6-substituted quinazolinone inhibitors

Patent metadata

Field	Value
Publication number	US-10532999-B2
Application number	US-201816149009-A
Country	US
Kind code	B2
Filing date	Oct 1, 2018
Priority date	Dec 13, 2012
Publication date	Jan 14, 2020
Grant date	Jan 14, 2020

Abstract

The present technology relates to compounds and compositions of Formulas I-III and methods using such compounds. The compounds and compositions described herein may be used in the treatment or prophylaxis of diseases associated with an alphavirus, for example, Venezuelan equine encephalitis virus (VEEV).

First claim

What is claimed is:

1. A method comprising administering to a subject in need thereof an antiviral effective amount of a compound of Formula II:

or a stereoisomer thereof and/or a pharmaceutically acceptable salt thereof, wherein:
W is CH or N;
X 1 is halo, nitro, cyano, alkanoyl, carbamoyl, ester, sulfonyl, trialkyl ammonium, or trifluoromethyl;
X 2 is hydrogen, halo, nitro, cyano, alkanoyl, carbamoyl, ester, sulfonyl, trialkyl ammonium, or trifluoromethyl;
Y is O or S;
R 1 is an alkyl group, an aryl group, an aralkyl group, or a heteroaryl group;
R 2 is hydrogen or alkyl;
R 3 is a hydrogen, alkyl, aryl, cycloalkyl, or non-aromatic heterocyclyl;
R 4 is a hydrogen, alkyl, aryl, cycloalkyl, or non-aromatic heterocyclyl;
α is 0 or 1; and
B is CH, C-alkyl, O, or N; with the provision that when B is O, R 4 is absent.

2. The method of claim 1 , wherein the subject suffers from or is at risk of suffering from an alphavirus.

3. The method of claim 1 , wherein the subject suffers from or is at risk of suffering from an encephalitic alphavirus.

4. The method of claim 1 , wherein the subject suffers from or is at risk of suffering from a Venezuelan equine encephalitis virus.

5. The method of claim 1 , wherein risk of infection by and/or transmission of an alphavirus by said subject is decreased.

6. The method of claim 1 , wherein the administration comprises oral administration, parenteral administration, or nasal administration.

7. The method of claim 1 , wherein the administration comprises subcutaneous injection, intravenous injection, intraperitoneal injection, or intramuscular injection.

8. The method of claim 1 , wherein the administration comprises oral administration.

9. The method of claim 1 , wherein X 1 is halo, nitro, cyano, alkanoyl, carbamoyl, ester, sulfonyl, or trifluoromethyl.

10. The method of claim 1 , wherein X 2 is hydrogen, halo, nitro, or cyano.

11. The method of claim 1 , wherein X 2 is hydrogen.

12. The method of claim 1 , wherein R 2 is hydrogen.

13. The method of claim 1 , wherein
Y is O;
R 1 is a heteroaryl group or a phenyl group, wherein the phenyl group is of Formula IA:

where R 6 R 7 , R 8 , R 9 and R 10 are each independently hydrogen, halo, alkoxy, alkanoyl, carbamoyl, cyano, trifluoromethyl, or nitro;

R 2 is hydrogen;
α is 1.

14. The method of claim 13 , wherein R 6 is hydrogen.

15. The method of claim 13 , wherein
R 3 is methyl or ethyl; and
R 4 is methyl.

16. The method of claim 13 , wherein W is CH.

17. The method of claim 13 , wherein R 1 is a phenyl group of Formula IA:

where R 6 is hydrogen;
R 7 , and R 8 are each independently hydrogen, methoxy, or halo; and
R 9 and R 10 are each independently hydrogen.

18. The method of claim 1 , wherein
X 2 is hydrogen;
Y is O;
R 1 is an alkyl group, a substituted or unsubstituted benzyl group, a heteroaryl group, or a phenyl group wherein the phenyl group is of Formula IA:

where R 6 is hydrogen, methoxy, halo, alkanoyl, or nitro;
R 7 and R 8 are each independently hydrogen, alkoxy, aryloxy, halo, alkanoyl, or nitro;
R 9 and R 10 are each independently hydrogen;

R 2 is hydrogen;
α is 1; and
B is CH, C-alkyl, or N.

