3'3'-CYCLIC DINUCLEOTIDES

• US 20190322696A1
• Filed: 04/04/2019
• Published: 10/24/2019
• Est. Priority Date: 04/06/2018
• Status: Active Grant

• Current Assignee: Institute Of Organic Chemistry And Biochemistry Of The Ascr, V.V.I.
• Original Assignee: Institute Of Organic Chemistry And Biochemistry Of The Ascr, V.V.I.
• Inventors: Birkus, Gabriel, Pav, Ondrej, Rosenberg, Ivan, Simak, Ondrej
• Granted Patent: US 11,292,812 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/7084 Compounds having two nucleosides or nucleotides, e.g. nicotinamide-adenine dinucleotide, flavine-adenine dinucleotide
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07H 21/00 Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
• CPC Class Codes: C07H 21/02 with ribosyl as saccharide radical
• CPC Class Codes: C07H 21/04 with deoxyribosyl as saccharide radical

Abstract

The present invention relates to 3′3′-cyclic dinucleotides modified with a 3′-phosphonoalkyl bond and derivatives thereof, that can modulate the activity of the STING adaptor protein.

Claims

1. A compound of Formula (I):

2. The compound of claim 1, wherein Y¹and Y² are O.

3. The compound of claim 1, wherein L¹ is —

O—

or —

O—

C(R⁶R⁷)—

, and L² is —

O—

C(R⁶R⁷)—

.

10. The compound of claim 1, wherein the compound of Formula (I) has a structure of Formula (Ia-2):

11. The compound of claim 10, wherein L¹ is —

O—

or —

O—

CH₂—

.

12. The compound of claim 1, wherein the compound of Formula (I) has a structure of Formula (Ib):

13. The compound of claim 1, wherein the compound of Formula (I) has a structure of Formula (Ic):

14. The compound of claim 1, wherein the compound of Formula (I) has a structure of Formula (Id):

18. The compound of claim 1, wherein Base¹ and Base² are each independently:

19. The compound of claim 1, wherein Base¹ and Base² are each independently:

20. The compound of claim 1, wherein R³ and R¹⁰ are each independently H, OH, F, Cl, Br, I, CN, N₃, or OR¹³, wherein R¹³ is C₁-C₆ alkyl.

21. The compound of claim 1, wherein R³ and R¹⁰ are each independently H, OH or F.

22. The compound of claim 1, wherein the compound has the structure:

23. A pharmaceutical composition comprising the compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, and/or diluent.

4-9. -9. (canceled)

15-17. -17. (canceled)

24-25. -25. (canceled)

26. A method of treating or preventing a disease or disorder in a human or animal in need thereof, the method comprising administering to the human or animal a therapeutically effective amount of a compound of Formula (I):

28. The method of claim 26, wherein the disease or disorder is responsive to the modulation of STING adaptor protein.

30. The method of claim 26, wherein the disease or condition is a viral infection.

31. The method of claim 26, wherein the disease or condition is an infection with hepatitis B virus or HIV.

32. The method of claim 26, wherein the disease or condition is a hyperproliferative disease or cancer.

33. The method of claim 26, the method comprising enhancing the efficacy of a vaccine.

27. (canceled)

29. (canceled)

34-44. -44. (canceled)