# US 2010/0168098 A1 · Viral Polymerase Inhibitors

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- Number: US 2010/0168098 A1
- Document ID: US20100168098A1
- Status: Published application
- Kind: A1
- Application number: 12/063,468
- Filed: 2006-08-03
- Published: 2010-07-01
- Earliest claimed: 2005-08-12
- Assignees: Boehringer Ingelheim International GmbH
- Inventors: Youla S. Tsantrizos
- Web page: https://patentgrep.com/patent/US20100168098A1

## CPC

- C07D 307/85: attached in position 2
- A61P 31/12: Antivirals
- A61P 31/14: for RNA viruses
- C07D 209/30: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D 209/42: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 333/70: attached in position 2
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- C07D 487/04: Ortho-condensed systems
- C07D 491/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to compounds represented by formula (I) wherein A, B, D, E, R2, R3, R4, R5, R6, R9, a, b, d and e are as defined herein, their salt or ester and pharmaceutical compositions thereof useful in the treatment of hepatitis C viral (HCV) infection. Said compounds were found to have inhibitory activity against HCV polymerase, especially as inhibitors of HCV NS5B polymerase

## Claims

### Claim 1

A compound represented by formula (I):
wherein:
either A is N or CR1 and B is N, wherein bond a is a double bond and bond b is a single bond; or
A is NR1 and B is C, wherein bond a is a single bond and bond b is a double bond;
R1 is H, (C1-6)alkyl or a group of formula —CH2C(═O)N(R11)R12;
wherein R11 is selected from H, —O—(C1-6)alkyl, —SO2—(C1-6)alkyl, (C1-6)alkyl, (C3-7)cycloalkyl, (C3-7)cycloalkyl-(C1-4)alkyl-, (C2-6)alkenyl, (C2-6)alkynyl, aryl, Het, aryl-(C1-4)alkyl- and Het-(C1-4)alkyl-; wherein each of the (C1-6)alkyl, (C3-7)cycloalkyl, (C3-7)cycloalkyl-(C1-4)alkyl-, (C2-6)alkenyl, (C2-6)alkynyl, aryl, Het, aryl-(C1-4)alkyl- and Het-(C1-4)alkyl- is optionally substituted with R15; and
R12 is selected from H, (C1-6)alkyl, (C3-7)cycloalkyl and (C3-7)cycloalkyl-(C1-4)alkyl-; wherein each of the (C1-6)alkyl, (C3-7)cycloalkyl and (C3-7)cycloalkyl-(C1-4)alkyl- is optionally substituted with one or more substituents each independently selected from —OH, halo, —COOH, —COO(C1-6)alkyl, (C1-6)alkyl, —O—(C1-6)alkyl, —NH2, —NH(C1-6)alkyl and —N((C1-6)alkyl)2; or
the groups R11 and R12 may be covalently bonded together along with the N to which they are attached to form a 4-, 5-, 6- or 7-membered saturated, unsaturated or aromatic N-containing heterocycle or a 8-, 9-, 10- or 11-membered saturated, unsaturated or aromatic N-containing bicyclic heteropolycycle, each of the heterocycle and heteropolycycle optionally containing from 1 to 3 additional heteroatoms selected from O, N, and S and each of the heterocycle and heteropolycycle being optionally substituted with R15;
wherein R15 is one to four substituents each independently selected from halo, oxo, (C1-6)alkyl, (C1-6)haloalkyl, —CO(C1-6)alkyl, —COOH, —COO(C1-6)alkyl, —CONH2, —CONH(C1-6)alkyl, —CON((C1-6)alkyl)2, —OH, —SH, —NH2, —NH(C1-6)alkyl, —N((C1-6)alkyl)2, —NHCO(C1-6)alkyl, —N((C1-6)alkyl)-CO(C1-6)alkyl, —NHCO—O(C1-6)alkyl, —N((C1-6)alkyl)-CO—O(C1-6)alkyl, —O—(C1-6)alkyl, —S—(C1-6)alkyl, —SO—(C1-6)alkyl, —SO2—(C1-6)alkyl, nitro, cyano, azido, aryl, aryl-(C1-6)alkyl-, Het and Het-(C1-6)alkyl-;
wherein the (C1-6)alkyl is optionally substituted with —OH, —O—(C1-6)alkyl, —COOH, —COO(C1-6)alkyl, —CONH2, —CONH(C1-6)alkyl, —CON((C1-6)alkyl)2, —NH2, —NH(C1-6)alkyl or —N((C1-6)alkyl)2; and
