# US 7,745,636 B2 · Hepatitis C virus inhibitors

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 7,745,636 B2
- Document ID: US7745636B2
- Status: Granted
- Kind: B2
- Application number: 12/029,680
- Filed: 2008-02-12
- Published: 2008-12-04
- Granted: 2010-06-29
- Earliest claimed: 2006-08-11
- Assignees: Bristol-Myers Squibb Company
- Inventors: Carol Bachand; Makonen Belema; Daniel H. Deon; Andrew C. Good; Jason Goodrich; Clint A. James; Rico Lavoie; Omar D. Lopez; Alain Martel; Nicholas A. Meanwell; Van N. Nguyen; Jeffrey Lee Romine; Edward H. Ruediger; Lawrence B. Snyder; Denis R. St. Laurent; Fukang Yang; David R. Langley; Gan Wang; Lawrence G. Hamann
- Web page: https://patentgrep.com/patent/US7745636B2

## CPC

- C07D 403/14: containing three or more hetero rings
- A61P 31/12: Antivirals
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present disclosure relates to compounds, compositions and methods for the treatment of hepatitis C virus (HCV) infection. Also disclosed are pharmaceutical compositions containing such compounds and methods for using these compounds in the treatment of HCV infection.

## Claims

### Claim 1

A compound selected from
dimethyl(4,4′-biphenyldiylbis(1H-imidazole-4,2-diyl((1S)-2-methyl-1,1-propanediyl)imino((2S)-1-oxo-1,2-propanediyl)))biscarbamate;
dimethyl(4,4′-biphenyldiylbis(1H-imidazole-4,2-diyl((1S)-2-methyl-1,1-propanediyl)imino((2S,3R)-3-methoxy-1-oxo-1,2-butanediyl)))biscarbamate;
dimethyl(4,4′-biphenyldiylbis(1H-imidazole-4,2-diyl((1S)-2-methyl-1,1-propanediyl)imino((2S)-3-methyl-1-oxo-1,2-butanediyl)))biscarbamate;
dimethyl(4,4′-biphenyldiylbis(1H-imidazole-4,2-diyl((1S)-2-methyl-1,1-propanediyl)imino((2S)-4-methoxy-1-oxo-1,2-butanediyl)))biscarbamate;
dimethyl(4,4′-biphenyldiylbis(1H-imidazole-4,2-diyl((1R)-2-methyl-1,1-propanediyl)imino((2S)-3-methyl-1-oxo-1,2-butanediyl)))biscarbamate;
dimethyl(4,4′-biphenyldiylbis(1H-imidazole-4,2-diyl((1R)-2-methyl-1,1-propanediyl)imino((2S)-1-oxo-1,2-propanediyl)))biscarbamate;
dimethyl(4,4′-biphenyldiylbis(1H-imidazole-4,2-diyl((1R)-2-methyl-1,1-propanediyl)imino((2S)-4-methoxy-1-oxo-1,2-butanediyl)))biscarbamate;
dimethyl(4,4′-biphenyldiylbis(1H-imidazole-4,2-diyl((1R)-2-methyl-1,1-propanediyl)imino((2S,3R)-3-methoxy-1-oxo-1,2-butanediyl)))biscarbamate;
dimethyl(4,4′-biphenyldiylbis(1H-imidazole-4,2-diyl((1R)-2-methyl-1,1-propanediyl)imino((2R)-3-methyl-1-oxo-1,2-butanediyl)))biscarbamate;
dimethyl(4,4′-biphenyldiylbis(1H-imidazole-4,2-diyl((1S)-2-methyl-1,1-propanediyl)imino((2R)-3-methyl-1-oxo-1,2-butanediyl)))biscarbamate;
N2-(methoxycarbonyl)-N-((1S)-1-(4-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-L-valyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-2-methylpropyl)-L-valinamide;
methyl((1S,2R)-2-methoxy-1-(((2S)-2-(4-(4′-(2-((1S)-1-((N-(methoxycarbonyl)-O-methyl-L-threonyl)amino)-2-methylpropyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate;
methyl((1S)-3-methoxy-1-(((2S)-2-(4-(4′-(2-((1S)-1-((N-(methoxycarbonyl)-O-methyl-L-homoseryl)amino)-2-methylpropyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate;
methyl((1S)-2-((2S)-2-(4-(4′-(2-((1S)-1-((N-(methoxycarbonyl)-L-alanyl)amino)-2-methylpropyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate;
N2-(methoxycarbonyl)-N-((1R)-1-(4-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-L-valyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-2-methylpropyl)-L-valinamide;
