Compositions and methods for altering second messenger signaling
The invention relates to compositions, methods, kits, and assays related to the use and/or exploitation of isomers of cGAMP as well as the structure of the enzyme cGAS.
1. A pharmaceutical composition comprising a compound of Formula II:
or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier,
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 —CR— or —N—, wherein each R is independently hydrogen or C 1-6 aliphatic;
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 or sulfur;
each X e and X f is —O—;
each W is P;
each R 1 and R 2 is independently selected from the group consisting of hydrogen, halogen, —CN, —OR a wherein R a is hydrogen or C 1-6 aliphatic, —N(R) 2 wherein each R is independently hydrogen or C 1-6 aliphatic, and C 1-12 aliphatic optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OR ∘ , and —N(R ∘ ) 2 , wherein each R ∘ is independently hydrogen or C 1-6 aliphatic;
each R 3 , R 4 , R 5 , R 6 , and R 7 is independently selected from the group consisting of hydrogen, halogen, —CN, —OR wherein R is hydrogen or C 1-6 aliphatic, —SR wherein R is hydrogen or C 1-6 aliphatic, —N(R) 2 wherein each R is independently hydrogen or C 1-6 aliphatic, —C(O)N(R) 2 wherein each R is independently hydrogen or C 1-6 aliphatic, —NHC(O)R wherein R is hydrogen, C 1-6 aliphatic, or phenyl, and C 1-12 aliphatic optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OR ∘ , and —N(R ∘ ) 2 , wherein each R ∘ is independently hydrogen or C 1-6 aliphatic;
the subindex of the carbon atoms to which each R 8 and R 9 is attached is 0; and
each R 10 and R 11 is independently hydrogen or C 1-2 alkyl.
2. The pharmaceutical composition of claim 1 , wherein Ring A is
3. The pharmaceutical composition of claim 2 , wherein Ring B is
4. The pharmaceutical composition of claim 1 , wherein Ring B is
5. The pharmaceutical composition of claim 1 , wherein each X 1 is —N—.
6. The pharmaceutical composition of claim 1 , wherein each X 2 is —N—.
7. The pharmaceutical composition of claim 1 , wherein X a is —O—.
8. The pharmaceutical composition of claim 1 , wherein X b is —O—.
9. The pharmaceutical composition of claim 1 , wherein X c and X d are both oxygen.
10. The pharmaceutical composition of claim 1 , wherein X c and X d are both sulfur.
11. The pharmaceutical composition 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.
12. The pharmaceutical composition of claim 11 , wherein at least one of R 1 and R 2 is —OH.
13. The pharmaceutical composition 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.
14. The pharmaceutical composition of claim 1 , wherein each R 3 , R 4 , R 5 , R 6 , and R 7 is independently selected from the group consisting of hydrogen, halogen, —OH, —SH, —NH 2 , and —C(O)NH 2 .
15. The pharmaceutical composition of claim 14 , 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.
16. The pharmaceutical composition of claim 1 , wherein each R 3 , R 5 , and R 7 is independently selected from the group consisting of hydrogen and halogen.
17. The pharmaceutical composition of claim 16 , wherein each R 3 , R 5 , and R 7 is hydrogen.
18. The pharmaceutical composition of claim 1 , wherein each R 4 and R 6 is independently selected from the group consisting of hydrogen, halogen, and —NH 2 .
19. The pharmaceutical composition of claim 18 , wherein R 4 and R 6 are each —NH 2 .
20. The pharmaceutical composition of claim 1 , wherein R 10 and R 11 are hydrogen.
21. The pharmaceutical composition of claim 1 , wherein the compound is of formula II-a:
or a pharmaceutically acceptable salt thereof.
22. The pharmaceutical composition of claim 1 , wherein the compound is of formula X, XI, XII, XIII, XIV, XV, or XVI:
or a pharmaceutically acceptable salt thereof.
23. The pharmaceutical composition of claim 21 , wherein:
Ring A is
wherein each X 1 is —N—, R 3 and R 5 are hydrogen, and
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.
24. The pharmaceutical composition of claim 23 , wherein at least one of X c and X d is sulfur.
25. The pharmaceutical composition of claim 23 , wherein both of X c and X d are oxygen.
26. The pharmaceutical composition of claim 23 , wherein both of X c and X d are sulfur.
27. The pharmaceutical composition of claim 1 , wherein the compound is of formula XIV:
or a pharmaceutically acceptable salt thereof,
wherein:
each R 3 , R 5 , and R 7 are independently hydrogen or halogen;
each R 4 and R 6 are independently hydrogen, halogen, or —NH 2 ; and
each R 1 and R 2 are independently selected from the group consisting of hydrogen, halogen, —NH 2 , and —OR a , wherein R a is hydrogen or C 1-6 alkyl.
28. The pharmaceutical composition of claim 1 , wherein the compound is of formula XVI:
or a pharmaceutically acceptable salt thereof,
wherein:
each R 3 , R 5 , and R 7 are independently hydrogen or halogen;
each R 4 and R 6 are independently hydrogen, halogen, or —NH 2 ; and
each R 1 and R 2 are independently selected from the group consisting of hydrogen, halogen, —NH 2 , and —OR a , wherein R a is hydrogen or C 1-6 alkyl.
29. The pharmaceutical composition of claim 1 ,
wherein at least one of X c and X d is sulfur.