Nicotinyl alcohol ether derivative, preparation method therefor, and pharmaceutical composition and uses thereof

1. A nicotinyl alcohol ether derivative of Formula (I):

or a stereoisomer or a pharmaceutically acceptable salt thereof,

wherein:

R 1 is selected from

and

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 ), guanidine (—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,

and

and

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

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

wherein:

R 1 is selected from

and

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,

and

and

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

3. A nicotinyl alcohol 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.

4. A nicotinyl alcohol ether derivative of claim 2 , represented by formula (IA-1), 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,

and

and

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

5. A nicotinyl alcohol 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.

6. A nicotinyl alcohol ether derivative of claim 2 , represented by formula (IA-2), 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,

and

and

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

7. A nicotinyl alcohol 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.

8. A nicotinyl alcohol 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.

9. A nicotinyl alcohol ether derivative of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein the compound is selected from:

Ethyl N-(4-(2-bromo-3-phenylbenzyloxy)-5-chloro-2-(pyridin-3-yl-methyleneoxy)benzyl) serinate dihydrochloride

N-(4-(2-bromo-3-phenylbenzyloxy)-5-chloro-2-(pyridin-3-yl-methyleneoxy)benzyl) serine

(S)-Ethyl N-(4-(2-bromo-3-phenylbenzyloxy)-5-chloro-2-(pyridin-3-yl-methyleneoxy) benzyl)serinate

(S)—N-(4-(2-bromo-3-phenylbenzyloxy)-5-chloro-2-(pyridin-3-yl-methyleneoxy) benzyl) serine

(S)-Ethyl N-(4-(2-bromo-3-phenylbenzyloxy)-5-chloro-2-(pyridin-3-yl-methyleneoxy)benzyl) serinate dihydrochloride

(S)-isopropyl N-(4-(2-bromo-3-phenylbenzyloxy)-5-chloro-2-(pyridin-3-yl-methyleneoxy)benzyl) serinate dihydrochloride

(R)-Ethyl N-(4-(2-bromo-3-phenylbenzyloxy)-5-chloro-2-(pyridin-3-yl-methyleneoxy)benzyl) serinate

(R)—N-(4-(2-bromo-3-phenylbenzyloxy)-5-chloro-2-(pyridin-3-yl-methyleneoxy) benzyl) serine

N-(4-(2-bromo-3-phenylbenzyloxy)-5-chloro-2-(pyridin-3-yl-methyleneoxy)benzyl) glycine

N-(4-(2-bromo-3-phenylbenzyloxy)-5-chloro-2-(pyridin-3-yl-methyleneoxy)benzyl) valine

(E)-3-(4-(2-bromo-3-phenylbenzyloxy)-5-chloro-2-(pyridin-3-yl-methyleneoxy) benzylamino) but-2-enenitrile

N,N-bis(hydroxyethyl)-4-(2-bromo-3-phenylbenzyloxy)-5-chloro-2-(pyridin-3-yl-methyleneoxy) benzylamine

N-(2-methanesulfonaminoethyl)-4-(2-bromo-3-phenylbenzyloxy)-5-chloro-2-(pyridin-3-yl-methyleneoxy) benzylamine

N-(2-acetylaminoethyl)-4-(2-bromo-3-phenylbenzyloxy)-5-chloro-2-(pyridin-3-yl-methyleneoxy) benzylamine

(E)-3-(4-(2-bromo-3-phenylbenzyloxy)-5-chloro-2-(pyridin-3-yl-methyleneoxy) benzylamino) hut-2-enoic acid

2-(4-(2-bromo-3-phenylbenzyloxy)-5-chloro-2-(pyridin-3-yl-methyleneoxy) benzylamino) ethanesulfonic acid

N-(4-(2-bromo-3-phenylbenzyloxy)-5-chloro-2-(pyridin-3-yl-methyleneoxy)benzyl) leucine

N-(4-(2-bromo-3-phenylbenzyloxy)-5-chloro-2-(pyridin-3-yl-methyleneoxy)benzyl) tyrosine

N-(4-(2-bromo-3-phenylbenzyloxy)-5-chloro-2-(pyridin-3-yl-methyleneoxy)benzyl) isoleucine

N-(4-(2-bromo-3-phenylbenzyloxy)-5-chloro-2-(pyridin-3-yl-methyleneoxy) benzyl) asparagine

N-(hydroxyethyl)-4-(2-bromo-3-phenylbenzyloxy)-5-chloro-2-(pyridin-3-yl-methyleneoxy) benzylamine

N-(4-(2-bromo-3-phenylbenzyloxy)-5-chloro-2-(pyridin-3-yl-methyleneoxy)benzyl) alanine

N-(4-(2-bromo-3-phenylbenzyloxy)-5-chloro-2-(pyridin-3-yl-methyleneoxy)benzyl) proline

(S)-Sodium N-(4-(2-bromo-3-phenylbenzyloxy)-5-chloro-2-(pyridin-3-yl-methyleneoxy)benzyl) serinate

(S)-Calcium N-(4-(2-bromo-3-phenylbenzyloxy)-5-chloro-2-(pyridin-3-yl-methyleneoxy)benzyl) serinate

and

(S)-(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl N-(4-(2-bromo-3-phenylbenzyloxy)-5-chloro-2-(pyridin-3-yl-methyleneoxy) benzyl) serinate

10. A nicotinyl alcohol 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.

11. A nicotinyl alcohol ether derivative of claim 10 , 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.

12. A pharmaceutical composition, characterized in that it comprises a nicotinyl alcohol 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.

13. A pharmaceutical composition, characterized in that it comprises a nicotinyl alcohol ether derivative of claim 9 , or a stereoisomer or a pharmaceutically acceptable salt thereof, as an active ingredient, and one or more pharmaceutically acceptable carriers or excipients.

14. A process for the preparation of a nicotinyl alcohol 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 pyridin-3-yl-methylene halide under basic conditions to obtain an aldehyde-containing intermediate compound 2; and

(b) the aldehyde-containing intermediate compound 2 as the starting material is condensed with an amino group- or an imino group-containing HR 3 and the resultant product is reduced to obtain a target compound I;

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

15. 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 nicotinyl alcohol 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.

16. 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 nicotinyl alcohol ether derivative of claim 9 , 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.