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US 10,000,500 B2Granted
Coelenterazine analogues
AssigneePromega Corporation
InventorsMary Hall, Thomas Kirkland, Thomas Machleidt, Anton Shakhmin, Joel R. Walker
Life of this patent
Estimating the term…
Abstract
Described are coelenterazine analogs, methods for making the analogs, kits comprising the analogs, and methods of using the compounds for the detection of luminescence in luciferase-based assays.
Claims20
A compound of formula (I)
- or a tautomer, or a salt thereof, wherein
- R5 is hydrogen, halogen, hydroxy, cyano, nitro, amino, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, aryl, bicyclic aryl, tricyclic aryl, heteroaryl, bicyclic heteroaryl, tricyclic heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl;
- R6 is alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, aryl, bicyclic aryl, tricyclic aryl, heteroaryl, bicyclic heteroaryl, tricyclic heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl;
- or
- R5 and R6 together with the atoms to which they are attached, form a 5- or 6-membered partially unsaturated or fully unsaturated ring, the 5- or 6-membered ring optionally containing 1, 2 or 3 heteratoms or heteroatom groups each independently selected from the group consisting of O, N, S, NO, SO and SO2 as ring members, the 5- or 6-membered ring optionally fused to an aryl, heteroaryl, heterocycle, or cycloalkyl, the 5- or 6-membered ring substituted with 0, 1, 2, 3, or 4 substituents, each independently selected from the group consisting of halogen, ═O, ═S, cyano, nitro, fluoroalkyl, alkoxyfluoroalkyl, fluoroalkoxy, alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, heteroalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycle, cycloalkylalkyl, heteroarylalkyl, arylalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkylene, aryloxy, phenoxy, benzyloxy, amino, alkylamino, dialkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, —COOH, ketone, amide, carbamate, silyl, substituted silyl, t-butyldimethylsilyl, alkylsulfanyl, sulfanyl, and acyl;
- and
- R8 is alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, aryl, bicyclic aryl, tricyclic aryl, heteroaryl, bicyclic heteroaryl, tricyclic heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl;
- wherein said alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, aryl, bicyclic aryl, tricyclic aryl, heteroaryl, bicyclic heteroaryl, tricyclic heteroaryl, heterocycle, cycloalkyl, and cycloalkenyl, at each occurrence, are independently substituted with 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 substituents, each independently selected from the group consisting of halogen, ═O, ═S, cyano, nitro, fluoroalkyl, alkoxyfluoroalkyl, fluoroalkoxy, alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, heteroalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycle, cycloalkylalkyl, heteroarylalkyl, arylalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkylene, aryloxy, phenoxy, benzyloxy, amino, alkylamino, dialkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, —COOH, ketone, amide, carbamate, silyl, substituted silyl, t-butyldimethylsilyl, alkylsulfanyl, sulfanyl, and acyl;
- provided that the following compounds are excluded from formula (I):
- 8-benzyl-2-(furan-2-ylmethyl)-6-phenylimidazo[1,2-a]pyrazin-3(7H)-one;
- and
- 8-benzyl-2-(furan-2-ylmethyl)-6-(4-hydroxyphenyl)imidazo[1,2-a]pyrazin-3(7H)-one.
