# US 2014/0194431 A1 · Pyrimidone derivatives and their use in the treatment, amelioration or prevention of a viral disease

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- Number: US 2014/0194431 A1
- Document ID: US20140194431A1
- Status: Published application
- Kind: A1
- Application number: 14/149,284
- Filed: 2014-01-07
- Published: 2014-07-10
- Earliest claimed: 2013-01-08
- Assignees: Savira pharmaceuticals GmbH; European Molecular Biology Laboratory; F. Hoffman-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; Zhuming Zhang
- Web page: https://patentgrep.com/patent/US20140194431A1

## CPC

- C07D 487/04: Ortho-condensed systems
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- 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 403/04: directly linked by a ring-member-to-ring-member bond
- C07D 471/04: Ortho-condensed systems
- 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 a compound having the general formula (I), 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 (I),
wherein
X10 is NR15, N(R15)C(O), C(O)NR15, O, C(O), C(O)O, OC(O); N(R15)SO2, SO2N(R15), S, SO, or SO2;
R10 is —H, a —C1-6 alkyl group or a —C(O)—C1-6 alkyl group;
R11 is —H, a —C1-6 alkyl group, or a —C1-6 alkyl group which is substituted by one or more halogen atoms;
R12 is —H, a —C1-6 alkyl group, or a —C1-6 alkyl group which is substituted by one or more halogen atoms;
or wherein R11 and R12 can be joined together to form a 3- to 7-membered carbo- or heterocyclic ring;
R13 is —R16, or —X10—R16;
R14 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);
R15 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);
R16 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);
R17 is —H, —C1-6 alkyl, or —(CH2CH2O)rH;
R18 is —H, or —C1-6 alkyl;
R is independently selected from —C1-6 alkyl, —C(O)—C1-6 alkyl, -Hal, —CF3, —CN,
—COOR17, —OR17, —(CH2)qNR17R18, —C(O)—NR17R18, and —NR17—C(O)—C1-6 alkyl;
R* is independently selected from —H, —C1-6 alkyl, and —C3-7 cycloalkyl;
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:

### Claim 2 (depends on 1)

The compound according to claim 1, wherein R13 is —R16.

### Claim 3 (depends on 1)

The compound according to claim 1, wherein R13 is —X10—R16 and X10 is N(R15)SO2.

### Claim 4 (depends on 1)

The compound according to claim 1, wherein R11 and R12 are —H.

### Claim 5 (depends on 1)

The compound according to claim 1, wherein R10 is —H, or -(optionally substituted C1-6 alkyl).

### Claim 6 (depends on 1)

The compound according to claim 1, wherein R14 is —H, -(optionally substituted C1-6 alkyl), or -(optionally substituted aryl).

### Claim 7 (depends on 1)

The compound according to claim 1, wherein R16 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 8 (depends on 1)

A pharmaceutical composition comprising:
a compound according to claim 1,
and one or more pharmaceutically acceptable excipient(s) and/or carrier(s);
with the proviso that the compound is not:

### Claim 9 (depends on 8)

The pharmaceutical composition according to claim 8, which additionally comprises a further medicament selected from the group consisting of a polymerase inhibitor which is different from the compound having the general formula (I); 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, a cannabinoid ligand, and combinations thereof.

### Claim 10

A compound,
for use in the treatment, amelioration or prevention of a viral disease caused by Herpesviridae, Filoviridae, Paramyxoviridae, Rhabdoviridae, Orthomyxoviridae, Bunyaviridae, Arenaviridae, Coronaviridae, Picornaviridae, Togaviridae, or Flaviviridae.
wherein the compound has the general formula (I):
wherein
X10 is NR15, N(R15)C(O), C(O)NR15, O, C(O), C(O)O, OC(O); N(R15)SO2, SO2N(R15), S, SO, or SO2;
R10 is —H, a —C1-6 alkyl group or a —C(O)—C1-6 alkyl group;
R11 is —H, a —C1-6 alkyl group, or a —C1-6 alkyl group which is substituted by one or more halogen atoms;
R12 is —H, a —C1-6 alkyl group, or a —C1-6 alkyl group which is substituted by one or more halogen atoms;
or wherein R11 and R12 can be joined together to form a 3- to 7-membered carbo- or heterocyclic ring;
R13 is —R16, or —X10—R16;
R14 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);
R15 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);
R16 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);
R17 is —H, —C1-6 alkyl, or —(CH2CH2O)rH;
R18 is —H, or —C1-6 alkyl;
R is independently selected from —C1-6 alkyl, —C(O)—C1-6 alkyl, -Hal, —CF3, —CN,
—COOR17, OR17, —(CH2)qNR17R18, —C(O)—NR17R18, and —NR17—C(O)—C1-6 alkyl;
R* is independently selected from —H, —C1-6 alkyl, and —C3-7 cycloalkyl;
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

