Hydroxylated tropolone inhibitors of nucleotidyl transferases in herpesvirus and Hepatitis B and uses therefor

Patent metadata

Field	Value
Publication number	US-11420922-B2
Application number	US-201615735195-A
Country	US
Kind code	B2
Filing date	Jun 10, 2016
Priority date	Jun 11, 2015
Publication date	Aug 23, 2022
Grant date	Aug 23, 2022

Abstract

The present disclosure relates to inhibitors of herpesvirus nucleic acid metabolism and inhibitors of Hepatitis B virus. Also provided are methods of treatment using these agents.

First claim

What is claimed:

1. A compound of the formula:

wherein:
R 1 and R 6 are each independently selected from hydrogen, acyl (C≤8) , or substituted acyl (C≤8) ;
R 2 and R 5 are each independently selected from hydrogen, hydroxy, alkyl (C≤8) , substituted alkyl (C≤8) , cycloalkyl (C≤12) , substituted cycloalkyl (C≤12) , aryl (C≤8) , substituted aryl (C≤8) , heteroaryl (C≤8) , substituted heteroaryl (C≤8) , alkoxy (C≤8) , substituted alkoxy (C≤8) , acyl (C≤8) , or substituted acyl (C≤8) ;
R 3 is hydroxy, cycloalkyl (C≤12) , substituted cycloalkyl (C≤12) , aryl (C7-18) , substituted aryl (C7-18) , heteroaryl (C≤12) , substituted heteroaryl (C≤12) , or —C(O)R a , wherein:
R a is alkenyl (C≤11) , aryl (C≤18) , aralkyl (C≤11) , heteroaryl (C≤18) , aryloxy (C≤18) , or a substituted version of any of these groups; and

R 4 is hydroxy, alkyl (C≤12) , substituted alkyl (C≤12) , cycloalkyl (C≤12) , substituted cycloalkyl (C≤12) , aryl (C≤18) , substituted aryl (C≤18) , heteroaryl (C≤12) , substituted heteroaryl (C≤12) , or —C(O)R a , wherein:
R a is alkyl (C≤18) , cycloalkyl (C≤18) , alkenyl (C≤11) , aryl (C≤18) , aralkyl (C≤11) , heteroaryl (C≤18) , aryloxy (C≤18) , -alkanediyl (C≤6) -cycloalkyl (C≤12) ; or a substituted version of any of these groups; or

R 3 and R 4 are taken together and are a group of the formula:
—(CH 2 ) m C(O)A(CH 2 ) n —, wherein:

A is O or NR b , wherein:
R b is hydrogen, alkyl (C≤6) , or substituted alkyl (C≤6) ; and

m and n are each independently selected from 0, 1, 2, or 3;

provided that the compound is not a compound of the following structures:

or a pharmaceutically acceptable salt or tautomer thereof.

2. The compound of claim 1 further defined as:

wherein:
R 1 and R 6 are each independently selected from hydrogen, acyl (C≤8) , or substituted acyl (C≤8) ;
R 2 and R 5 are each independently selected from hydrogen, hydroxy, alkyl (C≤8) , substituted alkyl (C≤8) , cycloalkyl (C≤12) , substituted cycloalkyl (C≤12) , aryl (C≤8) , substituted aryl (C≤8) , heteroaryl (C≤8) , substituted heteroaryl (C≤8) , alkoxy (C≤8) , substituted alkoxy (C≤8) , acyl (C≤8) , or substituted acyl (C≤8) ;
R 3 is hydroxy, cycloalkyl (C≤12) , substituted cycloalkyl (C≤12) , aryl (C7-18) , substituted aryl (C7-18) , heteroaryl (C≤8) , substituted heteroaryl (C≤8) , or —C(O)R a , wherein:
R a is alkenyl (C≤11) , aryl (C≤18) , aralkyl (C≤11) , heteroaryl (C≤18) , aryloxy (C≤18) , or a substituted version of any of these groups; and

R 4 is hydroxy, alkyl (C≤12) , substituted alkyl (C≤12) , cycloalkyl (C≤12) , substituted cycloalkyl (C≤12) , aryl (C≤18) , substituted aryl (C≤18) , heteroaryl (C≤8) , substituted heteroaryl (C≤8) , or —C(O)R a , wherein:
R a is alkyl (C≤18) , cycloalkyl (C≤18) , alkenyl (C≤11) , aryl (C≤18) , aralkyl (C≤11) , heteroaryl (C≤18) , aryloxy (C≤18) , -alkanediyl (C≤6) -cycloalkyl (C≤12) ; or a substituted version of any of these groups;

or a pharmaceutically acceptable salt or tautomer thereof.