wherein the Het is optionally substituted with (C1-6)alkyl, (C3-7)cycloalkyl or (C3-7)cycloalkyl-(C1-4)alkyl-;
R2 is selected from H, (C1-6)alkyl, (C2-6)alkenyl, (C3-7)cycloalkyl, aryl and Het;
wherein the aryl and Het are each optionally substituted with R21;
wherein R21 is one, two or three substituents each independently selected from —OH, —SH, —CN, —NH2, —NH(C1-6)alkyl, —N((C1-6)alkyl)2, halo, (C1-6)alkyl, (C1-6)haloalkyl, (C3-6)cycloalkyl, —O—(C1-6)alkyl, —O—(C1-6)haloalkyl, —S—(C1-6)alkyl, —S—(C1-6)haloalkyl, —SO—(C1-6)alkyl-, SO—(C1-6)haloalkyl, —SO2—(C1-6)alkyl, —SO2—(C1-6)haloalkyl, aryl, Het, —CONH2, —CONH(C1-6)alkyl and —CON((C1-6)alkyl)2; wherein the —O—(C1-6)alkyl is optionally substituted with Het or aryl;
wherein each of the Het and aryl is optionally substituted with one to four substituents each independently selected from halo, aryl, Het, —N(R210)R211, —N(R210)—C(═O)—(C1-6)alkyl and —C(═O)—N(R210)R211;
wherein the aryl and Het are each optionally substituted with one to four substituents each independently selected from (C1-6)alkyl, halo, —N(R210)2, —N(R210)—C(═O)—(C1-6)alkyl and —C(═O)—N(R210)2;
R210 is selected independently in each instance from H and (C1-6)alkyl; and
R211 is selected independently in each instance from H, (C1-6)alkyl, (C3-7)cycloalkyl and aryl; or
R210 and R211 are linked, together with the N to which they are attached, to form a 5- or 6-membered saturated or unsaturated heterocycle, wherein said heterocycle is optionally substituted with one or two substituents each independently selected from (C1-6)alkyl and oxo;
R3 is (C5-6)cycloalkyl, optionally substituted with from one to four halo substituents;
R4 and R5 are each independently selected from (C1-6)alkyl; or R4 and R5 are covalently bonded together along with the carbon atom to which they are attached to form (C3-7)cycloalkyl, (C5-7)cycloalkenyl or a 4-, 5- or 6-membered heterocycle having from 1 to 3 heteroatoms each independently selected from O, N, and S;
wherein the (C3-7)cycloalkyl, (C5-7)cycloalkenyl and 4-, 5- or 6-membered heterocycle are each optionally substituted with (C1-4)alkyl;
R6 is H or (C1-6)alkyl;
either D is CR7 and E is selected from O, S and NR8, wherein bond d is a double bond and bond e is a single bond; or
D is selected from O, S and NR7 and E is CR8, wherein bond d is a single bond and bond e is a double bond; wherein
R7 and R8 are each independently selected from H, (C1-6)alkyl and halo; and
R9 is —COOH, —CONH2, —CONH(C1-6)alkyl, —CON((C1-6)alkyl)2, tetrazolyl, —CONHSO2R90, or —CONHSO2N(R91)R90, wherein R90 is selected from (C1-6)alkyl, (C3-7)cycloalkyl, (C3-7)cycloalkyl-(C1-4)alkyl-, aryl, aryl-(C1-4)alkyl, Het, and Het-(C1-4)alkyl; and R91 is selected from H and (C1-6)alkyl;
wherein Het is defined as a 4- to 7-membered heterocycle having 1 to 4 heteroatoms each independently selected from O, N and S, which may be saturated, unsaturated or aromatic, and which is optionally fused to at least one other cycle to form a 7 to 14-membered heteropolycycle having wherever possible 1 to 5 heteroatoms, each independently selected from O, N and S, the heteropolycycle being saturated, unsaturated or aromatic;
or a salt thereof or ester thereof.

### Claim 2 (depends on 1)

A compound according to claim 1 represented by a formula selected from the following:
wherein D, E, R1, R2, R3, R4, R5, R6, R7, R8 and R9 are defined as in claim 1.

### Claim 3 (depends on 1)

A compound according to claim 1 wherein R1 is selected from H and (C1-6)alkyl.

