# US 2014/0194432 A1 · Naphthyridinone derivatives and their use in the treatment, amelioration or prevention of a viral disease

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- Number: US 2014/0194432 A1
- Document ID: US20140194432A1
- Status: Published application
- Kind: A1
- Application number: 14/149,381
- Filed: 2014-01-07
- Published: 2014-07-10
- Earliest claimed: 2013-01-08
- Assignees: Savira pharmaceuticals GmbH; European Molecular Biology Laboratory; F. Hoffmann-La Roche AG
- Applicants: Savira pharmaceuticals GmbH; F. Hoffmann-La Roche AG; European Molecular Biology Laboratory
- Inventors: Andrea Wolkerstorfer; Oliver Szolar; Norbert Handler; Helmut Buschmann; Stephen Cusack; Mark Smith; Sung-Sau So; Ronald Charles Hawley; Achyutharao Sidduri
- Web page: https://patentgrep.com/patent/US20140194432A1

## CPC

- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- 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 31/4985: Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
- A61K 31/513: having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 31/12: Antivirals
- A61P 31/14: for RNA viruses
- A61P 31/16: for influenza or rhinoviruses
- A61P 31/22: for herpes viruses
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 471/02: in which the condensed system contains two 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

The present invention relates to a compound having the general formula (V), optionally in the form of a pharmaceutically acceptable salt, solvate, polymorph, codrug, cocrystal, prodrug, tautomer, racemate, enantiomer, or diastereomer or mixture thereof, which are useful in treating, ameloriating or preventing a viral disease. Furthermore, specific combination therapies are disclosed.

## Claims

### Claim 1

A compound having the general formula (V),
wherein
X51 is CH or N;
X52—R54 is N or C—R57;
X53 is NR55, N(R55)C(O), C(O)NR55, O, C(O), C(O)O, OC(O); N(R55)SO2, SO2N(R55), S, SO, or SO2;
R50 is —H, -(optionally substituted C1-6 alkyl), -(optionally substituted C3-7 cycloalkyl),
-(optionally substituted aryl), —C1-4 alkyl-(optionally substituted C3-7 cycloalkyl), or —C1-4 alkyl-(optionally substituted aryl);
R51 is —H, a —C1-6 alkyl group, or a —C1-6 alkyl group which is substituted by one or more halogen atoms;
R52 is —H, a —C1-6 alkyl group, or a —C1-6 alkyl group which is substituted by one or more halogen atoms;
or wherein R51 and R52 can be joined together to form a 3- to 7-membered carbo- or heterocyclic ring;
R53 is —R56, or —X53—R56;
R55 is —H, -(optionally substituted C1-6 alkyl), -(optionally substituted C3-7 cycloalkyl),
-(optionally substituted aryl), —C1-4 alkyl-(optionally substituted C3-7 cycloalkyl), or —C1-4 alkyl-(optionally substituted aryl);
R56 is -(optionally substituted hydrocarbon group which contains from 5 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S and which contains at least one ring);
R57 is —H, -Hal or —C1-6 alkyl;
R58 is —H, —C1-6 alkyl, or —(CH2CH2O)rH;
R59 is —H, or —C1-6 alkyl;
R is independently selected from —C1-6 alkyl, —C(O)—C1-6 alkyl, -Hal, —CF3, —CN,
—COOR58, —OR58, —(CH2)qNR58R59, —C(O)—NR58R59, and —NR58—C(O)—C1-6 alkyl;
q is 0 to 4; and
r is 1 to 3;
wherein the alkyl group, aryl group, hydrocarbon group and/or cycloalkyl group can be optionally substituted with one or more substituents R,
or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, codrug, cocrystal, tautomer, racemate, enantiomer, or diastereomer or mixture thereof
with the proviso that the compound is not:
and ethyl 4-oxo-1-{[4-(1H-pyrazolo-1-yl)phenyl}methyl]-1,4-dihydro-1,5-naphthyridine-3-carboxylate.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein R53 is —R56.

### Claim 3 (depends on 1)

The compound according to claim 1, wherein R53 is —X53—R56 and X53 is N(R55)SO2.

### Claim 4 (depends on 1)

The compound according to claim 1, wherein R51 and R52 are —H.

### Claim 5 (depends on 1)

The compound according to claim 1, wherein R50 is —H, or -(optionally substituted C1-6 alkyl).