3. The compound of claim 1 further defined as:

wherein:
R 1 and R 6 are each independently selected from hydrogen, acyl (C≤8) , or substituted acyl (C≤8) ;
R 2 and R 5 are each independently selected from hydrogen, hydroxy, alkyl (C≤8) , substituted alkyl (C≤8) , cycloalkyl (C≤12) , substituted cycloalkyl (C≤12) , aryl (C≤8) , substituted aryl (C≤8) , heteroaryl (C≤8) , substituted heteroaryl (C≤8) , alkoxy (C≤8) , substituted alkoxy (C≤8) , acyl (C≤8) , or substituted acyl (C≤8) ;
R 3 is hydroxy, cycloalkyl (C≤12) , substituted cycloalkyl (C≤12) , aryl (C7-18) , substituted aryl (C7-18) , heteroaryl (C≤8) , substituted heteroaryl (C≤8) , or —C(O)R a , wherein:
R a is alkenyl (C≤11) , aryl (C≤18) , aralkyl (C≤11) , heteroaryl (C≤8) , aryloxy (C≤12) , or a substituted version of any of these groups; and

R 4 is hydroxy, alkyl (C≤12) , substituted alkyl (C≤12) , cycloalkyl (C≤12) , substituted cycloalkyl (C≤12) , aryl (C≤12) , substituted aryl (C≤12) , heteroaryl (C≤8) , substituted heteroaryl (C≤8) , or —C(O)R a , wherein:
R a is alkenyl (C≤11) , aryl (C≤18) , aralkyl (C≤11) , heteroaryl (C≤8) , aryloxy (C≤12) , or a substituted version of any of these groups;

or a pharmaceutically acceptable salt or tautomer thereof.

4. The compound of claim 1 , wherein the compound is further defined as:

wherein: R 2 , R 3 , R 4 , and R 5 are as defined above;
or a pharmaceutically acceptable salt or tautomer thereof.

5. The compound of claim 1 , wherein R 2 is hydrogen, hydroxy, alkyl (C≤8) , substituted alkyl (C≤8) , acyl (C≤8) , or substituted acyl (C≤8) .

6. The compound of claim 1 , wherein R 5 is hydrogen.

7. The compound of claim 1 , wherein R 4 is alkyl (C≤12) or substituted alkyl (C≤12) .

8. The compound of claim 1 , wherein R 3 is aryl (C7-18) , substituted aryl (C7-18) , or —C(O)R a , wherein: R a is aryl (C≤18) , heteroaryl (C≤18) , aryloxy (C≤12) , or a substituted version of any of these groups.

9. The compound of claim 8 , wherein R 3 is aryl (C7-12) or substituted aryl (C7-12) .

10. The compound of claim 8 , wherein R 3 is —C(O)R a , wherein:
R a is aryl (C≤18) , heteroaryl (C≤18) , or a substituted version of either of these groups.

11. The compound of claim 1 , wherein the compound is further defined as:

or a pharmaceutically acceptable salt or tautomer thereof.

12. A pharmaceutical composition comprising:
(a) a compound of claim 1 ; and
(b) a pharmaceutically acceptable carrier.

13. The pharmaceutical composition of claim 12 , wherein the pharmaceutical composition is formulated for administration: intravenously, intra-arterially, orally, buccally, nasally, rectally, vaginally, ocularly, topically, intramuscularly, intradermally, cutaneously or subcutaneously.

14. The pharmaceutical composition of claim 13 , wherein the pharmaceutical composition is formulated for topical administration to the cornea.

Assignees

• Univ Saint Louis
• Univ City New York Res Found

Inventors

• Tavis John Edwin
• Morrison Lynda Anne
• Murelli Ryan P

Classifications

• C07C2601/18

  with a ring being at least seven-membered · CPC title

• A61P31/22

  for herpes viruses · CPC title

• A61K31/675

  having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate · CPC title

• C07C49/717 Primary

  a keto group being part of a seven- to twelve-membered ring · CPC title

• A61K31/513

  having oxo groups directly attached to the heterocyclic ring, e.g. cytosine · CPC title