US 8,796,466 B2Granted

Hepatitis C virus inhibitors

AssigneeBristol-Myers Squibb Company

InventorsJohn A. Bender, Piyasena Hewawasam, John F. Kadow, Omar D. Lopez, Nicholas A. Meanwell, Van N. Nguyen, Jeffrey Lee Romine, Lawrence B. Snyder, Denis R. St. Laurent, Gan Wang, Ningning Xu, Makonen Belema

Life of this patent

Estimating the term…

patentgrep

Loading patent…

Abstract

This disclosure concerns novel compounds of Formula (I) as defined in the specification and compositions comprising such novel compounds. These compounds are useful antiviral agents, especially in inhibiting the function of the NS5A protein encoded by Hepatitis C virus (HCV). Thus, the disclosure also concerns a method of treating HCV related diseases or conditions by use of these novel compounds or a composition comprising such novel compounds.

Claims4

Dependent claims

A compound of Formula (Id):

or a pharmaceutically acceptable salt or a tautomer thereof, wherein
X is hydrogen or chloro (Cl);
X′ is hydrogen or chloro (Cl);
L is selected from —O—, —CH2CH2—, —CH═CH—, —OCH2—, —CH2O—, —CH2OCH2—,
R1 is hydrogen or —C(O)Rx;
R2 is hydrogen or —C(O)Ry;
Rx and Ry are independently selected from cycloalkyl, heteroaryl, heterocyclyl, alkoxy, and alkyl, said alkyl being substituted by one or more substituents independently selected from aryl, alkenyl, cycloalkyl, heterocyclyl, heteroaryl, —OR3,—C(O)OR4,—NRaRb, and —C(O)NRcRd,
wherein any said aryl and heteroaryl may optionally be substituted with one or more substituents independently selected from alkenyl, alkyl, haloalkyl, arylalkyl, heterocyclyl, heterocyclylalkyl, halogen, cyano, nitro, —C(O)OR4, —OR5, —NRaRb, (NRaRb)alkyl, and (MeO)(HO)P(O)O—, and
wherein any said cycloalkyl and heterocyclyl may optionally be fused onto an aromatic ring and may optionally be substituted with one or more substituents independently selected from alkyl, hydroxyl, halogen, aryl, —NRaRb, oxo, and —C(O)OR4;
R3 is hydrogen, alkyl, or arylalkyl;
R4 is alkyl or arylalkyl;
R5 is hydrogen, alkyl, or arylalkyl;
Ra and Rb are independently selected from hydrogen, alkyl, cycloalkyl, arylalkyl, heteroaryl, —C(O)R6, —C(O)OR7, —C(O)NRcRd, and (NRcRd)alkyl, or alternatively,
Ra and Rb, together with the nitrogen atom to which they are attached, form a five- or six-membered ring or bridged bicyclic ring structure, wherein said five- or six-membered ring or bridged bicyclic ring structure optionally may contain one or two additional heteroatoms independently selected from nitrogen, oxygen, and sulfur and may contain one, two, or three substituents independently selected from C1 to C6 alkyl, C1 to C4 haloalkyl, aryl, hydroxyl, C1 to C6 alkoxy, C1 to C4 haloalkoxy, and halogen;
R6 is alkyl;
R7 is alkyl, arylalkyl, cycloalkyl, or haloalkyl;
and
Rc and Rd are independently selected from hydrogen, alkyl, arylalkyl, and cycloalkyl.