### Claim 6 (depends on 1)

The compound according to claim 1, wherein R56 is selected from the group consisting of
wherein
X is absent, CH2, NH, C(O)NH, S or O;
Y is CH2;
Z is O or S; and
R is independently selected from —H, —C1-6 alkyl, —CF3, -halogen, —CN, —OH, and —O—C1-6 alkyl.

### Claim 7

A pharmaceutical composition comprising:
a compound having the general formula (V):
wherein
X51 is CH or N;
X52—R54 is N or C—R57;
X53 is NR55, N(R55)C(O), C(O)NR55, O, C(O), C(O)O, OC(O); N(R55)SO2, SO2N(R55), S, SO, or SO2;
R50 is —H, -(optionally substituted C1-6 alkyl), -(optionally substituted C3-7 cycloalkyl),
-(optionally substituted aryl), —C1-4 alkyl-(optionally substituted C3-7 cycloalkyl), or —C1-4 alkyl-(optionally substituted aryl);
R51 is —H, a —C1-6 alkyl group, or a —C1-6 alkyl group which is substituted by one or more halogen atoms;
R52 is —H, a —C1-6 alkyl group, or a —C1-6 alkyl group which is substituted by one or more halogen atoms;
or wherein R51 and R52 can be joined together to form a 3- to 7-membered carbo- or heterocyclic ring;
R53 is —R56, or —X53—R56;
R55 is —H, -(optionally substituted C1-6 alkyl), -(optionally substituted C3-7 cycloalkyl),
-(optionally substituted aryl), —C1-4 alkyl-(optionally substituted C3-7 cycloalkyl), or —C1-4 alkyl-(optionally substituted aryl);
R56 is -(optionally substituted hydrocarbon group which contains from 5 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S and which contains at least one ring);
R57 is —H, -Hal or —C1-6 alkyl;
R58 is —H, —C1-6 alkyl, or —(CH2CH2O)rH;
R59 is —H, or —C1-6 alkyl;
R is independently selected from —C1-6 alkyl, —C(O)—C1-6 alkyl, -Hal, —CF3, —CN,
—COOR58, —OR58, —(CH2)qNR58R59, —C(O)—NR58R59, and —NR58—C(O)—C1-6 alkyl;
q is 0 to 4; and
r is 1 to 3;
wherein the alkyl group, aryl group, hydrocarbon group and/or cycloalkyl group can be optionally substituted with one or more substituents R,
or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, codrug, cocrystal, tautomer, racemate, enantiomer, or diastereomer or mixture thereof
and one or more pharmaceutically acceptable excipient(s) and/or carrier(s);
with the proviso that the compound is not:

### Claim 8 (depends on 7)

The pharmaceutical composition according to claim 7, further comprising a further medicament selected from the group consisting of a polymerase inhibitor which is different from the compound having the general formula (V); a neuramidase inhibitor; a M2 channel inhibitor; an alpha glucosidase inhibitor; a ligand of another influenza target; an antibiotic, an anti-inflammatory agent, a lipoxygenase inhibitor, an EP ligand, a bradykinin ligand, and a cannabinoid ligand, and combinations thereof.

### Claim 9

A compound for use in the treatment, amelioration or prevention of a viral disease the compound having the general formula (V):
wherein
X51 is CH or N;
X52—R54 is N or C—R57;
X53 is NR55, N(R55)C(O), C(O)NR55, O, C(O), C(O)O, OC(O); N(R55)SO2, SO2N(R55), S, SO, or SO2;
R50 is —H, -(optionally substituted C1-6 alkyl), -(optionally substituted C3-7 cycloalkyl),
-(optionally substituted aryl), —C1-4 alkyl-(optionally substituted C3-7 cycloalkyl), or —C1-4 alkyl-(optionally substituted aryl);
R51 is —H, a —C1-6 alkyl group, or a —C1-6 alkyl group which is substituted by one or more halogen atoms;
R52 is —H, a —C1-6 alkyl group, or a —C1-6 alkyl group which is substituted by one or more halogen atoms;
or wherein R51 and R52 can be joined together to form a 3- to 7-membered carbo- or heterocyclic ring;
R53 is —R56, or —X53—R56;
R55 is —H, -(optionally substituted C1-6 alkyl), -(optionally substituted C3-7 cycloalkyl),
-(optionally substituted aryl), —C1-4 alkyl-(optionally substituted C3-7 cycloalkyl), or —C1-4 alkyl-(optionally substituted aryl);
R56 is -(optionally substituted hydrocarbon group which contains from 5 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S and which contains at least one ring);
R57 is —H, -Hal or —C1-6 alkyl;
R58 is —H, —C1-6 alkyl, or —(CH2CH2O)rH;
R59 is —H, or —C1-6 alkyl;
R is independently selected from —C1-6 alkyl, —C(O)—C1-6 alkyl, -Hal, —CF3, —CN,
—COOR58, —OR58, —(CH2)qNR58R59, —C(O)—NR58R59, and —NR58—C(O)—C1-6 alkyl;
q is 0 to 4; and
r is 1 to 3;
wherein the alkyl group, aryl group, hydrocarbon group and/or cycloalkyl group can be optionally substituted with one or more substituents R,
or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, codrug, cocrystal, tautomer, racemate, enantiomer, or diastereomer or mixture thereof.