### Claim 4 (depends on 1)

A compound according to claim 1 wherein R1 is a group of formula —CH2C(═O)N(R11)R12;
wherein R11 is selected from H, (C1-6)alkyl, (C3-7)cycloalkyl, (C3-7)cycloalkyl-(C1-4)alkyl-, aryl, Het, aryl-(C1-4)alkyl- and Het-(C1-4)alkyl-; wherein Het is a 5- or 6-membered saturated, unsaturated or aromatic heterocycle containing 1 or 2 heteroatoms each independently selected from N, O and S, or Het is a 9- or 10-membered saturated, unsaturated or aromatic bicyclic heteropolycycle containing 1 or 2 heteroatoms each independently selected from N, O and S;
each of the (C1-6)alkyl, (C3-7)cycloalkyl, (C3-7)cycloalkyl-(C1-4)alkyl-, aryl, Het, aryl-(C1-4)alkyl- and Het-(C1-4)alkyl- being optionally substituted with R15; and
R12 is selected from H, (C1-6)alkyl, (C3-7)cycloalkyl and (C3-7)cycloalkyl-(C1-4)alkyl-;
wherein each of the (C1-6)alkyl, (C3-7)cycloalkyl and (C3-7)cycloalkyl-(C1-4)alkyl- is optionally substituted with one or more substituents each independently selected from —OH, halo, —COOH, —COO(C1-6)alkyl, (C1-6)alkyl, —O—(C1-6)alkyl, —NH2, —NH(C1-6)alkyl and —N((C1-6)alkyl)2; or
the groups R11 and R12 may be covalently bonded together along with the N to which they are attached to form a 5-, 6- or 7-membered saturated, unsaturated or aromatic N-containing heterocycle or a 8-, 9-, 10- or 11-membered saturated, unsaturated or aromatic N-containing bicyclic heteropolycycle, each of the heterocycle and heteropolycycle optionally containing from 1 to 3 additional heteroatoms each independently selected from O, N, and S and each of the heterocycle and heteropolycycle being optionally substituted with R15;
wherein R15 is defined as in claim 1.

### Claim 5 (depends on 4)

A compound according to claim 4 wherein R15 is one to three substituents each independently selected from fluorine, chlorine, bromine, methyl, ethyl, propyl, —COOH, —COO(C1-3)alkyl, —CONH2, —CONH(C1-3)alkyl, —CON((C1-3)alkyl)2, —OH, —NH2, —NH(C1-3)alkyl, —N((C1-3)alkyl)2, —O—(C1-3)alkyl, nitro, cyano, azido, phenyl, phenylmethyl,
wherein each of the methyl, ethyl and propyl are optionally substituted with —OH, —O—(C1-3)alkyl, —COOH, —COO(C1-3)alkyl, —CONH2, —CONH(C1-3)alkyl, —CON((C1-3)alkyl)2, —NH2, —NH(C1-3)alkyl or —N((C1-3)alkyl)2; and wherein each of the
are optionally substituted with (C1-3)alkyl.

### Claim 6 (depends on 1)

A compound according to claim 1 wherein R2 is H, (C1-6)alkyl, (C2-6)alkenyl or (C3-7)cycloalkyl.

### Claim 7 (depends on 1)

A compound according to claim 1 wherein R2 is aryl or Het, wherein Het is a 5- or 6-membered aromatic heterocycle having 1 to 4 heteroatoms each independently selected from O, N and S; wherein the aryl and Het are unsubstituted or substituted with R21, wherein R21 is defined as in claim 1.

### Claim 8 (depends on 7)

A compound according to claim 7 wherein R21 is one, two or three substituents each independently selected from (C1-3)alkyl, (C1-3)haloalkyl, (C3-6)cycloalkyl, —CN, —NH2, —NH(C1-3)alkyl, —N((C1-3)alkyl)2, halo, —O—(C1-3)alkyl, —O—(C1-3)haloalkyl, —S—(C1-3)alkyl, —S—(C1-3)haloalkyl, —SO—(C1-3)alkyl-, SO—(C1-3)haloalkyl, —SO2—(C1-3)alkyl and —SO2—(C1-3)haloalkyl.

