# US 8,772,505 B2 · Antiviral compounds composed of three aligned aryl moieties to treat diseases such as hepatitis C

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- Number: US 8,772,505 B2
- Document ID: US8772505B2
- Status: Granted
- Kind: B2
- Application number: 13/375,088
- Filed: 2010-05-28
- Published: 2013-06-27
- Granted: 2014-07-08
- Earliest claimed: 2009-05-29
- Assignees: Merck Sharp & Dohme Corp.
- Applicants: Kevin X. Chen; Anilkumar Gopinadhan Nair; Qingbei Zeng; Stuart B. Rosenblum; Joseph A. Kozlowski; F. George Njoroge
- Inventors: Kevin X. Chen; Anilkumar Gopinadhan Nair; Qingbei Zeng; Stuart B. Rosenblum; Joseph A. Kozlowski; F. George Njoroge
- Web page: https://patentgrep.com/patent/US8772505B2

## CPC

- C07D 401/14: containing three or more hetero rings
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 31/14: for RNA viruses
- C07D 403/14: containing three or more hetero rings
- C07D 409/14: containing three or more hetero rings
- C07D 417/14: containing three or more hetero rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to novel Tricyclic Compounds, compositions comprising at least one Tricyclic Compound, and methods of using Tricyclic Compounds for treating or preventing a viral infection or a virus-related disorder in a patient. The present invention provides Tricyclic Compounds of Formula (I): Non-limiting examples of the Compounds of Formula (I) include compound 44 The Compounds of Formula (II) can be useful for inhibiting HCV viral replication or replicon activity, and for treating or preventing HCV infection in a patient.

## Claims

### Claim 1

A compound having the formula:
or a pharmaceutically acceptable salt thereof, wherein:
A is a 9- to 10-membered bicyclic heteroaryl containing one N atom and optionally, one to two additional heteroatoms independently selected from the group consisting of N, O, and S, wherein A is substituted on one ring carbon atom with R3, and wherein A is optionally substituted on one to two ring carbon atoms with R3a and is optionally substituted on one ring nitrogen atom with R1;
B is a ring selected from the group consisting of:
wherein B is optionally substituted on one or more ring carbon atoms by one to three R10; and wherein when B is
then A and D are each bonded to a common ring of B;
D is a 9 to 10-membered bicyclic heteroaryl containing one N atom and optionally, one to two additional heteroatoms independently selected from the group consisting of N, O, and S, wherein D is substituted on one ring carbon atom with R4, and wherein D is optionally substituted on one two carbon atoms with R4a and is optionally substituted on one ring nitrogen atom with R2;
R3 and R4 are independently selected from the group consisting of:
wherein R3 and R4 are optionally and independently substituted with:
(a) one to two fluorine or C1-C3 alkyl;
(b) and one to seven 2H;
each occurrence of R3a and R4a is independently selected from the group consisting of H, C1-C3 alkyl, C1-C3 alkoxy, halo, and C1-C3 trifluoroalkoxy;
R1 and R2 are independently H or C1-C3 alkyl;
each occurrence of R5 is independently selected from the group consisting of:
(a) —C(O)—(C1-C6 alkyl) optionally substituted by one to eight R12 groups, wherein R12 is selected from the group consisting of:
(i) C1-C3 alkoxy,
(ii) phenyl, optionally substituted by one to four halo, C1-C3 alkyl, or C1-C3 alkoxy;
(iii) amino,
(iv) C1-C3 monoalkylamino,
(v) C1-C3 dialkylamino,
(vi) —NHC(O)—O—(C1-C6 alkyl),
(vii) —N(C1-C3 alkyl)—C(O)—O—(C1-C6 alkyl),
(viii) C1-C3 fluoroalkyl,
(ix) C2-C6 alkynyl,
(x) C3-C7 cycloalkyl,
(xi) pyrrolidinyl,
(xii) piperidinyl,
(xiii) pyranyl; and
(xiv) 2H;
(b)
wherein x is 1 or 2, and each occurrence of R6 is independently selected from the group consisting of H, C1-C3 alkyl, C1-C3 alkoxy, and fluoro; and
(c) H;
each occurrence of R10 is independently 2H, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6alkynyl, C1-C6 alkoxy, cyano, and phenyl; and
R10a is H or C1-C6 alkyl.

### Claim 2 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein B is selected from the group consisting of:

### Claim 3 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A and D are each independently selected from the group consisting of:

### Claim 4 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R3 and R4 are independently selected from the group consisting of:
wherein R3 and R4 are optionally and independently substituted with one to two fluorine.

### Claim 5 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein each occurrence of R5 is independently:
wherein Ra is H, C1-C4 alkyl, C1-C3 fluoroalkyl, or phenyl, and
Rb is C1-C3 alkyl.

### Claim 6 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein each occurrence of R5 is selected from the group consisting of:

### Claim 7 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
A is benzimidazolyl, wherein said benzimidazolyl is optionally substituted on a ring carbon atom with one to two fluoro;
B is a ring selected from the group consisting of:
wherein B is optionally substituted on one or more ring carbon atoms by one to three R10 and wherein when B is
then A and D are each bonded to a common ring of B;
wherein R10 is selected from the group consisting of H, C1-C6 alkyl and phenyl;
D is benzimidazolyl, wherein said benzimidazolyl is optionally substituted on a ring carbon atom with one to two fluoro;
R3 and R4 are independently selected from the group consisting of:
each occurrence of R5 is independently selected from the group consisting of H and —C(O)—(C1-C6 alkyl) optionally substituted by one to seven R12 groups,
wherein R12 is selected from the group consisting of:
(i) —NHC(O)—O—(C1-C3 alkyl)
(ii) C2-C4 alkynyl; and
(iii) 2H; and
R10a is H or C1-C3 alkyl.

### Claim 8 (depends on 7)

The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein A and D are independently selected from the group consisting of:

### Claim 9 (depends on 8)

The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein R4 are both

### Claim 10

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

### Claim 11 (depends on 1)

A pharmaceutical composition comprising an effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

### Claim 12 (depends on 11)

The pharmaceutical composition of claim 11, further comprising at least one additional therapeutic agent, wherein the additional therapeutic agent(s) is selected from: an interferon, an immunomodulator, a viral replication inhibitor, an antisense agent, a therapeutic vaccine, a viral polymerase inhibitor, a nucleoside inhibitor, a viral protease inhibitor, a viral helicase inhibitor, a viral polymerase inhibitor, a virion production inhibitor, a viral entry inhibitor and a viral assembly inhibitor.

### Claim 13 (depends on 1)

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

### Claim 14 (depends on 13)

The method of claim 13, further comprising administering to the patient at least one additional therapeutic agent, wherein the additional therapeutic agent(s) is selected from: an interferon, an immunomodulator, a viral replication inhibitor, an antisense agent, a therapeutic vaccine, a viral polymerase inhibitor, a nucleoside inhibitor, a viral protease inhibitor, a viral helicase inhibitor, a viral polymerase inhibitor, a virion production inhibitor, a viral entry inhibitor, and a viral assembly inhibitor.