.51 g) was added to a solution of BB-1C-4 (10.8 g) in diethyl carbonate (500 mL), and was stirred at 25° C. for 12 hours. The reaction solution was added with water (500 mL) and extracted with ethyl acetate (300 mL×2). The combined organic layer was washed with brine (500 mL), dried with anhydrous sodium sulfate, filtered and concentrated. The residue was subjected to silica gel Column chromatography (PE/EtOAc=10/1) to obtain the compound BB-1C-5.

[0135] MS-ESI m/z: 430.2, 432.2 [M+1, M+3].sup.+

Reference Example 4: Fragment BB-2

[0136] ##STR00053##

[0137] Step 1: Synthesis of Compound BB-2-2

[0138] The compound BB-2-1 (100 g, 0.846 mol), p-toluenesulfonyl chloride (146.67 g, 769.31 mmol), and triethylamine (233.54 g, 2.31 mol) were dissolved in dichloromethane (0.5 L), and stirred at room temperature for 12 hours, and cooled to room temperature and filtered under reduced pressure to remove the solvent, the residue was dissolved in water (400 mL) and was extracted three times with ethyl acetate (1.5 L). The combined organic phase was washed twice with saturated brine (400 mL), dried with anhydrous sodium sulfate, and evaporated under reduced pressure after filtering off the desiccant to remove the solvent, in order to obtain the compound BB-2-2.

[0139] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 7.73 (d, J=8.28 Hz, 2H) 7.27 (d, J=8.03 Hz, 2H) 4.05-4.10 (m, 2H) 3.50-3.55 (m, 2H) 3.30 (t, J=6.53 Hz, 2H) 2.37 (s, 3H) 1.35-1.44 (m, 2H) 1.16-1.27 (m, 2H) 0.81 (t, J=7.40 Hz, 3H).

[0140] Step 2: Synthesis of the Compound BB-2.

[0141] Compound BB-2-2 (170.10 g, 624.54 mmol), p-hydroxyphenylboronic acid pinacol ester (137.44 g, 624.54 mmol) was dissolved in acetonitrile (1.6 L), and potassium carbonate (86.32 g, 624.54 mmol) and potassium iodide (10.37 g, 62.45 mmol) were added thereto at room temperature. The resulting solution was heated to reflux and stirred for 12 hours under nitrogen atmosphere at 60° C., and filtered under reduced pressure after cooling to room temperature to remove the solvent. The residue was dissolved in water (500 mL) and the aqueous phase was extracted three times with ethyl acetate (2 L×3), combined and then filtered under reduced pressure remove the solvent, and subjected to by column chromatography to obtain the compound BB-2.

[0142] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 7.78-7.71 (m, 2H), 6.95-6.88 (m, 2H), 4.19-4.12 (m, 2H), 3.83-3.75 (m, 2H), 3.54 (t, J=6.8 Hz, 2H), 1.65-1.57 (m, 2H), 1.44-1.36 (m, 2H), 1.34 (s, 12H), 0.93 (t, J=7.3 Hz, 3H).

Reference Example 5: Fragment BB-4A, and Fragment BB-4B

[0143] ##STR00054## ##STR00055##

[0144] Step 1: Synthesis of Compound BB-4-2

[0145] Triphenylphosphine (765.61 g, 1.5 eq) was dissolved in 3.5 L of anhydrous tetrahydrofuran under mechanical stirring (219 r/min) in an ice bath, and DIAD (567.54 mL) was slowly added dropwise within 100 minutes thereto with controlling the internal temperature below 10° C., and then continually stirred for 30 minutes at an increased speed of 400 r/min such that the reaction was allowed to proceed sufficiently to form a white viscous solid. 453.91 mL of absolute ethanol was continually and slowly added in an ice bath within 90 minutes e (the reaction exotherm is violent at the beginning of dripping, it is important to notice the dripping speed). BB-4-1 (300 g) was added when the solid was slowly dissolved to form a clear solution. The solution was mechanically stirred at 200 r/min for 5 hours under the condition that the ice bath was replaced with an oil bath to control the temperature of 30-35° C. (when the temperature exceeds 40° C., the selectivity is poor and the by-products increase). The reaction solution was placed under reduced pressure at 40° C. to give tetrahydrofuran, adjusted to pH 2 with 4 mol/L aqueous hydrochloric acid solution (700 mL), and added with 2 L of ethyl acetate solution after being fully stirred for 30 min for extraction. After carrying out extraction for 5 times and observing a clean aqueous phase by TLC plate and LCMS, the organic phase was discarded, the aqueous phase was added with 65 g of NaOH and stirred for 40 min, and adjusted to pH above 10 (the reaction exotherm is violent, it is important to notice the temperature), and extracted with 3 L of ethyl acetate as a solvent. After repeating extraction for 3 times and observing a clean organic phase by TLC plate and LCMS, the organic phases were combined and dried with 40 g of anhydrous sodium sulfate, and filter and evaporated under reduced pressure to remove ethyl acetate, in order to obtain BB-4-2.

[0146] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 7.46 (s, 1H), 4.41-4.24 (m, 4H), 2.48 (s, 3H), 1.39 (q, J=7.4 Hz, 6H)

[0147] MS-ESI (m/z): 182.9 [M+H].sup.+

[0148] Step 2: Synthesis of Compound BB-4-3

[0149] Tetrahydroaluminum lithium (59.36 g) was weighed, added to 1 L of anhydrous tetrahydrofuran solution in an ice bath, and mechanically stirred at a rotational speed (289 r/min) to form a solution. The compound BB-4-2 (285 g) was dissolved in 1 L of anhydrous tetrahydrofuran, and slowly dripped into the above solution in an ice bath at the controlled temperature below 10° C. within 1.5 hours. The solution was continually and mechanically stirred at the unchanged speed at room temperature for 12 hours under the condition that the ice bath was removed. 60 mL of deionized water was slowly added into the solution with mechanical stirring in an ice bath until the reaction was complete. The reaction product was slowly added dropwise with sodium hydroxide aqueous solution (4 mol/L, 60 mL) and stirred for 15 minutes, added with 180 mL of deionized water and continually stirred for 20 minutes, and then added with 80 g of anhydrous magnesium sulfate and stirred well, and finally filtered under reduced pressure. The filter cake was repeatedly washed 5-6 times with 5 L of dichloromethane, and the filtrate was combined and evaporated under reduced pressure at 40° C. to obtain BB-4-3.

[0150] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 7.51 (s, 1H), 4.82 (s, 3H), 4.27 (q, J=7.3 Hz, 2H), 2.33 (s, 3H), 1.69 (t, J=7.3 Hz, 3H).

[0151] Step 3: Synthesis of Compound BB-4-4

[0152] Compound BB-4-3 (180 g) was dissolved in 1.5 L of anhydrous dichloromethane and stirred magnetically, and thionyl chloride (186.3 mL) was slowly added dropwise thereto in an ice bath to form a mixture. After the addition, the mixture was heated to 40° C. under the condition that the ice bath was replaced with an oil bath and stirred for 6 hours under nitrogen atmosphere until the reaction was complete by detection of TLC plate. The reaction solution was cooled to room temperature, and evaporated under reduced pressure at 40° C. to remove the solvent. Dichloromethane (1 L) was added to the evaporated residue and distilled under reduced pressure which is repeated three times, and rotarily evaporated under reduced pressure for 45 min under the condition that the water pump was changed to an oil pump to obtain 190 g of a crude product of red viscous solid. The crude product was dissolved by adding 380 mL of acetonitrile solution, heating to 70° C. and refluxing for 2 hours, and cooled to room temperature by turning off the heating device and continually stirred for 12 hours. The mixed solution was slowly added dropwise to 3 L of ethyl acetate under stirring and the stirring was kept for 30 minutes after the addition was completed. The compound BB-4-4 was obtained by suction filtration under reduced pressure.

[0153] 1H NMR (400 MHz, DMSO-d6) δ ppm 9.19 (s, 1H), 5.06 (s, 2H), 4.24-4.20 (m, 2H), 2.34 (s, 3H), 1.45 (t, J=7.3 Hz, 3H).

