Cyclic di-nucleotide compounds and methods of use

Patent metadata

Field	Value
Publication number	US-11299512-B2
Application number	US-201916438153-A
Country	US
Kind code	B2
Filing date	Jun 11, 2019
Priority date	Mar 18, 2016
Publication date	Apr 12, 2022
Grant date	Apr 12, 2022

Abstract

Disclosed are cyclic-di-nucleotide cGAMP analogs, methods of synthesizing the compounds, pharmaceutical compositions comprising the compounds thereof, and use of compounds and compositions in medical therapy.

First claim

The invention claimed is:

1. A compound, wherein the compound is of Formula Ic:

wherein
Z 12 and Z 15 are N;
Z 13 , Z 14 , Z 16 and Z 17 are independently CH or N;
R 3 is C 2 alkyl functionalized with one or more halogen, thiol, hydroxyl, carboxyl, C 1-6 alkoxy, C 1-6 hydroxyalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, or azido groups;
R 4 is hydroxyl;
R 9 and R 10 are independently hydroxyl; thiol; C 1-6 alkyl; C 1-6 alkyl functionalized with one or more halogen, thiol, hydroxyl, carboxyl, C 1-6 alkoxy, C 1-6 hydroxyalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, or azido groups; C 1-6 alkoxy; C 1-6 alkoxy functionalized with one or more halogen, thiol, hydroxyl, carboxyl, C 1-6 hydroxyalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, or azido groups; C 3-5 alkenyl-O—; C 3-5 alkynyl-O—; oligo(ethylene glycol); poly(ethylene glycol); borano (—BH 3 − ); or —NR 7 R 8 ;
R 7 and R 8 are independently hydrogen; C 1-6 alkyl; C 1-6 alkyl functionalized with one or more halogen, thiol, hydroxyl, carboxyl, C 1-6 alkoxy, C 1-6 hydroxyalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, or azido groups; cyclic —(C 1-6 alkyl)-; cyclic —(C 1-6 alkyl)- functionalized with one or more halogen, thiol, hydroxyl, carboxyl, C 1-6 alkoxy, C 1-6 hydroxyalkoxy, amino, C 1-6 alkylamino, or di(C 1-6 alkyl)amino groups; cyclic —(C 1-6 oxaalkyl)-; or cyclic —(C 1-6 oxaalkyl)-functionalized with one or more halogen, thiol, hydroxyl, carboxyl, C 1-6 hydroxyalkoxy, amino, C 1-6 alkylamino, or di(C 1-6 alkyl)amino groups;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein Z 13 and Z 16 are CH.

3. The compound of claim 1 , wherein Z 14 and Z 17 are N.

4. The compound of claim 1 , wherein Z 13 and Z 16 are CH, and Z 14 and Z 17 are N.

5. The compound of claim 1 , wherein R 9 and R 10 are independently hydroxyl or thiol.

6. The compound of claim 1 , wherein R 9 and R 10 are hydroxyl.

7. The compound of claim 1 , wherein R 9 and R 10 are thiol.

8. The compound of claim 1 , wherein R 3 is C 2 alkyl functionalized with one or more thiol, hydroxyl, carboxyl, C 1-6 hydroxyalkoxy, amino, or C 1-6 alkylamino groups.

9. The compound of claim 1 , wherein R 3 is C 2 alkyl functionalized with one or more halogen, thiol, or hydroxyl.

10. A compound, wherein the compound is of Formula Ic:

wherein
Z 12 and Z 15 are N;
Z 13 and Z 16 are CH;
Z 14 and Z 17 are independently CH or N;
R 3 is C 2 alkyl functionalized with one or more halogen, thiol, hydroxyl, carboxyl, C 1-6 alkoxy, C 1-6 hydroxyalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, or azido groups;
R 4 is hydroxyl;
R 9 and R 10 are independently hydroxyl or thiol;

or a pharmaceutically acceptable salt thereof.

11. The compound of claim 10 , wherein R 3 is C 2 alkyl functionalized with one or more thiol, hydroxyl, carboxyl, C 1-6 hydroxyalkoxy, amino, or C 1-6 alkylamino groups.

