Substituted pyrimidines containing acidic groups as TLR7 modulators
The present disclosure relates to a class of pyrimidine derivatives having immunomodulating properties that act via TLR7 which are useful in the treatment of viral infections and cancers. One aspect of the present disclosure relates to a compound represented by Formula 1:
1. A compound of Formula (1):
or a pharmaceutically acceptable salt thereof,
wherein:
R 1a is selected from the group consisting of C 1 -C 4 alkyl and A, wherein C 1 -C 4 alkyl is optionally substituted with —OH, —NH 2 , —NHCOCH 3 , —COOH, —SO 2 CH 3 , —SCH 3 , —OCH 3 , tetrazol-5-yl or A;
R 1b is C 2 -C 5 alkyl;
X is C 1 -C 4 alkyl, optionally substituted with A, —OH or —C(CH 3 ) 2 OH;
L 1 is selected from the group consisting of —CH 2 — and —CF 2 —;
Y is aryl, optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of A, C 1 -C 3 alkyl and C 1 -C 3 alkoxy;
A is -L 2 -COOH;
L 2 is —(CH 2 ) n —; and
n is 1, 2, 3 or 4;
with the proviso that the compound is substituted with at least one A; and further
with the proviso that if X is —CH 3 , L 1 is —CH 2 —, Y is aryl substituted with A and L 2 is —CH 2 —, then A is not -L 2 -COOH, except when R 1a comprises —COOH or —SO 2 CH 3 .
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1a is C 1 -C 4 alkyl, optionally substituted with —OH, —OCH 3 , —SCH 3 , or —SO 2 CH 3 .
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1a is —CH 2 C(CH 3 ) 2 OH.
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1a is C 1 -C 4 alkyl, optionally substituted with —COOH.
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1b is —CH 2 CH 3 .
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1b is —(CH 2 ) 2 CH 3 .
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1b is —(CH 2 ) 3 CH 3 .
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L 1 is CF 2 —.
11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L 1 is —CH 2 —.
12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein -L 2 is —CH 2 —.
13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L 2 is —(CH 2 ) 2 —.
14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L 2 is —(CH 2 ) 3 —.
15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is C 1 -C 4 alkyl, substituted with A.
16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is C 1 -C 4 alkyl, substituted with -L 2 -COOH.
17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is CH 3 .
18. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is aryl, substituted with 1 or 2 C 1 -C 3 alkyl.
19. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is aryl, substituted with 1 or 2 C 1 -C 3 alkoxy.
20. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is aryl, substituted with 1 or 2 A.
21. The compound of claim 1 , wherein the compound is a compound of Formula (1a):
or a pharmaceutically acceptable salt thereof,
wherein:
X is CH 3 ;
A is -L 2 -COOH;
L 2 is —(CH 2 ) n —;
n is 1 or 2; and
R 3 is H, C 1 -C 3 alkyl or C 1 -C 3 alkoxy.
22. The compound of claim 1 , wherein the compound is a compound of Formula (1a):
or a pharmaceutically acceptable salt thereof,
wherein:
X is —CH 2 -A 1a , —(CH 2 ) 2 -A 1a , —(CH 2 ) 3 -A 1a or —CH 2 C(CH 3 ) 2 -A 1a ;
A 1a is —COOH;
A is -L 2 -COOH;
L 2 is —(CH 2 ) n —;
n is 1 or 2; and
R 3 is H, C 1 -C 3 alkyl or C 1 -C 3 alkoxy.
23. The compound of claim 1 , wherein the compound is a compound of Formula (1b):
or a pharmaceutically acceptable salt thereof,
wherein:
X is CH 3 ;
A is -L 2 -COOH;
L 2 is —(CH 2 ) n —;
n is 1 or 2; and
R 3 is H, C 1 -C 3 alkyl or C 1 -C 3 alkoxy.
24. The compound of claim 1 , wherein the compound is a compound of Formula (1b):
or a pharmaceutically acceptable salt thereof,
wherein:
X is —CH 2 -A 1a , —(CH 2 ) 2 -A 1a , —(CH 2 ) 3 -A 1a or —CH 2 C(CH 3 ) 2 -A 1a ;
A 1a is —COOH;
A is -L 2 -COOH;
L 2 is —(CH 2 ) n —;
n is 1 or 2; and
R 3 is H, C 1 -C 3 alkyl or C 1 -C 3 alkoxy.
25. The compound of claim 1 , wherein the compound is a compound of Formula (1c):
or a pharmaceutically acceptable salt thereof,
wherein:
X is —CH 2 -A 1a , —(CH 2 ) 2 -A 1a , —(CH 2 ) 3 -A 1a or —CH 2 C(CH 3 ) 2 -A 1a ;
A 1a is —COOH;
R 3 is H, C 1 -C 3 alkyl or C 1 -C 3 alkoxy; and
R 4 is H or C 1 -C 3 alkoxy.
26. The compound of claim 1 , wherein the compound is a compound of Formula (1e):
or a pharmaceutically acceptable salt thereof,
wherein:
R 3 is H, C 1 -C 3 alkyl or C 1 -C 3 alkoxy.
27. The compound of claim 1 , wherein the compound is a compound of Formula (1g):
or a pharmaceutically acceptable salt thereof,
wherein:
R 3 is H, C 1 -C 3 alkyl or C 1 -C 3 alkoxy.
28. The compound of claim 1 , wherein the compound is a compound of Formula (1k):
or a pharmaceutically acceptable salt thereof.
29. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
30. The pharmaceutical composition of claim 29 , wherein the pharmaceutical composition further comprises one or more additional therapeutic agents.
31. The pharmaceutical composition of claim 30 , wherein the additional therapeutic agent is an antiviral nucleoside.
32. The pharmaceutical composition of claim 30 , wherein the additional therapeutic agent is programmed cell death protein-1 antibody or programmed cell death protein ligand-1 antibody.
33. A method for modulating toll-like receptor 7 activity in a subject, comprising administering to the subject in need thereof an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
34. The method of claim 33 , wherein the administration to the subject is inhaled, oral, topical, bucchal, sublingual, subcutaneous, intravenous, intramuscular, intratumoral, intradermal, intranasal, intravesical, intrarectal, intrathecal or intracranial.
35. The method of claim 33 , wherein the subject has a condition associated with toll-like receptor 7 modulation.
36. The method of claim 35 , wherein the condition associated with toll-like receptor 7 modulation is selected from the group consisting of a viral infection and cancer.
37. A method for modulating toll-like receptor 7 activity in a subject having cancer, comprising administering to the subject in need thereof an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, in combination with a programmed cell death protein-1 antibody or a programmed cell death protein-ligand 1 antibody.
38. A method for treating hepatitis B virus in a subject, comprising administering to the subject in need thereof an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, in combination with an antiviral nucleoside.
39. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.