Compositions and methods for altering second messenger signaling
The present disclosure provides, among other things, novel cyclic-GMP-AMP (cGAMP) analogs, mimics, mimetics and variants, and compositions and kits thereof; methods of using the compounds as described herein for treating cancer, and immune disease, disorders, or conditions; methods of using the compounds as described herein for modulating cGAS and STING; and methods of designing or characterizing a cGAS modulator.
1. A compound of Formula II:
or a pharmaceutically acceptable salt thereof,
wherein:
Ring A is selected from the group consisting of:
Ring B is selected from the group consisting of:
each X 1 and X 2 is independently —CH— or —N—;
X 3 is —NH—;
X a and X b are independently —O— or —S—;
X a1 and X b1 are —CH—;
X c and X d are independently oxygen optionally substituted with cyanoethyl, or sulfur;
each X e and X f is —O—;
each W is independently P;
each R 1 and R 2 is independently selected from the group consisting of hydrogen, halogen, —NH 2 and —OR a , wherein R a is an oxygen protecting group, hydrogen, or C 1-6 alkyl;
each R 3 , R 5 , and R 7 is independently selected from the group consisting of hydrogen, halogen, —NH 2 , —OR wherein R is hydrogen or C 1-6 alkyl, —SR wherein R is hydrogen or C 1-6 alkyl, and —NHC(O)R wherein R is hydrogen, C 1-6 alkyl, or phenyl;
each R 4 is independently selected from the group consisting of hydrogen, halogen, —NH 2 , —OR wherein R is C 1-6 alkyl, —SR wherein R is hydrogen or C 1-6 alkyl, and —NHC(O)R wherein R is hydrogen, C 1-6 alkyl, or phenyl;
each R 6 is independently selected from the group consisting of halogen, —NH 2 , —OR wherein R is hydrogen or C 1-6 alkyl, —SR wherein R is hydrogen or C 1-6 alkyl, and —NHC(O)R wherein R is hydrogen, C 1-6 alkyl, or phenyl;
each R 10 and R 11 is independently hydrogen or C 1-2 alkyl; and
the subindex of the carbon atoms to which each R 8 and R 9 is attached is 0;
with the proviso that the compound is other than:
2. The compound of claim 1 , wherein Ring A is
3. The compound of claim 1 , wherein Ring B is
4. The compound of claim 1 , wherein Ring B is
5. The compound of claim 1 , wherein R 1 is selected from the group consisting of hydrogen, halogen, and —OH.
6. The compound of claim 5 , wherein R 2 is selected from the group consisting of hydrogen, halogen, and —OH.
7. The compound of claim 1 , wherein the compound is of formula II-a:
or a pharmaceutically acceptable salt thereof.
8. The compound of claim 1 , wherein the compound is of formula X, XII, XIII, XIV, XV, or XVI:
or a pharmaceutically acceptable salt thereof.
9. A compound:
or a pharmaceutically acceptable salt thereof.
10. The compound of claim 9 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
11. The compound of claim 10 , in isolated form.
12. The compound of claim 11 , in purified form.
13. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
14. The compound of claim 7 , wherein
Ring A is
each X 1 is N;
R 3 and R 5 are hydrogen;
R 4 is NH 2 ;
X a and X b are O;
R 1 and R 2 are OH; and
R 10 and R 11 are hydrogen;
or a pharmaceutically acceptable salt thereof.
15. The compound of claim 14 , wherein one or both of X c and X d is sulfur.
16. The compound of claim 14 , wherein both of X c and X d are oxygen.
17. The compound of claim 14 , wherein both of X c and X d are sulfur.
18. The compound of claim 7 , wherein
Ring A is
each X 1 is N;
R 3 and R 5 are hydrogen;
R 4 is NH 2 ;
X a and X b are O;
X c and X d , are independently oxygen or sulfur;
R 1 and R 2 are OH; and
R 10 and R 11 are hydrogen;
or a pharmaceutically acceptable salt thereof.
