Cyclopentane-based modulators of STING (stimulator of interferon genes)
Compounds of the general formula (I): or a pharmaceutically acceptable salt thereof, processes for the preparation of these compounds, compositions containing these compounds, and the uses of these compounds.
1. A compound of formula (I):
or a pharmaceutically acceptable salt thereof, wherein
each J is independently oxygen (O) or sulfur (S);
R 1 is selected from:
R 2 is selected from:
W is OH, SH, O − M + or S − M + , where M + represents a cationic counter-ion;
X is OH, SH, O − M + or S − M + , where M + represents a cationic counter-ion;
each Y is independently selected from hydrogen, halogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, N(R 3 ) 2 , and OR 4 , or the two Y substituents join to form a 3-5 membered spirocyclic ring system comprising 0-1 heteroatoms;
each Z is independently selected from hydrogen, halogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, N(R 3 ) 2 , and OR 4 , or the two Z substituents join to form a 3-5 membered spirocyclic ring system comprising 0-1 heteroatoms; and
R 3 and R 4 are each independently hydrogen or C 1 -C 6 alkyl.
2. A compound of formula (II):
or a pharmaceutically acceptable salt thereof, wherein
R 1 is selected from:
R 2 is selected from:
W is OH, SH, O − M + or S − M + , where M + represents a cationic counter-ion;
X is OH, SH, O − M + or S − M + , where M + represents a cationic counter-ion;
each Y is independently selected from hydrogen, halogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, N(R 3 ) 2 , and OR 4 , or the two Y substituents join to form a 3-5 membered spirocyclic ring system comprising 0-1 heteroatoms;
each Z is independently selected from hydrogen, halogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, N(R 3 ) 2 , and OR 4 , or the two Z substituents join to form a 3-5 membered spirocyclic ring system comprising 0-1 heteroatoms; and
R 3 and R 4 are each independently hydrogen or C 1 -C 6 alkyl.
3. The compound or salt of claim 1 , wherein M + is selected from the group consisting of sodium, potassium, calcium, ammonium, triethylammonium, trimethylammonium and magnesium.
4. The compound or salt of claim 1 , wherein each counter-ion M + is the same.
5. The compound or salt of claim 1 , wherein R 1 is
and R 2 is
6. The compound or salt of claim 1 , wherein R 1 is
and R 2 is
7. The compound or salt of claim 1 , wherein R 1 is
and R 2 is
8. The compound or salt of claim 1 , wherein R 1 is
and R 2 is
9. The compound or salt of claim 1 , wherein R 1 is
and R 2 is
10. The compound or salt of claim 1 , wherein R 1 is
and R 2 is
11. The compound or salt of claim 1 , wherein R 1 is
and R 2 is
12. The compound or salt of claim 1 , wherein R 1 is
and R 2 is
13. The compound or salt of claim 1 , wherein R 1 is
and R 2 is
14. The compound or salt of claim 1 , wherein R 1 is
and R 2 is
15. The compound or salt of claim 1 , wherein R 1 is
and R 2 is
16. The compound or salt of claim 1 , wherein R 1 is
and R 2 is
17. The compound or salt of claim 1 , wherein R 1 is
and R 2 is
18. The compound or salt of claim 1 , wherein one or both Y is halogen.
19. The compound or salt of claim 1 , wherein one Y is hydrogen and the other Y is a halogen.
20. The compound or salt of claim 19 , wherein said halogen is fluorine.
21. The compound or salt of claim 1 , wherein one Z is hydrogen and the other Z is OR 4 .
22. The compound or salt of claim 1 , wherein W is —SH and X is —SH.
23. The compound or salt of claim 1 , wherein W is —OH and X is —OH.
24. The compound or salt of claim 1 , wherein W is —SH and X is —OH.
25. The compound or salt of claim 1 , wherein W is —OH and X is —SH.
26. A compound selected from:
or a pharmaceutically acceptable salt thereof.
27. A compound selected from:
or a pharmaceutically acceptable salt thereof.
28. A compound selected from:
or a pharmaceutically acceptable salt thereof.
29. A single diastereomer of a compound or salt according to any one of claims 1 , 2 and 26 - 28 .
30. A pharmaceutical composition comprising a compound or salt according to any one of claims 1 and 26 , and a pharmaceutically acceptable carrier.
31. A pharmaceutical composition comprising a compound or salt according to any one of claims 1 and 26 , wherein said compound is a component of an antibody-drug conjugate.
32. A pharmaceutical composition comprising a compound or salt according to any one of claims 1 and 26 , wherein said compound is a component of a particle-based delivery system.
33. The compound:
or a pharmaceutically acceptable salt thereof.
34. The compound:
35. A pharmaceutically acceptable salt of the compound:
36. A pharmaceutical composition comprising a compound or salt according to any one of claims 33 - 35 , and a pharmaceutically acceptable carrier.
37. A pharmaceutical composition comprising a compound or salt according to any one of claims 33 - 35 , wherein said compound is a component of an antibody-drug conjugate.
38. A pharmaceutical composition comprising a compound or salt according to any one of claims 33 - 35 , wherein said compound is a component of a particle-based delivery system.