2-pyrimidone analogs as potent antiviral agents against Alphaviruses

Patent metadata

Field	Value
Publication number	US-11932626-B2
Application number	US-202218080692-A
Country	US
Kind code	B2
Filing date	Dec 13, 2022
Priority date	Apr 2, 2020
Publication date	Mar 19, 2024
Grant date	Mar 19, 2024

Abstract

The present disclosure is concerned with 2-pyrimidone compounds that are capable of inhibiting a viral infection and methods of treating alphavirus viral infections such as, for example, chikungunya, Eastern equine encephalitis (EEEV), Western equine encephalitis (WEEV), and Venezuelan equine encephalitis using these compounds. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

First claim

What is claimed is:

1. A compound having a structure represented by a formula:

wherein n is 0, 1, or 2;
wherein p is 0 or 1;
wherein A is O, S, or NH;
wherein R 1 is selected from hydrogen and C1-C4 alkyl;
wherein each of R 2a and R 2b is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C4 haloalkyl, C1-C8 alkoxy, C1-C8 haloalkoxy, C1-C8 cyanoalkoxy, —OCy 2 , —OAr 1 , —O(C1-C4 alkyl)OR 10 , —O(C1-C4 alkyl)Ar 1 , —CO 2 R 10 , and Cy 2 ;
wherein each occurrence of R 10 , when present, is independently selected from hydrogen and C1-C4 alkyl;
wherein each occurrence of Ar 1 , when present, is independently selected from C2-C5 heteroaryl and C6-C12 aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH 2 , —OH, —NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl;
wherein each occurrence of Cy 2 , when present, is independently selected from C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, and phenyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH 2 , —OH, —NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl;

or wherein R 2a and R 2b are covalently bonded and, together with the intermediate atoms, comprise a C5-C6 cycloalkyl, a C2-C5 heterocycloalkyl, a C6 aryl or a C2-C5 heteroaryl, and are substituted with 0, 1, 2, or 3 groups independently selected from selected from halogen, —CN, —NH 2 , —OH, —NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; and
wherein each of R 3a and R 3b , when present, is independently selected from hydrogen, halogen, C1-C4 alkyl, and C1-C4 haloalkyl;
or wherein R 3a and R 3b , when present, are covalently bonded and, together with the intermediate atoms, comprise a C3-C4 cycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from selected from halogen, —CN, —NH 2 , —OH, —NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl;
wherein Cy 1 is selected from C2-C9 heteroaryl, C6 aryl, and adamantyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH 2 , —OH, —NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and C3-C6 cycloalkyl;
provided that when Cy 1 is C2-C9 heteroaryl, then either (i) p is 1 and A is O or (ii) n is 1 or 2 and each of R 3a and R 3b are not hydrogen;
provided that when Cy 1 is C6 aryl, then p is 1 and either (i) A is O or (ii) each of R 2a and R 2b is hydrogen and at least one of R 3a and R 3b is not hydrogen; and
provided that when Cy 1 is

and p is 0, then n is 0 or 2,
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein n is 0.

3. The compound of claim 1 , wherein p is 1.

4. The compound of claim 1 , wherein A is O.

5. The compound of claim 1 , wherein each of R 2a and R 2b is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, —OAr 1 , —O(C1-C4 alkyl)OR 10 , —O(C1-C4 alkyl)Ar 1 , —CO 2 R 10 , and Cy 2 .

6. The compound of claim 1 , wherein each of R 2a and R 2b is hydrogen.

7. The compound of claim 1 , wherein Cy 1 is adamantyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH 2 , —OH, —NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and C3-C6 cycloalkyl.

8. The compound of claim 1 , wherein Cy 1 is unsubstituted adamantyl.

9. The compound of claim 1 , wherein Cy 1 is a structure:

10. The compound of claim 1 , wherein the compound has a structure represented by a formula:

wherein each of R 11a , R 11b , R 11c , R 11d , and R 11e is independently selected from hydrogen, halogen, —CN, —NH 2 , —OH, —NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and C3-C6 cycloalkyl, provided that at least two of R 11a , R 11b , R 11c , R 11d , and R 11e are hydrogen.

11. The compound of claim 10 , wherein the compound has a structure represented by a formula:

12. The compound of claim 1 , wherein the compound has a structure represented by a formula selected from:

13. The compound of claim 1 , wherein the compound has a structure represented by a formula:

14. The compound of claim 1 , wherein the compound has a structure represented by a formula:

15. The compound of claim 1 , wherein the compound is selected from:

16. The compound of claim 1 , wherein the compound is:

17. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 , and a pharmaceutically acceptable carrier.

18. A method for treating a viral infection in a subject, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula:

wherein n is 0, 1, or 2;
wherein p is 0 or 1;
wherein A is O, S, or NH;
wherein R 1 is selected from hydrogen and C1-C4 alkyl;
wherein each of R 2a and R 2b is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C4 haloalkyl, C1-C8 alkoxy, C1-C8 haloalkoxy, C1-C8 cyanoalkoxy, —OCy 2 , —OAr

Assignees

• Southern Res Inst
• Univ Oregon Health & Science

Inventors

• Pathak Ashish Kumar
• Augelli-Szafran Corinne E
• Garzan Atefeh
• Steblow Daniel
• Haese Nicole

Classifications

• C07D403/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D213/69

  Two or more oxygen atoms · CPC title

• C07D213/70

  Sulfur atoms · CPC title

• C07D213/74

  Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals · CPC title

• C07D491/052

  the oxygen-containing ring being six-membered · CPC title