methyl((1S,2R)-2-methoxy-1-(((2S)-2-(4-(4′-(2-((1R)-1-((N-(methoxycarbonyl)-O-methyl-L-threonyl)amino)-2-methylpropyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate;
methyl((1S)-3-methoxy-1-(((2S)-2-(4-(4′-(2-((1R)-1-((N-(methoxycarbonyl)-O-methyl-L-homoseryl)amino)-2-methylpropyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate;
methyl((1S)-2-((2S)-2-(4-(4′-(2-((1R)-1-((N-(methoxycarbonyl)-L-alanyl)amino)-2-methylpropyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate;
dimethyl(4,4′-biphenyldiylbis(1H-imidazole-4,2-diyl((1S)-2-methyl-1,1-propanediyl)imino((2S)-1-oxo-1,2-propanediyl)))biscarbamate;
dimethyl(4,4′-biphenyldiylbis(1H-imidazole-4,2-diyl((1S)-2-methyl-1,1-propanediyl)imino((2S,3R)-3-methoxy-1-oxo-1,2-butanediyl)))biscarbamate;
dimethyl(4,4′-biphenyldiylbis(1H-imidazole-4,2-diyl((1S)-2-methyl-1,1-propanediyl)imino((2S)-3-methyl-1-oxo-1,2-butanediyl)))biscarbamate;
dimethyl(4,4′-biphenyldiylbis(1H-imidazole-4,2-diyl((1S)-2-methyl-1,1-propanediyl)imino((2S)-4-methoxy-1-oxo-1,2-butanediyl)))biscarbamate;
dimethyl(4,4′-biphenyldiylbis(1H-imidazole-4,2-diyl((1R)-2-methyl-1,1-propanediyl)imino((2S)-3-methyl-1-oxo-1,2-butanediyl)))biscarbamate;
dimethyl(4,4′-biphenyldiylbis(1H-imidazole-4,2-diyl((1R)-2-methyl-1,1-propanediyl)imino((2S)-1-oxo-1,2-propanediyl)))biscarbamate;
dimethyl(4,4′-biphenyldiylbis(1H-imidazole-4,2-diyl((1R)-2-methyl-1,1-propanediyl)imino((2S)-4-methoxy-1-oxo-1,2-butanediyl)))biscarbamate;
dimethyl(4,4′-biphenyldiylbis(1H-imidazole-4,2-diyl((1R)-2-methyl-1,1-propanediyl)imino((2S,3R)-3-methoxy-1-oxo-1,2-butanediyl)))biscarbamate;
dimethyl(4,4′-biphenyldiylbis(1H-imidazole-4,2-diyl((1R)-2-methyl-1,1-propanediyl)imino((2R)-3-methyl-1-oxo-1,2-butanediyl)))biscarbamate;
dimethyl(4,4′-biphenyldiylbis(1H-imidazole-4,2-diyl((1S)-2-methyl-1,1-propanediyl)imino((2R)-3-methyl-1-oxo-1,2-butanediyl)))biscarbamate;
N2-(methoxycarbonyl)-N-((1S)-1-(4-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-L-valyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-2-methylpropyl)-L-valinamide;
methyl((1S,2R)-2-methoxy-1-(((2S)-2-(4-(4′-(2-((1S)-1-((N-(methoxycarbonyl)-O-methyl-L-threonyl)amino)-2-methylpropyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate;
methyl((1S)-3-methoxy-1-(((2S)-2-(4-(4′-(2-((1S)-1-((N-(methoxycarbonyl)-O-methyl-L-homoseryl)amino)-2-methylpropyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate;
methyl((1S)-2-((2S)-2-(4-(4′-(2-((1S)-1-((N-(methoxycarbonyl)-L-alanyl)amino)-2-methylpropyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate;
N2-(methoxycarbonyl)-N-((1R)-1-(4-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-L-valyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-2-methylpropyl)-L-valinamide;
methyl((1S,2R)-2-methoxy-1-(((2S)-2-(4-(4′-(2-((1R)-1-((N-(methoxycarbonyl)-O-methyl-L-threonyl)amino)-2-methylpropyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate;
methyl((1S)-3-methoxy-1-(((2S)-2-(4-(4′-(2-((1R)-1-((N-(methoxycarbonyl)-O-methyl-L-homoseryl)amino)-2-methylpropyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate; and
methyl((1S)-2-((2S)-2-(4-(4′-(2-((1R)-1-((N-(methoxycarbonyl)-L-alanyl)amino)-2-methylpropyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate;
or a pharmaceutically acceptable salt thereof.

