Small molecule inhibitors of influenza A RNA-dependent RNA polymerase

Patent metadata

Field	Value
Publication number	US-9315464-B1
Application number	US-201414170353-A
Country	US
Kind code	B1
Filing date	Jan 31, 2014
Priority date	Jan 31, 2013
Publication date	Apr 19, 2016
Grant date	Apr 19, 2016

Abstract

Compositions, compounds, and methods with significant antiviral effect against RNA viruses and especially orthomyxoviruses are contemplated, and target the viral promoter that is formed by the 5′ and 3′-UTR sequences of the viral genome.

First claim

The invention claimed is:

1. An RNA-ligand complex comprising an RNA of an RNA virus that is non-covalently bound to a compound according to Formula I

wherein A is optionally substituted and selected from the group consisting of 6-membered heterocycle, fused heterocycle, and aryl;
B is optionally substituted fused heterocycle;
C is optionally substituted aryl;
D is optionally substituted and selected from the group consisting of 5-membered heterocycle, 6-membered heterocycle, fused heterocycle, acyl, and hydrogen;
or
a compound selected from the group consisting of
N-{3-[(4,5-dihydro-3H-pyrrol-2-yl)sulfamoyl]phenyl}-2-(pyridin-3-yl)quinoline-4-carboxamide (A0242),
N-{3-[4-(4-acetamido-2-fluorophenyl)-1,3-thiazol-2-yl]phenyl}cyclopropanecarboxamide (A0251),
(3R)-1-{[3-(1-benzofuran-2-yl)-1H-pyrazol-4-yl]methyl}-3-[(1-methylimidazol-2-yl)carbonyl]piperidine (A252),
(4S)-2-amino-7-methyl-5-oxo-4-phenyl-6-(pyridin-3-ylmethyl)-4H-pyrano[3,2-c]pyridine-3-carbonitrile (A253),
N-[3-(4-{[(2,3-difluorophenyl)methyl]amino}piperidin-1-yl)phenyl]pyridine-3-carboxamide (A254),
2-bromo-N-(5-{[4-(4-fluorophenyl)piperazin-1-yl]carbonyl}-2-[(1S,9R)-6-oxo-7,11-diazatricyclo[7.3.1.0^{2,7}]trideca-2,4-dien-11-yl]phenyl)benzamide (A256),
2-(4-methylphenyl)-N-{4-[(pyrimidin-2-yl)sulfamoyl]phenyl}quinoline-4-carboxamide (A257),
6-chloro-N-[4-(piperidin-1-ylcarbonyl)phenyl]-2-(pyridin-4-yl)quinoline-4-carboxamide (A258),
2-phenyl-N-{4-[(1,3-thiazol-2-yl)sulfamoyl]phenyl}quinoline-4-carboxamide (A259),
N-[4-(tert-butylsulfamoyl)phenyl]-2-(pyridin-2-yl)quinoline-4-carboxamide (A260),
6-chloro-N-{4-[(5-methyl-1,2-oxazol-3-yl)sulfamoyl]phenyl}-2-(pyridin-3-yl)quinoline-4-carboxamide (A263),
N-(4-(N-(quinoxalin-2-yl)sulfamoyl)phenyl)-2-(p-tolyl)quinoline-4-carboxamide (A0796),
N-(4-(N-(5-methylisoxazol-3-yl)sulfamoyl)phenyl)-2-phenylquinoline-4-carboxamide (A800),
N-(4-(N-methylsulfamoyl)phenyl)-2-phenylquinoline-4-carboxamide (A802),
2-(pyridin-4-yl)-N-(4-(N-(thiazol-2-yl)sulfamoyl)phenyl)quinoline-4-carboxamide (A843),
2-(4-methoxyphenyl)-N-(4-(N-(thiazol-2-yl)sulfamoyl)phenyl)quinoline-4-carboxamide (A1004),
2-(benzo[d][1,3]dioxol-5-yl)-N-(4-(N-(pyrimidin-2-yl) sulfamoyl)phenyl)quinoline-4-carboxamide (A1005),
6-(2,5-dimethylthiophen-3-yl)-3-methyl-N-(4-(N-methylsulfamoyl)phenyl)isoxazolo[5,4-b]pyridine-4-carboxamide (A1006),
1-phenyl-N-(4-sulfamoylphenyl)-3-(thiophen-2-yl)-1H-pyrazole-4-carboxamide (A1007),
2-(3-methoxyphenyl)-1-oxo-N-(4-sulfamoylphenyl)-1,2-dihydroisoquinoline-4-carboxamide (A1008),
N-(2-hydroxy-1H-benzo[d]imidazol-6-yl)-2-(pyridin-3-yl)quinoline-4-carboxamide (A1009);

2. The RNA-ligand complex of claim 1 wherein the RNA is present in a tetrahelical structure when the compound is bound to the RNA.

3. The RNA-ligand complex of claim 1 wherein the complex is disposed in a cell infected with an RNA virus.

4. The RNA-ligand complex of claim 1 wherein the compound has a structure according to Formula Ia;

wherein A and D are independently optionally substituted aryl or heteroaryl, or D is H or alkyl, and wherein the quinoline moiety is optionally substituted with a halogen.

5. The RNA-ligand complex of claim 4 wherein A is phenyl or pyridinyl, optionally substituted with alkyl or alkoxy.

6. The RNA-ligand complex of claim 4 wherein D is H, alkyl, quinoxalinyl, isoxazolyl, thiazolyl, pyrimidinyl, or dihydropyrrolyl, optionally substituted with alkyl or alkoxy.

7. The RNA-ligand complex of claim 1 wherein the RNA virus is an Influenza virus.

Assignees

• Nant Holdings Ip Llc

Inventors

• Niazi Kayvan
• Rabizadeh Shahrooz
• Le Ny Anne-Laure
• Buzko Oleksandr
• Golovato Justin
• Soon-Shiong Patrick

Classifications

• C07D215/52 Primary

  with aryl radicals attached in position 2 · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title

• C07D413/12

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

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D498/04

  Ortho-condensed systems · CPC title