Benzyl phenyl ether derivative, preparation method therefor, and pharmaceutical composition and uses thereof

1. A benzyl phenyl ether derivative of Formula (I):

or a stereoisomer or a pharmaceutically acceptable salt thereof,

wherein:

R 1 is selected from

R 2 is selected from hydrogen, cyano, methylsulfonyl, acetylamino, carbamoyl, dimethyl amino formyl (—CON(CH 3 ) 2 ), fluorine, chlorine, bromine, iodine, trifluoromethyl, C 1 -C 5 alkyh and C 1 -C 5 alkoxy;

R 3 is selected from substituted C 1 -C 8 saturated alkylamino, substituted C 2 -C 6 unsaturated alkylamino, and substituted N-containing C 2 -C 6 heterocycle-1-yl, wherein each is mono-, di-, tri-, or tetra-substituted with substituent(s) selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, amino, C 1 -C 6 alkylamino, acetylamino, cyano, ureido (—NH(C═O)NH 2 ), guanidino (—NH(C═NH)NH 2 ), ureido amino (—NH—NH(C═O)NH 2 ), guanidino amino (—NH—NH(C═NH)NH 2 ), sulfonylamino (—NHSO 3 H), sulfamoyl (—SO 2 NH 2 ), methanesulfonylamino (—NH—SO 2 CH 3 ), hydroxyformyl (—COOH), C 1 -C 8 alkoxyl carbonyl, sulfydryl, imidazolyl, thiazolyl, oxazolyl, tetrazolyl,

X is selected from hydrogen, fluorine, chlorine, bromine, iodine, C 1 -C 4 alkyl, ethenyl, trifluoromethyl, and methoxy.

2. A benzyl phenyl ether derivative of claim 1 , represented by formula (IA), or a pharmaceutically acceptable salt or a stereoisomer thereof:

wherein:

R 1 is selected from

R 2 is selected from hydrogen, cyano, methylsulfonyl, acetylamino, carbamoyl, dimethyl amino formyl (—CON(CH 3 ) 2 ), fluorine, chlorine, bromine, iodine, trifluoromethyl, C 1 -C 5 alkyl, and C 1 -C 5 alkoxy;

R 3 is selected from substituted C 1 -C 8 saturated alkylamino, substituted C 2 -C 6 unsaturated alkylamino, and substituted N-containing C 2 -C 6 heterocycle-1-yl, wherein each is mono-, di-, tri-, or tetra-substituted with substituent(s) selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, amino, C 1 -C 6 alkylamino, acetylamino, cyano, ureido (—NH(C═O)NH 2 ), guanidino (—NH(C═NH)NH 2 ), ureido amino (—NH—NH(C═O)NH 2 ), guanidino amino (—NH—NH(C═NH)NH 2 ), sulfonylamino (—NHSO 3 H), sulfamoyl (—SO 2 NH 2 ), methanesulfonylamino (—NH—SO 2 CH 3 ), hydroxyformyl (—COOH), C 1 -C 8 alkoxyl carbonyl, sulfydryl, imidazolyl, thiazolyl, oxazolyl, tetrazolyl,

X is selected from hydrogen, fluorine, chlorine, bromine, iodine, C 1 -C 4 alkyl, ethenyl, trifluoromethyl, and methoxy.

3. A benzyl phenyl ether derivative of claim 2 , represented by formula (IA-1), or a pharmaceutically acceptable salt or a stereoisomer thereof:

wherein:

R 2 is selected from hydrogen, cyano, methylsulfonyl, acetylamino, carbamoyl, dimethyl amino formyl (—CON(CH 3 ) 2 ), fluorine, chlorine, bromine, iodine, trifluoromethyl, C 1 -C 5 alkyl and C 1 -C 5 alkoxy;

R 3 is selected from substituted C 1 -C 8 saturated alkylamino, substituted C 2 -C 6 unsaturated alkylamino, and substituted N-containing C 2 -C 6 heterocycle-1-yl, wherein each is mono-, di-, tri-, or tetra-substituted with substituent(s) selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, amino, C 1 -C 6 alkylamino, acetylamino, cyano, ureido (—NH(C═O)NH 2 ), g (—NH(C═NH)NH 2 ), ureido amino (—NH—NH(C═O)NH 2 ), guanidino amino (—NH—NH(C═NH)NH 2 ), sulfonylamino (—NHSO 3 H), sulfamoyl (—SO 2 NH 2 ), methanesulfonylamino (—NH—SO 2 CH 3 ), hydroxyformyl (—COOH), C 1 -C 8 alkoxyl carbonyl, sulfydryl, imidazolyl, thiazolyl, oxazolyl, tetrazolyl,

X is selected from hydrogen, fluorine, chlorine, bromine, iodine, C 1 -C 4 alkyl, ethenyl, trifluoromethyl, and methoxy.

