# US 8,785,478 B2 · Viral polymerase inhibitors

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

- Number: US 8,785,478 B2
- Document ID: US8785478B2
- Status: Granted
- Kind: B2
- Application number: 13/861,325
- Filed: 2013-04-11
- Published: 2013-10-17
- Granted: 2014-07-22
- Earliest claimed: 2012-04-11
- Assignees: Biota Scientific Management Pty Ltd.
- Applicants: Biota Scientific Management Pty Ltd
- Inventors: Silas Bond; Rosliana Halim; Tyrone Pieter Jeynes; Alistair George Draffan; Michael Harding
- Web page: https://patentgrep.com/patent/US8785478B2

## CPC

- C07D 405/12: linked by a chain containing hetero atoms as chain links
- A61K 31/416: condensed with carbocyclic ring systems, e.g. indazole
- A61K 31/427: not condensed and containing further heterocyclic rings
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/706: containing six-membered rings with nitrogen as a ring hetero atom
- A61K 38/05: Dipeptides
- A61K 38/06: Tripeptides
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 31/14: for RNA viruses
- C07D 231/56: Benzopyrazoles; Hydrogenated benzopyrazoles
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 401/14: containing three or more hetero rings
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 405/14: containing three or more hetero rings
- C07D 417/04: directly linked by a ring-member-to-ring-member bond
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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

## Abstract

The present invention relates to viral polymerase inhibitors of formula (I) or salts, N-oxides, solvates, hydrates, racemates, enantiomers or isomers thereof, processes for their preparation and their use in the treatment of Flaviviridae viral infections such as Hepatitis C virus (HCV) infections.

## Claims

### Claim 1

A compound of formula (I), salts, N-oxides, solvates, hydrates, racemates, enantiomers or diastereomers thereof:
wherein
Z1 and Z2 are each independently selected from C—H, C-halo, C—C1-4alkyl, C—C1-4alkylhalo, C—C1-4alkoxy, C—C1-4alkoxyhalo and N;
R1 is selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, halo,
C1-4alkylhalo, C1-4 alkoxyhalo, C3-7cycloalkyl, C3-7cycloalkenyl, 5-6-membered heterocyclyl and 5-6 membered heteroaryl and wherein alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl and heteroaryl in each occurrence may be optionally substituted;
R2 is H or an optional substituent;
R3 is an optionally substituted 6-membered heteroaryl group containing N in the 2-(ortho) ring position with reference to the point of attachment or R3 is an optionally substituted 5-membered heteroaryl group containing N in the ring position adjacent to the point of attachment;
R4 is H, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, or C3-7cycloalkyl;
R5 in each occurrence is independently H or optionally substituted C1-6alkyl;
m represents an integer selected from 0, 1, 2, 3, 4, 5 and 6; and
each (CH2) moiety when present may be independently optionally substituted with one or two substituents;
and further when m is an integer selected from 1, 2, 3, 4, 5 and 6 then one or more (CH2) may be replaced with O, C═O, NH, optionally substituted NC1-6alkyl, S, S═O or SO2.

### Claim 2 (depends on 1)

A compound according to claim 1 wherein R3 is an optionally substituted 2-pyridyl moiety.

### Claim 3 (depends on 1)

A compound according to claim 1 wherein R3 is a para-substituted 2-pyridyl moiety.

### Claim 4 (depends on 1)

A compound according to claim 1 wherein R2 is H.

### Claim 5 (depends on 1)

A compound according to claim 1 wherein R2 is an optional substituent selected from optionally substituted C1-3 alkyl, halo, haloC1-3 alkyl, OH, C1-3 alkoxyl, haloC1-3alkoxyl, CO2H, CO2C1-3alkyl, NH2, NHC1-3alkyl, N(C1-3 alkyl)2, NHC(═O)C1-3alkyl, an optionally substituted C3-7cycloalkyl, an optionally substituted C6-10aryl, an optionally substituted 4-10-membered heterocyclyl including 4-, 5- and 6-monocyclic heterocyclyls, 5-6-membered monocyclic heteroaryls, 8-10-membered fused bicyclic heterocyclyls and 8-10-membered fused bicyclic heteroaryls.

