Cyclic dinucleotides as sting agonists

Patent metadata

Field	Value
Publication number	US-11021511-B2
Application number	US-201816478864-A
Country	US
Kind code	B2
Filing date	Jan 26, 2018
Priority date	Jan 27, 2017
Publication date	Jun 1, 2021
Grant date	Jun 1, 2021

Abstract

Disclosed are compounds, compositions and methods for treating of diseases, syndromes, or disorders that are affected by the modulation of STING. Such compounds are represented by Formula (I) as follows:

wherein R 1A , R 1B , R 1C , R 1D , B 1 , R 2A , R 2B , R 2C , R 2D , and R 2E are defined herein

and Formula (II)

wherein R 1H , R 1K , R 1J , and R 2L are defined herein.

First claim

The invention claimed is:

1. A method of treating hepatitis B comprising administering to a subject in need thereof a therapeutically effective amount of the compound of Formula (I)

wherein
R 1A , R 2A , R 1D , R 2D , and R 2E are each, independently, hydrogen or methyl; such that one of said R 1A , R 2A , R 1D , R 2D , and R 2E is methyl;
R 1B is hydrogen, hydroxy or fluoro; or, R 1B is —O—, and R 1D is CH 2 , wherein R 1B , R 1D and the atoms to which they are attached form a 5-membered ring;
R 1C is hydroxy, thiol, or BH 3 − ;
B 1 is ring b1 or b2

R 2B is hydroxy, fluoro or methoxy;
R 2C is hydroxy, thiol, or BH 3 − ;

or an enantiomer, diastereomer, or pharmaceutically acceptable salt form thereof.

2. The method of claim 1 , wherein R 1B is hydrogen or fluoro.

3. The method of claim 1 , wherein R 1B is —O—, and R 1D is CH 2 , wherein R 1B , R 1D and the atoms to which they are attached form a 5-membered ring.

4. The method of claim 1 , wherein R 1C is selected from the group consisting of hydroxy and thiol.

5. The method of claim 1 , wherein R 1D is hydrogen.

6. The method of claim 1 , wherein B 1 is ring b2

7. The method of claim 1 , wherein R 2A is hydrogen.

8. The method of claim 1 , wherein R 2C is selected from the group consisting of hydroxy and thiol.

9. The method of claim 1 , wherein R 2D is hydrogen.

10. The method of claim 1 ,
wherein:
R 1C is selected from the group consisting of hydroxy and thiol; and
B 1 is ring b2

11. The method of claim 1 selected from the group consisting of compounds 1 to 3

or a pharmaceutically acceptable salt form thereof.

12. A method of treating hepatitis B comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a of Formula (I) and at least one of a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, and a pharmaceutically acceptable diluent:

wherein
R 1A , R 2A , R 1D , R 2D , and R 2E are each, independently, hydrogen or methyl; such that one of said R 1A , R 2A , R 1D , R 2D , and R 2E is methyl;
R 1B is hydrogen, hydroxy or fluoro; or, R 1B is —O—, and R 1D is CH 2 , wherein R 1B , R 1D and the atoms to which they are attached form a 5-membered ring;
R 1C is hydroxy, thiol, or BH 3 − ;
B 1 is ring b1 or b2

R 2B is hydroxy, fluoro or methoxy;
R 2C is hydroxy, thiol, or BH 3 − ;

or an enantiomer, diastereomer, or pharmaceutically acceptable salt form thereof.

13. The method of claim 12 , wherein the pharmaceutical composition is a solid oral dosage form.

14. The method of claim 12 , wherein the composition is a syrup, an elixir or a suspension.

Assignees

• Janssen Biotech Inc

Inventors

• Emanuel Stuart
• Richter Mark
• Connolly Peter J
• Edwards James Patrick
• Wang Guangyi
• Thatikonda Santhosh Kumar
• Beigelman Leonid
• Zhong Minghong
• Bignan Gilles

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/7084

  Compounds having two nucleosides or nucleotides, e.g. nicotinamide-adenine dinucleotide, flavine-adenine dinucleotide · 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

• A61K31/708

  having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid · CPC title

• A61K31/7076

  containing purines, e.g. adenosine, adenylic acid · CPC title