# US 8,541,402 B2 · Viral polymerase inhibitors

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- Number: US 8,541,402 B2
- Document ID: US8541402B2
- Status: Granted
- Kind: B2
- Application number: 13/463,093
- Filed: 2012-05-03
- Published: 2012-08-23
- Granted: 2013-09-24
- Earliest claimed: 2007-12-19
- Assignees: Boehringer Ingelheim International GmbH
- Applicants: Pierre L. Beaulieu; Pasquale Forgione; Alexandre Gagnon; Cedrickx Godbout; Marc-Andre Joly; Montse Llinas-Brunet; Julie Naud; Martin Poirier; Jean Rancourt
- Inventors: Pierre L. Beaulieu; Pasquale Forgione; Alexandre Gagnon; Cedrickx Godbout; Marc-Andre Joly; Montse Llinas-Brunet; Julie Naud; Martin Poirier; Jean Rancourt
- Web page: https://patentgrep.com/patent/US8541402B2

## CPC

- A61K 31/444: containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 31/12: Antivirals
- A61P 31/14: for RNA viruses
- A61P 31/18: for HIV
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 211/38: Halogen atoms or nitro radicals
- C07D 213/643: 2-Phenoxypyridines; Derivatives thereof
- C07D 213/69: Two or more oxygen atoms
- C07D 213/81: Amides; Imides
- C07D 215/227: only one oxygen atom which is attached in position 2
- C07D 217/24: Oxygen atoms
- C07D 239/34: One oxygen atom
- C07D 239/38: One sulfur atom
- C07D 239/47: One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
- C07D 239/52: Two oxygen atoms
- C07D 249/04: 1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
- C07D 277/24: Radicals substituted by oxygen atoms
- C07D 307/20: Oxygen atoms
- C07D 333/32: Oxygen atoms
- C07D 401/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- C07D 413/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 417/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 417/14: containing three or more hetero rings
- C07D 471/04: Ortho-condensed systems
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Compounds of formula I: wherein X, R2, R3, R3a, R3b, R5 and R6 are defined herein, are useful as inhibitors of the hepatitis C virus NS5B polymerase.