[0154] Step 4: Synthesis of Compound BB-4-5

[0155] p-fluoronitrobenzene (97.64 g) was weighed and dissolved in dimethyl sulfoxide (1.1 L), and sodium sulfide (59.38 g) was added thereto under stirring in an ice bath, and stirred for 44 hours to formed a reaction solution. The compound BB-4-4 (90 g) was dissolved in DMSO (450 mL) and slowly dropped into the reaction solution within 7 hours. Then, the reaction solution was adjusted to pH 3 by addition of aqueous hydrochloric acid solution (4M, 0.5 L), extracted with 4 L of water and 4 L of ethyl acetate, and stirred for half an hour. After the phage separation, the aqueous phase is adjusted to pH 10 by addition of solid sodium hydroxide and extracted with 2 L of ethyl acetate twice. The twice extracted organic phases were combined and washed with 1 L of saturated brine, and evaporated. The organic phase was dried by adding anhydrous sodium sulfate, filtered, and evaporated. The spin-dried solid was crushed, and added with 2 mL of ethyl acetate and 100 mL of petroleum ether, stirred at room temperature for 1 hour, and filtered. The filter cake was dried under reduced pressure to obtain BB-4-5.

[0156] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.07 (d, J=8.78 Hz, 2H) 7.37 (s, 1H) 7.30 (d, J=8.78 Hz, 2H) 4.13 (s, 2H) 3.92 (q, J=7.28 Hz, 2H) 2.06 (s, 3H) 1.40 (t, J=7.28 Hz, 3H).

[0157] Step 5: Synthesis of Compound BB-4-6

[0158] BB-4-5 (64.72 g) was added to a solution of (1R, 2R)-1,2-diphenylethane-1,2-diol (100 g) in isopropanol (5000 mL), and stirred at 25° C. for 1 hour to form a mixture. Then, the mixture was added dropwise with titanium tetraisopropoxide (66.32 g) and stirred at 25° C. for 3 hours, and filtered to give a yellow solid (95 g). The obtained solid (72 g) was dissolved in dichloromethane (360 mL), and tert-butanol peroxy (14.17 mL, 65% purity) was added to the solution and was stirred at room temperature for 4 hours under nitrogen atmosphere. Then, the reaction solution was quenched with saturated aqueous sodium sulfite (200 mL), and adjusted to pH 3 with 2M aqueous hydrochloric acid. After the phage separation, the organic phase was discarded and the aqueous phase was adjusted to pH 8 with 8M of sodium hydroxide aqueous solution. The aqueous phase was extracted with ethyl acetate (300 mL×3). The combined organic phase was washed with saturated brine (300 mL), dried, filtered and evaporated under vacuum to obtain BB-4-6 (crude).

[0159] Step 6: Synthesis of Compound BB-4A

[0160] To a solution of compound BB-4-6 (19 g) and ammonium chloride (34.65 g) in methanol (250 mL) was added zinc powder (42.35 g) and stirred at 20° C. for 24 hours. After filtration, the filtrate was evaporated under reduced pressure to obtain a residue. The residue was purified by preparative high performance liquid chromatography to obtain the compound BB-4A. 59 .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 7.41 (s, 1H), 7.14-7.09 (m, J=8.5 Hz, 2H), 6.71-6.66 (m, J=8.5 Hz, 2H), 4.07-3.94 (m, 4H), 3.84 (dd, J=1.9, 7.4 Hz, 2H), 1.69 (s, 3H), 1.38 (t, J=7.3 Hz, 3H)

[0161] MS-ESI (m/z): 263.7 (M+H)+

[0162] Phase separation: Synthesis of Compound BB-4A and BB-4B

[0163] The compound BB-4 (prepared by referring to the synthesis of compound BB-3I in WO2018103757A1) was subjected to supercritical fluid chromatography (separation conditions: Column: ChiralPaK AD-3 150*4.6 mm ID, 3 μm; mobile phase: A: CO.sub.2 B: ethanol (0.05% DEA); gradient: 5%-40% B, 5.5 min, keeping 40% for 3 min and then keeping 5% B for 1.5 min; flow rate: 2.5 mL/min; column temperature: 40° C.; wavelength: 220 nm) to obtain the isomers BB-4A (retention time: 5.828 min) and BB-4B (retention time: 6.163 min).

[0164] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 7.43 (s, 1H), 7.15-7.10 (m, 2H), 6.71-6.66 (m, 2H), 4.07-3.95 (m, 4H), 3.85 (dd, J=1.9, 7.3 Hz, 2H), 1.70 (s, 3H), 1.39 (t, J=7.3 Hz, 3H).

[0165] MS-ESI m/z: 264.0 [M+H].sup.+.

Example 1

[0166] ##STR00056##

[0167] Synthetic Route:

##STR00057## ##STR00058##

[0168] Step 1: Synthesis of Compound WX001_1

[0169] The compound BB-1A (3.89 g, 13.14 mmol) and BB-3A (3 g, 26.28 mmol) were dissolved in 1,2-dichloroethane (50 mL) at 25° C., and sodium triacetoxyborohydride (11.14 g, 52.57 mmol) was added thereto and was stirred at 25° C. for 5 hours to form a reaction solution. The reaction solution was adjusted to pH 8 with 8M sodium hydroxide aqueous solution, and extracted with ethyl acetate (100 mL×3). The organic phases were combined, washed with 100 mL saturated brine once, dried with anhydrous sodium sulfate, and filtered to remove the desiccant. The filtrate was evaporated under reduced pressure to obtain the compound WX001_1.

[0170] MS-ESI (m/z): 394.20[M+1].sup.+

[0171] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=7.69 (s, 1H), 7.24 (s, 1H), 7.23-7.20 (m, 1H), 6.61 (d, J=9.5 Hz, 1H), 4.00 (dd, J=4.4, 10.9 Hz, 2H), 3.80 (s, 3H), 3.44-3.32 (m, 5H), 3.07 (d, J=7.0 Hz, 2H), 2.54-2.48 (m, 2H), 2.05-1.98 (m, 2H), 1.65 (br d, J=12.3 Hz, 2H), 1.46-1.41 (m, 2H).

[0172] Step 2: Synthesis of Compound WX001_2

[0173] At 25° C., the compound WX001_1 (0.6 g, 1.52 mmol), the compound BB-2 (487.29 mg, 1.52 mmol) and anhydrous potassium carbonate (630.91 mg, 4.57 mmol) were dissolved in a mixed solvent of dimethyl sulfoxide (10 mL) and water (2 mL), and Pd(dppf)Cl2 (222.68 mg, 304.34 μmol) was added thereto to form a reaction solution. The reaction solution was stirred for 20 hours under nitrogen atmosphere at 80° C. and poured into water (50 mL), and extracted with ethyl acetate (30 mL×3). The organic phases were combined and washed with saturated brine (100 mL) once, dried with anhydrous sodium sulfate, and filtered to remove the desiccant. The filtrate was evaporated under reduced pressure to obtain a crude product. The crude product was separated by column chromatography to obtain WX001_2 (0.603 g).

[0174] MS-ESI (m/z): 508.20[M+1].sup.+

[0175] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=7.88 (s, 1H), 7.45 (d, J=8.8 Hz, 2H), 7.40 (dd, J=2.4, 8.9 Hz, 1H), 7.34 (d, J=2.3 Hz, 1H), 6.96 (d, J=8.8 Hz, 2H), 6.82-6.77 (m, 1H), 4.18-4.14 (m, 2H), 4.01 (dd, J=3.8, 11.0 Hz, 2H), 3.83-3.78 (m, 7H), 3.56 (t, J=6.8 Hz, 2H), 3.48 (br t, J=5.3 Hz, 2H), 3.38 (t, J=11.0 Hz, 2H), 3.14 (d, J=7.0 Hz, 2H), 2.58-2.53 (m, 2H), 1.70 (br d, J=13.1 Hz, 2H), 1.65-1.60 (m, 2H), 1.51-1.44 (m, 3H), 1.29-1.26 (m, 2H), 0.94 (t, J=7.3 Hz, 3H).