9 more elements
A compound selected from the group consisting of:
- 8-benzyl-2-(furan-2-ylmethyl)-6-(naphthalen-1-yl)imidazo[1,2-a]pyrazin-3(7H)-one;
- 8-benzyl-2-(furan-2-ylmethyl)-6-(naphthalen-2-yl)imidazo[1,2-a]pyrazin-3(7H)-one;
- 6-(anthracen-9-yl)-8-benzyl-2-(furan-2-ylmethyl)imidazo[1,2-a]pyrazin-3(7H)-one;
- 8-benzyl-2-(furan-2-ylmethyl)-6-(phenanthren-9-yl)imidazo[1,2-a]pyrazin-3(7H)-one;
- 6-([1,1′-biphenyl]-4-yl)-8-benzyl-2-(furan-2-ylmethyl)imidazo[1,2-a]pyrazin-3(7H)-one;
- 8-benzyl-2-(furan-2-ylmethyl)-6-(2-methoxypyrimidin-5-yl)imidazo[1,2-a]pyrazin-3(7H)-one;
- 4-(8-benzyl-2-(furan-2-ylmethyl)-3-oxo-3,7-dihydroimidazo[1,2-a]pyrazin-6-yl)benzonitrile;
- 8-benzyl-2-(furan-2-ylmethyl)-6-(quinolin-6-yl)imidazo[1,2-a]pyrazin-3(7H)-one;
- 8-benzyl-2-(furan-2-ylmethyl)-6-(4-methoxyphenyl)imidazo[1,2-a]pyrazin-3(7H)-one;
- 8-benzyl-2-(furan-2-ylmethyl)-6-(3-methoxyphenyl)imidazo[1,2-a]pyrazin-3(7H)-one;
- 8-benzyl-2-(furan-2-ylmethyl)-6-(2-methoxyphenyl)imidazo[1,2-a]pyrazin-3(7H)-one;
- 8-benzyl-6-(4-fluorophenyl)-2-(furan-2-ylmethyl)imidazo[1,2-a]pyrazin-3(7H)-one;
- 8-benzyl-2-(furan-2-ylmethyl)-6-(3-hydroxyphenyl)imidazo[1,2-a]pyrazin-3(7H)-one;
- 6-(2-aminophenyl)-8-benzyl-2-(furan-2-ylmethyl)imidazo[1,2-a]pyrazin-3(7H)-one;
- 6-(3-aminophenyl)-8-benzyl-2-(furan-2-ylmethyl)imidazo[1,2-a]pyrazin-3(7H)-one;
- and
- 6-(4-aminophenyl)-8-benzyl-2-(furan-2-ylmethyl)imidazo[1,2-a]pyrazin-3(7H)-one;
- 2-(furan-2-methyl)-6,8-diphenlimidazo[1,2-a]pyrazin-3(7H)-one:
- 8-cyclopentyl-2-(furan-2-ylmethyl)-6-phenylimidazo[1,2-a]pyrazin-3(7H)-one;
- 2-(furan-2-ylmethyl)-8-(naphthalen-1-yl)-6-phenylimidazo[1,2-a]pyrazin-3(7H)-one:
- 2-(furan-2-ylmethyl)-8-(naphthalen-2-yl)-6-phenylimidazo[1,2-a]pyrazin-3(7H)-one;
- 8-([1,1′-biphenyl]-4-yl)-2-(furan-2-ylmethyl)-6-phenylimidazo[1,2-a]pyrazin-3(7H)-one;
- 2-(furan-2-ylmethyl)-8-(phenanthren-9-yl)-6-phenylimidazo[1,2-a]pyrazin-3(7H)-one;
- 2-(furan-2-ylmethyl)-6-phenyl-8-(phenylethynyl)imidazo[1,2-a]pyrazin-3(7H)-one:
- (E)-2-(furan-2-ylmethyl)-6-phenyl-8-styrylimidazo[1,2-a]pyrazin-3(7H)-one;
- 8-(benzofuran-2-yl)-2-(furan-2-ylmethyl)-6-phenylimidazo[1,2-a]pyrazin-3(7H)-one:
- 8-(benzo[b]thiophen-2-yl)-2-(furan-2-ylmethyl)-6-phenylimidazo[1,2-a]pyrazin-3(7H)-one;
- 8-(benzo[c][1,2,5]oxadiazol-5-yl)-2-(furan-2-ylmethyl)-6-phenylimidazo[1,2-a]pyrazin-3(7H)-one;
- 2-(furan-2-ylmethyl)-8-(imidazo[1,2-a]pyridin-6-yl)-6-phenylimidazo[1,2-a]pyrazin-3-(7H)-one;
- 2-(furan-2-ylmethyl)-8-(1H-indol-5-yl)-6-phenylimidazo[1,2-a]pyrazin-3(7H)-one;
- 8-(benzo[d]thiazol-5-yl)-2-(furan-2-ylmethyl)-6-phenylimidazo[1,2-a]pyrazin-3(7H)-one;
- 2-(furan-2-ylmethyl)-8-(2-methyl-2H-indazol-6yl)-6-phenylimidazo[1,2-a]pyrazin-3(7H)-one;