12. The compound of claim 10 , wherein R 3 is C 2 alkyl functionalized with hydroxyl.

13. The compound of claim 10 , wherein R 3 is C 2 alkyl functionalized with thiol.

14. The compound of claim 10 , wherein R 3 is C 2 alkyl functionalized with halogen.

15. A compound, wherein the compound is of Formula Ic:

wherein
Z 12 and Z 15 are N;
Z 13 , Z 14 , Z 16 and Z 17 are independently CH or N;
R 3 is C 1-6 alkyl functionalized with one or more halogen, thiol, or hydroxyl;
R 4 is hydroxyl;
R 9 and R 10 are independently hydroxyl; thiol; C 1-6 alkyl; C 1-6 alkyl functionalized with one or more halogen, thiol, hydroxyl, carboxyl, C 1-6 alkoxy, C 1-6 hydroxyalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, or azido groups; C 1-6 alkoxy; C 1-6 alkoxy functionalized with one or more halogen, thiol, hydroxyl, carboxyl, C 1-6 hydroxyalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, or azido groups; C 3-5 alkenyl-O—; C 3-5 alkynyl-O—; oligo(ethylene glycol); poly(ethylene glycol); borano (—BH 3 − ); or —NR 7 R 8 ;
R 7 and R 8 are independently hydrogen; C 1-6 alkyl; C 1-6 alkyl functionalized with one or more halogen, thiol, hydroxyl, carboxyl, C 1-6 alkoxy, C 1-6 hydroxyalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, or azido groups; cyclic —(C 1-6 alkyl)-; cyclic —(C 1-6 alkyl)- functionalized with one or more halogen, thiol, hydroxyl, carboxyl, C 1-6 alkoxy, C 1-6 hydroxyalkoxy, amino, C 1-6 alkylamino, or di(C 1-6 alkyl)amino groups; cyclic —(C 1-6 oxaalkyl)-; or cyclic —(C 1-6 oxaalkyl)-functionalized with one or more halogen, thiol, hydroxyl, carboxyl, C 1-6 hydroxyalkoxy, amino, C 1-6 alkylamino, or di(C 1-6 alkyl)amino groups;

or a pharmaceutically acceptable salt thereof.

16. The compound of claim 15 having the structure:

or a pharmaceutically acceptable salt thereof.

17. The compound of claim 15 having the structure:

or a pharmaceutically acceptable salt thereof.

18. The compound of claim 15 having the structure:

or a pharmaceutically acceptable salt thereof.

19. The compound of claim 15 having the structure:

or a pharmaceutically acceptable salt thereof.

20. A compound, wherein the compound is of Formula Ic:

wherein
Z 12 and Z 15 are N;
Z 13 and Z 16 are CH;
Z 14 and Z 17 are independently CH or N;
R 3 is C 1-6 alkyl functionalized with one or more halogen, thiol, or hydroxyl;
R 4 is hydroxyl;
R 9 and R 10 are independently hydroxyl or thiol;

or a pharmaceutically acceptable salt thereof.

21. The compound of claim 20 , wherein R 3 is C 1-6 alkyl functionalized with hydroxyl.

22. The compound of claim 20 , wherein R 3 is C 1-6 alkyl functionalized with thiol.

23. The compound of claim 20 , wherein R 3 is C 1-6 alkyl functionalized with halogen.

24. A pharmaceutical composition that provides a therapeutically effective amount of a compound of claim 1 and one or more pharmaceutically acceptable excipients.

25. A pharmaceutical composition that provides a therapeutically effective amount of a compound of claim 1 in combination with at least one further therapeutic agent and one or more pharmaceutically acceptable excipients.

26. An immunogenic composition comprising an antigen or antigen composition and a compound of claim 1 .

27. A pharmaceutical composition that provides a therapeutically effective amount of a compound of claim 8 and one or more pharmaceutically acceptable excipients.

28. A pharmaceutical composition that provides a therapeutically effective amount of a compound of claim 10

Assignees

• Immunesensor Therapeutics Inc
• Univ Texas

Inventors

• Zhong Boyu
• Shi Heping
• Dai Yuanwei
• Wei Qi
• Chen Chuo
• Chen Zhijian
• Sun Lijun

Classifications

• A61P37/02

  Immunomodulators · CPC title

• C07H19/213 Primary

  containing cyclic phosphate · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07H21/00 Primary

  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 title

• C07H21/02 Primary

  with ribosyl as saccharide radical · CPC title