[0176] Step 3: Synthesis of Compound WX001_3

[0177] The compound WX001_2 (0.603 g, 872 μM) was dissolved in methanol (10 mL) and water (2 mL) at 25° C. and sodium hydroxide (520.50 mg, 13.01 mmol) was added thereto to form a reaction solution. The reaction solution was heated to 50° C. and stirred for 43 hours, and adjusted to pH 3 with 2M dilute hydrochloric acid solution, and extracted with ethyl acetate (30 mL×3). The organic phases were combined, washed with saturated brine (100 mL) once, dried with anhydrous sodium sulfate, and filtered to remove the dryness The filtrate was concentrated under reduced pressure and evaporated to remove the desiccant to obtain WX001_3 (0.537 g).

[0178] MS-ESI (m/z): 494.20[M+1].sup.+

[0179] Step 4: Synthesis of Compound WX001

[0180] At 25° C., the compound WX001_3 (0.1 g, 202.58 μmol) and the compound BB-4A (53.35 mg, 202.58 μmol) were dissolved in pyridine (5 mL), and EDCI (77.67 mg, 405.16 μmol) was added thereto to form a reaction solution. The reaction solution was heated to 60° C. and stirred for 6 hours under nitrogen atmosphere, and poured into water (50 mL), and extracted with ethyl acetate (30 mL×3). The organic phases were combined, washed with saturated brine (100 mL) once, dried with anhydrous sodium sulfate, and filter to remove the desiccant. The filtrate was evaporated under reduced pressure to remove the solvent, in order to obtain the crude product. The crude product was separated by preparative HPLC (alkaline) to obtain WX001 (0.032 g).

[0181] MS-ESI (m/z): 739.90[M+1].sup.+.

[0182] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=7.92 (br s, 1H), 7.75 (d, J=8.8 Hz, 2H), 7.54 (s, 1H), 7.48-7.41 (m, 4H), 7.34 (s, 2H), 7.32 (s, 1H), 6.98 (d, J=8.8 Hz, 2H), 6.84 (d, J=8.8 Hz, 1H), 4.18-4.14 (m, 2H), 4.06 (s, 2H), 4.05-3.99 (m, 2H), 3.92-3.84 (m, 2H), 3.83-3.79 (m, 2H), 3.59-3.50 (m, 4H), 3.39 (br t, J=11.0 Hz, 2H), 3.17 (br d, J=7.0 Hz, 2H), 2.61 (br s, 2H), 2.10 (br s, 1H), 1.72 (br s, 1H), 1.69 (s, 4H), 1.66-1.63 (m, 2H), 1.46-1.42 (m, 2H), 1.42-1.36 (m, 7H), 0.94 (t, J=7.3 Hz, 3H).

Example 18

[0183] ##STR00059##

[0184] Synthetic Route:

##STR00060## ##STR00061##

[0185] Step 1: Synthesis of Compound WX018_1

[0186] At 25° C., the compound BB-1B (200 mg, 937.77 μmol) was dissolved in dichloromethane (5 mL) to form a solution. The compound BB-3B (370.88 mg, 937.77 μmol), zinc chloride (63.91 mg, 468.88 μmol, 21.96 μL) and magnesium sulfate (225.75 mg, 1.88 mmol) were added to the solution and stirred for 2 hours, and sodium acetate borohydride (596.25 mg, 2.81 mmol) was added to form a reaction solution. The reaction solution was stirred for 12 hours under nitrogen atmosphere and added with water (50 mL), and extracted with dichloromethane (30 mL×2). The organic phases were combined and dried with anhydrous sodium sulfate. The organic phase was spin-dried, and separated and purified by a silica gel column (silica gel, petroleum ether/ethyl acetate=10/1 to 3/1) to obtain WX018_1 (360 mg).

[0187] MS-ESI (m/z): 615.4[M+23].sup.+

[0188] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 7.77 (s, 1H), 7.53 (d, J=2.26 Hz, 1H), 7.47 (d, J=8.53 Hz, 2H), 7.41 (dd, J=8.78, 2.26 Hz, 1H), 6.99 (d, J=8.53 Hz, 2H), 6.88 (d, J=8.53 Hz, 1H), 4.23-4.06 (m, 4H), 3.84-3.80 (m, 5H), 3.56 (t, J=6.65 Hz, 2H), 3.35-3.22 (m, 4H), 2.82 (br s, 2H), 2.73-2.60 (m, 2H), 1.89 (br s, 1H), 1.74 (br d, J=12.05 Hz, 2H), 1.66-1.59 (m, 2H), 1.46 (s, 9H), 1.44-1.36 (m, 2H), 1.14 (br d, J=10.54 Hz, 2H), 0.94 (t, J=7.40 Hz, 3H).

[0189] Step 2: Synthesis of Compound WX018_2

[0190] The compound WX018_1 (360 mg, 607.32 μmol) was dissolved in hydrochloric acid/ethyl acetate (4 M, 5 mL), and stirred at 25° C. for 0.5 hours to form a reaction. The reaction solution was adjusted to pH 8 with saturated sodium carbonate solution, and added with water (20 mL), and extract with ethyl acetate (20 mL×2), the organic phases were combined, washed with saturated brine (20 mL), dried with anhydrous sodium sulfate and filtered. The filtrate was evaporated to obtain compound WX018_2 (300 mg).

[0191] Step 3: Synthesis of Compound WX018_3

[0192] Aqueous formaldehyde solution (45.34 μL, concentration: 37%) was added to a solution of compound WX018_2 (300 mg, 608.95 μmol) in methanol (3 mL) and dichloromethane (3 mL) and stirred for 30 minutes, and sodium acetate borohydride (193.59 mg, 913.43 μmol) was added and stirred at 25° C. for 12 hours to from a reaction solution. The reaction solution was evaporated to dryness, and added with water (20 mL), and extracted with ethyl acetate (20 mL×2). The organic phases were combined, washed with saturated brine (20 mL), and dried with anhydrous sodium sulfate. After filtration, the filtrate was evaporated to obtain the compound WX018_3 (254 mg).

[0193] MS-ESI (m/z): 507.1[M+1].sup.+

[0194] Step 4: Synthesis of Compound WX018_4

[0195] At 25° C., sodium hydroxide (80.20 mg, 2.01 mmol) was added to a solution of compound WX018_3 (254 mg, 501.31 μmol) in ethanol (5 mL) and water (5 mL), and stirred at 50° C. for 4 hours to form a reaction solution. The reaction solution was evaporated to remove ethanol, adjusted to pH 3 with 3N HCl, added with water (30 mL), and extracted with ethyl acetate (30 mL×2). The organic phases were combined, washed with saturated brine (50 mL), dried with anhydrous sulfuric acid, and filtered. The filtrate was evaporated to obtain the compound WX018_4 (212 mg).

[0196] MS-ESI (m/z): 493.0[M+1].sup.+

[0197] Step 5: Synthesis of Compound WX018

[0198] At 25° C., the compound WX018_4 (113.33 mg, 430.33 μmol) was added to a solution of BB-4A (212 mg, 430.33 μmol) in pyridine (5 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (82.49 mg, 430.33 μmol) was add and stirring at 60° C. for 12 hours form a reaction solution. The reaction solution was added with water (20 mL), and extracted with ethyl acetate (20 mL×2). The organic phases were combined, and washed with saturated brine (50 mL), dried with anhydrous sodium sulfate, and filtered and evaporated to give a crude product. The crude product was separated and purified by preparative HPLC (alkaline) to obtain WX018 (20 mg).