### Claim 6 (depends on 1)

A compound according to claim 1 selected from the group consisting of:
2) 5-cyclopropyl-6-[(2-hydroxyethyl)(methylsulfonyl)amino]-N-methyl-2-(5-methylpyridin-2-yl)-2H-indazole-3-carboxamide;
3) 5-cyclopropyl-6-[(2,2-difluoroethyl)(methylsulfonyl)amino]-N-methyl-2-(5-methylpyridin-2-yl)-2H-indazole-3-carboxamide;
4) 5-cyclopropyl-N-methyl-2-(5-methylpyridin-2-yl)-6-{(methylsulfonyl)[2-(oxetan-3-yl)ethyl]amino}-2H-indazole-3-carboxamide;
5) 5-cyclopropyl-6-[ethyl(methylsulfonyl)amino]-N-methyl-2-(5-methylpyridin-2-yl)-2H-indazole-3-carboxamide;
6) 5-cyclopropyl-N-methyl-6-[methyl(methylsulfonyl)amino]-2-(5-methylpyridin-2-yl)-2H-indazole-3-carboxamide;
7) 5-cyclopropyl-6-[(2-fluoroethyl)(methylsulfonyl)amino]-N-methyl-2-(5-methylpyridin-2-yl)-2H-indazole-3-carboxamide;
8) 2-(5-chloropyridin-2-yl)-5-cyclopropyl-6-[ethyl(methylsulfonyl)amino]-N-methyl-2H-indazole-3-carboxamide;
9) 2-(5-chloropyridin-2-yl)-5-cyclopropyl-N-methyl-6-[methyl(methylsulfonyl)amino]-2H-indazole-3-carboxamide;
10) 5-cyclopropyl-N-methyl-6-{[2-(2-methyloxetan-3-yl)ethyl](methylsulfonyl)amino}-2-(5-methylpyridin-2-yl)-2H-indazole-3-carboxamide;
11) 5-cyclopropyl-N-methyl-6-{[2-(3-methyloxetan-3-yl)ethyl](methylsulfonyl)amino}-2-(5-methylpyridin-2-yl)-2H-indazole-3-carboxamide;
13) 5-cyclopropyl-N-methyl-6-[methyl(methylsulfonyl)amino]-2-(5-methylthiazol-2-yl)indazole-3-carboxamide;
14) 5-cyclopropyl-N-methyl-6-[methyl(methylsulfonyl)amino]-2-(2-pyridyl)indazole-3-carboxamide;
15) 2-(5-chloro-4-methyl-2-pyridyl)-5-cyclopropyl-N-methyl-6-[methyl(methylsulfonyl)amino]indazole-3-carboxamide;
16) tert-butyl 3-[2-[[5-cyclopropyl-3-(methylcarbamoyl)-2-(5-methyl-2-pyridyl)indazol-6-yl]-methylsulfonyl-amino]ethyl]azetidine-1-carboxylate;
17) 6-[2-(1-acetylazetidin-3-yl)ethyl-methylsulfonyl-amino]-5-cyclopropyl-N-methyl-2-(5-methyl-2-pyridyl)indazole-3-carboxamide;
18) 5-cyclopropyl-6-[2-(3-methoxyoxetan-3-yl)ethyl-methylsulfonyl-amino]-N-methyl-2-(5-methyl-2-pyridyl)indazole-3-carboxamide;
19) 2-(5-chloro-2-pyridyl)-5-cyclopropyl-N-methyl-6-[methylsulfonyl-[2-(oxetan-3-yl)ethyl]amino]indazole-3-carboxamide; and
20) tert-butyl N-[[3-[2-[[5-cyclopropyl-3-(methylcarbamoyl)-2-(5-methyl-2-pyridyl)indazol-6-yl]-methylsulfonyl-amino]ethyl]oxetan-3-yl]methyl]carbamate; or salts, N-oxides, solvates, hydrates, racemates, enantiomers or diastereomers thereof.