15 more elements

A compound selected from

methyl((1S)-1-(((1R,3S,5R)-3-(4-(4-((4-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)phenyl)ethynyl) phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate;
dimethyl(1,2-ethynediylbis(4,1-phenylene-1H-imidazole-4,2-diyl(1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3,2-diyl((2S)-1-oxo-1,2-butanediyl)))biscarbamate;
dimethyl(1,2-ethynediylbis(4,1-phenylene-1H-imidazole-4,2-diyl(1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3,2-diyl((1S)-1-cyclobutyl-2-oxo-2,1-ethanediyl)))biscarbamate;
dimethyl(1,2-ethynediylbis(4,1-phenylene-1H-imidazole-4,2-diyl(1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3,2-diyl(1S)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)-2,1-ethanediyl)))biscarbamate;
methyl((1S)-1-(((1R,3S,5R)-3-(4-(4-((4-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)phenyl)ethynyl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate;
methyl((1S)-1-(((1R,3S,5R)-3-(4-chloro-5-(4-((4-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino) -3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)phenyl)ethynyl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate;
methyl((1S)-1-(((1R,3S,5R)-3-(4-chloro-5-(4-((4-(4-chloro-2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-5-yl)phenyl)ethynyl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate;
methyl((1S)-2-((1R,3S,5R)-3-(4-(4-((4-(4-chloro-2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-5-yl)phenyl)ethynyl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate;
dimethyl(1,2-ethynediylbis(4,1-phenylene(4-chloro-1H-imidazole-5,2-diyl)(1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3,2-diyl((1S)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)-2, 1-ethanediyl)))biscarbamate;
methyl((1S)-1-(((1R,3S,5R)-3-(4-(4-((1S,2S)-2-(4-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)phenyl)cyclopropyl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate;
dimethyl((1S,2S)-1,2-cyclopropanediylbis(4,1-phenylene-1H-imidazole-4,2-diyl(1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3,2-diyl((1S)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)-2,1-ethanediyl)))biscarbamate;
methyl((1S)-1-(((1R,3S,5R)-3-(4-(4-((1R,2R)-2-(4-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)phenyl)cyclopropyl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate;
dimethyl((1R,2R)-1,2-cyclopropanediylbis(4,1-phenylene-1H-imidazole-4,2-diyl(1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3,2-diyl((1S)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)-2,1-ethanediyl)))biscarbamate;
methyl((1S)-1-(((1R,3S,5R)-3-(4-(4-((E)-2-(4-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl) amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)phenyl)vinyl) phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate;
dimethyl((E)-1,2-ethenediylbis(4,1-phenylene-1H-imidazole-4,2-diyl(1R,3S,5R)-2-azabicyclo [3.1.0]hexane-3,2-diyl((1S)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)-2,1-ethanediyl))) biscarbamate;
methyl((1S)-2-((1R,3S,5R)-3-(4-(4((E)-2-(4-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl) amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)phenyl)vinyl) phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate;
methyl((1 S)-1-(((1 S,3 S,5 S)-3-(4-(4-((4-(2-((1 S,3 S,5 S)-2(2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)phenyl)ethynyl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo [3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate;
dimethyl(1,2-ethynediylbis(4,1 -phenylene-1H-imidazole-4,2-diyl(1 S ,3 S,5 S)-2-azabicyclo [3.1.0]hexane-3 ,2-diyl((1 S)-2-oxo-1 -(tetrahydro-2H-pyran-4-yl)-2,1 -ethanediyl)))biscarbamate;
methyl((1 S)-1 -(1R,3 S,5R)-3-(4-(3-((3-(2-((1R,3 S,5R)-2(2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo [3.1.0]hex-3 -yl)-1H-imidazol-4-yl)phenyl)ethynyl)phenyl)-1 H-imidazol-2-yl)-2-azabicyclo [3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate;
and
dimethyl(1,2-ethynediylbis(3,1-phenylene-1H-imidazole-4,2-diyl(1R,3 S,5R)-2-azabicyclo [3.1.0]hexane-3 ,2-diyl((1 S)-2-oxo-1 -(tetrahydro-2H-pyran-4-yl)-2,1 -ethanediyl)))biscarbamate;
or a pharmaceutically acceptable salt thereof.

19 more elements

Dependencies are inferred from the claim text.

Facts

Application: 12/729,940Filed 23 Mar 2010 · us provisional application
Priority: 30 Mar 2009
Published: US 2011/0077280 A131 Mar 2011
Granted: 5 Aug 2014
Term ends: Not estimatedThe source records don’t support an estimate.

Classification6 codes

C07D 403/04
Containing two hetero rings: directly linked by a ring-member-to-ring-member bond
A61P 31/14
Antivirals: for RNA viruses
C07D 403/14
Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group…
C07D 405/14
Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having…:…