## Claims

### Claim 1

A compound of formula (I):
wherein:
X is selected from O and S;
R2 is phenyl, optionally substituted with 1 to 5 R20 substituents, wherein R20 in each case is independently selected from:
a) halo, cyano or nitro;
b) R7, —C(═O)—R7, —C(═O)—O—R7, —O—R7, —S—R7, —SO—R7, —SO2—R7, —(C1-6)alkylene-R7, —(C1-6)alkylene-C(═O)—R7, —(C1-6)alkylene-C(═O)—O—R7, —(C1-6)alkylene-O—R7, —(C1-6)alkylene-S-R7, —(C1-6)alkylene-SO—R7 or —(C1-6)alkylene-SO2—R7;
wherein R7 is in each instance independently selected from H, (C1-6)alkyl, (C2-6)alkenyl, (C2-6)alkynyl, (C1-6)haloalkyl, (C3-7)cycloalkyl, (C3-7)cycloalkyl-(C1-6)alkyl, aryl and Het;
wherein the (C1-6)alkyl, (C2-6)alkenyl, (C2-6)alkynyl, (C1-6)haloalkyl, (C3-7)cycloalkyl, (C3-7)cycloalkyl-(C1-6)alkyl, and (C1-6)alkylene are optionally substituted with 1 or 2 substituents each independently selected from —OH, —(C1-6)alkyl (optionally substituted with —O—(C1-6)alkyl), halo, —(C1-6)haloalkyl, (C3-7)cycloalkyl, —O—(C1-6)alkyl, cyano, COOH, —NH2, —NH(C1-4)alkyl, —NH(C3-7)cycloalkyl, —N((C1-4)alkyl)(C3-7)cycloalkyl, —N((C1-4)alkyl)2, aryl, —(C1-6)alkyl-aryl, Het, —(C1-6)alkyl-Het; and
wherein each of the aryl and Het is optionally substituted with 1 to 3 substituents each independently selected from:
i) halo, cyano, oxo, thioxo, imino, —OH, —O—(C1-6)alkyl, —O—(C1-6)haloalkyl, (C3-7)cycloalkyl, (C1-6)haloalkyl, —C(═O)—(C1-6)alkyl, —SO2(C1-6)alkyl, —C(═O)—NH2, —C(═O)—NH(C1-4)alkyl, —C(═O)—N((C1-4)alkyl)2, —C(═O)—NH(C3-7)cycloalkyl, —C(═O)—N((C1-4)alkyl)(C3-7)cycloalkyl, —NH2, —NH(C1-4)alkyl, —N((C1-4)alkyl)2, —NH(C3-7)cycloalkyl, —N((C1-4)alkyl)(C3-7)cycloalkyl or —NH—C(═O)(C1-4)alkyl;
ii) (C1-6)alkyl optionally substituted with —OH, —O—(C1-6)haloalkyl, or —O—(C1-6)alkyl; and
iii) aryl or Het, wherein each of the aryl and Het is optionally substituted with halo or (C1-6)alkyl; and
c) —N(R8)R9, —C(═O)—N(R8)R9, —O—C(═O)—N(R8)R9, —SO2—N(R8)R9, —(C1-6)alkylene-N(R8)R9, —(C1-6)alkylene-C(═O)—N(R8)R9, —(C1-6)alkylene-O—C(═O)—N(R8)R9, or —(C1-6)alkylene-SO2—N(R8)R9; wherein the (C1-6)alkylene is optionally substituted with 1 or 2 substituents each independently selected from —OH, —(C1-6)alkyl, halo, —(C1-6)haloalkyl, (C3-7)cycloalkyl, —O—(C1-6)alkyl, cyano, COOH, —NH2, —NH(C1-4)alkyl, —NH(C3-7)cycloalkyl, —N((C1-4)alkyl)(C3-7)cycloalkyl and —N((C1-4)alkyl)2;
R8 is in each instance independently selected from H, (C1-6)alkyl and (C3-7)cycloalkyl; and
R9 is in each instance independently selected from R7, —O—(C1-6)alkyl, —(C1-6)alkylene-R7, —SO2—R7, —C(═O)—R7, —C(═O)OR7 and —C(═O)N(R8)R7; wherein R7 and R8 are as defined above;
or R8 and R9, together with the N to which they are attached, are linked to form a 4- to 7-membered heterocycle optionally further containing 1 to 3 heteroatoms each independently selected from N, O and S, wherein each S heteroatom may, independently and where possible, exist in an oxidized state such that it is further bonded to one or two oxygen atoms to form the groups SO or SO2;
wherein the heterocycle is optionally substituted with 1 to 3 substituents each independently selected from (C1-6)alkyl, (C1-6)haloalkyl, halo, oxo, —OH, SH, —O(C1-6)alkyl, —S(C1-6)alkyl, (C3-7)cycloalkyl, —NH2, —NH(C1-6)alkyl, —N((C1-6)alkyl)2, —NH(C3-7)cycloalkyl, —N((C1-4)alkyl)(C3-7)cycloalkyl, —C(═O)(C1-6)alkyl and —NHC(═O)—(C1-6)alkyl;
R3, R3a and R3b are selected from H, halo, CN, (C1-4)alkyl, —OH, —O—(C1-4)alkyl, —S—(C1-4)alkyl, —NH2, —NH(C1-4)alkyl, —NH(C3-7)cycloalkyl, —N((C1-4)alkyl)(C3-7)cycloalkyl) and —N((C1-4)alkyl)2;
R5 is R51 mono-, di-, or tri-substituted with O—R52,
wherein R51 is (C1-6)alkyl, (C3-7)cycloalkyl, (C1-6)alkyl-(C3-7)cycloalkyl, aryl, (C1-6)alkyl-aryl, Het or (C1-6)alkyl-Het, each R51 being optionally substituted with (C1-6)alkyl, (C3-7)cycloalkyl or (C1-6)alkyl-(C3-7)cycloalkyl; and
R52 is (C3-7)cycloalkyl, (C1-6)alkyl-(C3-7)cycloalkyl, aryl, (C1-6)alkyl-aryl, Het or (C1-6)alkyl-Het, said aryl and Het being optionally substituted with (C1-6)alkyl or O—(C1-6)alkyl;
R6 is (C3-7)cycloalkyl, (C1-6)alkyl-(C3-7)cycloalkyl, aryl, (C1-6)alkyl-aryl, Het or (C1-6)alkyl-Het; being optionally substituted with 1 to 5 substituents each independently selected from halo, (C1-6)alkyl, (C1-6)haloalkyl, (C3-7)cycloalkyl, —OH, —SH, —O—(C1-4)alkyl, —S—(C1-4)alkyl and —N(R8)R9; wherein R8 and R9 are as defined above; and
Het is a 4- to 7-membered saturated, unsaturated or aromatic heterocycle having 1 to 4 heteroatoms each independently selected from O, N and S, or a 7- to 14-membered saturated, unsaturated or aromatic heteropolycycle having wherever possible 1 to 5 heteroatoms, each independently selected from O, N and S; wherein each N heteroatom may, independently and where possible, exist in an oxidized state such that it is further bonded to an oxygen atom to form an N-oxide group and wherein each S heteroatom may, independently and where possible, exist in an oxidized state such that it is further bonded to one or two oxygen atoms to form the groups SO or SO2;
or a salt thereof.