[0199] MS-ESI (m/z): 738.3[M+1].sup.+

[0200] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.44 (br s, 1H), 7.63 (d, J=8.78 Hz, 2H), 7.34-7.26 (m, 6H), 7.17-7.13 (d, J=8.78 Hz, 2H), 6.83 (m, 2H), 6.75 (d, J=8.53 Hz, 1H), 4.05-3.96 (m, 2H), 3.91-4.81 (m, 2H), 3.72-3.64 (m, 4H), 3.42 (t, J=6.65 Hz, 2H), 3.21 (br t, J=4.39 Hz, 2H), 2.13 (s, 2H) 2.80-2.70 (m, 4H), 2.13 (s, 3H), 2.03 (br s, 2H), 1.77 (br t, J=11.17 Hz, 2H), 1.67-1.57 (m, 3H), 1.52-1.45 (m, 5H), 1.19 (t, J=7.40 Hz, 5H), 0.80 (t, J=7.40 Hz, 3H).

[0201] With reference to the synthesis method of steps BB-1A to WX001 in Example 1, the compounds of Examples in the following table were synthesized.

TABLE-US-00001 Examples Fragment 1 Fragment 2 Fragment 3  2 [00062] [00063] [00064]  4 [00065] [00066] [00067]  5 [00068] [00069] [00070]  6 [00071] [00072] [00073]  7 [00074] [00075] [00076]  8 [00077] [00078] [00079] 13 [00080] [00081] [00082] 14 [00083] [00084] [00085] 17 [00086] [00087] [00088] 25 [00089] [00090] [00091] 26 [00092] [00093] [00094] 27 [00095] [00096] [00097] 28 [00098] [00099] [00100] Examples Fragment 4 Structures in Exmples and compound numbers  2 [00101] [00102]  4 [00103] [00104]  5 [00105] [00106]  6 [00107] [00108]  7 [00109] [00110]  8 [00111] [00112] 13 [00113] [00114] 14 [00115] [00116] 17 [00117] [00118] 25 [00119] [00120] 26 [00121] [00122] 27 [00123] [00124] 28 [00125] [00126]

[0202] With reference to the synthesis method of steps BB-1B to WX018 in Example 18, the compounds of Examples in the following table were synthesized.

TABLE-US-00002 Examples Fragment 1 Fragment 2 Fragment 3  3 [00127] [00128] [00129] 10 [00130] [00131] [00132] 11 [00133] [00134] [00135] 12 [00136] [00137] [00138] 15 [00139] [00140] [00141] Examples Structures in Examples and compound numbers  3 [00142] 10 [00143] 11 [00144] 12 [00145] 15 [00146] [00147]

[0203] With reference to the synthesis method of steps BB-1B to WX018 in Example 18, the compounds of Examples in the following table were synthesized.

TABLE-US-00003 Examples Fragment 1 Fragment 2 Fragment 3  9 [00148] [00149] [00150] 16 [00151] [00152] [00153] 19 [00154] [00155] [00156] 20 [00157] [00158] [00159] 21 [00160] [00161] [00162] 22 [00163] [00164] [00165] 23 [00166] [00167] [00168] 24 [00169] [00170] [00171] Examples Structures in Examples and compound numbers  9 [00172] 16 [00173] 19 [00174] 20 [00175] 21 [00176] 22 [00177] 23 [00178] 24 [00179] [00180]

