Sting modulator compounds, and methods of making and using
The present disclosure provides STING modulators/agonists, and methods of synthesis and methods for using for the prophylaxis or treatment of cancer and other STING-related diseases. The present disclosure relates to a compound represented by the Formula (I): wherein each symbol is as defined in the description, or a pharmaceutically acceptable salt thereof.
1. A compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
X 1 is —SH or —OH;
X 2 is —SH or —OH;
Y a is —O—, —S—, or —CH 2 —;
Y b is —O—, —S—, —NH—, or —NR a —, wherein Ra is C 1 -C 4 alkyl;
R 1 is hydrogen, fluoro, —OH, —NH 2 , —OR b , or —NHR b ;
R 2 is hydrogen or fluoro;
R 3 is hydrogen; R 4 is hydrogen, fluoro, —OH, —NH 2 , —OR b , or —NHR b ; or R 3 and R 4 are taken together to form —CH 2 O—;
R 5 is hydrogen or fluoro;
R b is C 1 -C 6 alkyl, halo(C 1 -C 6 )alkyl, or C 3 -C 6 cycloalkyl;
Ring A is an optionally substituted 5- or 6-membered monocyclic heteroaryl ring containing 1-4 heteroatoms selected from N, O, or S, or an optionally substituted 9- or 10-membered bicyclic heteroaryl ring containing 1-5 heteroatoms selected from N, O, or S; wherein Ring A comprises at least one N atom in the ring, and wherein Y b is attached to a carbon atom of Ring A; and Ring B is an optionally substituted 9- or 10-membered bicyclic heteroaryl ring containing 2-5 heteroatoms selected from N, O, or S; wherein Ring B comprises at least two N atoms in the ring.
2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein:
X 1 and X 2 are —SH; and
the phosphorus atom of each phosphorothioate linkage is R p .
3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Y a is —CH 2 —.
4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein:
R 1 is fluoro or —OH;
R 4 is hydrogen or fluoro; and
R 2 , R 3 , and R 5 are hydrogen.
5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein:
Ring A is an optionally substituted 6-membered monocyclic heteroaryl ring containing 1-3 N atoms.
6. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein:
Ring A is:
7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein:
Ring B is an optionally substituted 9- membered bicyclic heteroaryl ring containing 3-5 N atoms; and
the Y a -containing 5-membered ring is attached to a nitrogen atom of Ring B.
8. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein Ring B is:
9. The compound of claim 1 , having Formula (VI):
or a pharmaceutically acceptable salt thereof, wherein
X 1 is —SH or —OH;
X 2 is —SH or —OH;
Y b is —O—, —S—, —NH—, or —NMe—;
R 1 is hydrogen, fluoro, —OH, or —OR b ;
R 2 is hydrogen or fluoro;
R 3 is hydrogen; R 4 is hydrogen, fluoro, or —OH;
R 5 is hydrogen or fluoro;
R b is C 1 -C 6 alkyl, halo(C 1 -C 6 )alkyl, or C 3 -C 6 cycloalkyl;
each R 10 is independently hydrogen, halogen, —OH, —NH 2 , C 1 -C 6 alkyl, halo(C 1 -C 6 )alkyl, C 3 -C 6 cycloalkyl, —OR 11 , —NHR 11 , —CN, —NO 2 , or —C(O)NHR 12 ;
R 11 is C 1 -C 6 alkyl, halo(C 1 -C 6 )alkyl, or C 3 -C 6 cycloalkyl;
R 12 is hydrogen, C 1 -C 6 alkyl, halo(C 1 -C 6 )alkyl, or C 3 -C 6 cycloalkyl;
m is 0, 1, or 2;
Z 1 is N, CH, or CF;
R 21 is hydrogen or —CH 3 ; and
R 22 is hydrogen, —NH 2 , or —CH 3 .
10. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein Y b is —O—.
11. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein X 1 and X 2 are —SH, and wherein the phosphorus atom of each phosphorothioate linkage is chiral and is independently R p or S p .
12. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 , and R 5 are hydrogen.
13. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen, fluoro, or —OH.
14. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen or fluoro.
15. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein m is 0.
16. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein Z 1 is N.
17. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein R 21 is hydrogen.
18. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein R 22 is —NH 2 .
19. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:
20. A pharmaceutical composition comprising (a) the compound of claim 1 or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable carrier.
21. A method of treating a cell proliferation disorder in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof.
22. The method of claim 21 , wherein the cell proliferation disorder is cancer.
23. A vaccine composition comprising an antigen and the compound of claim 1 or a pharmaceutically acceptable salt thereof.