Respiratory syncytial virus inhibitors

Patent metadata

Field	Value
Publication number	US-2016272646-A1
Application number	US-201315032855-A
Country	US
Kind code	A1
Filing date	Oct 29, 2013
Priority date	Oct 29, 2013
Publication date	Sep 22, 2016
Grant date	—

Abstract

Compounds of Formula (I), wherein R 1 , R 2 , R 3 , R 4 and n are defined herein, are useful as inhibitors of RSV.

First claim

1 . A compound of Formula (I), or a racemate, enantiomer, diastereoisomer or tautomer thereof:

wherein:
R 1 is a 9 to 14 heterocycle or heteroaryl selected from the group consisting of

wherein said heteroaryl and heterocyclyl are optionally mono- or di-substituted with (C 1-6 )alkyl, halo, —CN, (C 1-6 )haloalkyl, OH, —O(C 1-6 )alkyl, —C(═O)OH, —C(═O)—O—(C 1-6 )alkyl or (C 3-7 )cycloalkyl;
or a pharmaceutically acceptable salt thereof;
R 2 is (C 1-6 )alkyl, —O—, —S— or —NR 2A ;
R 2A is H or (C 1-6 )alkyl;
R 3 is (C 1-6 )alkyl, (C 3-7 )cycloalkyl, aryl, heteroaryl, heterocyclyl, —(C 1-6 )alkyl-(C 3-7 )cycloalkyl, —(C 1-6 )alkyl-aryl, —(C 1-6 )alkyl-heteroaryl or —(C 1-6 )alkyl-heterocyclyl, wherein each said alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are optionally mono-, di- or tri-substituted with R 3A ;
or wherein R 2A and R 3 are linked together with the N to which they are attached to form a heterocycle optionally mono-, di- or tri-substituted with R 3A ;
R 3A is each independently selected from the group consisting of halo, oxo, —CN, OH, —COOH, —(C 1-6 )alkyl (optionally substituted with —OH), —O—(C 1-6 )alkyl, (C 3-7 )cycloalkyl, (C 1-6 )haloalkyl, —O—C(═O)—R 3B , —C(═O)—O—R 3B , —SO 2 NH 2 , —SO 2 —N(H)R 3B , —SO 2 —
N((C 1-6 )alkyl) 2 , —SOR 3B , —SO 2 R 3B , —C(═O)—NH 2 , —C(═O)—N(H)R 3B , —C(═O)—N((C 1-6 )alkyl) 2 , —C(═O)—NH—SO 2 R 3B , —SO 2 —NH—
C(═O)R 3B , —NH 2 , —N(H)R 3B , —N((C 1-6 )alkyl) 2 , —NH—C(═O)R 3B , —NH—C(═O)O—R 3B , —C(═O)—R 3B , and R 3B (optionally substituted with (C 1-6 )alkyl);
R 3B is (C 1-6 )alkyl, (C 3-7 )cycloalkyl, aryl, heteroaryl or heterocyclyl;
R 4 is each independently selected from the group consisting of H, halo, —CN, OH, —COOH, —(C 1-6 )alkyl, —O—(C 1-6 )alkyl, (C 3-7 )cycloalkyl, (C 1-6 )haloalkyl, —C(═O)—O—(C 1-6 )alkyl, —SO 2 NH 2 , —SO 2 —NH(C 1-6 )alkyl, —SO 2 —
N((C 1-6 )alkyl) 2 , —SO(C 1-6 )alkyl, —SO 2 (C 1-6 )alkyl, —C(═O)—NH 2 , —C(═O)—NH(C 1-6 )alkyl, —C(═O)—N((C 1-6 )alkyl) 2 , —C(═O)—NH—SO 2 (C 1-6 )alkyl, —SO 2 —NH—C(═O)—
(C 1-6 )alkyl, —NH 2 , —NH(C 1-6 )alkyl, —N((C 1-6 )alkyl) 2 , —NH(C 3-7 )cycloalkyl, —N((C 1-6 )alkyl)(C 3-7 )cycloalkyl, —NH—C(═O)(C 1-6 )alkyl, —NH—C(═O)O(C 1-6 )alkyl and R 4a ;
R 4a is —(C 1-6 )alkyl-heterocyclyl, —(C 1-6 )alkyl-heteroaryl, heterocyclyl or heteroaryl, wherein each said heterocyclyl and heteroaryl is optionally mono-, di- or tri-substituted with (C 1-6 )alkyl;
n is 0, 1, 2 or 3; or a salt thereof.

2 . The compound according to claim 1 , wherein
R 2 is (C 1-6 )alkyl, —O— or —NR 2A ; R 2A is H or (C 1-6 )alkyl; R 3 is aryl, heteroaryl, heterocyclyl, —(C 1-6 )alkyl-(C 3-7 )cycloalkyl, —(C 1-6 )alkyl-aryl, —(C 1-6 )alkyl-heteroaryl or —(C 1-6 )alkyl-heterocyclyl, wherein each said cycloalkyl, aryl, heteroaryl and heterocyclyl are optionally mono-, di- or tri-substituted with R 3A ; R 3A is each independently selected from the group consisting of halo, —CN, OH, —COOH, —(C 1-6 )alkyl, —O—(C 1-6 )alkyl, (C 3-7 )cycloalkyl, (C 1-6 )haloalkyl, —O—C(═O)—(C 1-6 )alkyl, —C(═O)—O—(C 1-6 )alkyl, —SO 2 NH 2 , —SO 2 —NH(C 1-6 )alkyl, —SO 2 — N((C 1-6 )alkyl) 2 , —SO(C 1-6 )alkyl, —SO 2 (C 1-6 )alkyl, —C(═O)—NH 2 , —C(═O)—NH(C 1-6 )alkyl, —C(═O)—N((C 1-6 )alkyl) 2 , —C(═O)—NH—SO 2 (C 1-6 )alkyl, —SO 2 —NH—C(═O)— (C 1-6 )alkyl, —NH 2 , —NH(C 1-6 )alkyl, —N((C 1-6 )alkyl) 2 , —NH—C(═O)(C 1-6 )alkyl, —NH—C(═O)O(C 1-6 )alkyl, heterocyclyl (optionally substituted with (C 1-6 )alkyl) and heteroaryl (optionally substituted with (C 1-6 )alkyl; or a pharmaceutically acceptable salt thereof.

