1,3-dihydro-2H-benzimidazol-2-one derivatives substituted with heterocycles as respiratory syncytial virus antiviral agents

Patent metadata

Field	Value
Publication number	US-9845321-B2
Application number	US-201614991815-A
Country	US
Kind code	B2
Filing date	Jan 8, 2016
Priority date	Jun 15, 2012
Publication date	Dec 19, 2017
Grant date	Dec 19, 2017

Abstract

The present invention is concerned with novel 1,3-dihydro-2H-benzimidazol-2-one derivatives substituted with heterocycles having formula (I)

stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvates thereof,

wherein R 4 , R 5 , Z and Het have the meaning defined in the claims. The compounds according to the present invention are useful as inhibitors on the replication of the respiratory syncytial virus (RSV). The invention further concerns the preparation of such novel compounds, compositions comprising these compounds, and the compounds for use in the treatment of respiratory syncytial virus infection.

First claim

The invention claimed is:

1. A compound of Formula (I),

or a stereoisomeric form thereof, wherein
Het is a heterocycle having formula (cc):

m is an integer from 2 to 6;
wherein R 1cc is chloro and each R 1c is H;
R 3c is selected from the group consisting of H, halogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyloxy and CO(R 7c );
R 2c is —(CR 8 R 9 ) m —R 10c ;
R 7c is selected from the group consisting of OH, O(C 1 -C 6 alkyl), NH 2 , NHSO 2 N(C 1 -C 6 alkyl) 2 , NHSO 2 NHCH 3 , NHSO 2 (C 1 -C 6 alkyl), NHSO 2 (C 3 -C 7 cycloalkyl), N(C 1 -C 6 -alkyl) 2 , NR 8 R 9 and NR 9 R 10c ;
each R 8 and R 9 are independently selected from the group consisting of H, C 1 -C 10 alkyl and C 3 -C 7 cycloalkyl; or R 8 and R 9 taken together form a 4 to 6 membered aliphatic ring that optionally contains one or more heteroatoms selected from the group consisting of N, S and O;
R 10c is selected from the group consisting of H, R 11 , OH, CN, F, CF 2 H, CF 3 , C(═NOH)NH 2 , CONR 8 R 9 , COOR 8 , CONR 8 SO 2 R 9 , CON(R 8 )SO 2 N(R 8 R 9 ), NR 8 R 9 , NR 8 COOR 9 , OCOR 8 , NR 8 SO 2 R 9 , SO 2 NR 8 R 9 , SO 2 R 8 and a 4 to 6 membered saturated ring containing one oxygen atom;
R 11 is selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, phenyl, pyridinyl and pyrazolyl; each optionally substituted with one or more substituents each independently selected from the group consisting of CF 3 , CH 3 , OCH 3 , OCF 3 and halogen;
R 4 is selected from the group consisting of tert-butyl, Het 1 , aryl, Het 2 , CH(CH 3 )(CF 3 ), and C 3 -C 7 cycloalkyl substituted with one or more substituents selected from the group consisting of halo and C 1 -C 4 alkyl;
aryl represents phenyl or naphthalenyl; wherein said phenyl or naphthalenyl is optionally substituted with one or more substituents each independently selected from the group consisting of halo, C 1 -C 4 alkyloxy, C 1 -C 4 alkyl, OH, CN, CF 2 H, CF 3 , CF 3 O, CONR 8 R 9 , COOR 8 , CON(R 8 )SO 2 R 9 , CON(R 8 )SO 2 N(R 8 R 9 ), NR 8 R 9 , NR 8 COOR 9 , OCOR 8 , NR 8 SO 2 R 9 , SO 2 NR 8 R 9 , SO 2 R 8 , OCONR 8 R 9 , OCONR 8 R 12 , N(R 8 )CON(R 8 R 9 ), N(R 8 )COOR 12 and C 1-4 alkyloxyC 1-4 alkyloxy;
Het 1 represents a 4 to 6 membered saturated ring containing one N atom, optionally being substituted with one or more substituents each independently selected from the group consisting of halo, C 1 -C 4 alkyloxy, SO 2 R 8 , C 1 -C 4 alkylcarbonyl, CO(aryl), COHet 2 , C 1 -C 4 alkyloxycarbonyl, pyridinyl, CF 3 , SO 2 N(C 1 -C 4 alkyl) 2 , SO 2 NH(C 1 -C 4 alkyl), (C═O)NH(C 1-4 alkyl), (C═S)NH(C 1-4 alkyl), C 1 -C 4 alkyl and C 1 -C 4 alkyl substituted with one hydroxy; or
Het 1 represents a 4 to 6 membered saturated ring containing one O atom, substituted with one or more substituents each independently selected from the group consisting of halo, C 1 -C 4 alkyloxy, CF 3 , NH(C═O)(C 1-4 alkyl), (C═O)NH(C 1-4 alkyl) and C 1 -C 4 alkyl; or
Het 1 represents a bicyclic 7 to 11 membered non-aromatic heterocycle containing one or two heteroatoms each independently selected from the group consisting of O, S and N, optionally substituted with one or more substituents each independently selected from the group consisting of halo, C 1 -C 4 alkyloxy, SO 2 R 8 , C 1 -C 4 alkylcarbonyl, CO(aryl), COHet 2 , C 1 -C 4 alkyloxycarbonyl, pyridinyl, CF 3 , SO 2 N(C 1 -C 4 alkyl) 2 , SO 2 NH(C 1 -C 4 alkyl), (C═O)NH(C 1-4 alkyl), (C═S)NH(C 1-4 alkyl), C 1 -C 4 alkyl and C 1 -C 4 alkyl substituted with one hydroxy;

