US 2010/0249190 A1Published application

Hepatitis C Virus Inhibitors

AssigneeBristol-Myers Squibb Company

InventorsOmar D. Lopez, Qi Chen, Makonen Belema, Lawrence G. Hamann

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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.

Claims18

Dependent claims

A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
s is 0 or 1;
L is -L1-L2-, wherein L1 and L2 are independently selected from:
provided that at least one of L1 and L2 is other than
Y and Y′ are independently oxygen (O) or NH;
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 substituted with one or more substituents independently selected from aryl, alkenyl, cycloalkyl, heterocyclyl, heteroaryl, —OR3, —C(O)OR4, —NRaRb, and —C(O)NRcRd,
wherein aryl and heteroaryl may optionally be substituted with one or more substituents independently selected from alkyl, haloalkyl, arylalkyl, heterocyclyl, heterocyclylalkyl, halogen, cyano, nitro, —C(O)OR4, OR5, —NRaRb, (NRaRb)alkyl, and (MeO)(HO)P(O)O—, and
wherein 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;
R100 and R110 are independently selected from hydrogen, alkyl, cyanoalkyl, and halo;
Rc and Rd are independently selected from hydrogen, alkyl, arylalkyl, and cycloalkyl.

15 more elements

A compound of Formula (II):

or a pharmaceutically acceptable salt thereof, wherein:
s is 0 or 1;
L is -L1-L2-, wherein L1 and L2 are independently selected from:
provided that at least one of L1 and L2 is other than
Y and Y′ are independently oxygen (O) or NH;
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 substituted with one or more substituents independently selected from aryl, alkenyl, cycloalkyl, heterocyclyl, heteroaryl, —OR3, —C(O)OR4, —NRaRb, and —C(O)NRcRd,
wherein aryl and heteroaryl may optionally be substituted with one or more substituents independently selected from alkyl, haloalkyl, arylalkyl, heterocyclyl, heterocyclylalkyl, halogen, cyano, nitro, —C(O)OR4, OR5, —NRaRb, (NRaRb)alkyl, and (MeO)(HO)P(O)O—, and
wherein 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, or haloalkyl;
and
Rc and Rd are independently selected from hydrogen, alkyl, arylalkyl, and cycloalkyl.