- 5-(2-(furan-2-ylmethyl)-3-oxo-6phenyl-3,7-dihydroimidazo[1,2-a]pyrazin-8-yl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione;
- 2-(furan-2-ylmethyl)-8-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-phenylimidazo[1,2-a]pyrazin-3(7H)-one;
- 2-(furan-2-ylmethyl)-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-phenylimidazo[1,2-a]pyrazin-3(7H)-one;
- 2-(furan-2-ylmethyl-6-phenyl-8-(3,4,5-trifluorophenyl)imidazo[1,2-a]pyrazin-3(7H)-one;
- 8-(4-fluorophenyl)-2-(furan-2-ylmethyl)-6-phenylimidazo[1,2-a]pyrazin-3(7H)-one;
- 2-(furan-2-ylmethyl)-8-(4-nitrophenyl)-6-phenylimidazo[1,2-a]pyrazin-3(7H)-one;
- 4-(2-(furan-2-ylmethyl)-3-oxo-6-phenyl-3,7-dihydroimidazo-[1,2-a]pyrazin-8-yl)benzonitrile;
- 3-(2-(furan-2-ylmethyl)-3-oxo-6-phenyl-3,7-dihydroimidazo[1,2-a]pyrazin-8-yl)benzonitrile;
- 8-(4-(dimethylamino)phenyl)-2-(furan-2-ylmethyl-6-phenylimidazo[1,2-a]pyrazin-3(7H)-one;
- 2-(furan-2-ylmethyl)-6-phenyl-8-(thiophen-3-yl)imidazo[1,2-a]pyrazin-3(7H-one;
- 2-(furan-2-ylmethyl)-6-phenyl-8-(thiophen-2-yl)imidazo[1,2-a]pyrazin-3(7H)-one;
- 5-(2-(furan-2-ylmethy)-3-oxo-6-phenyl-3,7-dihydroimidazo[1,2-a]pyrazin-8 yl)thiophene-2-carbonitile;
- 8-(5-chlorothiophen-2-yl)-2-(furan-2-ylmethyl)-6-phenylimidazo[1,2a]pyrazin-3(7H)-one;
- 8-(3-chlorothiophen-2-yl)-2-(furan-2-ylmethyl)-6-phenylimidazo[1,2-a]pyrazin-3(7H)-one;
- 2-(furan-2ylmethyl)-6-phenyl-8-(pyridin-3-yl)imidazo[1,2-a]pyrazin-3(7H)-one;
- 8-(6-fluoropyridin-3-yl)-2-(furan-2-ylmethyl)-6-phenylimidazo[1,2-a]pyrazin-3(7H)-one;
- 8-(2-fluoropyridin-3-yl)-2-(furan-2-ylmethyl)-6-phenylimidazo[1,2-a]pyrazin-3(7H)-one;
- 8-(2-chloropyridin-3-yl)-2-(furan-2-ylmethyl)-6-phenylimidazo[1,2-a]pyrazin-3(7H)-one;
- 2-(furan-2-ylmethyl)-6-phenyl-8-(pyridin-4-yl)imidazo[1,2-a]pyrazin-3(7H)-one;
- 8-(2-fluoropyridin-4 yl)-2-(furan-2-ylmethyl)-6-phenylimidazo[1,2-a]pyrazin-3(7H)-one;
- 8-(2-chloropyridin-4-yl)-2-(furan-2-ylmethyl)-6-phenylimidazo[1,2-a]pyrazin-3(7H)-one;
- 2-(furan-2-ylmethyl)-6-phenyl-8-(quinolin-4-yl)imidazol[1,2-a]pyrazin-3(7H)-one;
- 8-(2,6-dichloropyridin-4-yl)-2-(furan-2-ylmethyl)-6-phenylimidazo[1,2-a]pyrazin-3(7H)-one;
- 2-(furan-2-ylmethyl)-6-phenyl-8-(2-(trifluoromethyl)pyridin-4-yl)imidazol[1,2-a]pyrazin-3(7H)-one;
- 8-(2-bromopyridin-4-yl)-2-(furan-2-ylmethyl)-6-phenylimidazo[1,2-a]pyrazin-3 (7H)-one;
- 2-(furan-2-ylmethyl)-6-phenyl-8-(thiazol-5-yl)imidazol[1,2-a]pyrazin-3(7H)-one;
- and
- 5-(2-(furan-2-ylmethyl)-3-oxo-6 phenyl-3,7-dihydroimidazo[1,2-a]pyrazin-8-yl)-1-methyl-1H-pyrrole-2-carbonitrile;
- 6,8-difuran-2-yl)-2-(furan-2-ylmethyl)imidazo[1,2-a]pyrazin-3(7H)-one;
- 2-(furan-2-ylmethyl)-6,8-di(thiophen-2-yl)imidazo[1,2a]pyrazin-3(7H)-one;
- 2-(furan-2-ylmethyl)-6-(1-methyl-1H-pyrazol-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-3(7H)-one;
