Viral replication inhibitors

Patent metadata

Field	Value
Publication number	US-11279704-B2
Application number	US-201916515272-A
Country	US
Kind code	B2
Filing date	Jul 18, 2019
Priority date	Sep 26, 2011
Publication date	Mar 22, 2022
Grant date	Mar 22, 2022

Abstract

The present invention relates to a series of novel compounds, methods to prevent or treat viral infections in animals by using the novel compounds and to said novel compounds for use as a medicine, more preferably for use as a medicine to treat or prevent viral infections, particularly infections with RNA viruses, more particularly infections with viruses belonging to the family of the Flaviviridae, and yet more particularly infections with the Dengue virus. The present invention furthermore relates to pharmaceutical compositions or combination preparations of the novel compounds, to the compositions or preparations for use as a medicine, more preferably for the prevention or treatment of viral infections. The invention also relates to processes for preparation of the compounds.

First claim

The invention claimed is:

1. A compound of formula (B)

wherein:
the moiety

 is selected from

 wherein the wavy line ( ) indicates the point of attachment to the carbonyl of the main formula (B); wherein said moiety is unsubstituted;
cycle B is selected from

wherein the wavy line ( ) indicates the point of attachment to the carbon atom of the main formula (B), and wherein the depicted cycles may be optionally substituted with one, two, or three Z 1a ;
R 1 is selected from C 3-7 cycloalkyl, aryl, pyridyl, dihydroypyridyl, tetrahydropyridyl, thiazolyl, tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, bis-tetrahydrofuranyl, tetrahydropyranyl, bis-tetrahydropyranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazoly, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, thiochromanyl, 1,2,4-thiadiazolyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, dihydrobenzoxazolyl, benzothienyl, benzothiazolyl and isatinoyl;
and wherein said C 3-7 cycloalkyl, aryl, pyridyl, dihydroypyridyl, tetrahydropyridyl, thiazolyl, tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, bis-tetrahydrofuranyl, tetrahydropyranyl, bis-tetrahydropyranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazoly, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, thiochromanyl, 1,2,4-thiadiazolyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, dihydrobenzoxazolyl, benzothienyl, benzothiazolyl and isatinoyl, are optionally substituted with one, two, or three Z 1b ;

R 2 is hydrogen;
each Z 1a is independently selected from the group consisting of halogen, hydroxyl, sulfhydryl, —OZ 2 , —O—C(═O)Z 3 , ═O, —SZ 2 , ═S, —S(═O)Z 2 , —S(═O) 2 Z 3 , —S(═O) 2 NZ 4 Z 5 , trifluoromethoxy, nitro, —NZ 4 Z 5 , —NZ 4 S(═O) 2 Z 2 , —NZ 4 C(═O)Z 2 , —NZ 4 C(═O)—OZ 2 , —NZ 4 C(═O)NZ 4 Z 5 , cyano, —C(═O)Z 3 , —C(═O)OZ 2 , —C(═O)NZ 4 Z 5 , —C(═O)H, heteroC 1-6 alkyl, aryl, heterocycle, and heterocycle-C 1-6 alkyl;
and wherein said heteroC 1-6 alkyl, aryl, heterocycle, and heterocycle-C 1-6 alkyl, are optionally substituted with one, two, or three substituents selected from hydroxyl, ═O, halogen, —SH, ═S, trifluoromethyl, —OCF 3 , —O—C(O)Me, cyano, nitro, —C(O)OH, —C(O)OC 1-6 alkyl, —NH 2 , —NHCH 3 ; —N(CH 3 ) 2 , —NH—C(═O)O—C 1-4 alkyl; —S(O) 2 C 1-4 alkyl, and —O—C 1-6 alkyl;

each Z 1b is independently selected from the group consisting of halogen, hydroxyl, sulfhydryl, —OZ 2 , —O—C(═O)Z 3 , ═O, —SZ 2 , ═S, —S(═O)Z 2 , —S(═O) 2 Z 3 , —S(═O) 2 NZ 4 Z 5 , trifluoromethyl, trifluoromethoxy, nitro, —NZ 4 Z 5 , NZ 4 C(═O)—OZ 2 , —NZ 4 C(═O)NZ 4 Z 5 , cyano, —C(═O)Z 3 , C(═O)H, C 2-6 alkyl, heteroC 1-6 alkyl, aryl, and heterocycle;
and wherein said C 2-6 alkyl, heteroC 1-6 alkyl, aryl, and heterocycle, are optionally substituted with one, two, or three substituents selected from hydroxyl, halogen, —SH, ═S, trifluoromethyl, —OCF 3 , —O—C(O)Me, nitro, —C(O)OH, —C(O)OC 1-6 alkyl, —NH 2 , —NHCH 3 ; —N(CH 3 ) 2 , —NH—C(═O)O—C 1-4 alkyl; —S(O) 2 C 1-4 alkyl, and —O—C 1-6 alkyl;

