Benzo annulenes as antiviral agents

Patent metadata

Field	Value
Publication number	US-10450263-B2
Application number	US-201815892302-A
Country	US
Kind code	B2
Filing date	Feb 8, 2018
Priority date	Feb 10, 2017
Publication date	Oct 22, 2019
Grant date	Oct 22, 2019

Abstract

The present disclosure is concerned with benzo annulene compounds that are capable of inhibiting a viral infection and methods of treating viral infections such as, for example, chikungunya, Venezuelan equine encephalitis, dengue, influenza, and zika, 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 selected from:

wherein each of Q 1 and Q 2 is independently selected from CH 2 , CH(OH), and C(O), provided that at least one of Q 1 and Q 2 is C(O);
wherein Z is selected from CH 2 and NH;
wherein each of R 1a and R 1b is independently selected from hydrogen and —F;
wherein R 2 is selected from hydrogen, halogen, —CN, —(CH 2 ) n OR 20 , and —OC(O)R 21 ;
wherein n is selected from 0, 1, 2, 3, and 4;
wherein R 20 , when present, is selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, Ar 1 , and —(C1-C4 alkyl)Ar 1 ;
wherein Ar 1 , when present, is selected from phenyl and 5-6 membered heteroaryl having 1-3 heteroatoms selected from nitrogen, oxygen, sulfur, and phosphorous, and substituted with 0, 1, 2, or 3 groups independently selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, and C1-C4 alkoxy;

wherein R 21 , when present, is selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, and Ar 1 ;

wherein R 3 is selected from hydrogen and C1-C4 alkyl; and
wherein each of R 4a , R 4b , R 4c , R 4d is independently selected from hydrogen, halogen, —CO 2 H, —CN, —OH, —NH 2 , C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkylnitrile, C1-C8 hydroxyalkyl, C1-C8 alkoxy, C1-C8 halohydroxyalkyl, C1-C8 aminoalkyl, C1-C8 alkylamino, (C1-C8)(C1-C8) dialkylamino, and Cy 2 ;
wherein Cy 2 , when present, is selected from C3-C5 cycloalkyl, 3-8 membered heterocycle, partially or fully saturated, having 1-3 heteroatoms selected from nitrogen, oxygen, sulfur, and phosphorous, phenyl, and 5-6 membered heteroaryl having 1-3 heteroatoms selected from nitrogen, oxygen, sulfur, and phosphorous, and substituted with 0, 1, 2, or 3 groups independently selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, and C1-C4 alkoxy; and

wherein Cy 1 is selected from C3-C10 cycloalkyl, phenyl, and 5-6 membered heteroaryl having 1-3 heteroatoms selected from nitrogen, oxygen, sulfur, and phosphorous, and substituted with 0, 1, or 2 groups independently selected from halogen, —CO 2 H, —CN, —OH, —NH 2 , C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkylnitrile, C1-C8 hydroxyalkyl, C1-C8 alkoxy, C1-C8 halohydroxyalkyl, C1-C8 aminoalkyl, C1-C8 alkylamino, (C1-C8)(C1-C8) dialkylamino, and Cy 2 , provided that when Cy 1 is unsubstituted phenyl, then at least one of R 1a , R 1b , and R 2 is not hydrogen,
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein Z is CH 2 .

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

4. The compound of claim 1 , wherein R 2 is —OR 20 .

5. The compound of claim 1 , wherein Cy 1 is selected from phenyl and 5-6 membered heteroaryl having 1-3 heteroatoms selected from nitrogen, oxygen, sulfur, and phosphorous, and substituted with 0, 1, or 2 groups independently selected from halogen, —CO 2 H, —CN, —OH, —NH 2 , C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkylnitrile, C1-C8 hydroxyalkyl, C1-C8 alkoxy, C1-C8 halohydroxyalkyl, C1-C8 aminoalkyl, C1-C8 alkylamino, (C1-C8)(C1-C8) dialkylamino, and Cy 2 .

6. The compound of claim 1 , wherein Cy 1 is phenyl substituted with 0, 1, or 2 groups independently selected from halogen, —CO 2 H, —CN, —OH, —NH 2 , C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkylnitrile, C1-C8 hydroxyalkyl, C1-C8 alkoxy, C1-C8 halohydroxyalkyl, C1-C8 aminoalkyl, C1-C8 alkylamino, (C1-C8)(C1-C8) dialkylamino and Cy 2 .