[0204] .sup.1H NMR and MS data in each of Examples

TABLE-US-00004 Compound MS Examples Nos NMR m/z: 2 WX002 .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 7.90 (s, 1H), 7.78-7.72 739.9 (m, 1H), 7.75 (d, J = 8.8 Hz, 1H), 7.54 (s, 1H), 7.48-7.40 (m, 4H), 7.35-7.33 (m, 2H), 7.32 (s, 1H), 6.98 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.8 Hz, 1H), 4.19-4.14 (m, 2H), 4.06 (s, 2H), 4.02 (br d, J = 11.3 Hz, 2H), 3.92-3.84 (m, 2H), 3.84-3.79 (m, 2H), 3.58-3.50 (m, 4H), 3.39 (br t, J = 11.3 Hz, 2H), 3.17 (d, J = 6.5 Hz, 2H), 2.64-2.56 (m, 2H), 2.10 (br s, 1H), 1.69 (s, 5H), 1.63 (m, 4H), 1.47-1.37 (m, 7H), 0.94 (t, J = 7.3 Hz, 3H). 3 WX003 .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 7.81 (s, 1H), 7.74 725.5 (d, J = 8.3 Hz, 2H), 7.53 (s, 1H), 7.49 (s, 1H), 7.48-7.42 (m, 4H), 7.33 (d, J = 9.0 Hz, 2H), 6.99 (d, J = 8.5 Hz, 2H), 4.17 (t, J = 5.1 Hz, 2H), 4.06 (s, 2H), 3.97 (q, J = 8.3 Hz, 4H), 3.87 (br d, J = 10.3 Hz, 2H), 3.83-3.80 (m, 2H), 3.56 (t, J = 6.7 Hz, 2H), 3.47 (d, J = 6.0 Hz, 2H), 3.43 (br d, J = 4.3 Hz, 2H), 2.97 (br s, 1H), 1.82 (br d, J = 8.3 Hz, 2H), 1.71-1.69 (m, 1H), 1.71-1.68 (m, 1H), 1.44-1.37 (m, 5H), 1.30 (br s, 2H), 1.26-1.26 (m, 3H), 0.96-0.92 (m, 3H), 0.89 (br s, 2H). 4 WX004 .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.91 (s, 1H), 7.75 711.2 (d, J = 8.4 Hz, 2H), 7.42-7.40 (m, 4H), 7.36 (s, 1H), 7.30-7.29 (m, 3H), 6.97-6.95 (m, 2H), 6.89-6.87 (m, 1H), 4.82 (t, J = 6.8 Hz, 2H), 4.55 (t, J = 6.0 Hz, 2H), 4.15 (t, J = 4.8 Hz, 2H), 4.07-3.98 (m, 2H), 3.86-3.78 (m, 4H), 3.57-3.54 (m, 4H), 3.43-3.39 (m, 3H), 2.61 (brs, 2H), 1.65-1.58 (m, 7H), 1.44-1.32 (m, 5H), 0.93 (t, J = 7.2 Hz, 3H). 5 WX005 .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.72 (s, 1H), 7.78 725.3 (d, J = 8.8 Hz, 2H), 7.54-7.59 (m, 3H), 7.44 (s, 1H), 7.35-7.32 (m, 5H), 7.00 (d, J = 8.8 Hz, 2H), 4.74 (t, J = 7.2 Hz, 2H), 4.45(t, J = 6.0 Hz, 2H), 4.17 (t, J = 4.8 Hz, 2H), 4.06 (s, 2H), 3.90-3.80 (m, 4H), 3.56 (t, J = 6.8 Hz, 2H), 3.21 (d, J = 6.0 Hz, 2H), 3.10-3.05 (m, 3H), 2.32-2.31 (m, 2H), 1.72- 1.65 (m, 5H), 1.64-1.58 (m, 4H), 1.45-1.35 (m, 5H), 0.94 (t, J = 7.2 Hz, 3H). 6 WX006 .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.91 (d, J = 7.2 Hz, 753.4 1H), 7.78 (dd, J = 8.4, 2.0 Hz, 2H), 7.54-7.27 (m, 9H), 7.00 (d, J = 8.4 Hz, 2H), 4.17 (t, J = 4.8 Hz, 2H), 4.11-4.02 (m, 2H), 3.88-3.68 (m, 8H), 3.56 (t, J = 6.8 Hz, 2H), 3.00-2.61 (m, 5H), 2.01-1.58 (m, 10H), 1.48-1.26 (m, 10H), 0.94 (t, J = 7.2 Hz, 3H). 7 WX007 .sup.1H NMR: (400 MHz, CDCl.sub.3) δ ppm 8.99 (s, 1H), 7.78 753.4 (dd, J = 8.8, 2.8 Hz, 2H), 7.52-7.27 (m, 9H), 7.00 (d, J = 8.8 Hz, 2H), 4.16 (t, J = 4.8 Hz, 2H), 4.04 (brs, 2H), 3.86- 3.72 (m, 8H), 3.55 (t, J = 6.8 Hz, 2H), 2.96-2.58 (m, 5H), 2.04 (brs, 3H), 1.84-1.35 (m, 17H), 0.93 (t, J = 7.2 Hz, 3H). 8 WX008 .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 7.83 ppm (s, 1H), 370.3(M/2 + 1).sup.+ 7.75 (d, J = 8.78 Hz, 2H), 7.57 (s, 1H), 7.48-7.43 (m, 3H), 7.43- 7.38 (m, 1H), 7.36-7.31 (m, 3H), 6.97 (d, J = 8.78 Hz, 2H), 6.86 (d, J = 8.78 Hz, 1H), 4.18-4.13 (m, 2H), 4.07 (s, 2H), 4.01 (br d, J = 14.31 Hz, 1H), 3.91-3.83 (m, 2H), 3.83-3.79 (m, 2H), 3.73 (br s, 2H), 3.56 (t, J = 6.65 Hz, 3H), 3.46-3.35 (m, 1H), 3.30 (br d, J = 5.27 Hz, 2H), 2.63- 2.52 (m, 2H), 1.71 (m, 5H), 1.63 (br s, 2H), 1.62-1.60 (m, 2H), 1.54-1.49 (m, 2H), 1.42-1.35 (m, 5H), 1.26 (s, 2H), 0.94 (t, J = 7.40 Hz, 3H). 9 WX009 .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.83 ppm (br s, 1H), 752.3 7.86 (br d, J = 8.28 Hz, 2H), 7.53 (br s, 1H), 7.45 (br s, 4H), 7.39 (br s, 2H), 7.31 (br d, J = 8.03 Hz, 2H), 6.97 (br d, J = 8.03 Hz, 2H), 4.15 (br s, 2H), 4.05 (br s, 2H), 3.92 (m, 2H), 3.91-3.84 (m, 2H), 3.84-3.79 (m, 4H), 3.45-3.27 (m, 4H), 2.62 (br s, 5H), 2.48 (br s, 2H), 2.02 (br s, 2H), 1.69 (br s, 3H), 1.61 (br s, 5H), 1.48-1.31 (m, 7H), 0.93 (br t, J = 7.15 Hz, 3H). 10 WX010 .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.66 (s, 1H), 7.75 697.1 (d, J = 8.8 Hz, 2H), 7.45-7.38 (m, 6H), 7.27 (d, J = 8.4 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.4 Hz, 1H), 4.83- 4.79 (m, 2H), 4.41 (t, J = 6.0 Hz, 2H), 4.16 (t, J = 4.8 Hz, 2H), 4.05-3.95 (m, 2H), 3.85-3.79 (m, 4H), 3.71 (d, J = 7.6 Hz, 2H), 3.55 (t, J = 6.4 Hz, 2H), 3.29 (t, J = 4.8 Hz, 2H), 2.85 (t, J = 4.0 Hz, 2H), 2.00-1.85 (brs, 1H), 1.65- 1.58 (m, 5H), 1.44-1.31 (m, 5H), 0.93 (t, J = 7.2 Hz, 3H). 11 WX011 .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.04 (br s, 1H), 7.75 711.1 (br d, J = 8.3 Hz, 2H), 7.50 (br d, J = 11.3 Hz, 2H), 7.45 (br d, J = 7.8 Hz, 4H), 7.32 (br d, J = 8.0 Hz, 2H), 7.02-6.92 (m, 3H), 4.16 (br d, J = 4.8 Hz, 2H), 4.05 (br s, 2H), 3.93-3.85 (m, 2H), 3.84-3.73 (m, 5H), 3.63 (br d, J = 8.0 Hz, 2H), 3.56 (br t, J = 6.8 Hz, 2H), 3.44-3.33 (m, 4H), 2.93 (br s, 2H), 2.72 (br s, 1H), 1.67 (br s, 3H), 1.64-1.60 (m, 2H), 1.42- 1.36 (m, 4H), 1.26 (br s, 2H), 0.94 (br t, J = 7.3 Hz, 3H). 12 WX012 .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 7.74 (br d, J = 9.0 711.5 Hz, 3H), 7.54 (s, 1H), 7.49 (d, J = 8.8 Hz, 2H), 7.44 (s, 2H), 7.34 (d, J = 8.8 Hz, 2H), 7.02-6.94 (m, 4H), 4.19-4.15 (m, 2H), 4.07 (s, 2H), 3.94 (s, 2H), 3.87 (s, 2H), 3.84-3.75 (m, 5H), 3.65 (s, 2H), 3.56 (t, J = 6.9 Hz, 2H), 3.39 (br d, J = 9.3 Hz, 4H), 2.94 (br s, 2H), 1.71 (s, 3H), 1.62 (s, 2H), 1.40 (t, J = 6.9 Hz, 3H), 1.26 (s, 2H), 0.94 (t, J = 7.5 Hz, 3H). 13 WX013 .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 7.96 (s, 1H), 7.75 725.1 (d, J = 8.8 Hz, 2H), 7.47-7.43 (m, 5H), 7.33 (d, J = 8.5 Hz, 2H), 7.00-6.94 (m, 3H), 4.19-4.14 (m, 2H), 4.07 (s, 2H), 3.97 (br d, J = 4.8 Hz, 2H), 3.87 (br d, J = 12.0 Hz, 2H), 3.84- 3.80 (m, 3H), 3.79-3.75 (m, 1H), 3.68-3.63 (m, 2H), 3.56 (t, J = 6.8 Hz, 2H), 3.49-3.43 (m, 2H), 3.31-3.24 (m, 2H), 2.71 (br s, 2H), 2.63 (br s, 2H), 2.09 (br d, J = 4.5 Hz, 1H), 1.71 (s, 2H), 1.63 (br d, J = 7.8 Hz, 4H), 1.41-1.37 (m, 3H), 1.26 (s, 2H), 0.94 (t, J = 7.4 Hz, 3H). 14 WX014 .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 7.88 (s, 1H), 7.75 725.1 (d, J = 8.8 Hz, 2H), 7.49-7.43 (m, 5H), 7.38-7.31 (m, 3H), 7.01- 6.94 (m, 3H), 4.18-4.14 (m, 2H), 4.07 (s, 2H), 3.97 (br d, J = 5.3 Hz, 2H), 3.87 (br dd, J = 4.6, 7.4 Hz, 2H), 3.84- 3.80 (m, 2H), 3.80-3.74 (m, 2H), 3.68-3.62 (m, 1H), 3.56 (t, J = 6.7 Hz, 2H), 3.45 (br d, J = 5.5 Hz, 2H), 3.32-3.25 (m, 2H), 2.70 (s, 2H), 2.63 (br s, 2H), 2.11 (br d, J = 7.5 Hz, 2H), 1.71 (s, 3H), 1.67-1.61 (m, 4H), 1.39 (s, 3H), 0.94 (t, J = 7.4 Hz, 3H). 15 WX015 .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.05 (s, 1H), 7.74 725.1 (d, J = 8.8 Hz, 2H), 7.51-7.41 (m, 6H), 7.31 (d, J = 8.5 Hz, 2H), 6.99 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 8.5 Hz, 1H), 4.17 (t, J = 4.9 Hz, 2H), 4.04 (s, 2H), 4.00 (br dd, J = 3.4, 11.2 Hz, 2H), 3.90-3.79 (m, 4H), 3.56 (t, J = 6.8 Hz, 2H), 3.41-3.33 (m, 4H), 3.30 (br d, J = 7.0 Hz, 2H), 2.92 (br s, 2H), 2.00 (br s, 1H), 1.72 (br s, 2H), 1.66-1.57 (m, 5H), 1.46-1.28 (m, 7H), 0.94 (t, J = 7.4 Hz, 3H). 