each Z 2 is independently selected from C 1-6 alkyl, aryl, heterocycle, and heterocycle-C 1-6 alkyl;
wherein said C 1-6 alkyl, aryl, heterocycle, and heterocycle-C 1-6 alkyl, are optionally substituted with one, two, or three substituents selected from hydroxyl, ═O, halogen, —SH, ═S, trifluoromethyl, difluoromethyl, —O—C 1-6 alkyl, —OCF 3 , —S(═O) 2 C 1-4 alkyl, cyano, nitro, —C(═O)OH, —C(═O)O—C 1-4 alkyl, —NH 2 , and —N(CH 3 ) 2 , pyrrolidinyl, piperidinyl, and piperazinyl;

each Z 3 is independently selected from hydroxyl, C 1-6 alkyl, aryl, and heterocycle;
wherein said C 1-6 alkyl, aryl, and heterocycle are optionally substituted with one, two, or three substituents selected from C 1-6 alkyl and —N(CH 3 ) 2 ;

each Z 4 and Z 5 is independently selected from hydrogen, C 1-6 alkyl, aryl, C 3-7 cycloalkyl, and heterocycle;

or 1-(1H-indol-4-yl)-2-(3-methoxyanilino)-2-phenyl-ethanone;
or 1-(5-isoquinolyl)-2-(3-methoxyanilino)-2-phenyl-ethanone;
or 2-[2-(2-fluorophenoxy)ethylamino]-1-(1H-indol-3-yl)-2-phenyl-ethanone;
or 1-(1H-indol-3-yl)-2-(3-methoxy-N-methyl-anilino)-2-phenyl-ethanone;
or 3-[[2-(1H-indol-3-yl)-2-oxo-1-phenyl-ethyl]amino]-N,N-dimethyl-benzamide;
or 2-[2-furylmethyl(methyl)amino]-1-(1H-indol-3-yl)-2-phenyl-ethanone;
or 2-(dimethylamino)-N-[2-(1H-indol-3-yl)-2-oxo-1-phenyl-ethyl]-N-(3-methoxyphenyl)acetamide;
or 1-(1H-indol-3-yl)-2-((5-methylisoxazol-3-yl)amino)-2-phenylethanone;
or [3-methoxy-5-[[2-(1-methylindol-3-yl)-2-oxo-1-phenyl-ethyl]amino]phenyl]methyl acetate;
or a stereo-isomer thereof, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof:
wherein the term “alkyl” means a normal, secondary, or tertiary, linear or cyclic (or a combination of linear and cyclic), branched or straight hydrocarbon with no site of unsaturation;
with the proviso that compound per se of formula (B) is not
3-(2-(1H-indol-3-yl)-2-oxo-1-phenylethylamino)benzenesulfonamide (CAS nr. 1211427-21-2);
1-(1H-indol-3-yl)-2-phenyl-2-(m-tolylamino)ethanone (CAS nr. 1252467-88-1);
2-(4-ethoxy-3-(hydroxymethyl)phenylamino)-1-(1H-indol-3-yl)-2-phenylethanone (CAS nr. 1241127-58-1);
1-(1H-indol-3-yl)-2-[(6-methoxy-3-pyridinyl)amino]-2-phenyl-ethanone (CAS nr. 1181884-55-8);
1-(1H-indol-3-yl)-2-[(1-methyl-1H-pyrazol-3-yl)amino]-2-phenyl-ethanone (CAS nr. 1134766-19-0);
2-[(3,5-dim

Assignees

• Univ Leuven Kath

Inventors

• Bardiot Dorothée
• Carlens Gunter
• Dallmeier Kai
• Kaptein Suzanne
• Mcnaughton Michael
• Marchand Arnaud
• Neyts Johan
• Smets Wim
• Koukni Mohamed

Classifications

• Y02A50/30

  Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change · CPC title

• C07D401/12

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

• C07D401/08

  linked by a carbon chain containing alicyclic rings · CPC title

• C07D409/12

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

• C07D409/06

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