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 H, C 1 -C 4 alkyl, COOH, NH 2 , NHCOCH 3 , OCH 3 , SCH 3 , SO 2 CH 3 ,
or A, wherein the C 1 -C 4 alkyl is optionally substituted with a substituent selected from the group consisting of COOH, NH 2 , NHCOCH 3 , OCH 3 , SCH 3 , SO 2 CH 3 ,
and A;
R 1b is C 2 -C 5 alkyl;
X is C 1 -C 4 alkyl, wherein the C 1 -C 4 alkyl is optionally substituted with a substituent selected from the group consisting of C(CH 3 ) 2 OH, OH, and A;
L 1 is —CH 2 —, —CF 2 —, or —CH 2 CH 2 —;
Y is aryl, wherein the aryl is substituted with 1 A substituent, and optionally further substituted with 1, 2, 3, 4, or 5 additional substituents independently selected from the group consisting of A, C 1 -C 3 alkyl, and C 1 -C 3 alkoxy;
A is:
L 2 is a bond, —(CH 2 ) n —, —C(CH 3 ) 2 —, —(CH 2 ) m —C(CH 3 ) 2 —(CH 2 ) n —, —CONH(CH 2 ) n —, —O(C 1 -C 4 alkylene)-, or
m is 0, 1, 2, 3, or 4; and
n is 1, 2, 3, or 4;
with the provisos that:
(1) the compound is substituted with at least 1 A;
(2) when 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
except when R 1a comprises COOH or SO 2 CH 3 ; and
(3) when X is CH 3 , L 1 is —CH 2 —, Y is phenyl substituted with A, A is
and L 2 is —CH 2 —, then A and L 1 are not para to each other.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1a is H.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1a is C 1 -C 4 alkyl, wherein the C 1 -C 4 alkyl is optionally substituted with a substituent selected from the group consisting of OCH 3 , SCH 3 , and SO 2 CH 3 .
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1a is C 1 -C 4 alkyl, wherein the C 1 -C 4 alkyl is optionally substituted with a COOH substituent.
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1b is (CH 2 ) 2 CH 3 .
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1b is (CH 2 ) 3 CH 3 .
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
is:
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
is:
9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is C 1 -C 4 alkyl, wherein the C 1 -C 4 alkyl is substituted with an A substituent.
10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is CH 3 .
11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L 1 is —CH 2 — or —CH 2 CH 2 —.
12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L 1 is —CH 2 —.
13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is aryl, wherein the aryl is substituted with 1 A substituent and 1 C 1 -C 3 alkoxy substituent.
14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is aryl, wherein the aryl is substituted with 1 A substituent.
15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is phenyl, wherein the phenyl is substituted with 1 A substituent.
16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is
17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is
18. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is
19. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is
20. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is
21. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is
22. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is
23. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L 2 is —(CH 2 ) n —.
24. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L 2 is —C(CH 3 ) 2 —.
25. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L 2 is —CONH(CH 2 ) n —.
26. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L 2 is
27. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
X is C 1 -C 4 alkyl, wherein the C 1 -C 4 alkyl is substituted with 1
substituent; and
L 2 is a bond.
28. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2.
29. The compound of claim 1 , wherein the compound is of Formula (1a):
or a pharmaceutically acceptable salt thereof,
wherein:
X is CH 2 -A 1a , CH 2 CH 2 -A 1a , CH 2 CH 2 CH 2 -A 1a , or CH 2 C(CH 3 ) 2 -A 1a ;
A 1a is
A is
L 2 is a bond, —CH 2 —, —CH 2 CH 2 —, —C(CH 3 ) 2 —, —CONH(CH 2 ) n —, —O(C 1 -C 4 alkylene)-, or
and
R 3 is H, C 1 -C 3 alkyl, or C 1 -C 3 alkoxy.
30. The compound of claim 1 , wherein the compound is of Formula (1a):
or a pharmaceutically acceptable salt thereof,
wherein:
X is CH 3 ;
A is:
L 2 is a bond, —CH 2 —, —CH 2 CH 2 —, —C(CH 3 ) 2 —, —CONH(CH 2 ) n —, —O(C 1 -C 4 alkylene)-, or
and
R 3 is H, C 1 -C 3 alkyl, or C 1 -C 3 alkoxy.
31. The compound of claim 1 , wherein the compound is of Formula (1b):
or a pharmaceutically acceptable salt thereof,
wherein:
X is CH 2 -A 1a , CH 2 CH 2 -A 1a , CH 2 CH 2 CH 2 -A 1a , or CH 2 C(CH 3 ) 2 -A 1a ;
A 1a is
A is
L 2 is a bond, —CH 2 —, —CH 2 CH 2 —, —C(CH 3 ) 2 —, —CONH(CH 2 ) n —, —O(C 1 -C 4 alkylene)-, or
and
R 3 is H, C 1 -C 3 alkyl, or C 1 -C 3 alkoxy.
32. The compound of claim 1 , wherein the compound is of Formula (1b):
or a pharmaceutically acceptable salt thereof,
wherein:
X is CH 3 ;
A is
L 2 is a bond, —CH 2 —, —CH 2 CH 2 —, —C(CH 3 ) 2 —, —CONH(CH 2 ) n —, —O(C 1 -C 4 alkylene)-, or
and
R 3 is H, C 1 -C 3 alkyl, or C 1 -C 3 alkoxy.
33. The compound of claim 1 , wherein the compound is 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.
34. The compound of claim 1 , wherein the compound is of Formula (1f):
or a pharmaceutically acceptable salt thereof.
35. The compound of claim 1 , wherein the compound is of Formula (1j):
or a pharmaceutically acceptable salt thereof.
36. The compound of claim 1 , wherein the compound is of Formula (1k):
or a pharmaceutically acceptable salt thereof.
37. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
38. The pharmaceutical composition of claim 37 , wherein the pharmaceutical composition further comprises one or more additional therapeutic agents.
39. The pharmaceutical composition of claim 38 , wherein the additional therapeutic agent is an antiviral nucleoside.
40. The pharmaceutical composition of claim 38 , wherein the additional therapeutic agent is programmed cell death protein-1 antibody or programmed cell death protein ligand-1 antibody.
41. A method for modulating toll-like receptor 7 activity in a subject in need thereof, comprising administering to the subject an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
42. The method of claim 41 , wherein the subject has a condition associated with toll-like receptor 7 modulation selected from the group consisting of cancer and a viral infection.
43. The method of claim 41 , wherein the administration to the subject is bucchal, inhaled, intracranial, intradermal, intramuscular, intranasal, intrarectal, intrathecal, intratumoral, intravenous, intravesical, oral, subcutaneous, sublingual, or topical.
44. A method for modulating toll-like receptor 7 activity in a subject in need thereof having cancer, comprising administering to the subject 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.
45. A method for treating hepatitis B virus in a subject in need thereof, comprising administering to the subject an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, in combination with an antiviral nucleoside.
46. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
47. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.