16 WX016 .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.67 (s, 1H), 7.58 754.3 (d, J = 8.4 Hz, 2H), 7.27-7.21 (m, 5H), 7.10-7.08 (m, 3H), 6.83 (d, J = 8.4 Hz, 1H), 6.77 (d, J = 8.8 Hz, 2H), 3.97 (t, J = 4.2 Hz, 2H), 3.81 (dd, J = 23.2, 14.0 Hz, 2H), 3.69-3.58 (m, 6H), 3.52-3.43 (m, 2H), 3.37 (t, J = 6.8 Hz, 2H), 3.29-3.09 (m, 3H), 2.97-2.91 (m, 1H), 2.56 (d, J = 12.0 Hz, 1H), 2.43-2.39 (m, 3H), 2.27 (s, 3H), 2.23-2.17 (m, 1H), 1.45-1.39 (m, 7H), 1.26-1.19 (m, 2H), 1.14 (t, J = 7.2 Hz, 3H), 0.75 (t, J = 7.2 Hz, 3H). 17 WX017 .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 7.83 (s, 1H), 7.75 739.3 (d, J = 8.53 Hz, 2H), 7.54 (s, 1H), 7.50-7.41 (m, 4H), 7.33 (d, J = 8.78 Hz, 3H), 6.98 (d, J = 8.78 Hz, 2H), 6.84 (d, J = 8.78 Hz, 1H), 4.16 (d, J = 5.52 Hz, 2H), 4.07 (br d, J = 5.02 Hz, 4H), 3.89 (br d, J = 4.52 Hz, 2H), 3.85-3.78 (m, 2H), 3.58-3.51 (m, 4H), 3.39 (s, 2H), 3.17 (br d, J = 6.78 Hz, 2H), 2.61 (br s, 2H), 2.11 (br s, 1H), 1.69 (s, 5H), 1.64 (br s, 4H), 1.44-1.37 (m, 7H), 0.94 (q, J = 7.28 Hz, 3H). 19 WX019 .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 7.67 (br d, J = 8.5 740.4 Hz, 3H), 7.48-7.45 (m, 1H), 7.42 (s, 1H), 7.40-7.35 (m, 4H), 7.27 (d, J = 8.5 Hz, 2H), 6.94-6.89 (m, 3H), 4.11-4.07 (m, 2H), 3.99 (s, 2H), 3.83 (br s, 1H), 3.78 (d, J = 7.5 Hz, 1H), 3.76-3.72 (m, 3H), 3.48 (t, J = 6.7 Hz, 2H), 3.32 (br s, 2H), 2.90 (br s, 2H), 2.71 (s, 2H), 2.42 (br s, 3H), 1.66-1.64 (m, 1H), 1.65 (s, 2H), 1.58-1.53 (m, 4H), 1.31 (t, J = 7.3 Hz, 5H), 1.20-1.17 (m, 4H), 0.88-0.85 (m, 3H). 20 WX020 .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 7.76 (d, J = 8.5 740.4 Hz, 1H), 7.88-7.69 (m, 1H), 7.83-7.69 (m, 1H), 7.54 (d, J = 9.3 Hz, 1H), 7.51-7.43 (m, 5H), 7.34 (d, J = 8.5 Hz, 2H), 7.02-6.96 (m, 3H), 4.17 (t, J = 4.9 Hz, 2H), 4.07 (s, 2H), 3.88 (s, 2H), 3.87-3.79 (m, 5H), 3.56 (t, J = 6.8 Hz, 2H), 3.40 (br s, 2H), 2.99 (br s, 2H), 2.53 (br s, 1H), 2.59-2.45 (m, 2H), 1.73 (s, 3H), 1.69-1.66 (m, 4H), 1.40 (t, J = 7.4 Hz, 5H), 1.26 (s, 4H), 0.94 (s, 3H). 21 WX021 .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 7.85 (s, 1H), 7.74 740.5 (d, J = 8.8 Hz, 2H), 7.51 (d, J = 2.0 Hz, 1H), 7.47 (d, J = 8.8 Hz, 2H), 7.45-7.41 (m, 3H), 7.33 (d, J = 8.5 Hz, 2H), 7.04-6.95 (m, 3H), 4.19-4.13 (m, 2H), 4.05 (s, 2H), 3.97-3.89 (m, 2H), 3.89-3.84 (m, 2H), 3.84-3.80 (m, 2H), 3.72-3.65 (m, 1H), 3.56 (t, J = 6.8 Hz, 2H), 3.53-3.45 (m, 2H), 3.44-3.36 (m, 2H), 2.93 (br s, 2H), 2.86-2.65 (m, 2H), 2.32 (s, 3H), 2.21-2.11 (m, 1H), 1.91 (t, J = 10.8 Hz, 1H), 1.70 (s, 3H), 1.65 (br s, 2H), 1.45-1.36 (m, 5H), 0.94 (t, J = 7.4 Hz, 3H). 22 WX022 .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 7.81 (s, 1H), 7.74 740.5 (d, J = 8.5 Hz, 2H), 7.52 (d, J = 2.0 Hz, 1H), 7.48 (d, J = 8.8 Hz, 2H), 7.45-7.40 (m, 3H), 7.33 (d, J = 8.5 Hz, 2H), 7.03-6.97 (m, 3H), 4.17 (t, J = 4.9 Hz, 2H), 4.06 (s, 2H), 3.97-3.89 (m, 2H), 3.89-3.84 (m, 2H), 3.83-3.79 (m, 2H), 3.73-3.64 (m, 1H), 3.56 (t, J = 6.7 Hz, 2H), 3.53-3.44 (m, 2H), 3.44-3.36 (m, 2H), 2.93 (br s, 2H), 2.82 (br d, J = 11.5 Hz, 1H), 2.69 (br d, J = 11.8 Hz, 1H), 2.32 (s, 3H), 2.21-2.12 (m, 1H), 1.91 (t, J = 10.7 Hz, 1H), 1.71 (s, 3H), 1.66- 1.62 (m, 2H), 1.44-1.36 (m, 5H), 0.94 (t, J = 7.4 Hz, 3H). 23 WX023 .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.02 (s, 1H), 7.75 754.5 (d, J = 8.8 Hz, 2H), 7.54 (s, 1H), 7.47-7.37 (m, 4H), 7.33 (d, J = 8.8 Hz, 3H), 6.97 (d, J = 8.8 Hz, 2H), 6.90 (d, J = 8.8 Hz, 1H), 4.18-4.14 (m, 2H), 4.06 (s, 2H), 3.90 (br d, J = 13.3 Hz, 2H), 3.85 (dd, J = 5.0, 7.3 Hz, 2H), 3.83-3.79 (m, 2H), 3.71-3.61 (m, 2H), 3.56 (t, J = 6.7 Hz, 2H), 3.51 (br d, J = 9.3 Hz, 1H), 3.35-3.29 (m, 1H), 3.38-3.27 (m, 1H), 2.84 (br d, J = 10.5 Hz, 1H), 2.67 (br d, J = 11.3 Hz, 1H), 2.62- 2.51 (m, 2H), 2.33 (s, 3H), 2.16 (dt, J = 3.5, 11.4 Hz, 1H), 1.92 (t, J = 10.5 Hz, 1H), 1.70 (s, 3H), 1.65-1.63 (m, 2H), 1.58 (br s, 2H), 1.44-1.36 (m, 5H), 0.94 (t, J = 7.4 Hz, 3H). 24 WX024 .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 7.97 (br s, 1H), 754.5 7.76 (d, J = 8.5 Hz, 2H), 7.54 (s, 1H), 7.47-7.38 (m, 4H), 7.33 (d, J = 8.5 Hz, 3H), 6.97 (d, J = 8.8 Hz, 2H), 6.90 (d, J = 8.8 Hz, 1H), 4.16 (t, J = 4.9 Hz, 2H), 4.06 (s, 2H), 3.91 (br d, J = 13.3 Hz, 2H), 3.86 (dd, J = 5.0, 7.3 Hz, 2H), 3.83-3.79 (m, 2H), 3.72-3.61 (m, 2H), 3.56 (t, J = 6.7 Hz, 2H), 3.50 (br s, 1H), 3.37-3.27 (m, 2H), 2.85 (br d, J = 9.5 Hz, 1H), 2.68 (br d, J = 11.3 Hz, 1H), 2.63-2.52 (m, 2H), 2.33 (s, 3H), 2.20- 2.13 (m, 1H), 1.92 (t, J = 10.9 Hz, 1H), 1.70 (s, 3H), 1.64 (br s, 2H), 1.59-1.57 (m, 2H), 1.43-1.36 (m, 5H), 0.94 (t, J = 7.3 Hz, 3H). 25 WX025 .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.46-8.35 ppm 741.4 (br s, 1H), 7.68 (d, J = 8.53 Hz, 2H), 7.46 (s, 1H), 7.38-7.29 (m, 4H), 7.22 (d, J = 8.53 Hz, 3H), 6.79 (d, J = 8.78 Hz, 2H), 6.89 (d, J = 8.78 Hz, 1H), 4.08 (t, J = 4.89 Hz, 2H), 4.03-3.93 (m, 2H), 3.82-3.76 (m, 2H), 3.76-3.72 (m, 4H), 3.69-3.61 (m, 2H), 3.68-3.59 (m, 5H), 3.44-3.29 (m, 2H), 3.28- 3.12 (m, 2H), 2.49 (br t, J = 5.77 Hz, 2H), 1.60-1.48 (m, 7H), 1.37-1.31(m, 2H), 1.30-1.25 (t, J = 7.40 Hz, 3H), 0.86 (t, J = 7.28 Hz, 3H). 26 WX026 .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.70 ppm (br s, 741.3 1H), 7.77 (d, J = 8.53 Hz, 2H), 7.54 (s, 1H), 7.45-7.35 (m, 4H), 7.29 (d, J = 8.53 Hz, 2H), 7.26 (s, 1H), 6.96 (d, J = 8.78 Hz, 3H), 6.86 (d, J = 8.78 Hz, 1H), 4.15 (t, J = 4.89 Hz, 2H), 4.10- 3.99 (m, 2H), 3.89-3.83 (m, 2H), 3.83-3.79 (m, 4H), 3.76-3.68 (m, 2H), 3.68-3.59 (m, 5H), 3.53-3.37 (m, 1H), 3.34-3.20 (m, 2H), 2.56 (br t, J = 5.77 Hz, 2H), 1.66-1.56 (m, 7H), 1.46-1.36 (m, 2H), 1.34 (t, J = 7.40 Hz, 3H), 0.94 (t, J = 7.28 Hz, 3H). 27 WX027 .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.13 (br s, 1H), 725.4 7.76 (d, J = 8.53 Hz, 2H), 7.54 (s, 1H), 7.48-7.37 (m, 4H), 7.32 (d, J = 8.78 Hz, 3H), 7.01-6.89 (m, 3H), 4.27-12 (br s, 3H), 4.06 (m, 2H), 3.98-3.89 (m, 1H), 3.89-3.74 (m, 5H), 3.70(m, 1H), 3.56 (t, J = 6.78 Hz, 3H), 3.47-3.28 (m, 2H), 2.59 (br s, 2H), 2.28-2.05 (m, 1H), 2.03-1.81 (m, 2H), 1.69 (br s, 3H), 1.64-1.56 (m, 5H), 1.44-1.33 (m, 5H), 0.94 (t, J = 7.28 Hz, 3H). 28 WX028 .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.29 (br s, 1H), 725.4 7.76 (d, J = 8.53 Hz, 2H), 7.54 (s, 1H), 7.48-7.36 (m, 4H), 7.31 (br d, J = 8.78 Hz, 3H), 7.01-6.89 (m, 3H), 4.22 (br s, 1H), 4.19-4.11 (m, 2H), 4.05 (s, 2H), 3.98-3.89 (m, 1H), 3.88-3.74 (m, 5H), 3.74-3.63 (m, 1H), 3.62-3.49 (m, 3H), 3.49-3.31 (m, 2H), 2.59 (br s, 2H), 2.11 (br d, J = 6.78 Hz, 1H), 2.03-1.81 (m, 2H), 1.68 (br s, 3H), 1.64- 1.56 (m, 5H), 1.44-1.33 (m, 5H), 0.94 (t, J = 7.28 Hz, 3H).