### Claim 9 (depends on 7)

A compound according to claim 7 wherein R2 is phenyl substituted with R21 and R21 is —O—(C1-6)alkyl substituted with phenyl wherein the phenyl is optionally substituted with one to four substituents each independently selected from halo, phenyl, Het, —N(R210)R211, —N(R210)—C(═O)—(C1-6)alkyl and —C(═O)—N(R210)R211; wherein the Het is a 5- or 6-membered monocyclic saturated heterocycle; and
wherein the phenyl and Het are each optionally substituted with one to four substituents each independently selected from (C1-6)alkyl, halo, —N(R210)2, —N(R210)—C(═O)—(C1-6)alkyl and —C(═O)—N(R210)2;
R210 is selected independently in each instance from H and (C1-6)alkyl; and
R211 is selected independently in each instance from H, (C1-6)alkyl, (C3-7)cycloalkyl and aryl; or
R210 and R211 are linked, together with the N to which they are attached, to form a 5- or 6-membered saturated or unsaturated heterocycle, wherein said heterocycle is optionally substituted with one or two substituents each independently selected from (C1-6)alkyl and oxo;
and R21 is additionally optionally one or two substituents each independently selected from (C1-3)alkyl, (C1-3)haloalkyl, (C3-6)cycloalkyl, —CN, —NH2, —NH(C1-3)alkyl, —N((C1-3)alkyl)2, halo, —O—(C1-3)alkyl, —S—(C1-3)alkyl, —S—(C1-3)haloalkyl, —SO—(C1-3)alkyl-, SO—(C1-3)haloalkyl, —SO2—(C1-3)alkyl and —SO2—(C1-3)haloalkyl.

### Claim 10 (depends on 1)

A compound according to claim 1 wherein R3 is cyclopentyl or cyclohexyl, each being optionally substituted with one or two fluoro substituents.

### Claim 11 (depends on 1)

A compound according to claim 1 wherein R4 and R5 are each independently selected from (C1-3)alkyl; or R4 and R5 are covalently bonded together along with the carbon atom to which they are attached to form (C3-6)cycloalkyl, (C5-6)cycloalkenyl or a 5- or 6-membered saturated or unsaturated heterocycle having 1 or 2 heteroatoms each independently selected from O and N; wherein the (C3-6)cycloalkyl, (C5-6)cycloalkenyl and 5- or 6-membered heterocycle are each optionally substituted with (C1-4)alkyl.

### Claim 12 (depends on 1)

A compound according to claim 1 wherein R6 is H, methyl or ethyl.

### Claim 13 (depends on 1)

A compound according to claim 1 wherein R7 is H or (C1-6)alkyl.

### Claim 14 (depends on 1)

A compound according to claim 1 wherein R8 is H or (C1-6)alkyl.

### Claim 15 (depends on 1)

A compound according to claim 1 wherein D is CR7 and E is NR8 or D is NR7 and E is CR8, and at least one of R7 and R8 is H.

### Claim 16 (depends on 1)

A compound according to claim 1 wherein R9 is —COOH.

### Claim 17 (depends on 1)

A compound according to claim 1, or a pharmaceutically acceptable salt or ester thereof; as a medicament.

### Claim 18 (depends on 1)

A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt or ester thereof; and one or more pharmaceutically acceptable carriers.

### Claim 19 (depends on 18)

The pharmaceutical composition according to claim 18 additionally comprising at least one other antiviral agent.

### Claim 20

(canceled)

### Claim 21 (depends on 1)

A method of treating a hepatitis C viral infection in a mammal having or at risk of having the infection, the method comprising administering to the mammal a therapeutically effective amount of a compound according to claim 1, a pharmaceutically acceptable salt or ester thereof, or a composition thereof.

### Claim 22 (depends on 1)

A method of treating a hepatitis C viral infection in a mammal having or at risk of having the infection, the method comprising administering to the mammal a therapeutically effective amount of a combination of a compound according to claim 1 or a pharmaceutically acceptable salt or ester thereof, and at least one other antiviral agent; or a composition thereof.

### Claim 23

(canceled)

### Claim 24

(canceled)

### Claim 25 (depends on 1)

An article of manufacture comprising a composition effective to treat a hepatitis C viral infection; and packaging material comprising a label which indicates that the composition can be used to treat infection by the hepatitis C virus; wherein the composition comprises a compound according to claim 1 or a pharmaceutically acceptable salt or ester thereof.

### Claim 26 (depends on 1)

A method of inhibiting the replication of hepatitis C virus comprising exposing the virus to an effective amount of the compound according to claim 1, or a salt or ester thereof, under conditions where replication of hepatitis C virus is inhibited.

### Claim 27

(canceled)