### Claim 7 (depends on 1)

A pharmaceutical agent comprising the compound according to claim 1 or salts, N oxides, solvates, hydrates, racemates, enantiomers or diastereomers thereof and optionally a further compound in addition to the compound of claim 1, wherein the further compound is an HCV antiviral agent.

### Claim 8 (depends on 7)

The pharmaceutical agent according to claim 7 additionally comprising at least one immunomodulatory agent.

### Claim 9 (depends on 7)

The pharmaceutical agent according to claim 7 wherein the HCV antiviral agent is selected from the group consisting of Ribavarin, an NS5B inhibitor, an NS3/4A protease inhibitor and an NS5A inhibitor.

### Claim 10 (depends on 7)

The pharmaceutical agent according to claim 7 adapted for oral administration.

### Claim 11 (depends on 1)

A HCV polymerase inhibitor comprising the compound according to claim 1 or salts, N-oxides, solvates, hydrates, racemates, enantiomers or diastereomers thereof and optionally a further compound in addition to the compound of claim 1, wherein the further compound is an HCV antiviral agent.

### Claim 12 (depends on 11)

The HCV polymerase inhibitor according to claim 11 additionally comprising at least one immunomodulatory agent.

### Claim 13 (depends on 11)

The HCV polymerase inhibitor according to claim 11 wherein the HCV antiviral agent is selected from the group consisting of Ribavarin, an NS5B inhibitor, an NS3/4A protease inhibitor and an NS5A inhibitor.

### Claim 14 (depends on 11)

The HCV polymerase inhibitor according to claim 11 adapted for oral administration.

### Claim 15 (depends on 1)

A pharmaceutical composition comprising the compound according to claim 1 or salts, N-oxides, solvates, hydrates, racemates, enantiomers or diastereomers thereof, a pharmaceutically acceptable carrier and optionally a further compound in addition to the compound of claim 1, wherein the further compound is an HCV antiviral agent.

### Claim 16 (depends on 15)

The pharmaceutical composition according to claim 15 additionally comprising at least one immunomodulatory agent.

### Claim 17 (depends on 15)

The pharmaceutical composition according to claim 15 wherein the HCV antiviral agent is selected from the group consisting of Ribavarin, an NS5B inhibitor, an NS3/4A protease inhibitor and an NS5A inhibitor.

### Claim 18 (depends on 15)

The pharmaceutical composition according to claim 15 adapted for oral administration.

### Claim 19 (depends on 1)

A method for inhibiting, relieving or ameliorating the effects of or reducing the incidence of a HCV infection which comprises administering an effective amount of:
the compound according to claim 1 or salts, N-oxides, solvates, hydrates, racemates, enantiomers or diastereomers thereof and optionally a further compound in addition to the compound of claim 1, wherein the further compound is an HCV antiviral agent;
a pharmaceutical agent comprising the compound according to claim 1 or salts, N oxides, solvates, hydrates, racemates, enantiomers or diastereomers thereof and optionally a further compound in addition to the compound of claim 1, wherein the further compound is an HCV antiviral agent;
a HCV polymerase inhibitor comprising the compound according to claim 1 or salts, N-oxides, solvates, hydrates, racemates, enantiomers or diastereomers thereof and optionally a further compound in addition to the compound of claim 1, wherein the further compound is an HCV antiviral agent; or
a pharmaceutical composition comprising the compound according to claim 1 or salts, N-oxides, solvates, hydrates, racemates, enantiomers or diastereomers thereof, a pharmaceutically acceptable carrier and optionally a further compound in addition to the compound of claim 1, wherein the further compound is an HCV antiviral agent.

### Claim 20 (depends on 19)

The method according to claim 19 wherein the administration is oral administration.

