# US 2019/0169185 A1 · Substituted 2-n-hydroxy-1,3-dioxo-1,2,3,4-tetrahydronaphthyridines, and methods of making and using same

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- Number: US 2019/0169185 A1
- Document ID: US20190169185A1
- Status: Published application
- Kind: A1
- Application number: 16/204,584
- Filed: 2018-11-29
- Published: 2019-06-06
- Earliest claimed: 2017-12-04
- Assignees: Arbutus Biopharma Corporation
- Applicants: Arbutus Biopharma, Inc.
- Inventors: RAMESH D. KAKARLA; BRUCE D. DORSEY
- Web page: https://patentgrep.com/patent/US20190169185A1

## CPC

- C07D 471/04: Ortho-condensed systems
- A61K 31/4375: the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 31/20: for DNA viruses
- 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 includes novel substituted 2-N-hydroxy-1,3-dioxo-1,2,3,4-tetrahydronaphthyridines, which can be used to treat or prevent hepatitis B virus (HBV) infections in a patient. In certain embodiments, the compounds and compositions of the invention inhibit HBV RNAse H activity.

## Claims

### Claim 1

A compound of formula (I):
wherein:
R1 is selected from the group consisting of —OR′ and —NR′R′, wherein each occurrence of R′ is independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted benzyl, optionally substituted aryl, and optionally substituted heteroaryl;
each of X1, X2, X3, and X4 is independently selected from the group consisting of N and CR3, with the proviso that 1-2 of X1, X2, X3, and X4 are N;
R2 and R3 are independently selected from the group consisting of H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, halo, —CN, —OR″, —NR″R″, —N(C0-C6 alkyl)C(═O)R″, —N(C0-C6 alkyl) S(═O)2R″, —NO2, —S(═O)2NR″R″, —OC(═O)R″, and —C(═O)O—C1-C6 alkyl, wherein each occurrence of R″ is independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, and optionally substituted phenyl; and
n is 0, 1, 2, 3, or 4;
or a salt, solvate, geometric isomer, stereoisomer, tautomer, or any mixtures thereof

### Claim 2 (depends on 1)

The compound of claim 1, wherein each occurrence of alkyl, alkenyl, alkynyl, or cycloalkyl is independently optionally substituted with at least one substituent selected from the group consisting of C1-C6 alkyl, halo, keto (C═O), —OR, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, —N(R)(R), —N(R)-(C=O)R, —C(═O)R, —C(═O)(optionally substituted phenyl), —C(═O)(optionally substituted heteroaryl), —C(═O)N(R)(R), —C(═O)(CH2)0-3OR, —S(═O)2R, and —SO2N(R)(R), wherein each occurrence of R is independently selected from the group consisting of H, C1-C6 alkyl, and C3-C8 cycloalkyl.

### Claim 3 (depends on 1)

The compound of claim 1, wherein each occurrence of aryl or heteroaryl is independently optionally substituted with at least one substituent selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, halo, —CN, —OR, —N(R)(R), —NO2, —S(═O)2N(R)(R), acyl, and C1-C6 alkoxycarbonyl, wherein each occurrence of R is independently selected from the group consisting of H, C1-C6 alkyl, and C3-C8 cycloalkyl.

### Claim 4 (depends on 1)

The compound of claim 1, wherein each occurrence of aryl or heteroaryl is independently optionally substituted with at least one substituent selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, halo, —CN, —OR, —N(R)(R), and C1-C6 alkoxycarbonyl, wherein each occurrence of R is independently selected from the group consisting of H, C1-C6 alkyl, and C3-C8 cycloalkyl.