19. The method of claim 1 , wherein
X 1 is halo, cyano, nitro, or trifluoromethyl;
X 2 is hydrogen;
Y is O;
R 1 is a methyl group, an ethyl group, a benzyl group, or a phenyl group, wherein the phenyl group is of Formula IA:

where R 6 , R 7 , and R 8 are each independently hydrogen, methoxy, halo, or nitro;
R 9 and R 10 are each independently hydrogen;

R 2 is hydrogen;
α is 1; and
B is CH, C-alkyl, or N.

20. The method of claim 1 , wherein the compound is selected from the group consisting of (E)-2-((1,4-dimethylpiperazin-2-ylidene)amino)-5-nitro-N-phenylbenzamide, (E)-5-cyano-2-((1,4-dimethylpiperazin-2-ylidene)amino)-N-phenylbenzamide, (E)-2-((1,4-dimethylpiperazin-2-ylidene)amino)-N-(4-methoxyphenyl)-5-nitrobenzamide, (E)-2-((1,4-dimethylpiperazin-2-ylidene)amino)-N-(2-fluorophenyl)-5-nitrobenzamide, (E)-4-chloro-5-cyano-2-((1,4-dimethylpiperazin-2-ylidene)amino)-N-phenylbenzamide, (E)-2-((1-ethyl-4-methylpiperazin-2-ylidene)amino)-5-nitro-N-phenylbenzamide, (E)-2-((1,4-dimethylpiperazin-2-ylidene)amino)-5-fluoro-N-phenylbenzamide, (E)-5-cyano-2-((1,4-dimethylpiperazin-2-ylidene)amino)-N-(2-fluorophenyl)benzamide, (E)-5-cyano-2-((1,4-dimethylpiperazin-2-ylidene)amino)-N-(3-fluorophenyl)benzamide, (E)-2-((1,4-dimethylpiperazin-2-ylidene)amino)-N-(4-methoxyphenyl)-5-nitrobenzamide, (E)-2-((1,4-dimethylpiperazin-2-ylidene)amino)-N-(3-fluorophenyl)-5-nitrobenzamide, (E)-2-((1,4-dimethylpiperazin-2-ylidene)amino)-N-phenyl-5-(trifluoromethyl)benzamide, (E)-2-((1,4-dimethylpiperazin-2-ylidene)amino)-N-(4-fluorophenyl)-5-nitrobenzamide, (E)-2-((1,4-dimethylpiperazin-2-ylidene)amino)-N-(2-methoxyphenyl)-5-nitrobenzamide, (E)-2-((1,4-dimethylpiperazin-2-ylidene)amino)-N-(3-methoxyphenyl)-5-nitrobenzamide, (E)-2-((1,4-dimethylpiperazin-2-ylidene)amino)-N-isopropyl-5-nitrobenzamide, (E)-N-benzyl-2-((1,4-dimethylpiperazin-2-ylidene)amino)-5-nitrobenzamide, (E)-4-((1,4-dimethylpiperazin-2-ylidene)amino)-N-phenylpyridazine-3-carboxamide, (E)-methyl 4-((1,4-dimethylpiperazin-2-ylidene)amino)-3-(phenylcarbamoyl)benzoate, (E)-2-((1,4-dimethylpiperazin-2-ylidene)amino)-5-nitro-N-(thiophen-3-yl)benzamide, (E)-2-((1,4-dimethylpiperazin-2-ylidene)amino)-4,5-difluoro-N-phenylbenzamide, (E)-5-cyano-2-((1,4-dimethylpiperazin-2-ylidene)amino)-4-fluoro-N-phenylbenzamide, and (E)-2-((1,4-dimethylpiperazin-2-ylidene)amino)-N-methyl-5-nitrobenzamide.

Assignees

• Univ Kansas
• Univ Louisville Res Found Inc
• Southern Res Inst
• Univ Of Louisville Research Foundation

Inventors

• Golden Jennifer
• Aube Jeffrey
• Chung Donghoon
• Schroeder Chad
• Yao Tuanli
• White E Lucile
• Tower Nichole A

Classifications

• A61P31/12

  Antivirals · CPC title

• C07D409/04 Primary

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

• C07D239/95

  with hetero atoms directly attached in positions 2 and 4 · CPC title

• C07D239/90

  with acyclic radicals attached in position 2 or 3 · CPC title

• C07D403/12

  linked by a chain containing hetero atoms as chain links · CPC title