### Claim 21 (depends on 1)

A method of inhibiting the RNA-dependent RNA polymerase activity of the enzyme NS5B, encoded by HCV, comprising exposing the enzyme NS5B to an effective amount of the compound according to claim 1 or salts, N-oxides, solvates, hydrates, racemates, enantiomers or diastereomers thereof and optionally a further compound in addition to the compound of claim 1, wherein the further compound is an HCV antiviral agent.

### Claim 22 (depends on 1)

A method of inhibiting HCV replication comprising exposing a cell infected with HCV to an effective amount of the compound according to claim 1 and optionally a further compound in addition to the compound of claim 1, wherein the further compound is an HCV antiviral agent.

### Claim 23 (depends on 1)

A pharmaceutical composition comprising the compound according to claim 1 or salts, N-oxides, solvates, hydrates, racemates, enantiomers or diastereomers thereof, a pharmaceutically acceptable carrier and optionally a further compound in addition to the compound of claim 1, wherein the further compound is an HCV antiviral agent selected from the group consisting of Ribavarin, an NS5B inhibitor, an NS3/4A protease inhibitor and an NS5A inhibitor.

### Claim 24 (depends on 23)

The pharmaceutical composition according to claim 23 additionally comprising at least one immunomodulatory agent.

### Claim 25 (depends on 23)

A method for inhibiting, relieving or ameliorating the effects of or reducing the incidence of a HCV infection which comprises administering an effective amount of the pharmaceutical composition according to claim 23 to a subject in need thereof.

### Claim 26 (depends on 1)

A process for producing the compound according to claim 1 comprising the step of coupling a compound of formula (II):
with a compound of formula (III) under coupling conditions;
wherein
W is hydroxyl, mesylate, tosylate, triflate or halo; and
Z1, Z2, R1, R2, R3, R4, R5 and (CH)m are as defined in claim 1.

### Claim 27 (depends on 26)

The process according to claim 26 wherein the compound of formula (II) is produced from a compound of formula (IX) using sulfonylation conditions:

### Claim 28 (depends on 27)

The process according to claim 27 wherein the compound of formula (IX) is produced by reducing the nitro (NO2) group of the compound of formula (VIII) to an amino (NH2) group under reduction conditions:

### Claim 29 (depends on 28)

The process according to claim 28 wherein the compound of formula (VIII) is produced by reacting a compound of formula (VII) with a primary amine of formula NH2—R4 in the presence of a catalyst and carbon monoxide:

### Claim 30 (depends on 29)

The process according to claim 29 wherein the compound of formula (VII) is produced by reacting a compound of formula (VI) with a halogenating reagent:

### Claim 31 (depends on 30)

The process according to claim 30 wherein the compound of formula (VI) is produced by reacting a compound of formula (IV) with a compound of formula (V) in the presence of triphenylphosphine:
wherein Y is an independently selected substituent;
q is an integer 0, 1, 2, 3 or 4.

### Claim 32

A compound of formula (II):
wherein
Z1 and Z2 are each independently selected from C—H, C-halo, C—C1-4alkylhalo, C—C1-4alkoxy, C—C1-4alkoxyhalo and N;
R1 is selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, halo,
C1-4alkylhalo, C1-4alkoxyhalo, C3-7cycloalkyl, C3-7cycloalkenyl, 5-6 membered heterocyclyl and 5-6 membered heteroaryl and wherein alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl and heteroaryl in each occurrence may be optionally substituted;
R3 is an optionally substituted 6-membered heteroaryl group containing N in the 2-(ortho) ring position with reference to the point of attachment or R3 is an optionally substituted 5-membered heteroaryl group containing N in the ring position adjacent to the point of attachment;
R4 is H, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, or C3-7cycloalkyl;
R5 in each occurrence is independently H or optionally substituted C1-6alkyl.

### Claim 33 (depends on 32)

The compound of formula (II) according to claim 32 wherein R3 is a para-substituted 2-pyridyl moiety.

### Claim 34 (depends on 32)

The compound of formula (II) according to claim 32 wherein the compound is