4. A benzyl phenyl ether derivative of claim 3 , represented by formula (IA-1a), or a pharmaceutically acceptable salt or a stereoisomer thereof:

wherein:

R 3 is selected from substituted C 1 -C 8 saturated alkylamino, substituted C 2 -C 6 unsaturated alkylamino, and substituted N-containing C 2 -C 6 heterocycle-1-yl, wherein each is mono-, di-, tri-, or tetra-substituted with substituent(s) selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, amino, C 1 -C 6 alkylamino, acetylamino, cyano, ureido (—NH(C═O)NH 2 ), guanidino (—NH(C═NH)NH 2 ), ureido amino (—NH—NH(C═O)NH 2 ), guanidino amino (—NH—NH(C═NH)NH 2 ), sulfonylamino (—NHSO 3 H), sulfamoyl (—SO 2 NH 2 ), methanesulfonylamino (—NH—SO 2 CH 3 ), hydroxyformyl (—COOH), C 1 -C 8 alkoxyl carbonyl, sulfydryl, imidazolyl, thiazolyl, oxazolyl, tetrazolyl,

X is selected from hydrogen, fluorine, chlorine, bromine, iodine, C 1 -C 4 alkyl, ethenyl, trifluoromethyl, and methoxy.

5. A benzyl phenyl ether derivative of claim 3 , represented by formula (IA-1b), or a pharmaceutically acceptable salt or a stereoisomer thereof:

wherein:

R 3 is selected from substituted C 1 -C 8 saturated alkylamino, substituted C 2 -C 6 unsaturated alkylamino, and substituted N-containing C 2 -C 6 heterocycle-1-yl, wherein each is mono-, di-, tri-, or tetra-substituted with substituent(s) selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, amino, C 1 -C 6 alkylamino, acetylamino, cyano, ureido (—NH(C═O)NH 2 ), guanidino (—NH(C═NH)NH 2 ), ureido amino (—NH—NH(C═O)NH 2 ), guanidino amino (—NH—NH(C═NH)NH 2 ), sulfonylamino (—NHSO 3 H), sulfamoyl (—SO 2 NH 2 ), methanesulfonylamino (—NH—SO 2 CH 3 ), hydroxyformyl (—COOH), C 1 -C 8 alkoxyl carbonyl, sulfydryl, imidazolyl, thiazolyl, oxazolyl, tetrazolyl,

X is selected from hydrogen, fluorine, chlorine, bromine, iodine, C 1 -C 4 alkyl, ethenyl, trifluoromethyl, and methoxy.

6. A benzyl phenyl ether derivative of claim 2 , represented by formula (IA-2), or a pharmaceutically acceptable salt or a stereoisomer thereof:

wherein:

R 2 is selected from hydrogen, cyano, methylsulfonyl, acetylamino, carbamoyl, dimethyl amino formyl (—CON(CH 3 ) 2 ), fluorine, chlorine, bromine, iodine, trifluoromethyl, C 1 -C 5 alkyl and C 1 -C 5 alkoxy;

R 3 is selected from substituted C 1 -C 8 saturated alkylamino, substituted C 2 -C 6 unsaturated alkylamino, and substituted N-containing C 2 -C 6 heterocycle-1-yl, wherein each is mono-, di-, tri-, or tetra-substituted with substituent(s) selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, amino, C 1 -C 6 alkylamino, acetylamino, cyano, ureido (—NH(C═O)NH 2 ), guanidino (—NH(C═NH)NH 2 ), ureido amino (—NH—NH(C═O)NH 2 ), guanidino amino (—NH—NH(C═NH)NH 2 ), sulfonylamino (—NHSO 3 H), sulfamoyl (—SO 2 NH 2 ), methanesulfonylamino (—NH—SO 2 CH 3 ), hydroxyformyl (—COOH), C 1 -C 8 alkoxyl carbonyl, sulfydryl, imidazolyl, thiazolyl, oxazolyl, tetrazolyl,

X is selected from hydrogen, fluorine, chlorine, bromine, iodine, C 1 -C 4 alkyl, ethenyl, trifluoromethyl, and methoxy.

7. A benzyl phenyl ether derivative of claim 6 , represented by formula (IA-2a), or a pharmaceutically acceptable salt or a stereoisomer thereof:

wherein:

R 3 is selected from substituted C 1 -C 8 saturated alkylamino, substituted C 2 -C 6 unsaturated alkylamino, and substituted N-containing C 2 -C 6 heterocycle-1-yl, wherein each is mono-, di-, tri-, or tetra-substituted with substituent(s) selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, amino, C 1 -C 6 alkylamino, acetylamino, cyano, ureido (—NH(C═O)NH 2 ), guanidino (—NH(C═NH)NH 2 ), ureido amino (—NH—NH(C═O)NH 2 ), guanidino amino (—NH—NH(C═NH)NH 2 ), sulfonylamino (—NHSO 3 H), sulfamoyl (—SO 2 NH 2 ), methanesulfonylamino (—NH—SO 2 CH 3 ), hydroxyformyl (—COOH), C 1 -C 8 alkoxyl carbonyl, sulfydryl, imidazolyl, thiazolyl, oxazolyl, tetrazolyl,

X is selected from hydrogen, fluorine, chlorine, bromine, iodine, C 1 -C 4 alkyl, ethenyl, trifluoromethyl, and methoxy.