### Claim 2

A compound selected from
or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

A composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

### Claim 4 (depends on 3)

The composition of claim 3 further comprising one or two additional compounds having anti-HCV activity.

### Claim 5 (depends on 4)

The composition of claim 4 wherein at least one of the additional compounds is an interferon or a ribavirin.

### Claim 6 (depends on 5)

The composition of claim 5 wherein the interferon is selected from interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A, and lymphoblastoid interferon tau.

### Claim 7 (depends on 4)

The composition of claim 4 wherein at least one of the additional compounds is selected from interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA, anti-sense RNA, Imiqimod, ribavirin, an inosine 5′-monophosphate dehydrogenase inhibitor, amantadine, and rimantadine.

### Claim 8 (depends on 4)

The composition of claim 4 wherein at least one of the additional compounds is effective to inhibit the function of a target selected from HCV metalloprotease, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV NS5A protein, and IMPDH for the treatment of an HCV infection.

### Claim 9 (depends on 2)

A composition comprising a compound of claim 2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

### Claim 10 (depends on 9)

The composition of claim 9 further comprising one or two additional compounds having anti-HCV activity.

### Claim 11 (depends on 10)

The composition of claim 10 wherein at least one of the additional compounds is an interferon or a ribavirin.

### Claim 12 (depends on 11)

The composition of claim 11 wherein the interferon is selected from interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A, and lymphoblastoid interferon tau.

### Claim 13 (depends on 10)

The composition of claim 10 wherein at least one of the additional compounds is selected from interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA, anti-sense RNA, Imiqimod, ribavirin, an inosine 5′-monophosphate dehydrogenase inhibitor, amantadine, and rimantadine.

### Claim 14 (depends on 10)

The composition of claim 10 wherein at least one of the additional compounds is effective to inhibit the function of a target selected from HCV metalloprotease, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV NS5A protein, and IMPDH for the treatment of an HCV infection.

### Claim 15 (depends on 1)

A method of treating an HCV infection in a patient, comprising administering to the patient a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

### Claim 16 (depends on 1, 15)

The method of claim 15 further comprising administering one or two additional compounds having anti-HCV activity prior to, after or simultaneously with the compound of claim 1, or a pharmaceutically acceptable salt thereof.

### Claim 17 (depends on 16)

The method of claim 16 wherein at least one of the additional compounds is an interferon or a ribavirin.

### Claim 18 (depends on 17)

The method of claim 17 wherein the interferon is selected from interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A, and lymphoblastoid interferon tau.

### Claim 19 (depends on 16)

The method of claim 16 wherein at least one of the additional compounds is selected from interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA, anti-sense RNA, Imiqimod, ribavirin, an inosine 5′-monophosphate dehydrogenase inhibitor, amantadine, and rimantadine.

### Claim 20 (depends on 16)

The method of claim 16 wherein at least one of the additional compounds is effective to inhibit the function of a target selected from HCV metalloprotease, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV NS5A protein, and IMPDH for the treatment of an HCV infection.

### Claim 21 (depends on 2)

A method of treating an HCV infection in a patient, comprising administering to the patient a therapeutically effective amount of a compound of claim 2, or a pharmaceutically acceptable salt thereof.

### Claim 22 (depends on 2, 21)

The method of claim 21 further comprising administering one or two additional compounds having anti-HCV activity prior to, after or simultaneously with the compound of claim 2, or a pharmaceutically acceptable salt thereof.

### Claim 23 (depends on 22)

The method of claim 22 wherein at least one of the additional compounds is an interferon or a ribavirin.

### Claim 24 (depends on 23)

The method of claim 23 wherein the interferon is selected from interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A, and lymphoblastoid interferon tau.

### Claim 25 (depends on 22)

The method of claim 22 wherein at least one of the additional compounds is selected from interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA, anti-sense RNA, Imiqimod, ribavirin, an inosine 5′-monophosphate dehydrogenase inhibitor, amantadine, and rimantadine.

### Claim 26 (depends on 22)

The method of claim 22 wherein at least one of the additional compounds is effective to inhibit the function of a target selected from HCV metalloprotease, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV NS5A protein, and IMPDH for the treatment of an HCV infection.