### Claim 2 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein X is O, and R2, R3, R3a, R3b, R5, and R6 are as defined in claim 1.

### Claim 3 (depends on 1)

The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R2 is of the formula:
R21 is selected from H, halo, (C1-6)alkyl, (C1-6)haloalkyl, (C3-7)cycloalkyl and —O—(C1-6)haloalkyl; and R20 is as defined in claim 1.

### Claim 4 (depends on 3)

The compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein R21 is H or CF3, and R20 is selected from:
R7 or —(C1-6)alkylene-R7
wherein R7 is in each instance independently selected from H, (C1-6)alkyl, (C3-7)cycloalkyl, (C3-7)cycloalkyl-(C1-6)alkyl, phenyl and Het;
wherein each of the phenyl and Het are optionally substituted with 1 to 3 substituents each independently selected from:
i) halo, (C3-7)cycloalkyl, (C1-6)haloalkyl, —C(═O)—NH2, —C(═O)—NH(C1-4)alkyl, —C(═O)—N((C1-4)alkyl)2, —C(═O)—NH(C3-7)cycloalkyl, —C(═O)—N((C1-4)alkyl)(C3-7)cycloalkyl, —NH2, —NH(C1-4)alkyl, —N((C1-4)alkyl)2, —NH(C3-7)cycloalkyl, —N((C1-4)alkyl)(C3-7)cycloalkyl or —NH—C(═O)(C1-4)alkyl; and
ii) (C1-6)alkyl optionally substituted with —OH, —O—(C1-6)haloalkyl, or —O—(C1-6)alkyl;
wherein the Het is selected from:
c) —N(R8)R9 or —(C1-6)alkylene-N(R8)R9;
R8 is in each instance independently selected from H, (C1-6)alkyl and (C3-7)cycloalkyl; and
R9 is defined as R7, wherein R7 is as defined above.

### Claim 5 (depends on 4)

The compound according to claim 4, or a pharmaceutically acceptable salt thereof, wherein R21 is H or CF3, and R20 is selected from:
—(C1-3)alkylene-R7;
wherein R7 is Het; is selected from

### Claim 6 (depends on 1)

The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R3 is selected from H, F, Cl and CH3.

### Claim 7 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R3a is selected from H, F and CH3.

### Claim 8 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R3b is selected from H, F, Cl, CH3 and CN.

### Claim 9 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R5 is R51 being mono- or di-substituted with O—R52, wherein R51 is (C1-6)alkyl, (C3-7)cycloalkyl or (C1-6)alkyl-(C3-7)cycloalkyl, each R51 being optionally substituted with (C1-6)alkyl, (C3-7)cycloalkyl or (C1-6)alkyl-(C3-7)cycloalkyl; and
R52 is (C1-6)alkyl, (C3-7)cycloalkyl, (C1-6)alkyl-(C3-7)cycloalkyl, aryl or (C1-6)alkyl-aryl, said aryl being optionally substituted with (C1-6)alkyl or O—(C1-6)alkyl.

### Claim 10 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R6 is phenyl, cyclohexyl or pyridine optionally substituted with 1 to 3 substituents each independently selected from halo, (C1-4)alkyl and (C1-4)haloalkyl.

### Claim 11 (depends on 1)

The compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt or ester thereof, as a medicament.

### Claim 12 (depends on 1)

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

### Claim 13 (depends on 12)

The pharmaceutical composition according to claim 12 additionally comprising at least one other antiviral agent.

### Claim 14 (depends on 1)

A method of alleviating symptoms of HCV disease and or reducing viral load in a mammal said method comprised of the step of administering to a patient in need thereof a compound according to claim 1.

### Claim 15 (depends on 1)

A compound of claim 1 having of formula I
Wherein R20, R3, R5 are
Cpd
R20
R3
R5
3001
H
3002
H
3003
H
3004
H
3005
H
3006
H
3007
3008
F
3009
F
3010
F
3011
F
3012
F
3013
F
3014
F
3015
F
or a pharmaceutically acceptable salt thereof.