8. A benzyl phenyl ether derivative of claim 6 , represented by formula (IA-2b), or a pharmaceutically acceptable salt or a stereoisomer thereof:

wherein:

R 3 is selected from substituted C 1 -C 8 saturated alkylamino, substituted C 2 -C 6 unsaturated alkylamino, and substituted N-containing C 2 -C 6 heterocycle-1-yl, wherein each is mono-, di-, tri-, or tetra-substituted with substituent(s) selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, amino, C 1 -C 6 alkylamino, acetylamino, cyano, ureido (—NH(C═O)NH 2 ), guanidino (—NH(C═NH)NH 2 ), ureido amino (—NH—NH(C═O)NH 2 ), guanidino amino (—NH—NH(C═NH)NH 2 ), sulfonylamino (—NHSO 3 H), sulfamoyl (—SO 2 NH 2 ), methanesulfonylamino (—NH—SO 2 CH 3 ), hydroxyformyl (—COOH), C 1 -C 8 alkoxyl carbonyl, sulfydryl, imidazolyl, thiazolyl, oxazolyl, tetrazolyl,

X is selected from hydrogen, fluorine, chlorine, bromine, iodine, C 1 -C 4 alkyl, ethenyl, trifluoromethyl, and methoxy.

9. A benzyl phenyl ether derivative of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 3 is of one of the following formulae:

wherein R is selected from methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, heptyl, and octyl;

and X is selected from hydrogen, fluorine, chlorine, bromine, methyl, ethenyl, and trifluoromethyl.

10. A benzyl phenyl ether derivative of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein the compound is selected from:

N-acetylaminoethyl-4-(2-bromo-3-phenylbenzyloxy)-2-(3-cyanobenzyloxy) benzylamine

N-(4-(2-bromo-3-phenylbenzyloxy)-2-(3-cyanobenzyloxy) benzyl) serine

N-Ethyl-N-hydroxylethyl-4-(2-bromo-3-phenylbenzyloxy)-2-(3-cyanobenzyloxy) benzylamine

N-(4-(2-bromo-3-phenylbenzyloxy)-2-(3-cyanobenzyloxy) benzyl) proline

N-hydroxylethyl-4-(2-bromo-3-phenylbenzyloxy)-2-(3-cyanobenzyloxy) benzylamine

N-(4-(2-bromo-3-phenylbenzyloxy)-2-(3-cyanobenzyloxy) benzyl) alanine

N-(4-(2-bromo-3-phenylbenzyloxy)-2-(3-cyanobenzyloxy) benzyl) methionine

N-(4-(2-bromo-3-phenylbenzyloxy)-2-(3-cyanobenzyloxy) benzyl) threonine

N-(tetrahydro-2H-pyran-4-yl)-4-(2-bromo-3-phenylbenzyloxy)-2-(3-cyanobenzyloxy) benzylamine

N-[4-(2-bromo-3-phenylbenzyloxy)-2-(3-cyanobenzyloxy) benzyl] morpholine Hydrochloride

N-(4-(2-bromo-3-phenylbenzyloxy)-5-chloro-2-(3-cyanobenzyloxy) benzyl) serine

N-hydroxylethyl-4-(2-bromo-3-phenylbenzyloxy)-5-chloro-2-(3-cyanobenzyloxy) benzylamine

N-acetylaminoethyl-4-(2-bromo-3-phenylbenzyloxy)-5-chloro-2-(3-cyanobenzyloxy) benzylamine

N-(2-methanesulfonylaminoethyl)-4-(2-bromo-3-phenylbenzyloxy)-2-(3-cyanobenzyloxy) benzylamine Hydrochloride

(S)-N-(4-(2-bromo-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)benzyloxy)-5-chloro-2-(3-cyanobenzyloxy) benzyl) pipecolinic acid

N-(4-(2-bromo-3-phenylbenzyloxy)-5-chloro-2-(3-cyanobenzyloxy) benzyl) alanine

N-(4-(2-bromo-3-phenylbenzyloxy)-5-chloro-2-(3-cyanobenzyloxy) benzyl) threonine

N-(4-(2-bromo-3-phenylbenzyloxy)-5-chloro-2-(3-methanesulfonylbenzyloxy) benzyl) serine

N-(4-(2-bromo-3-phenylbenzyloxy)-5-chloro-2-(3-methanesulfonylbenzyloxy)benzyl)pipecolinic acid

11. A benzyl phenyl ether derivative of claim 1 , or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt comprises a salt formed with an inorganic acid, a salt formed with an organic acid, alkali metal ion salt, alkaline earth metal ion salt, or a salt formed with organic base which provides a physiologically acceptable cation, and an ammonium salt.

