Pyridopyrimidine derivative, preparation method therefor and medical use thereof
Disclosed are a pyridopyrimidine derivative as shown in general formula (I), a preparation method therefor and a pharmaceutical composition containing the derivative, and the use thereof as a therapeutic agent, particularly as a TLR8 agonist, wherein each substituent of general formula (I) is the same as those defined in the description.
1. A compound of formula (I);
or a tautomer, mesomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof,
wherein:
G 1 is N;
G 2 is CR 5 ;
G 3 is CR 5 or N;
L 1 is selected from the group consisting of alkylene and covalent bond;
R 1 is alkyl, wherein the alkyl is optionally substituted by one or more hydroxy;
R 2 and R 3 are identical or different, and are each independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R 4 is heterocyclyl, wherein the heterocyclyl is optionally substituted by one or more substituent(s) selected from the group consisting of alkyl, alkoxy, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; and
R 5 is selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
2. The compound of formula (I) according to claim 1 , which is a compound of formula (Ia):
or a tautomer, mesomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof,
wherein:
G 1 , G 3 , L 1 and R 1 to R 4 are as defined in claim 1 .
3. The compound of formula (I) according to claim 1 , which is a compound of formula (II):
or a tautomer, mesomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof,
wherein:
G 1 , L 1 and R 1 to R 4 are as defined in claim 1 .
4. The compound of formula (I) according to claim 1 , which is a compound of formula (III):
or a tautomer, mesomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof,
wherein:
G 1 , L 1 , R 1 and R 4 are as defined in claim 1 .
5. The compound of formula (I) according to claim 1 , wherein R 4 is a heterocyclyl, which is optionally substituted by one or more alkyl(s); and/or L 1 is —(CH 2 ) n — or a covalent bond; and n is an integer from 1 to 6.
6. The compound of formula (I) according to claim 1 , which is a compound of formula (IV):
or a tautomer, mesomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof,
wherein:
W 1 is CH and W 2 is NR 6 ; or
W 1 is N and W 2 is CH 2 or NR 6 ;
R 6 is selected from the group consisting of hydrogen atom and alkyl;
s is 0 or 1; and
G 1 , L 1 and R 1 are as defined in claim 1 .
7. The compound of formula (I) according to claim 1 , which is a compound of formula (V):
or a tautomer, mesomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof,
wherein:
W 1 is CH and W 2 is NR 6 ; or
W 1 is N and W 2 is CH 2 or NR 6 ;
R 6 is selected from the group consisting of hydrogen atom and alkyl;
s is 0 or 1; and
G 1 and L 1 are as defined in claim 1 .
8. The compound of formula (I) according to claim 1 , which is selected from the group consisting of:
or a tautomer, mesomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof.
9. A compound of formula (IA):
or a tautomer, mesomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof,
wherein:
R a is an amino protecting group;
G 1 is N;
G 2 is CR 5 ;
G 3 is CR 5 or N;
L 1 is selected from the group consisting of alkylene and covalent bond;
R 1 is alkyl, wherein the alkyl, is optionally substituted by one or more hydroxy;
R 2 and R 3 are identical or different, and are each independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R 4 is heterocyclyl, wherein the heterocyclyl is optionally substituted by one or more substituent(s) selected from the group consisting of alkyl, alkoxy, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; and
R 5 is selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
10. A compound, which is selected from the group consisting of:
or a tautomer, mesomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof.
11. The compound of formula (I) according to claim 5 , wherein R 4 is a 4 to 6 membered heterocyclyl comprising one or two identical or different heteroatom(s) selected from the group consisting of N, O and S, and the 4 to 6 membered heterocyclyl is optionally substituted by one or more alkyl(s).
12. The compound of formula (IA) according to claim 9 , wherein R a is 2,4-dimethoxybenzyl.
13. The compound of formula (I) according to claim 6 , wherein R 6 is alkyl.
14. The compound of formula (I) according to claim 7 , wherein R 6 is alkyl.
15. A method for preparing the compound of formula (I) according to claim 1 , comprising a step of:
subjecting the compound of formula (IA) to a deprotection reaction to obtain the compound of formula (I);
wherein:
R a is an amino protecting group; and
G 1 to G 3 , L 1 and R 1 to R 4 are as defined in claim 1 .
16. A pharmaceutical composition, comprising a therapeutically effective amount of the compound of formula (I) according to claim 1 , and one or more pharmaceutically acceptable carriers, diluents or excipients.
17. A method of activating TLR8 in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the compound of formula (I) according to claim 1 .
18. A method of treating an infection caused by a virus in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the compound of formula (I) according to claim 1 , wherein the virus is hepatitis B virus, hepatitis C virus, influenza virus, herpes virus and AIDS virus.
19. A method of regulating an immune system in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the compound of formula (I) according to claim 1 .