### Claim 5 (depends on 1)

The compound of claim 1, which is at least one selected from the group consisting of:

### Claim 6 (depends on 1)

The compound of claim 1, which is:

### Claim 7 (depends on 1)

The compound of claim 1, which is selected from the group consisting of
Ethyl 6-hydroxy-2-methoxy-5,7-dioxo-5,6,7,8-tetrahydro-1,6-naphthyridine-8-carboxylate;
N,N-diethyl-6-hydroxy-2-methoxy-5,7-dioxo-5,6,7,8-tetrahydro-1,6-naphthyridine-8-carboxamide;
N-(4-chlorophenyl)-6-hydroxy-2-methoxy-5,7-dioxo-5,6,7,8-tetrahydro-1,6-naphthyridine-8-carboxamide;
N-(4-fluorophenyl)-6-hydroxy-2-methoxy-5,7-dioxo-5,6,7,8-tetrahydro-1,6-naphthyridine-8-carboxamide;
N-(4-Chlorobenzyl)-6-dihydroxy-2-methoxy-5,7-dioxo-5,6,7,8-tetrahydro-1,6-naphthyridine-8-carboxamide;
N-(4-fluorobenzyl)-2,6-dihydroxy-5,7-dioxo-5,6,7,8-tetrahydro-1,6-naphthyridine-8-carboxamide;
N-(4-Methoxybenzyl)-2,6-dihydroxy-5,7-dioxo-5,6,7,8-tetrahydro-1,6-naphthyridine-8-carboxamide;
or a salt, solvate, geometric isomer, stereoisomer, tautomer, or any mixtures thereof

### Claim 8 (depends on 1)

A pharmaceutical composition comprising at least one compound of claim 1 and a pharmaceutically acceptable carrier.

### Claim 9 (depends on 8)

The pharmaceutical composition of claim 8, further comprising at least one additional agent useful for treating hepatitis infection.

### Claim 10 (depends on 9)

The pharmaceutical composition of claim 9, wherein the at least one additional agent comprises at least one selected from the group consisting of reverse transcriptase inhibitor;
capsid inhibitor; cccDNA formation inhibitor; sAg secretion inhibitor; oligomeric nucleotide targeted to the Hepatitis B genome; and immunostimulator.

### Claim 11 (depends on 1)

A method of treating or preventing hepatitis virus infection in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of at least one compound of claim 1.

### Claim 12 (depends on 11)

The method of claim 11, wherein the at least one compound is administered to the subject in a pharmaceutically acceptable composition.

### Claim 13 (depends on 11)

The method of claim 11, wherein the subject is further administered at least one additional agent useful for treating the hepatitis infection.

### Claim 14 (depends on 13)

The method of claim 13, wherein the at least one additional agent comprises at least one selected from the group consisting of reverse transcriptase inhibitor; capsid inhibitor; cccDNA formation inhibitor; sAg secretion inhibitor; oligomeric nucleotide targeted to the Hepatitis B genome; and immunostimulator.

### Claim 15 (depends on 13)

The method of claim 13, wherein the subject is co-administered the at least one compound and the at least one additional agent.

### Claim 16 (depends on 15)

The method of claim 15, wherein the at least one compound and the at least one additional agent are coformulated.

### Claim 17 (depends on 11)

The method of claim 11, wherein the virus comprises hepatitis B virus (HBV).

### Claim 18 (depends on 1)

A method of inhibiting RNAse H activity in a HBV-infected subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of at least one compound of claim 1.

### Claim 19 (depends on 18)

The method of claim 18, wherein the at least one compound is administered to the subject in a pharmaceutically acceptable composition.

### Claim 20 (depends on 18)

The method of claim 18, wherein the subject is further administered at least one additional agent useful for treating the HBV infection.

### Claim 21 (depends on 20)

The method of claim 20, wherein the at least one additional agent comprises at least one selected from the group consisting of reverse transcriptase inhibitor; capsid inhibitor; cccDNA formation inhibitor; sAg secretion inhibitor; oligomeric nucleotide targeted to the Hepatitis B genome; and immunostimulator.

### Claim 22 (depends on 20)

The method of claim 20, wherein the subject is co-administered the at least one compound and the at least one additional agent.

### Claim 23 (depends on 22)

The method of claim 22, wherein the at least one compound and the at least one additional agent are coformulated.

### Claim 24 (depends on 11)

The method of claim 11, wherein the subject is a mammal.

### Claim 25 (depends on 24)

The method of claim 24, wherein the mammal is a human.