19. The compound of claim 1 , wherein each X 1 is —N—.
20. The compound of claim 1 , wherein each X 2 is —N—.
21. The compound of claim 1 , wherein X a is —O—.
22. The compound of claim 1 , wherein X b is —O—.
23. The compound of claim 1 , wherein X c and X d are both oxygen.
24. The compound of claim 1 , wherein X c and X d are both sulfur.
25. The compound of claim 5 , wherein R 1 is —OH.
26. The compound of claim 6 , wherein R 2 is —OH.
27. The compound of claim 1 , wherein each R 3 , R 5 , and R 7 is independently selected from the group consisting of hydrogen and halogen.
28. The compound of claim 27 , wherein each of R 3 , R 5 , and R 7 is hydrogen.
29. The compound of claim 1 , wherein each of R 4 is independently selected from the group consisting of hydrogen, halogen, and —NH 2 , and each of R 6 is independently selected from the group consisting of halogen and —NH 2 .
30. The compound of claim 29 , wherein R 4 and R 6 are each —NH 2 .
31. The compound of claim 1 , wherein R 10 and R 11 are hydrogen.
32. The compound of claim 1 , wherein each R 3 , R 5 , and R 7 is independently selected from the group consisting of hydrogen, halogen, —NH 2 , —OR wherein R is hydrogen, —SR wherein R is hydrogen, and —NHC(O)R wherein R is hydrogen;
each R 4 is independently selected from the group consisting of hydrogen, halogen, —NH 2 , —SR wherein R is hydrogen, and —NHC(O)R wherein R is hydrogen;
each R 6 is independently selected from the group consisting of halogen, —NH 2 , —OR wherein R is hydrogen, —SR wherein R is hydrogen, and —NHC(O)R wherein R is hydrogen.
33. A pharmaceutical composition comprising the compound of claim 7 and a pharmaceutically acceptable carrier.
34. A pharmaceutical composition comprising the compound of claim 17 and a pharmaceutically acceptable carrier.
35. The compound of claim 1 , wherein X c and X d are independently oxygen or sulfur.
36. The compound of claim 1 , wherein each R 1 and R 2 is independently selected from the group consisting of hydrogen, halogen, —NH 2 , and —OR a , wherein R a is hydrogen or C 1-6 alkyl.
37. The compound of claim 1 , wherein each R 10 and R 11 is hydrogen.
38. The compound of claim 1 , wherein X c and X d are independently oxygen or sulfur; and each R 1 and R 2 is independently selected from the group consisting of hydrogen, halogen, —NH 2 , and —OR a , wherein R a is hydrogen or C 1-6 alkyl.
39. The compound of claim 1 , wherein X c and X d are independently oxygen or sulfur; and each R 10 and R 11 is hydrogen.
40. The compound of claim 1 , wherein each R 1 and R 2 is independently selected from the group consisting of hydrogen, halogen, —NH 2 , and —OR a , wherein R a is hydrogen or C 1-6 alkyl; and each R 10 and R 11 is hydrogen.
41. The compound of claim 1 , wherein X c and X d are independently oxygen or sulfur; each R l and R 2 is independently selected from the group consisting of hydrogen, halogen, —NH 2 , and —OR a , wherein R a is hydrogen or C 1-6 alkyl; and each R 10 and R 11 is hydrogen.
42. The compound of claim 1 , wherein the compound is of formula XIV
wherein:
R 3 and R 5 are independently hydrogen or halogen;
R 4 is selected from the group consisting of hydrogen, halogen, and —NH 2 ;
R 6 is selected from the group consisting of halogen and —NH 2 ;
X c and X d are independently O or S;
R 1 is selected from the group consisting of hydrogen, halogen, —OR a , and —NH 2 , wherein R a is hydrogen or C 1-6 alkyl; and
R 2 is selected from the group consisting of hydrogen, halogen, —OR a , and —NH 2 , wherein R a is hydrogen or C 1-6 alkyl.
43. The compound of claim 1 , wherein the compound is of formula XVI
wherein:
R 3 and R 5 are independently hydrogen or halogen;
R 4 is selected from the group consisting of hydrogen, halogen, and —NH 2 ;
X c and X d are independently O or S;
R l is selected from the group consisting of hydrogen, halogen, —OR a , and —NH 2 , wherein R a is hydrogen or C 1-6 alkyl; and
R 2 is selected from the group consisting of hydrogen, halogen, —OR a , and —NH 2 , wherein R a is hydrogen or C 1-6 alkyl.
44. A pharmaceutical composition comprising the compound of claim 12 and a pharmaceutically acceptable carrier.