7. The compound of claim 1 , wherein Cy 1 is phenyl substituted with a tert-butyl group.

8. The compound of claim 1 , wherein Cy 1 is 5-6 membered heteroaryl having 1-3 heteroatoms selected from nitrogen, oxygen, sulfur, and phosphorous, substituted with 0, 1, or 2 groups independently selected from halogen, —CO 2 H, —CN, —OH, —NH 2 , C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkylnitrile, C1-C8 hydroxyalkyl, C1-C8 alkoxy, C1-C8 halohydroxyalkyl, C1-C8aminoalkyl, C1-C8alkylamino, (C1-C8)(C1-C8) dialkylamino, Cy 1 , and Ar 3 .

9. The compound of claim 1 , wherein Cy 1 is selected from thiazole, pyrazole, imidazole, furan, thiophene, isoxazole, pyrimidine, and pyridine and substituted with 0, 1, or 2 groups independently selected from halogen, —CO 2 H, —CN, —OH, —NH 2 , C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkylnitrile, C1-C8 hydroxyalkyl, C1-C8 alkoxy, C1-C8 halohydroxyalkyl, C1-C8 aminoalkyl, C1-C8 alkylamino, (C1-C8)(C1-C8) dialkylamino, Cy 1 , and Ar 3 .

10. The compound of claim 1 , wherein Cy 1 is C3-C10 cycloalkyl and substituted with 0, 1, or 2 groups independently selected from halogen, —CO 2 H, —CN, —OH, —NH 2 , C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkylnitrile, C1-C8 hydroxyalkyl, C1-C8 alkoxy, C1-C8 halohydroxyalkyl, C1-C8 aminoalkyl, C1-C8 alkylamino, (C1-C8)(C1-C8) dialkylamino, and Cy 2 .

11. The compound of claim 1 , wherein Cy 1 is unsubstituted adamantine.

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

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 has a structure represented by a formula:

wherein each of R 22a , R 22b , and R 22 c is independently selected from hydrogen, halogen, —CO 2 H, —CN, —OH, —NH 2 , C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 C1-C8 hydroxyalkyl, C1-C8 alkoxy, C1-C8 halohydroxyalkyl, C1-C8 aminoalkyl, C1-C8 alkylamino, (C1-C8)(C1-C8) dialkylamino, Cy 1 , and Ar 3 .

16. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound having a structure represented by a formula selected from:

wherein each of Q 1 and Q 2 is independently selected from CH 2 , CH(OH), and C(O), provided that at least one of Q 1 and Q 2 is C(O);
wherein Z is selected from CH 2 and NH;
wherein each of R 1a and R 1b is independently selected from hydrogen and —F;
wherein R 2 is selected from hydrogen, halogen, —CN, —(CH 2 ) n OR 20 , and —OC(O)R 21 ;
wherein n is selected from 0, 1, 2, 3, and 4;
wherein R 20 , when present, is selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, Ar 1 , and —(C1-C4 alkyl)Ar 1 ;
wherein 1 , when present, is selected from phenyl and 5-6 membered heteroaryl having 1-3 heteroatoms selected from nitrogen, oxygen, sulfur, and phosphorous, and substituted with 0, 1, 2, or 3 groups independently selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, and C1-C4 alkoxy;

wherein R 21 , when present, is selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, and Ar 1 ;

wherein R 3 is selected from hydrogen and C1-C4 alkyl; and
wherein each of R 4a , R 4b ,R 4c , and R 4d is independently selected from hydrogen, halogen, —CO 2 H, —CN, —OH, —NH 2 , C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkylnitrile, C1-C8 hydroxyalkyl, C1-C8 alkoxy, C1-C8 halohydroxyalkyl, C1-C8 aminoalkyl, C1-C8

Assignees

• Southern Res Inst

Inventors

• Pathak Ashish Kumar
• Ahmed Syed Kaleem
• Augelli-Szafran Corinne E
• Maddry Joseph A

Classifications

• C07C311/21

  having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring · CPC title

• C07D223/16

  Benzazepines; Hydrogenated benzazepines · CPC title

• C07D241/24

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title

• C07D277/56

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen · CPC title

• C07C2603/74

  Adamantanes · CPC title