12. A benzyl phenyl ether derivative of claim 11 , or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the inorganic acid is selected from hydrochloric acid, hydrobromic acid, phosphoric acid, and sulfuric acid; the organic acid is selected from methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic, citric acid, maleic acid, tartaric acid, fumaric acid, citric acid, and lactic acid; the alkali metal ion is selected from lithium ion, sodium ion, and potassium ion; the alkaline earth metal ion is selected from calcium ion and magnesium ion; and the organic base which provides a physiologically acceptable cation is selected form methylamine, dimethylamine, trimethylamine, piperidine, morpholine, and tris(2-hydroxyethyl) amine.

13. A benzyl phenyl ether derivative of claim 2 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 3 is of one of the following formulae:

wherein R is selected from methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, heptyl, and octyl;

and X is selected from hydrogen, fluorine, chlorine, bromine, methyl, ethenyl, and trifluoromethyl.

14. A benzyl phenyl ether derivative of claim 3 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 3 is of one of the following formulae:

wherein R is selected from methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, heptyl, and octyl;

and X is selected from hydrogen, fluorine, chlorine, bromine, methyl, ethenyl, and trifluoromethyl.

15. A benzyl phenyl ether derivative of claim 4 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 3 is of one of the following formulae:

wherein R is selected from methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, heptyl, and octyl;

and X is selected from hydrogen, fluorine, chlorine, bromine, methyl, ethenyl, and trifluoromethyl.

16. A benzyl phenyl ether derivative of claim 5 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 3 is of one of the following formulae:

wherein R is selected from methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, heptyl, and octyl;

and X is selected from hydrogen, fluorine, chlorine, bromine, methyl, ethenyl, and trifluoromethyl.

17. A benzyl phenyl ether derivative of claim 6 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 3 is of one of the following formulae:

wherein R is selected from methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, heptyl, and octyl;

and X is selected from hydrogen, fluorine, chlorine, bromine, methyl, ethenyl, and trifluoromethyl.

18. A benzyl phenyl ether derivative of claim 7 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 3 is of one of the following formulae:

wherein R is selected from methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, heptyl, and octyl;

and X is selected from hydrogen, fluorine, chlorine, bromine, methyl, ethenyl, and trifluoromethyl.

19. A benzyl phenyl ether derivative of claim 8 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R 3 is of one of the following formulae:

wherein R is selected from methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, heptyl, and octyl;

and X is selected from hydrogen, fluorine, chlorine, bromine, methyl, ethenyl, and trifluoromethyl.

20. A pharmaceutical composition, characterized in that it comprises a benzyl phenyl ether derivative of claim 1 , or a stereoisomer or a pharmaceutically acceptable salt thereof, as an active ingredient, and one or more pharmaceutically acceptable carriers or excipients.

21. A pharmaceutical composition, characterized in that it comprises a benzyl phenyl ether derivative of claim 10 , or a stereoisomer or a pharmaceutically acceptable salt thereof, as an active ingredient, and one or more pharmaceutically acceptable carriers or excipients.

22. A process for the preparation of a benzyl phenyl ether derivative of claim 1 , or a stereoisomer or a pharmaceutically acceptable salt thereof, comprising the following steps:

(a) 2-hydroxy-4-(2-bromo-3-R1 benzyloxy)-X-substituted benzaldehyde 1 as a starting material is reacted with a benzyl halide which is R2-substituted at 3-position under basic conditions to obtain an aldehyde-containing intermediate compound 2;

(b) the aldehyde-containing intermediate compound 2 as the starting material is condensed with an amino group- or an imino group-containing HR3 and the resultant product is reduced to obtain a target compound I;

wherein R 1 , R 2 , R 3 and X each is defined as claim 1 .

23. A method for treating a disease associated with the PD-1/PD-L1 signaling pathway in a subject in need of such treatment comprising administering to the subject an effective amount of a benzyl phenyl ether derivative of claim 1 , or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof; wherein the disease is selected from the group consisting of melanoma, lung cancer, breast cancer, and colon cancer.

24. A method for treating a disease associated with the PD-1/PD-L1 signaling pathway in a subject in need of such treatment comprising administering to the subject an effective amount of the benzyl phenyl ether derivative of claim 10 , or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof; wherein the disease is selected from the group consisting of melanoma, lung cancer, breast cancer, and colon cancer.