3 . The compound according to claim 2 , wherein
R 2 is —O— or —NR 2A ; R 2A is H or (C 1-6 )alkyl; R 3 is heteroaryl, heterocyclyl, —(C 1-6 )alkyl-heteroaryl or —(C 1-6 )alkyl-heterocyclyl, wherein each said heteroaryl and heterocyclyl are optionally mono, di- or tri-substituted with R 3A ; R 3A is each independently selected from the group consisting of halo, oxo, —CN, OH, —COOH, —(C 1-6 )alkyl (optionally substituted with —OH), —O—(C 1-6 )alkyl, (C 3-7 )cycloalkyl, (C 1-6 )haloalkyl, —O—C(═O)—(C 1-6 )alkyl, —C(═O)—O—(C 1-6 )alkyl, —SO 2 NH 2 , —SO 2 —NH(C 1-6 )alkyl, —SO 2 —N((C 1-6 )alkyl) 2 , —SO(C 1-6 )alkyl, —SO 2 (C 1-6 )alkyl, —C(═O)—NH 2 , —C(═O)—NH(C 1-6 )alkyl, —C(═O)—N((C 1-6 )alkyl) 2 , —C(═O)—NH—SO 2 (C 1-6 )alkyl, —SO 2 —NH—C(═O)— (C 1-6 )alkyl, —NH 2 , —NH(C 1-6 )alkyl, —N((C 1-6 )alkyl) 2 , —NH—C(═O)(C 1-6 )alkyl, —NH—C(═O)O(C 1-6 )alkyl, heterocyclyl (optionally substituted with (C 1-6 )alkyl) and heteroaryl (optionally substituted with (C 1-6 )alkyl; or a pharmaceutically acceptable salt thereof.

4 . The compound according to claim 1 , wherein
R 4 is each independently selected from the group consisting of H, halo, —CN, OH, —(C 1-6 )alkyl, —O—(C 1-6 )alkyl, (C 3-7 )cycloalkyl, (C 1-6 )haloalkyl and R 4a ; R 4a is heterocyclyl or heteroaryl, wherein each said heterocyclyl and heteroaryl is optionally mono-, di- or tri-substituted with (C 1-6 )alkyl; or a pharmaceutically acceptable salt thereof.

5 . The compound according to claim 4 , wherein R 4 is each independently selected from the group consisting of H, halo, —CN, OH, —(C 1-6 )alkyl, —O—(C 1-6 )alkyl, (C 3-7 )cycloalkyl and (C 1-6 )haloalkyl; or a pharmaceutically acceptable salt thereof.

6 . The compound according to claim 1 , wherein n is 0 or 1; or a pharmaceutically acceptable salt thereof.

7 . The compound according to claim 6 , wherein n is 0; or a pharmaceutically acceptable salt thereof.

8 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, as a medicament.

9 . Use of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of RSV infection in a human being.

10 . A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

11 . A method of treatment of RSV infection comprising administering to a subject in need thereof an effective amount of a compound of claim 1 .

12 . The compound according to claim 3 , wherein
R 4 is each independently selected from the group consisting of H, halo, —CN, OH, —(C 1-6 )alkyl, —O—(C 1-6 )alkyl, (C 3-7 )cycloalkyl, (C 1-6 )haloalkyl and R 4a ; R 4a is heterocyclyl or heteroaryl, wherein each said heterocyclyl and heteroaryl is optionally mono-, di- or tri-substituted with (C 1-6 )alkyl; or a pharmaceutically acceptable salt thereof.

13 . The compound according to claim 12 , wherein R 4 is each independently selected from the group consisting of H, halo, —CN, OH, —(C 1-6 )alkyl, —O—(C 1-6 )alkyl, (C 3-7 )cycloalkyl and (C 1-6 )haloalkyl; or a pharmaceutically acceptable salt thereof.

14 . The compound according to claim 5 , wherein n is 0 or 1; or a pharmaceutically acceptable salt thereof.

15 . The compound according to claim 13 , wherein n is 0 or 1; or a pharmaceutically acceptable salt thereof.

16 . The compound according to claim 14 , wherein n is 0; or a pharmaceutically acceptable salt thereof.

17 . The compound according to claim 15 , wherein n is 0; or a pharmaceutically acceptable salt thereof.

Assignees

• Medivir Ab

Inventors

• Sturino Claudio
• Halmos Teddy
• Decor Anne
• Duplessis Martin
• Deroy Patrick
• Jakalian Araz
• Morency Louis
• Kuhn Cyrille
• Grand-Maitre Chantal
• Tremblay Martin
• Brochu Christian

Classifications

• C07D401/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• A61K31/517

  ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• A61P31/14

  for RNA viruses · CPC title