A method of treating, ameliorating or preventing a viral disease caused by Herpesviridae, Filoviridae, Paramyxoviridae, Rhabdoviridae, Orthomyxoviridae, Bunyaviridae, Arenaviridae, Coronaviridae, Picornaviridae, Togaviridae, or Flaviviridae; the method comprising administering to a patient in need thereof an effective amount of a compound having the general formula (I):
wherein
X10 is NR15, N(R15)C(O), C(O)NR15, O, C(O), C(O)O, OC(O); N(R15)SO2, SO2N(R15), S, SO, or SO2;
R10 is —H, a —C1-6 alkyl group or a —C(O)—C1-6 alkyl group;
R11 is —H, a —C1-6 alkyl group, or a —C1-6 alkyl group which is substituted by one or more halogen atoms;
R12 is —H, a —C1-6 alkyl group, or a —C1-6 alkyl group which is substituted by one or more halogen atoms;
or wherein R11 and R12 can be joined together to form a 3- to 7-membered carbo- or heterocyclic ring;
R13 is —R16, or —X10—R16;
R14 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);
R15 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);
R16 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);
R17 is —H, —C1-6 alkyl, or —(CH2CH2O)rH;
R18 is —H, or —C1-6 alkyl;
R is independently selected from —C1-6 alkyl, —C(O)—C1-6 alkyl, -Hal, —CF3, —CN,
—COOR17, —OR17, —(CH2)qNR17R18, —C(O)—NR17R18, and —NR17—C(O)—C1-6 alkyl;
R* is independently selected from —H, —C1-6 alkyl, and —C3-7 cycloalkyl;
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 12

A compound,
for use in the treatment, amelioration or prevention of influenza, wherein the compound has the general formula (I):
wherein
X10 is NR15, N(R15)C(O), C(O)NR15, O, C(O), C(O)O, OC(O); N(R15)SO2, SO2N(R15), S, SO, or SO2;
R10 is —H, a —C1-6 alkyl group or a —C(O)—C1-6 alkyl group;
R11 is —H, a —C1-6 alkyl group, or a —C1-6 alkyl group which is substituted by one or more halogen atoms;
R12 is —H, a —C1-6 alkyl group, or a —C1-6 alkyl group which is substituted by one or more halogen atoms;
or wherein R11 and R12 can be joined together to form a 3- to 7-membered carbo- or heterocyclic ring;
R13 is —R16, or —X10—R16;
R14 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);
R15 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);
R16 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);
R17 is —H, —C1-6 alkyl, or —(CH2CH2O)rH;
R18 is —H, or —C1-6 alkyl;
R is independently selected from —C1-6 alkyl, —C(O)—C1-6 alkyl, -Hal, —CF3, —CN,
—COOR17, —OR17, —(CH2)qNR17R18, —C(O)—NR17R18, and —NR17—C(O)—C1-6 alkyl;
R* is independently selected from —H, —C1-6 alkyl, and —C3-7 cycloalkyl;
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 13

A method of treating, ameliorating or preventing influenza; the method comprising administering to a patient in need thereof an effective amount of a compound having the general formula (I):
wherein
X10 is NR15, N(R15)C(O), C(O)NR15, O, C(O), C(O)O, OC(O); N(R15)SO2, SO2N(R15), S, SO, or SO2;
R10 is —H, a —C1-6 alkyl group or a —C(O)—C1-6 alkyl group;
R11 is —H, a —C1-6 alkyl group, or a —C1-6 alkyl group which is substituted by one or more halogen atoms;
R12 is —H a —C1-6 alkyl group, or a —C1-6 alkyl group which is substituted by one or more halogen atoms;
or wherein R11 and R12 can be joined together to form a 3- to 7-membered carbo- or heterocyclic ring;
R13 is —R16, or —X10—R16;
R14 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);
R15 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);
R16 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);
R17 is —H, —C1-6 alkyl, or —(CH2CH2O)rH;
R18 is —H, or —C1-6 alkyl;
R is independently selected from —C1-6 alkyl, —C(O)—C1-6 alkyl, -Hal, —CF3, —CN,
—COOR17, —OR17, —(CH2)qNR17R18, —C(O)—NR17R18, and —NR17—C(O)—C1-6 alkyl;
R* is independently selected from —H, —C1-6 alkyl, and —C3-7 cycloalkyl;
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 14 (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 (I); 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, a cannabinoid ligand, and combinations thereof.

### Claim 15 (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 16 (depends on 14)

The method according to claim 14, wherein the further medicament is administered concurrently with, sequentially with or separately from the compound having the general formula (I).