Compositions and methods for altering second messenger signaling

• US 9,840,533 B2
• Filed: 04/29/2014
• Issued: 12/12/2017
• Est. Priority Date: 04/29/2013
• Status: Active Grant

• Current Assignee: Bond University, Memorial Sloan-Kettering Cancer Center, Rockefeller University, Rutgers University
• Original Assignee: Bond University, Memorial Sloan-Kettering Cancer Center, Rockefeller University, Rutgers University
• 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
• Primary Examiner(s): Murray, Jeffrey H
• Application Number:
  US14/787,611
• Publication Number:
  US 20160068560A1
• Time in Patent Office: 1,323 Days
• Field of Search: None
• CPC Class Codes: A61K 31/522 having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• CPC Class Codes: A61K 47/55 the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
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• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
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• CPC Class Codes: A61P 13/12 of the kidneys
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• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 : Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/02 : Nutrients, e.g. vitamins, minerals
• CPC Class Codes: A61P 3/06 : Antihyperlipidemics
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 : Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 31/10 : Antimycotics
• CPC Class Codes: A61P 31/12 : Antivirals
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 7/04 : Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07F 9/65746 : the molecule containing more than one cyclic phosphorus atom
• 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: C12Q 1/485 : involving kinase
• CPC Class Codes: C12Y 207/07 : Nucleotidyltransferases (2.7.7)
• CPC Class Codes: G01N 2500/04 : Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)
• CPC Class Codes: G01N 2500/10 : involving cells
• CPC Class Codes: G06V 20/698 : Matching; Classification
• CPC Class Codes: G16B 15/00 : ICT specially adapted for analysing two-dimensional or three-dimensional molecular structures, e.g. structural or functional relations or structure alignment
• CPC Class Codes: G16B 20/00 : ICT specially adapted for functional genomics or proteomics, e.g. genotype-phenotype associations
• CPC Class Codes: G16B 20/30 : Detection of binding sites or motifs
• CPC Class Codes: G16B 20/50 : Mutagenesis

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.

Claims

1. A compound of Formula II:

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 R¹ is selected from the group consisting of hydrogen, halogen, and —

OH.

6. The compound of claim 5, wherein R² 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:

8. The compound of claim 1, wherein the compound is of formula X, XII, XIII, XIV, XV, or XVI:

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

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

19. The compound of claim 1, wherein each X¹ is —

N—

.

20. The compound of claim 1, wherein each X² 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 R¹ is —

OH.

26. The compound of claim 6, wherein R² is —

OH.

27. The compound of claim 1, wherein each R³, R⁵, and R⁷ is independently selected from the group consisting of hydrogen and halogen.

28. The compound of claim 27, wherein each of R³, R⁵, and R⁷ is hydrogen.

29. The compound of claim 1, wherein each of R⁴ is independently selected from the group consisting of hydrogen, halogen, and —

NH₂, and each of R⁶ is independently selected from the group consisting of halogen and —

NH₂.

30. The compound of claim 29, wherein R⁴ and R⁶ are each —

NH₂.

31. The compound of claim 1, wherein R¹⁰ and R¹¹ are hydrogen.

32. The compound of claim 1, wherein each R³, R⁵, and R⁷ is independently selected from the group consisting of hydrogen, halogen, —

NH₂, —

OR wherein R is hydrogen, —

SR wherein R is hydrogen, and —

NHC(O)R wherein R is hydrogen;

each R⁴ is independently selected from the group consisting of hydrogen, halogen, —

NH₂, —

SR wherein R is hydrogen, and —

NHC(O)R wherein R is hydrogen;

each R⁶ is independently selected from the group consisting of halogen, —

NH₂, —

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 R¹ and R² is independently selected from the group consisting of hydrogen, halogen, —

NH₂, and —

OR^a, wherein R^a is hydrogen or C_1-6 alkyl.

37. The compound of claim 1, wherein each R¹⁰ and R¹¹ is hydrogen.

38. The compound of claim 1, wherein X^c and X^d are independently oxygen or sulfur;

and each R¹ and R² is independently selected from the group consisting of hydrogen, halogen, —

NH₂, and —

OR^a, wherein R^a is hydrogen or C_1-6 alkyl.

39. The compound of claim 1, wherein X^c and X^d are independently oxygen or sulfur;

and each R¹⁰ and R¹¹ is hydrogen.

40. The compound of claim 1, wherein each R¹ and R² is independently selected from the group consisting of hydrogen, halogen, —

NH₂, and —

OR^a, wherein R^a is hydrogen or C_1-6 alkyl; and

each R¹⁰ and R¹¹ is hydrogen.

41. The compound of claim 1, wherein X^c and X^d are independently oxygen or sulfur;

each R^l and R² is independently selected from the group consisting of hydrogen, halogen, —

NH₂, and —

OR^a, wherein R^a is hydrogen or C_1-6 alkyl; and

each R¹⁰ and R¹¹ is hydrogen.

42. The compound of claim 1, wherein the compound is of formula XIV

43. The compound of claim 1, wherein the compound is of formula XVI

9. A compound:

10. The compound of claim 9, wherein the compound is:

11. The compound of claim 10, in isolated form.

12. The compound of claim 11, in purified form.

44. A pharmaceutical composition comprising the compound of claim 12 and a pharmaceutically acceptable carrier.