Het 2 represents a monocyclic 5 to 6 membered aromatic heterocycle containing one or more heteroatoms each independently selected from the group consisting of O, S and N; or a bicyclic 8 to 12 membered aromatic heterocycle containing one or more heteroatoms each independently selected from the group consisting of O, S and N; said Het 2 optionally being substituted with one or more substituents each independently selected from the group consisting of halo, C 1 -C 4 alkyloxy, C 1 -C 4 alkyl, OH, CN, CF 2 H, CF 3 , CONR 8 R 9 , COOR 8 , CON(R 8 )SO 2 R 9 , CON(R 8 )SO 2 N(R 8 R 9 ), NR 8 R 9 , NR 8 COOR 9 , OCOR 8 , NR 8 SO 2 R 9 , SO 2 NR 8 R 9 , SO 2 R 8 , OCONR 8 R 9 , OCONR 8 R 12 , N(R 8 )CON(R 8 R 9 ), and N(R 8 )COOR 12 ;
Z is N; and R 5 is absent; and
pharmaceutically acceptable addition salts thereof.

2. The compound according to claim 1 , wherein
Het is a heterocycle having formula (cc);
each R 8 and R 9 are independently chosen from the group consisting of H and C 1 -C 10 alkyl;
R 3c is selected from the group consisting of H, halogen and C 1 -C 6 alkyl;
R 10c is selected from the group consisting of H, C 1 -C 6 alkyl, OH, CN, F, CF 2 H, CF 3 , NR 8 R 9 , SO 2 NR 8 R 9 and SO 2 R 8 ;
aryl represents phenyl or naphthalenyl; said aryl optionally being substituted with one or more substituents each independently selected from the group consisting of halo, C 1 -C 4 alkyloxy, C 1 -C 4 alkyl, OH, CN, CF 2 H, CF 3 , CONR 8 R 9 , NR 8 R 9 , NR 8 COOR 9 , SO 2 NR 8 R 9 , SO 2 R 8 , OCONR 8 R 9 , OCONR 8 R 12 and N(R 8 )COOR 12 ;
Het 1 represents a 4 to 6 membered saturated ring containing one N atom, optionally being substituted with one or more substituents each independently selected from the group consisting of halo, C 1 -C 4 alkyloxy, CF 3 , SO 2 R 8 , C 1 -C 4 alkylcarbonyl, C 1 -C 4 alkyloxycarbonyl, pyridinyl, SO 2 N(C 1 -C 4 alkyl) 2 , SO 2 NH(C 1 -C 4 alkyl), (C═O)NH(C 1-4 alkyl), (C═S)NH(C 1-4 alkyl), C 1 -C 4 alkyl and C 1 -C 4 alkyl substituted with one hydroxy; or
Het 1 represents a 4 to 6 membered saturated ring containing one O atom, substituted with one or more substituents each independently selected from the group consisting of halo, C 1 -C 4 alkyloxy, CF 3 , NH(C═O)(C 1-4 alkyl), (C═O)NH(C 1-4 alkyl) and C 1 -C 4 alkyl; and
Het 2 represents a monocyclic 5 to 6 membered aromatic heterocycle containing one or more heteroatoms each independently selected from the group consisting of O, S and N; or a bicyclic 8 to 12 membered aromatic heterocycle containing one or more heteroatoms each independently selected from the group consisting of O, S and N; said Het 2 optionally being substituted with one or more substituents each independently selected from the group consisting of halo, C 1 -C 4 alkyloxy, C 1 -C 4 alkyl, OH, CN, CF 2 H, CF 3 , CONR 8 R 9 , NR 8 R 9 , NR 8 COOR 9 , SO 2 NR 8 R 9 , SO 2 R 8 , OCONR 8 R 9 , OCONR 8 R 12 and N(R 8 )COOR 12 ;
and a pharmaceutically acceptable addition salt thereof.

3. The compound according to claim 1 , wherein R 4 is selected from the group consisting of Het 1 , aryl, Het 2 , and C 3 -C 7 cycloalkyl substituted with one or more substituents selected from the group consisting of halo and C 1 -C 4 alkyl.

4. The compound according to claim 3 wherein R 4 is Het 1 .

5. The compound according to claim 3 wherein R 4 is Het 2 .

6. The compound according to claim 3 wherein R 4 is aryl.

7. The compound according to claim 6 wherein aryl is phenyl optionally being substituted with one or more substituents each independently selected from the group consisting of halo, C 1 -C 4 alkyloxy, C 1 -C 4 alkyl, CN, CONR 8 R 9 , COOR 8 and SO 2 R 8 .

8. The compound according to claim 7 wherein aryl is phenyl substituted with two substituents each independently selected from the group consisting of halo, C 1 -C 4 alkyloxy and C 1 -C 4 alkyl.

9. The compound according to claim 8 whe

Assignees

• Janssen Sciences Ireland Uc

Inventors

• Tahri Abdellah
• Jonckers Tim Hugo Maria
• Raboisson Pierre Jean-Marie Bernard
• Vendeville Sandrine Marie Helene
• Hu Lili
• Demin Samuel Dominique
• Cooymans Ludwig Paul

Classifications

• A61P31/12

  Antivirals · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title

• C07D403/14 Primary

  containing three or more hetero rings · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• A61K31/437

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title