15 more elements

A compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

methyl((1S)-1-(((2S)-2-(4-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-1,1′-bi(3-cyclohexen-1-yl)-4-yl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate;
methyl((1S)-2-((2S)-2-(4-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-1,1′-bi(3-cyclohexen-1-yl)-4-yl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate;
(1R,1′R)-2,2′-(1,1′-bi(3-cyclohexen-1-yl)-4,4′-diylbis(1H-imidazole-4,2-diyl(2S)-2,1-pyrrolidinediyl))bis(N,N-diethyl-2-oxo-1-phenylethanamine);
methyl((1S)-2-((2S)-2-(4-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-O-methyl-L-seryl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-1,1′-bi(3-cyclohexen-1-yl)-4-yl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-(methoxymethyl)-2-oxoethyl)carbamate;
methyl((1S,2R)-2-methoxy-1-(((2S)-2-(4-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-O-methyl-L-threonyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-1,1′-bi(3-cyclohexen-1-yl)-4-yl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate;
methyl((1S)-2-((2S)-2-(4-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-1,1′-bi(cyclohexyl)-4-yl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate;
methyl((1S)-2-((2S)-2-(4-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-O-methyl-L-seryl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-1,1′-bi(cyclohexyl)-4-yl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-(methoxymethyl)-2-oxoethyl)carbamate;
methyl((1S,2R)-2-methoxy-1-(((2S)-2-(4-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-O-methyl-L-threonyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-1,1′-bi(cyclohexyl)-4-yl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate;
methyl((1S)-1-(((2S)-2-(4-(4-(4-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)phenyl)-1-cyclohexen-1-yl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate;
methyl((1S)-2-((2S)-2-(4-(4-(4-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-3-cyclohexen-1-yl)phenyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate;
methyl((1S)-2-((2S)-2-(4-(4-(4-(2-((2S)-1-(N-(methoxycarbonyl)-O-methyl-L-seryl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-3-cyclohexen-1-yl)phenyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-(methoxymethyl)-2-oxoethyl)carbamate;
methyl((1S,2R)-2-methoxy-1-(((2S)-2-(4-(4-(4-(2-((2S)-1-(N-(methoxycarbonyl)-O-methyl-L-threonyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-3-cyclohexen-1-yl)phenyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate;
methyl((1S)-1-(((2S)-2-(4-(1-(4-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)phenyl)-4-piperidinyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate;
methyl((1S)-2-((2S)-2-(4-(4-(4-(2-((2S)-1-(N-(methoxycarbonyl)-O-methyl-L-seryl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-1-piperidinyl)phenyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-(methoxymethyl)-2-oxoethyl)carbamate;
methyl((1S)-1-(((2S)-2-(4-(1-(4-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3,3-dimethylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)phenyl)-4-piperidinyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2,2-dimethylpropyl)carbamate;
methyl((1S)-1-(((2S)-2-(4-(4-(4-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)phenyl)bicyclo[2.2.2]oct-1-yl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate;
methyl((1S)-2-((2S)-2-(4-(4-(4-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)bicyclo[2.2.2]oct-1-yl)phenyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate;
methyl((1R)-2-((2S)-2-(4-(4-(4-(2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)bicyclo[2.2.2]oct-1-yl)phenyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate;
methyl((1S)-1-(((2S)-2-(4-(4-(4-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)phenyl)bicyclo[2.2.2]oct-1-yl)-1,3-oxazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate;
methyl((1S)-1-(((1R,3S,5R)-3-(5-(4-(4-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-5-yl)bicyclo[2.2.2]oct-1-yl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate;
methyl((1S)-1-(((1R,3S,5R)-3-(5-(4-(4-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)butanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-5-yl)bicyclo[2.2.2]oct-1-yl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)propyl)carbamate;
methyl((1R)-2-((1R,3S,5R)-3-(5-(4-(4-(2-((1R,3S,5R)-2-((2R)-2-((methoxycarbonyl)amino)-2-phenylacetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-5-yl)bicyclo[2.2.2]oct-1-yl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-phenylethyl)carbamate;
methyl((1S)-1-(((2S)-2-(4-(4-(4-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-4-yl)phenyl)cyclohexyl)-1H-imidazol-2-yl)pyrrolidin-1-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)bicyclo[2.2.2] oct-1-yl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate;
and
corresponding stereoisomers thereof.

23 more elements

Dependencies are inferred from the claim text.

Facts

Application: 12/731,935Filed 25 Mar 2010
Priority: 30 Mar 2009
Published: 30 Sep 2010
Term ends: Not estimatedThe source records don’t support an estimate.

Classification9 codes

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…
A61P 1/16
Drugs for disorders of the alimentary tract or the digestive system: for liver or gallbladder disorders, e.g. hepatoprotective agents,…
A61P 31/00
Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
A61P 31/14
Antivirals: for RNA viruses

Family

Application61/164,579Us provisional application · filed 30 Mar 2009
US 2010/0249190 A1This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
s is 0 or 1;
L is -L1-L2-, wherein L1 and L2 are independently selected from:
provided that at least one of L1 and L2 is other than
Y and Y′ are independently oxygen (O) or NH;
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 substituted with one or more substituents independently selected from aryl, alkenyl, cycloalkyl, heterocyclyl, heteroaryl, —OR3, —C(O)OR4, —NRaRb, and —C(O)NRcRd,
wherein aryl and heteroaryl may optionally be substituted with one or more substituents independently selected from alkyl, haloalkyl, arylalkyl, heterocyclyl, heterocyclylalkyl, halogen, cyano, nitro, —C(O)OR4, OR5, —NRaRb, (NRaRb)alkyl, and (MeO)(HO)P(O)O—, and
wherein 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;
R100 and R110 are independently selected from hydrogen, alkyl, cyanoalkyl, and halo;
Rc and Rd are independently selected from hydrogen, alkyl, arylalkyl, and cycloalkyl.

15 more elements

Facts

Application

12/731,935Filed 25 Mar 2010

Priority

30 Mar 2009

Published

30 Sep 2010

Term ends

Not estimatedThe source records don’t support an estimate.

Classification9 codes

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…
A61P 1/16
Drugs for disorders of the alimentary tract or the digestive system: for liver or gallbladder disorders, e.g. hepatoprotective agents,…
A61P 31/00
Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
A61P 31/14
Antivirals: for RNA viruses