6-substituted quinazolinone inhibitors

Patent metadata

Field	Value
Publication number	US-10087168-B2
Application number	US-201715443232-A
Country	US
Kind code	B2
Filing date	Feb 27, 2017
Priority date	Dec 13, 2012
Publication date	Oct 2, 2018
Grant date	Oct 2, 2018

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 compound of Formula I:

stereoisomers thereof and pharmaceutically acceptable salts thereof, wherein:
W is CH or N;
X 1 is a halogen, a nitro group, cyano group, an alkanoyl group, a carbamoyl group, an ester, a sulfonyl group, a trialkyl ammonium group, or a trifluoromethyl group;
X 2 is hydrogen, a halogen, a nitro group, or a cyano group;
Y is O or S;
R 1 is thiophen-3-yl 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;
R 3 is hydrogen or alkyl;
R 4 is hydrogen or alkyl;
α is 0 or 1;
B is CH, C-alkyl, O, or N; with the provision that when B is O, R 4 is absent;
Z is selected from the group consisting of

where R 5 is hydrogen or alkyl;
A is CH, C-alkyl, or N; and
n is 1, 2, 3, or 4.

2. The compound of claim 1 , wherein X 2 is hydrogen.

3. The compound of claim 1 , wherein
Y is O,
α is 1; and
n is 1, 2, or 3.

4. The compound of claim 1 , wherein
X 1 is a halogen, a nitro group, or cyano group;
X 2 is hydrogen;
Y is O;
α is 1;
B is CH, C-alkyl, or N; and
n is 2 or 3.

5. The compound of claim 1 , wherein R 6 is hydrogen.

6. The compound of claim 1 , wherein Z is

and R 3 is hydrogen.

7. The compound of claim 1 , wherein W is CH.

8. The compound of claim 1 , 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;
R 9 and R 10 are each independently hydrogen.

9. The compound of claim 4 , wherein Z is

and R 3 is hydrogen.

10. The compound of claim 4 , wherein W is CH.

11. The compound of claim 4 , 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;
R 9 and R 10 are each independently hydrogen.

12. The compound of claim 1 , wherein the compound is selected from the group consisting of 2-((4-ethylpiperazin-1-yl)methyl)-6-nitro-3-phenylquinazolin-4(3H)-one,
6-nitro-3-phenyl-2-(piperazin-1-ylmethyl)quinazolin-4(3H)-one,
6-nitro-2-(piperazin-1-ylmethyl)-3-(thiophen-3-yl)quinazolin-4(3H)-one,
3-(2-fluorophenyl)-2-((4-methylpiperazin-1-yl)methyl)-6-nitroquinazolin-4(3H)-one,
2-((4-ethylpiperazin-1-yl)methyl)-3-(2-fluorophenyl)-6-nitroquinazolin-4(3H)-one,
2-((4-ethylpiperazin-1-yl)methyl)-3-(3-fluorophenyl)-6-nitroquinazolin-4(3H)-one, 24(4-ethylpiperazin-1-yl)methyl)-3-(4-fluorophenyl)-6-nitroquinazolin-4(3H)-one,
3-(2-fluorophenyl)-2-((4-isopropylpiperazin-1-yl)methyl)-6-nitroquinazolin-4(3H)-one,
3-(2-fluorophenyl)-6-nitro-2-(piperazin-1-ylmethyl)quinazolin-4(3H)-one,
3-(2-fluorophenyl)-2-(morpholinomethyl)-6-nitroquinazolin-4(3H)-one,
3-(2-fluorophenyl)-6-nitro-2-(piperidin-1-ylmethyl)quinazolin-4(3H)-one,
3-(3-methoxyphenyl)-6-nitro-2-(piperazin-1-ylmethyl)quinazolin-4(3H)-one,
3-(4-methoxyphenyl)-6-nitro-2-(piperazin-1-ylmethyl)quinazolin-4(3H)-one,
2-((4-ethylpiperazin-1-yl)methyl)-6-iodo-3-phenylquinazolin-4(3H)-one,
2-((4-ethylpiperazin-1-yl)methyl)-4-oxo-3-phenyl-3,4-dihydroquinazoline-6-carbonitrile,
6-nitro-3-phenyl-2-((tetrahydropyrimidin-1(2H)-yl)methyl)quinazolin-4(3H)-one,
2-((1,4-diazepan-1-yl)methyl)-6-nitro-3-phenylquinazolin-4(3H)-one,
2-((methyl(2-(methylamino)ethyl)amino)methyl)-6-nitro-3-phenylquinazolin-4(3H)-one,
2-((methyl(3-(methylamino)propyl)amino)methyl)-6-nitro-3-phenylquinazolin-4(3H)-one,
2-(((2-(ethylamino)ethyl)(methyl)amino)methyl)-6-nitro-3-phenylquinazolin-4(3H)-one,
3-(4-methoxyphenyl)-2-((methyl(2-(methylamino)ethyl)amino)methyl)-6-nitroquinazolin-4(3H)-one,
3-(2-fluorophenyl)-2-((methyl(2-(methylamino)ethyl)amino)methyl)-6-nitroquinazolin-4(3H)-one,
3-(3-fluorophenyl)-2-((methyl(2-(methylamino)ethyl)amino)methyl)-4-oxo-3,4-dihydroquinazoline-6-carbonitrile,
6-fluoro-2-((methyl(2-(methylamino)ethyl)amino)methyl)-3-phenylquinazolin-4(3H)-one,
2-((methyl(2-(methylamino)ethyl)amino)methyl)-4-oxo-3-phenyl-3,4-dihydroquinazoline-6-carbonitrile,
2-((4-ethylpiperazin-1-yl)methyl)-6-nitro-3-phenylpyrido[2,3-d]pyrimidin-4(3H)-one, and
6-nitro-3-phenyl-2-(piperidin-4-yl)quinazolin-4(3H)-one.

13. A composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

14. The compound of claim 3 , wherein Z is selected from the group consisting of

15. A composition comprising a compound of claim 14 and a pharmaceutically acceptable carrier.

16. A composition comprising a compound of claim 9 and a pharmaceutically acceptable carrier.

Assignees

• Univ Kansas
• Univ Louisville Res Found Inc
• Southern Res Inst

Inventors

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

Classifications

• A61P31/12

  Antivirals · CPC title

• C07D403/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D401/04

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

• C07D239/90

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

• C07D409/04 Primary

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