# US 2020/0399271 A1 · Xanthine analogs as potent anti-west nile viral agents

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- Number: US 2020/0399271 A1
- Document ID: US20200399271A1
- Status: Published application
- Kind: A1
- Application number: 16/905,857
- Filed: 2020-06-18
- Published: 2020-12-24
- Earliest claimed: 2019-06-20
- Assignees: Southern Research Institute; Oregon Health & Science University
- Applicants: Southern Research Institute; Oregon Health and Science University
- Inventors: Ashish Kumar Pathak; Theresa Ha Nguyen; Corinne E. Augelli-Szafran; Alec Jay Hirsch; Jessica Lee Smith
- Web page: https://patentgrep.com/patent/US20200399271A1

## CPC

- C07D 473/08: with methyl radicals in positions 1 and 3, e.g. theophylline
- A61P 31/14: for RNA viruses
- C07D 473/06: with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

The present disclosure is concerned with xanthine analogs, methods of making xanthine analogs, and methods of treating West Nile virus using these analogs. 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, 1, and 2;
wherein each occurrence of A, when present, is individually selected from —C(O)— and —CH2—, provided that no more than one occurrence of A, when present, is —C(O)—;
wherein Z is selected from N and CR10;
wherein R10, when present, is selected from hydrogen and C1-C4 alkyl;
wherein R1 is selected from hydrogen, C1-C4 alkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, —CH2(C3-C6 cycloalkyl), —(C1-C4 alkyl)-CO2H, and —(C1-C4 alkyl)-O—(C1-C4 alkyl)-OH;
wherein R2 is selected from —OH, C1-C4 alkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, —CH2(C3-C6 cycloalkyl), —(C1-C4 alkyl)-CO2H, and —(C1-C4 alkyl)-O—(C1-C4 alkyl)-OH;
wherein R3 is selected from C1-C4 alkyl and Ar1, provided that when R3 is methyl then R10 is not hydrogen and provided that when Z is N then R3 is Cy2;
wherein Ar1, when present, is selected from 6-membered aryl 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 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and —CO2(C1-C4 alkyl); and
wherein each of R4a, R4b, R4c, and R4d 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, —CO2H, and —CO2(C1-C4 alkyl);
wherein Cy1 is selected from cyclohexyl, 6-membered aryl, 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 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and —CO2(C1-C4 alkyl),
provided that when n is 1, A is CH2, R1 is hydrogen or methyl, R2 is methyl, R3 is 6-membered aryl, and Cy1 is 6-membered aryl, then R10, when present, is C1-C4 alkyl, and
provided that when each occurrence of A, when present, is CH2, R1 is hydrogen, R2 is methyl, R3 is 6-membered aryl, and Cy1 is 6-membered aryl, then Z is CR10,
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound of claim 1, wherein each occurrence of A, when present, is —CH2-.

### Claim 3 (depends on 1)

The compound of claim 1, wherein Z is N.

### Claim 4 (depends on 1)

The compound of claim 1, wherein R1 is hydrogen and R2 methyl.

### Claim 5 (depends on 1)

The compound of claim 1, wherein R3 is Ar1.

### Claim 6 (depends on 1)

The compound of claim 1, wherein Ar1, when present, 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, and —CO2(C1-C4 alkyl).

### Claim 7 (depends on 1)

The compound of claim 1, wherein Ar1 is 6-membered aryl substituted with 1 or 2 independently selected C1-C4 alkyl groups.

### Claim 8 (depends on 1)

The compound of claim 1, wherein each of R4a, R4b, R4c, and R4d is hydrogen.

### Claim 9 (depends on 1)

The compound of claim 1, wherein Cy1 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, and —CO2(C1-C4 alkyl).

### Claim 10 (depends on 1)

The compound of claim 1, wherein Cy1 is 6-membered aryl monosubstituted with a halogen group.

### Claim 11 (depends on 1)

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

### Claim 12 (depends on 1)

The compound of claim 1, wherein the compound has a structure represented by a formula:
wherein each of R20a, R20b, R20c, R20d, and R20e 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, and —CO2(C1-C4 alkyl), provided at least two of R20a, R20b, R20c, R20d, and R20e are hydrogen, and
wherein each of R21a, R21b, R21c, R21d, and R21e 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, and —CO2(C1-C4 alkyl), provided at least two of R21a, R21b, R21c, R21d, and R21e are hydrogen.

### Claim 13 (depends on 12)

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

### Claim 14 (depends on 12)

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

### Claim 15 (depends on 1)

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

### 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

A compound selected from:
or a pharmaceutically acceptable salt thereof.

### Claim 19 (depends on 18)

A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 18 and a pharmaceutically acceptable carrier.

### Claim 20

A method for treating West Nile virus (WNV) in a subject, the method comprising administering to the subject an effective amount of at least one compound having a structure represented by a formula:
wherein n is selected from 0, 1, and 2;
wherein each occurrence of A, when present, is individually selected from —C(O)— and —CH2—, provided that no more than one occurrence of A, when present, is —C(O)—;
wherein Z is selected from N and CR10;
wherein R10, when present, is selected from hydrogen and C1-C4 alkyl;
wherein R1 is selected from hydrogen, C1-C4 alkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, —CH2(C3-C6 cycloalkyl), —(C1-C4 alkyl)-CO2H, and —(C1-C4 alkyl)-O—(C1-C4 alkyl)-OH;
wherein R2 is selected from —OH, C1-C4 alkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, —CH2(C3-C6 cycloalkyl), —(C1-C4 alkyl)-CO2H, and —(C1-C4 alkyl)-O—(C1-C4 alkyl)-OH;
wherein R3 is selected from C1-C4 alkyl and Ar1;
wherein Ar1, when present, is selected from 6-membered aryl 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 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and —CO2(C1-C4 alkyl); and
wherein each of R4a, R4b, R4c, and R4d 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, —CO2H, and —CO2(C1-C4 alkyl);
wherein Cy1 is selected from cyclohexyl, 6-membered aryl, 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 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and —CO2(C1-C4 alkyl),
provided that when n is 1, A is CH2, R1 is hydrogen or methyl, R2 is methyl, R3 is 6-membered aryl, and Cy1 is 6-membered aryl, then R10, when present, is C1-C4 alkyl,
or a pharmaceutically acceptable salt thereof, thereby treating West Nile virus.