- 8-(2-fluoropyridin-4-yl)-2-(furan-2-ylmethyl)-6-(thiophen-2-yl)imidazo[1,2-a]pyrazin-3(7H)-one;
- 5-(2-(furan-2-ylmethyl)-3-oxo-6-(thiophen-2-yl)-3,7-dihydroimidazo[1,2-a]pyrazin-8-yl)thiophene-2-carbonitrile;
- 26,8-bis(2-fluoropyridin-4-yl)-2-(furan-2-ylmethyl)imidazol[1,2-a]pyrazin-3(7H)-one;
- 2-(furan-2-ylmethyl)-6-phenyl-8-(phenylethynyl)imidazo[1,2-a]pyrazin-3(7H)-one;
- 6-(4-aminophenyl)-2-(furan-2-ylmethyl)-8(quinolin-4-yl)imidazol[1,2-a]pyrazin-3(7H)-one;
- 5-(6-(4-aminophenyl)-2-(furan-2-ylmethyl)-3-oxo-3,7-dihydroimidazo[1,2-a]pyrazin-8-yl)thiophene-2-carbonitile;
- 6,8-bis(4-aminophenyl)-2-(furan-2-ylmethyl)imidazo[1,2-a]pyrazin-3(7H)-one,
- 2-(furan-2-ylmethyl)-6-(4-hydroxyphenyl)-8-(quinolin-4-yl)imidazo[1,2-a]pyrazin-3(7H)-one;
- and
- 5-(2-furan-2-ylmethyl)-6-(4-hydroxyphenyl)-3-oxo-3,7-dihydroimidazo[1,2-a]pyrazin-8-yl)thiophene-2-carbonitrile;
- 2-(furan-2-ylmethyl)-5,6,8-triphenylimidazo[1,2-a]pyrazin-3(7H)-one;
- and
- 2-(furan-2-ylmethyl)-3-oxo-6,8-diphenyl-3,7-dihydroimidazo[1,2-a]pyrazine-5-carbonitrile;
- 4-(2-chloropyridin-4-yl)-2-(furan-2-ylmethyl)imidazo[1,2-a]quinoxalin-1(5H)-one;
- 5-(2-(furan-2-ylmethyl)-1-oxo-1,5-dihydroimidazo[1,2-a]quinoxalin-4-yl)thiophene-2-carbonitrile;
- 12-(2-chloropyridin-4-yl)-2-(furan-2-ylmethyl)-5,11-dihydrobenzo[f]imidazo[1,2-a]quinoxalin-3(6H)-one;
- 5-(2-(furan-2-ylmethyl)-3-oxo-3,5,6,11-tetrahydrobenzo[f]imidazo[1,2-a]quinoxalin-12-yl)thiophene-2-carbonitrile;
- and
- 2-(furan-2-ylmethyl)-12-(quinolin-4-yl)-5,11-dihydrobenzo[f′]imidazo[1,2-a]quinoxalin-3(6H)-one;
- 8-(2-chloropyridin-4 yl)-2-(furan-2-ylmethyl)-6-(4-hydroxyphenyl)imidazo[1,2-a]pyrazin-3(7H)-one;
- 12-(2-chloropyridin-4-yl)-2-(furan-2-ylmethyl)benzo[f]imidazo[1,2-a]quinoxalin-3(11H)-one,
- 5-(2-(furan-2-ylmethyl)-3-oxo-3,11-dihydrobenzo[f]imidazo[1,2-a]quinoxalin-12-yl)thiophene-2-carbonitile;
- and
- 2-(furan-2-ylmethyl)-12-(quinolin-4-yl)benzo[f′]imidazo[1,2-a]quinoxalin-3(11H)-one;
- 2-benzyl-5-ethynyl-6,8-diphenylimidazo[1,2-a]pyrazin-3(7H)-one;
- 2-benzyl-3-oxo-6,8-diphenyl-3,7-dihydroimidazo[1,2-a]pyrazine-5-carbonitrile
- 2-benzyl-5-(dimethylamino)-6,8-diphenylimidazo[1,2-a]pyrazin-3(7H)-one;
- and
- 2-benzyl-5-methoxy-6,8-diphenylimidazo[1,2-a]pyrazin-3(7H)-one;
- or a tautomer, or a salt thereof.
90 more elements
A compound of formula (II),
- or a tautomer, or a salt thereof, wherein
- Rx is halogen, hydroxy, cyano, nitro, amino, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, aryl, bicyclic aryl, tricyclic aryl, heteroaryl, bicyclic heteroaryl, tricyclic heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl;
- p is 0, 1, 2, 3, 4, or 5;
