Cyclic phosphate substituted nucleoside compounds and methods of use thereof for the treatment of viral diseases

Patent metadata

Field	Value
Publication number	US-10899788-B2
Application number	US-201716311363-A
Country	US
Kind code	B2
Filing date	Jun 20, 2017
Priority date	Jun 20, 2016
Publication date	Jan 26, 2021
Grant date	Jan 26, 2021

Abstract

The present invention relates to Cyclic Phosphate Substituted Nucleoside Compounds of Formula (I), and pharmaceutically acceptable salts thereof, wherein in A, B, R 1 , R 2 , R 3 , Q and V are as defined herein. The present invention also relates to compositions comprising a Cyclic Phosphate Substituted Nucleoside Compound, and methods of using the Cyclic Phosphate Substituted Nucleoside Compounds for treating or preventing HCV infection in a patient.

First claim

What is claimed is:

1. A compound having the formula (I):

or a pharmaceutically acceptable salt thereof,
wherein:
A is selected from O, S and CH 2 ;
B is:

Q is O or S;
V is H, halo or —N(R 12 ) 2 ;
R 1 is —(CH 2 ) m —C(O)OR 13 ;
R 2 is selected from H, F, Cl, C 1 -C 3 alkyl and C 2 -C 3 alkynyl;
R 3 is selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, —OR 12 , F, Cl, —N 3 , —CN and N(R 12 ) 2 , such that if R 2 is F or C 1 , then R 3 is other than F or Cl;
R 4 , R 5 , R 7 and R 8 are each independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, halo, —OR 14 , —SR 14 and —N(R 14 ) 2 ;
R 6 , R 9 , R 10 and R 11 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 14 , —SR 14 , —S(O)R 14 , —S(O) 2 R 14 , —S(O) 2 N(R 14 ) 2 , —NHC(O)OR 14 , —NHC(O)N(R 14 ) 2 , C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, —O—(C 1 -C 6 haloalkyl), —CN, —NO 2 , —N(R 14 ) 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 14 , —C(O)OR 14 , —C(O)N(R 14 ) 2 and —NHC(O)R 14 , 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 R 12 is independently selected from H, C 1 -C 6 alkyl, —C(O)R 14 and —C(O)OR 14 ;
each occurrence of R 13 is independently selected from C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl and C 6 -C 10 aryl;
each occurrence of R 14 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) n -(C 3 -C 7 cycloalkyl), —(C 1 -C 3 alkylene) n -(C 6 -C 10 aryl), —(C 1 -C 3 alkylene) n -(4 to 7-membered heterocycloalkyl), —(C 1 -C 3 alkylene) n -(5- or 6-membered monocyclic heteroaryl) and —(C 1 -C 3 alkylene) n -(9- or 10-membered bicyclic heteroaryl);
m is 1, 2, 3, 4 or 5; and
each occurrence of n is independently 0 or 1.

2. The compound of claim 1 , wherein A and Q are each O.

3. The compound of claim 1 , wherein R 2 is methyl.

4. The compound of claim 1 , wherein R 3 is selected from —OH, F, Cl, —N 3 , —CN, —C≡CH and —NH 2 .

5. The compound of claim 1 , having the formula (Ia):

or a pharmaceutically acceptable salt thereof,
wherein:
B is uracil;
R 3 is selected from —OH, F, C 1 , N 3 , —CN, —C≡CH and —NH 2 ;
R 13 is C 1 -C 6 alkyl or C 3 -C 7 cycloalkyl; and
V is H or F; and
m is 1, 2, 3, 4 or 5.

6. The compound of claim 1 , wherein m is 1.

7. The compound of claim 1 , wherein m is 2.

8. The compound of claim 1 , wherein m is 3.

9. The compound of claim 1 , wherein m is 4.

10. The compound of claim 1 , wherein m is 5.

11. The compound of claim 1 , wherein R 13 is methyl, ethyl, isopropyl, n-butyl or cyclopentyl.

12. A compound having the structure:

or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition comprising an effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

14. The pharmaceutical composition of claim 13 , further comprising a second therapeutic agent selected from the group consisting of HCV antiviral agents, immunomodulators, and anti-infective agents.

15. The pharmaceutical composition of claim 14 , further comprising a third therapeutic agent selected from the group consisting of HCV protease inhibitors, HCV NS5A inhibitors and HCV NS5B polymerase inhibitors.

16. A method of treating a patient infected with HCV comprising the step of administering an amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof, effective to treat infection by HCV in said patient.

17. The method of claim 16 , 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.

Assignees

• Bogen Stephane
• Dukhan David
• Brandt Guillaume
• Rouviere Claire Pierra
• Dousson Cyril B
• Alexandre Francois Rene
• Merck Sharp & Dohme
• Idenix Pharmaceuticals Llc

Inventors

• Bogen Stephane
• Dukhan David
• Brandt Guillaume
• Rouviere Claire Pierra
• Dousson Cyril B
• Alexandre Francois-Rene

Classifications

• A61K31/7076

  containing purines, e.g. adenosine, adenylic acid · CPC title

• A61K45/06

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

• C07H19/213 Primary

  containing cyclic phosphate · CPC title

• A61P31/14

  for RNA viruses · CPC title

• C07H19/11

  containing cyclic phosphate · CPC title