Compositions and methods for altering second messenger signaling

Patent metadata

Field	Value
Publication number	US-9840533-B2
Application number	US-201414787611-A
Country	US
Kind code	B2
Filing date	Apr 29, 2014
Priority date	Apr 29, 2013
Publication date	Dec 12, 2017
Grant date	Dec 12, 2017

Abstract

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.

First claim

We claim:

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

Assignees

• Memorial Sloan Kettering Cancer Center
• Univ Rockefeller
• Univ Rutgers
• Univ Of Bonn

Inventors

• Patel Dinshaw
• Tuschl Thomas
• Ascano Jr Manuel
• Wu Yang
• Liu Yizhou
• Barchet Winfried
• Hartmann Gunther
• Zillinger Thomas
• Jones Roger
• Gaffney Barbara L
• Gao Pu

Classifications

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P5/14

  of the thyroid hormones, e.g. T3, T4 · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P7/06

  Antianaemics · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title