Use of cyclic phosphate substituted nucleoside derivativesfor the treatment of viral diseases

Patent metadata

Field	Value
Publication number	US-2019192548-A1
Application number	US-201716311410-A
Country	US
Kind code	A1
Filing date	Jun 20, 2017
Priority date	Jun 20, 2016
Publication date	Jun 27, 2019
Grant date	—

Abstract

The present invention relates to methods of treating or preventing a viral infection using Compounds of Formula (I); or a pharmaceutically acceptable salt thereof, wherein A, B, R 1 , R 2 , R 3 , Q and V are as defined herein. The present invention also relates to compositions comprising a Compound of Formula (I).

First claim

1 . A method for treating a patient infected with HCV, said method comprising administering to said patient a compound of formula (I), or a pharmaceutically acceptable salt thereof, in an amount effective to treat infection by HCV in said patient, wherein formula (I) is:

wherein:
A is O or S;
B is selected from:

Q is O or S;
V is hydrogen, halogen or amino;
W is N, CH or CF;
R 1 is C 1 -C 6 alkoxy, —O-(C 1 -C 6 alkylene)-S—C(O)—(C 1 -C 6 alkyl),

R 2 is halo;
R 3 is halo;
each occurrence of R 4 is independently selected from C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, aryl or —(C 1 -C 6 alkylene)-aryl;
R 5 is C 1 -C 10 alkyl or —COOR 7 ;
R 6 is selected from —(C 1 -C 10 alkylene)-C(O)O—(C 1 -C 10 alkyl), —OC(O)—(C 3 -C 10 cycloalkyl), aryl, aryloxy, —(C 1 -C 10 alkylene)-aryl, 5 or 6-membered monocyclic heteroaryl , 9 or 10-membered bicyclic heteroaryl, —(C 1 -C 10 alkylene)-(5 or 6-membered monocyclic heteroaryl) and —(C 1 -C 10 alkylene)-(9 or 10-membered bicyclic heteroaryl);
R 7 is C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, aryl or —(C 1 -C 6 alkylene)-aryl;
R 8 , R 9 , R 11 and R 12 are each independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, halo, —OR 16 , —SR 16 and —N(R 16 ) 2 ;
R 10 , R 13 , R 14 and R 15 are each independently selected from H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, 5- or 6-membered monocyclic heteroaryl, 9- or 10-membered bicyclic heteroaryl, halo, —OR 16 , —SR 16 , —S(O)R 16 , —S(O) 2 R 16 , —S(O) 2 N(R 16 ) 2 , —NHC(O)OR 16 , —NHC(O)N(R 16 ) 2 , C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, —O—(C 1 -C 6 haloalkyl), —CN, —NO 2 , —N(R 16 ) 2 , —NH(C 1 -C 6 alkylene)-(5- or 6-membered monocyclic heteroaryl), —NH(C 1 -C 6 alkylene)-(9- or 10-membered bicyclic heteroaryl), —C(O)R 16 , —C(O)OR 16 , —C(O)N(R 16 ) 2 and —NHC(O)R 16 , wherein said C 2 -C 6 alkenyl group and said C 2 -C 6 alkynyl group may be optionally substituted with halo;
each occurrence of e is independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, —(C 1 -C 3 alkylene) m - (C 3 -C 7 cycloalkyl), —(C 1 -C 3 alkylene) m - (C 6 -C 10 aryl), —(C 1 -C 3 alkylene) m -(4 to 7-membered heterocycloalkyl), —(C 1 -C 3 alkylene) m -(5- or 6-membered monocyclic heteroaryl) and —(C 1 -C 3 alkylene) m -(9- or 10-membered bicyclic heteroaryl); and
each occurrence of m is independently 0 or 1.

2 . The method of claim 1 , wherein for the compound of formula (I), A is O.

3 . The method of claim 1 , wherein for the compound of formula (I), Q is O.

4 . The method of claim 1 , wherein for the compound of formula (I), R 2 is F.

5 . The method of claim 1 , wherein for the compound of formula (I), R 3 is F.

6 . The method of claim 1 , wherein for the compound of formula (I), R 2 is Cl.

7 . The method of claim 1 , wherein for the compound of formula (I), R 3 is Cl.

8 . The method of claim 1 , wherein for the compound of formula (I), B is selected from adenine, cytosine, guanosine or uracil.

9 . The method of claim 1 , wherein for the compound of formula (I), B is:

10 . The method of claim 1 , wherein for the compound of formula (I), V is H.

11 . The method of claim 1 , wherein for the compound of formula (I), V is F.

12 . The method of claim 1 , wherein the compound of formula (I) is selected from:

or a pharmaceutically acceptable salt thereof.

13 . The method of claim 1 , further comprising the step of administering to said patient a second therapeutic agent selected from the group consisting of HCV antiviral agents, immunomodulators, and anti-infective agents.

14 . (canceled)

15 . The use of a compound of formula (I) of claim 1 , or a pharmaceutically acceptable salt thereof, for inhibiting HCV NS5B activity or for preventing and/or treating infection by HCV in a patient in need thereof.

Assignees

• Bogen Stephane
• Dukhan David
• Dousson Cyril B
• Parsy Christophe Claude
• Merck Sharp & Dohme
• Idenix Pharmaceuticals Llc

Inventors

• Bogen Stephane
• Dukhan David
• Dousson Cyril B
• Parsy Christophe Claude

Classifications

• A61K31/7068

  having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid · CPC title

• C07H19/173

  with 2-deoxyribosyl as the saccharide radical · CPC title

• A61P31/12

  Antivirals · CPC title

• A61K45/06

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

• A61P31/14

  for RNA viruses · CPC title