[0205] Experimental Example 1: CCR2/CCR5 in vitro test

[0206] Purpose:

[0207] The changes in intracellular calcium signal were detected by FLIPR Calcium assay, and the compound's IC50 value was used as an indicator to evaluate inhibitory effect of the compound on CCR2 and CCR5 receptors.

[0208] Experimental Materials:

[0209] 1, Cell line: Cells were seeded and incubated overnight in an incubator at 37° C. and 5% CO.sub.2.

[0210] CCR2/CCR5 density: 1 M (20K/Well)

TABLE-US-00005 Cell line Number of clones Cellular generation Host cell CCR2 C7 P6 HEK293 CCR5 C13 P4 HEK293

[0211] 2, Reagents: Fluo-4 Direct, (Invitrogen, Cat #f10471)

[0212] 3, Device and Equipment:

[0213] 384 cell plates coated with polylysine (Greiner #781946)

[0214] 384-well compound plates (Greiner #781280)

[0215] FLIPR, a molecular device

[0216] Echo, LabCyte

[0217] 4, Compound:

[0218] The compound was dissolved in DMSO to prepare a 10 mM solution, and the compound solution was placed in a nitrogen gas box.

TABLE-US-00006 Compound ID purity Compound weight (mg) CENICRIROC (CVC) 97.00 1.15

[0219] Reference Antagonist Compound:

TABLE-US-00007 MCP-1 Sigma SRP3109 10 μm stock in H.sub.2O Rantes Sigma SRP3269 10 μm stock in H.sub.2O

[0220] Experimental Steps and Methods:

[0221] Preparation of probenecid in FLIPR assay buffer: 1 mL of FLIPR assay buffer was added to 77 mg of probenecid to prepare a 250 mM solution. The 250 mM solution was freshly prepared every day.

[0222] 2×(8 μM) Fluo-4 Direct™ loading buffer (per 10 mL)

[0223] a bottle of Fluo-4 Direct™ crystal (F10471) was thawed.

[0224] 10 mL of FLIPR assay buffer was added to a sample bottle.

[0225] 0.2 mL of probenecid was added per 10 mL of Fluo-Direct. The final measured concentration is 2.5 mM,

[0226] Rotating and standing for >5 minutes (protecting from light)

[0227] Freshly prepared every day

[0228] Experimental Steps:

[0229] a) Preparation of agonist compound:

[0230] MCP-1 was serially diluted with FLIPR assay buffer starting from 0.5 μM at a dilution ratio of 1:2 and a total of 10 gradients were diluted (final 100 nM). RANTES is serially diluted with FLIPR assay buffer starting from 0.5 μM at a dilution ratio of 1:3 and a total of 10 gradients were diluted (final 100 nM). According to the compound plate-map, 20 μL of the serially diluted compound buffers were added to each well of the DRC plate respectively.

[0231] b) Preparation of antagonist compound: reference antagonist compound

[0232] The standard compound was diluted with DMSO 1:3 starting from 1 mM at a dilution ratio of 1:3 and a total of 11 gradients were diluted. The test compound was diluted with DMSO 1:3 starting from 2 mM at a dilution ratio of 1:3 and a total of 11 gradients were diluted. 250 nL of the compound solution was transferred to the cell plate (Greiner #781946) using Echo.

[0233] c) taking the cell plate from the incubator, and gently distributing 20 μL of 2× Fluo-4 Direct non-washing loading buffer to each well of the 384-well cell culture plate using a pipette, wherein each of wells in the cell plate has a final volume of 40 μL.

[0234] d) Incubating at 37° C. and 5% CO.sub.2 for 50 minutes, and at room temperature for 10 minutes.

[0235] e) removing the cell plate from the incubator and placing in FLIPR, and putting the composite plate and the tip box into FLIPR.

