# US 2020/0399264 A1 · 4-substituted-2-thiazole amides as antiviral agents

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- Number: US 2020/0399264 A1
- Document ID: US20200399264A1
- Status: Published application
- Kind: A1
- Application number: 16/902,080
- Filed: 2020-06-15
- Published: 2020-12-24
- Earliest claimed: 2019-06-20
- Applicants: Southern Research Institute; Oregon Health and Science University
- Inventors: Ashish Kumar Pathak; Corinne E. Augelli-Szafran; Syed Kaleem Ahmed; Atefeh Garzan; Daniel Streblow; Nicole Haese
- Web page: https://patentgrep.com/patent/US20200399264A1

## CPC

- C07D 277/46: by carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D 417/14: containing three or more hetero rings
- C07D 263/48: Nitrogen atoms not forming part of a nitro radical
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present disclosure is concerned with benzoannulene compounds that are capable of inhibiting a viral infection and methods of treating viral infections such as, for example, chikungunya, Venezuelan equine encephalitis, Eastern equine encephalitis, Western equine encephalitis, dengue, West Nile, 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.

## Claims

### Claim 1

A compound having a structure represented by a formula:
wherein n is selected from 0 and 1;
wherein A, when present, is selected from O, NH, N(C1-C4 alkyl), and N(Ar3);
wherein Ar3, when present, is phenyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH2, —OH, —NO2, 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 of Z1, Z2, Z3, and Z4 is independently selected from N and CR10, provided that at least two of Z1, Z2, Z3, and Z4 are CR∘;
wherein each occurrence of R10, when present, is independently selected from hydrogen, halogen, —CN, —NH2, —OH, —NO2, 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, —C(O)R20, —CO2R21, —C(O)NR22, —SO2R23, and Cy1;
wherein each occurrence of R20, R21, R22, and R23, when present, is independently selected from hydrogen and C1-C4 alkyl;
wherein Cy1, when present, is selected from 5-membered heterocycle and 6-membered heterocycle, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH2, —OH, —NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 thioalkyl, C1-C4 thiohaloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl;
and either:
(a) wherein Ar1 is selected from pyridinyl, piperazinyl, and 6-membered aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH2, —OH, —NO2, 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, —C(O)R1, —CO2R12, —C(O)NR13, and —SO2R14;
wherein each occurrence of R11, R12, R13, and R14, when present, is independently selected from hydrogen and C1-C4 alkyl; and
wherein Ar2 is selected from 5-membered heterocycle, 6-membered heterocycle, 5-membered heteroaryl, and 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH2, —OH, —NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 thioalkyl, C1-C4 thiohaloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, —C(O)R15, —CO2R16, —C(O)NR17, and —SO2R18; and
wherein each occurrence of R15, R16, R17, and R18, when present, is independently selected from hydrogen and C1-C4 alkyl; or
(b) wherein Ar1 is a structure represented by a formula:
wherein each of R31a, R31b, R31c, and R31d is independently selected from hydrogen, halogen, —CN, —NH2, —OH, —NO2, 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, —C(O)R11, —CO2R12, —C(O)NR13, and —SO2R14;
wherein R32 is selected from —CN and —CH2NH2; and
wherein Ar2 is selected from 5-membered heterocycle, 6-membered heterocycle, 5-membered heteroaryl, 6-membered heteroaryl, 6-membered aryl, and bicyclo[1.1.1]pentanyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH2, —OH, —NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 thioalkyl, C1-C4 thiohaloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, —C(O)R15, —CO2R16, —C(O)NR17, and —SO2R18,
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound of claim 1, wherein each of Z1, Z2, Z3, and Z4 is CR10.

### Claim 3 (depends on 1)

The compound of claim 1, wherein each occurrence of R10, when present, is hydrogen.

### Claim 4 (depends on 1)

The compound of claim 1, wherein Ar1 is pyridinyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH2, —OH, —NO2, 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, —C(O)R11, —CO2R12, —C(O)NR13, and —SO2R14.

### Claim 5 (depends on 1)

The compound of claim 1, wherein Ar1 is pyridinyl para-substituted with a —CN group.

### Claim 6 (depends on 1)

The compound of claim 1, wherein Ar1 is 6-membered aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH2, —OH, —NO2, 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, —C(O)R1, —CO2R12, —C(O)NR13, and —SO2R14.

### Claim 7 (depends on 1)

The compound of claim 1, wherein Ar1 is 6-membered aryl para-substituted with a —CN group.

### Claim 8 (depends on 1)

The compound of claim 1, wherein Ar1 is a structure represented by a formula:

### Claim 9 (depends on 1)

The compound of claim 1, wherein Ar2 is a structure represented by a formula:
wherein each of R33a, R33b, and R33c is independently selected from hydrogen, halogen, —CN, —NH2, —OH, —NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 thioalkyl, C1-C4 thiohaloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, —C(O)R15, —CO2R16, —C(O)NR17, and —SO2R18; and
wherein R34 is selected from halogen, —CN, —NH2, —OH, —NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 thioalkyl, C1-C4 thiohaloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, —C(O)R5, —CO2R16, —C(O)NR17, and —SO2R18.

### Claim 10 (depends on 1)

The compound of claim 1, wherein Ar2 is a structure represented by a formula:

### Claim 11 (depends on 1)

The compound of claim 1, wherein Ar1 is a structure represented by a formula:
and
wherein Ar2 is selected from 5-membered heterocycle, 6-membered heterocycle, 5-membered heteroaryl, 6-membered heteroaryl, 6-membered aryl, and bicyclo[1.1.1]pentanyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH2, —OH, —NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 thioalkyl, C1-C4 thiohaloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, —C(O)R15, —CO2R16, —C(O)NR17, and —SO2R18.

### Claim 12 (depends on 1)

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

### Claim 13 (depends on 1)

The compound of claim 1, wherein the compound has a structure represented by a formula:
wherein each of R35a, R35b, R35c, and R35d is independently selected from hydrogen, halogen, —CN, —NH2, —OH, —NO2, 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, —C(O)R20, —CO2R21, —C(O)NR22, and —SO2R23.

### Claim 14 (depends on 1)

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

### Claim 15 (depends on 1)

The compound of claim 1, wherein the compound has a structure represented by a formula:
wherein each of R35a, R35b, R35c, and R35d is independently selected from hydrogen, halogen, —CN, —NH2, —OH, —NO2, 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, —C(O)R20, —CO2R21, —C(O)NR22, and —SO2R23.

### Claim 16 (depends on 1)

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

### Claim 17 (depends on 1)

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

### Claim 18 (depends on 1)

A method for treating a viral infection in a subject, the method comprising administering to the subject an effective amount of the compound of claim 1.

### Claim 19 (depends on 18)

The method of claim 18, wherein the viral infection is selected from human immunodeficiency virus (HIV), human papillomavirus (HPV), chicken pox, infectious mononucleosis, mumps, measles, rubella, shingles, ebola, viral gastroenteritis, viral hepatitis, viral meningitis, human metapneumovirus, human parainfluenza virus type 1, parainfluenza virus type 2, parainfluenza virus type 3, respiratory syncytial virus, viral pneumonia, Chikungunya virus (CHIKV), Venezuelan equine encephalitis (VEEV), Eastern equine encephalitis (EEEV), Western equine encephalitis (WEEV), dengue (DENV), influenza, West Nile virus (WNV), and zika (ZIKV).

### Claim 20 (depends on 18)

The method of claim 18, wherein the viral infection is CHIKV.