Substituted pyrimidines containing acidic groups as TLR7 modulators

1. A compound of Formula (1):

or a pharmaceutically acceptable salt thereof,

wherein:

R 1a is H;

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 —CH 2 —, —CF 2 —, or —S—;

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 a bond or —(CH 2 ) n —; and

n is 2, 3, or 4;

with the proviso that the compound is substituted with at least one A.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1b is (CH 2 ) 2 CH 3 .

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1b is (CH 2 ) 3 CH 3 .

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is C 1 -C 4 alkyl, substituted with A.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is CH 3 .

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

X is C 1 -C 4 alkyl, substituted with -L 2 -COOH; and

L 2 is a bond.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L 1 is —CF 2 — or —S—.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L 1 is —CH 2 —.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is aryl, substituted with 1 or 2 A.

10. 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.

11. 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.

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L 2 is —(CH 2 ) 3 — or —(CH 2 ) 4 —.

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 , 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 a bond or —(CH 2 ) n —;

n is 2; and

R 3 is H, C 1 -C 3 alkyl, or C 1 -C 3 alkoxy.

15. 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 a bond or —(CH 2 ) n —;

n is 2; and

R 3 is H, C 1 -C 3 alkyl, or C 1 -C 3 alkoxy.

16. 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 a bond or —(CH 2 ) n —;

n is 2; and

R 3 is H, C 1 -C 3 alkyl, or C 1 -C 3 alkoxy.

17. 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 a bond or —(CH 2 ) n —;

n is 2; and

R 3 is H, C 1 -C 3 alkyl, or C 1 -C 3 alkoxy.

18. 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.

19. 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.

20. 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.

21. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

22. The pharmaceutical composition of claim 21 , wherein the pharmaceutical composition further comprises one or more additional therapeutic agents.

23. The pharmaceutical composition of claim 22 , wherein the additional therapeutic agent is an antiviral nucleoside.

24. The pharmaceutical composition of claim 22 , wherein the additional therapeutic agent is programmed cell death protein-1 antibody or programmed cell death protein ligand-1 antibody.

25. 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.

26. The method of claim 25 , wherein the subject has a condition associated with toll-like receptor 7 modulation.

27. The method of claim 26 , wherein the condition associated with toll-like receptor 7 modulation is selected from the group consisting of cancer and a viral infection.

28. The method of claim 25 , wherein the administration to the subject is bucchal, inhaled, intracranial, intradermal, intramuscular, intranasal, intrarectal, intrathecal, intratumoral, intravenous, intravesical, oral, subcutaneous, sublingual, or topical.

29. 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.

30. 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.

31. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.