[0236] f) For the DRC board:

[0237] 1) Running the program on FLIPRTETRA

[0238] 2) Reading the fluorescence signal

[0239] 3) Transferring 10 μL of the compound from the DRC plate to the cell plate

[0240] 4) Reading the fluorescence signal

[0241] 5) Calculating from Read 90 to the maximum allowable “maximum-minimum”, and calculating the EC80 value of each of cell lines by using FLIPR

[0242] 6) Preparing the reference agonist compound at a concentration of 5×EC80

[0243] g) For the composite plate (1-add):

[0244] 1) Running the program on FLIPRTETRA

[0245] 2) Transferring 10 L1 of the reference agonist compound at a concentration of 5×EC80 from the composite plate to the cell plate.

[0246] 3) Reading the fluorescence signal.

[0247] 4) Calculating from Read 90 to the maximum allowable “maximum-minimum”.

[0248] h) Analyzing the data and calculating the IC50 value of the compound by using Prism.

[0249] The experimental results are shown in Table 1.

TABLE-US-00008 TABLE 1 IC.sub.50 (nM) test results for FLIPR detection Compound numbers CCR2 CCR5 WX001 1.33 4.25 WX002 3 8.15 WX003 37 8.27 WX004 3.04 6.3 WX005 9.2 4.2 WX006 7.51 8.44 WX007 6.76 6.18 WX008 3.4 6.04 WX009 4.38 6.78 WX010 7.48 7.33 WX011 6.82 4.33 WX012 6.19 3.29 WX013 3.11 5.45 WX014 3.78 6.28 WX015 7.65 5.62 WX016 3.9 4.12 WX017 2.47 1.7 WX018 17.9 3.35 WX019 4.97 0.65 WX020 18.1 6.99 WX021 48.9 15.7 WX022 21 10.3 WX023 2.62 2.45 WX024 1.59 0.76 WX025 0.69 1.38 WX026 0.69 1.37 WX027 0.41 1.44 WX028 1.19 3.15

[0250] Conclusion: the compounds of the invention have significant antagonistic effect on CCR2 and CCR5 receptors.

[0251] Experimental Example 2. Inhibition of human liver microsomal cytochrome P450 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) activity

[0252] A total of 5 specific probe substrates of 5 CYP isozymes, which are phenacetin (PHenacetin, CYP1A2), diclofenac (Diclofenac, CYP2C9), (S)-mephenytoin ((S)-MepHenytoin, CYP2C19), dextromethorpHan (CYP2D6), and midazolam (Midazolam, CYP3A4), were incubated with human liver microsomes respectively. Then, reduced nicotinamide adenine dinucleotide phosphate (NADPH) was added to initiate reaction. After the reaction, the sample is processed and quantitatively detected for the concentrations of the five metabolites produced from the specific substrate, acetaminophen (AcetaminopHen), 4′-hydroxydiclofenac (4′-Hydroxydiclofenac), 4′-Hydroxymephenytoin (4′-HydroxymepHenytoin), Dextrorphan (DextrorpHan), and 1′-Hydroxymidazolam (1′-Hydroxymidazolam) by liquid chromatography-quadrupole mass spectrometry (LC-MS/MS) method to calculate the corresponding half inhibitory concentration (IC.sub.50).

TABLE-US-00009 TABLE 2 Half inhibitory concentrations of compounds IC50 (μM) Compound CYP3A4- numbers CYP1A2 CYP2C9 CYP2C19 CYP2D6 M Reference >50 >50 >50 >50 0.75 compound (CVC) Reference A >50 >50 >50 >50 0.786 WX001 >50 >50 1.42 >50 >50 WX002 >50 10.9 >50 >50 13.3 WX011 >50 22.8 >50 >50 >50

[0253] Conclusion: WX002 and WX011 have no risk of inhibiting the activity of human liver microsomal cytochrome P450 isoenzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4). The drugs that CYP2C19 involves in their metabolism account for only 2% of marketed drugs, while the drugs that CYP3A involves in their metabolism have accounted for 50% of marketed drugs. The reference compound and the reference A have a strong inhibitory effect on CYP3A4, which is reflected in the clinical practice of inhibiting CYP3A4 to increase exposure to other drugs metabolized by CYP3A4, thereby having a potential safety risk, that is, drug-drug interaction. WX001 has no inhibitory effect on CYP3A4, the main metabolic enzyme of drug metabolism, thereby avoiding occurrence of such risks.

Experimental Example 3 Anti-Tumor Activity of Compounds of the Invention in Animal Tumor Models In Vivo

[0254] Purpose:

[0255] The anti-tumor effect of the compound of the invention in combination with a anti-PD-1 antibody in mice (RMP1-14, Bioxcell, catalog number BP0146) was investigated in a colon cancer MC38 tumor model in mice in vivo.

[0256] Experimental Method:

[0257] Female C57BL/6 mice were subcutaneously inoculated with MC38 colon cancer cell lines in mice, and randomly grouped according to the body weight after inoculation. The administration was carried out according to the following description.

[0258] Group 1 (A control group): the vehicle 1 (5% DMSO/95% (10% HP-β-CD: β-Cyclodextrin)) was administrated intragastrically at a dose of 0.1 mL/10 g body weight twice daily, starting in the afternoon on the day of inoculation. Vehicle 2 (DPBS: Dulbecco's phosphate buffered saline) was administrated by intraperitoneal injection at a dose of 0.1 mL/10 g body weight at 11, 14 and 18 day after inoculation.

[0259] Group 2: Anti-mouse PD-1 antibody (RMP1-14) was injected intraperitoneally at 11, 14 and 18 day after inoculation once. The dose at 11 day is 3 mg/kg body weight, and the dose at 14 day and the dose 18 day is 6 mg/kg body weight.

[0260] Group 3: CVC (Cenicriviroc) (dissolved in 5% DMSO+95% (10% HP-β-CD), pH 4) was administrated intragastrically at a dose of 100 mg/kg body weight twice daily, starting in the afternoon on the day of inoculation. Anti-mouse PD-1 antibody (RMP1-14) was administrated by intraperitoneal injection at 11, 14 and 18 day after inoculation. The dose at 11 day was 3 mg/kg body weight, and the doses on 14 day and 18 day were 6 mg/kg body weight.

[0261] Group 4: WX001 (dissolved in 5% DMSO+95% (10% HP-β-CD), pH 4) was administrated intragastrically at a dose of 100 mg/kg body twice daily, starting in the afternoon on the day of inoculation. Anti-mouse PD-1 antibody (RMP1-14) was administrated by intraperitoneal injection at 11, 14 and 18 day after inoculation once. The dose at day 11 was 3 mg/kg body weight, and the doses on 14 day and 18 day was 6 mg/kg body weight.

[0262] During the experiment, the mice were weighed three times a week. After tumour formation, the tumor volume was measured three times a week in synchronization with weighing the body weight. The tumor volume was calculated according to the formula of “length×width.sup.2/2”, the tumor proliferation rate and tumor inhibition rate were calculated according to the following formulas: Tumor proliferation rate=the tumor volume in the treatment group/the tumor volume in the control group×100%; Tumor inhibition rate=(the tumor volume in the control group−the tumor volume in the treatment group)/the tumor volume in the control group.

[0263] Student's t-test was used for statistical analysis between the groups, and p<0.05 was considered as a significant difference.

[0264] Experimental Results:

TABLE-US-00010 TABLE 3 Tumor proliferation ratio in each of groups Group Tumor proliferation ratio Anti-PD-1 antibody group 49.40% CVC + PD-1 combination group 52.58% WX001 + PD-1 combination group 25.42%

[0265] The effect of WX001 on the tumor volume in the MC38 colon cancer tumor model in mice is shown in FIG. 1.

[0266] Experimental Conclusion: In the MC38 tumor model in mice, the WX001+PD-1 combination group had a significant enhanced efficacy compared to the PD-1 single-use group. The tumor proliferation rate at 31 day was 25.42% (compared to the vehicle group, p<0.01; compared to the CVC+PD-1 combination group, p<0.01).