### Claim 10

A method of treating, ameliorating or preventing a viral disease, the method comprising administering to a patient in need thereof an effective amount of a compound having the general formula (V):
wherein
X51 is CH or N;
X52—R54 is N or C—R57;
X53 is NR55, N(R55)C(O), C(O)NR55, O, C(O), C(O)O, OC(O); N(R55)SO2, SO2N(R55), S, SO, or SO2;
R50 is —H, -(optionally substituted C1-6 alkyl), -(optionally substituted C3-7 cycloalkyl),
-(optionally substituted aryl), —C1-4 alkyl-(optionally substituted C3-7 cycloalkyl), or —C1-4 alkyl-(optionally substituted aryl);
R51 is —H, a —C1-6 alkyl group, or a —C1-6 alkyl group which is substituted by one or more halogen atoms;
R52 is —H, a —C1-6 alkyl group, or a —C1-6 alkyl group which is substituted by one or more halogen atoms;
or wherein R51 and R52 can be joined together to form a 3- to 7-membered carbo- or heterocyclic ring;
R53 is —R56, or —X53—R56;
R55 is —H, -(optionally substituted C1-6 alkyl), -(optionally substituted C3-7 cycloalkyl),
-(optionally substituted aryl), —C1-4 alkyl-(optionally substituted C3-7 cycloalkyl), or —C1-4 alkyl-(optionally substituted aryl);
R56 is -(optionally substituted hydrocarbon group which contains from 5 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S and which contains at least one ring);
R57 is —H, -Hal or —C1-6 alkyl;
R58 is —H, —C1-6 alkyl, or —(CH2CH2O)rH;
R59 is —H, or —C1-6 alkyl;
R is independently selected from —C1-6 alkyl, —C(O)—C1-6 alkyl, -Hal, —CF3, —CN,
—COOR58, —OR58, —(CH2)qNR58R59, —C(O)—NR58R59, and —NR58—C(O)—C1-6 alkyl;
q is 0 to 4; and
r is 1 to 3;
wherein the alkyl group, aryl group, hydrocarbon group and/or cycloalkyl group can be optionally substituted with one or more substituents R,
or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, codrug, cocrystal, tautomer, racemate, enantiomer, or diastereomer or mixture thereof.

### Claim 11 (depends on 10)

The method according to claim 10, wherein the viral disease is caused by Herpesviridae, Retroviridae, Filoviridae, Paramyxoviridae, Rhabdoviridae, Orthomyxoviridae, Bunyaviridae, Arenaviridae, Coronaviridae, Picornaviridae, Togaviridae, or Flaviviridae.

### Claim 12 (depends on 11)

The method according to claim 11, further comprising administering an effective amount of a further medicament selected from the group consisting of a polymerase inhibitor which is different from the compound having the general formula (V); a neuramidase inhibitor; a M2 channel inhibitor; an alpha glucosidase inhibitor; a ligand of another influenza target; an antibiotic, an anti-inflammatory agent, a lipoxygenase inhibitor, an EP ligand, a bradykinin ligand, and a cannabinoid ligand, and combinations thereof.

### Claim 13 (depends on 1)

The compound according to claim 1, which exhibits an IC50 of less than about 40 μM in a FRET endonuclease activity assay.

### Claim 14 (depends on 10)

The method according to claim 10, wherein the viral disease is influenza.

### Claim 15 (depends on 12)

The method according to claim 12, wherein the further medicament is administered concurrently with, sequentially with or separately from the compound having the general formula (V).