- R5a is hydrogen, halogen, hydroxy, cyano, nitro, amino, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, aryl, bicyclic aryl, tricyclic aryl, heteroaryl, bicyclic heteroaryl, tricyclic heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl;
- R6a is alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, aryl, bicyclic aryl, tricyclic aryl, heteroaryl, bicyclic heteroaryl, tricyclic heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl;
- or
- R5a and R6a together with the atoms to which they are attached, form a 5- or 6-membered partially unsaturated or fully unsaturated ring, the 5- or 6-membered ring optionally containing 1, 2 or 3 heteratoms or heteroatom groups each independently selected from the group consisting of O, N, S, NO, SO and SO2 as ring members, the 5- or 6-membered ring optionally fused to an aryl, heteroaryl, heterocycle, or cycloalkyl, the 5- or 6-membered ring substituted with 0, 1, 2, 3, or 4 substituents, each independently selected from the group consisting of halogen, ═O, ═S, cyano, nitro, fluoroalkyl, alkoxyfluoroalkyl, fluoroalkoxy, alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, heteroalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycle, cycloalkylalkyl, heteroarylalkyl, arylalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkylene, aryloxy, phenoxy, benzyloxy, amino, alkylamino, dialkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, —COOH, ketone, amide, carbamate, silyl, substituted silyl, t-butyldimethylsilyl, alkylsulfanyl, sulfanyl, and acyl;
- and
- R8a is alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, aryl, bicyclic aryl, tricyclic aryl, heteroaryl, bicyclic heteroaryl, tricyclic heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl;
- wherein said alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, aryl, bicyclic aryl, tricyclic aryl, heteroaryl, bicyclic heteroaryl, tricyclic heteroaryl, heterocycle, cycloalkyl, and cycloalkenyl, at each occurrence, are independently substituted with 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 substituents, each independently selected from the group consisting of halogen, ═O, ═S, cyano, nitro, fluoroalkyl, alkoxyfluoroalkyl, fluoroalkoxy, alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, heteroalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycle, cycloalkylalkyl, heteroarylalkyl, arylalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkylene, aryloxy, phenoxy, benzyloxy, amino, alkylamino, dialkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, —COOH, ketone, amide, carbamate, silyl, substituted silyl, t-butyldimethylsilyl, alkylsulfanyl, sulfanyl, and acyl;
- provided that Rx is not 4-hydroxy when p is 1, R5a is not hydrogen, or R8a is not benzyl, or any combination thereof.
8 more elements
Dependencies are inferred from the claim text.