Substituted 1,5-naphthyridines as endonuclease inhibitors

Patent metadata

Field	Value
Publication number	US-9505758-B2
Application number	US-201514920000-A
Country	US
Kind code	B2
Filing date	Oct 22, 2015
Priority date	Jan 8, 2013
Publication date	Nov 29, 2016
Grant date	Nov 29, 2016

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, ameliorating or preventing a viral disease. Furthermore, specific combination therapies are disclosed.

First claim

The invention claimed is:

1. A method of inhibiting endonuclease activity in a patient, the method comprising administering to a patient in need thereof an effective amount of a compound having the formula (V):

or a pharmaceutically acceptable salt, tautomer, racemate, enantiomer, diastereomer, or mixture thereof;
wherein
X 51 is CH;
X 52 —R 54 is C—R 57 ;
X 53 is NR 55 , N(R 55 )C(O), C(O)NR 55 , O, C(O), C(O)O, OC(O), N(R 55 )SO 2 , SO 2 N(R 55 ), S, SO, or SO 2 ;
R 50 is —H, -(optionally substituted C 1-6 alkyl), -(optionally substituted C 3-7 cycloalkyl), -(optionally substituted aryl), —C 1-4 alkyl-(optionally substituted C 3-7 cycloalkyl), or —C 1-4 alkyl-(optionally substituted aryl);
R 51 is —H, a —C 1-6 alkyl group, or a —C 1-6 alkyl group which is substituted by one or more halogen atoms;
R 52 is —H, a —C 1-6 alkyl group, or a —C 1-6 alkyl group which is substituted by one or more halogen atoms;
or wherein R 51 and R 52 can be joined together to form a 3- to 7-membered carbocyclic or heterocyclic ring;
R 53 is —R 56 , or —X 53 —R 56 ;
R 55 is —H, -(optionally substituted C 1-6 alkyl), -(optionally substituted C 3-7 cycloalkyl), -(optionally substituted aryl), —C 1-4 alkyl-optionally substituted C 3-7 cycloalkyl), or —C 1-4 alkyl-(optionally substituted aryl);
R 56 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);
R 57 is —H, —F, —Cl, —Br, —I, or —C 1-6 alkyl;
R 58 is —H, —C 1-6 alkyl, or (CH 2 CH 2 O) r H;
R 59 is —H, or —C 1-6 alkyl;
R is —C 1-6 alkyl, —C(O)—C 1-6 alkyl, —F, —Cl, —Br, —I, —CF 3 , —CN, —C(O)OR 58 , —OR 58 , —(CH 2 ) q NR 58 R 59 , —C(O)—NR 58 R 59 , or —NR 58 —C(O)—C 1-6 alkyl;
q is 0, 1, 2, 3 or 4; and
r is 1, 2 or 3;
wherein the optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, and/or optionally substituted hydrocarbon group can be optionally substituted with one or more of the above R substituents.

2. The method according to claim 1 , wherein the patient suffers from a viral disease caused by Herpesviridae, Retroviridae, Filoviridae, Paramyxoviridae, Rhabdoviridae, Orthomyxoviridae, Bunyaviridae, Arenaviridae, Coronaviridae, Picomaviridae, Togaviridae, or Flaviviridae.

3. The method according to claim 2 , 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 formula (V); a neuraminidase 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.

4. The method according to claim 3 , wherein the further medicament is administered concurrently with, sequentially with or separately from the compound having the formula (V).

5. The method according to claim 1 , wherein the patient suffers from influenza.

Assignees

• Savira Pharmaceuticals Gmbh
• European Molecular Biology Laboratory
• Hoffmann La Roche
• F Hoffman-La Roche Ag

Inventors

• Wolkerstorfer Andrea
• Szolar Oliver
• Handler Norbert
• Buschmann Helmut
• Cusack Stephen
• Smith Mark
• So Sung-Sau
• Hawley Ronald Charles
• Sidduri Achyutharao

Classifications

• A61K31/4985

  Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems · CPC title

• A61K31/513

  having oxo groups directly attached to the heterocyclic ring, e.g. cytosine · CPC title

• A61P31/22

  for herpes viruses · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07D471/02

  in which the condensed system contains two hetero rings · CPC title