RSV antiviral compounds

Patent metadata

Field	Value
Publication number	US-9617289-B2
Application number	US-201314435604-A
Country	US
Kind code	B2
Filing date	Oct 15, 2013
Priority date	Oct 16, 2012
Publication date	Apr 11, 2017
Grant date	Apr 11, 2017

Abstract

Inhibitors of RSV replication of formula RI

including stereochemically isomeric forms, and salts or solvates thereof, wherein R 22 , W, Q, V, Z p, s, and Het have the meaning as defined herein.

The present invention also relates to processes for preparing said compounds, pharmaceutical compositions containing them and their use, alone or in combination with other RSV inhibitors, in RSV therapy.

First claim

The invention claimed is:

1. The compound according to formula (RI)

wherein Het is selected from the group consisting of: formula (a′), (b′), (c′), and (d′):

wherein each X independently is C or N; wherein at least one X is N;
each of R 1a , R 1b , R 1c , R 1d is halogen; and R 1b or R 1d is absent when the X to which it is bound is N;
each R 2 is —(CR 8 R 9 ) m —R 10 ;
m is an integer from 0 to 6;
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 are taken together form a 4 to 6 membered saturated ring that optionally contains one or more heteroatoms selected from the group consisting of: N, S and O;
each R 10 is independently selected from the group consisting of: H, halogen, OH, CN, CF 2 H, CF 3 , C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C(═O)C 1 -C 6 alkyl, C(═O)C 3 -C 7 cycloalkyl, C(═O)NR 8 R 9 , C(═O)OR 8 , SO 2 R 8 , C(═O)N(R 8 )SO 2 R 9 , C(═O)N(R 8 )SO 2 N(R 8 R 9 ), NR 8 R 9 , NR 8 C(═O)OR 9 , OC(═O)R 8 , O-benzyl, NR 8 SO 2 R 9 , SO 2 NR 8 R 9 , SO 2 R 8 , OC(═O)NR 8 R 9 , OC(═O)NR 8 R 12 , N(R 8 )C(═O)N(R 8 R 9 ), R 11 , N(R 8 )C(═O)OR 12 , OR 11 , C(═O)R 11 , and a 4 to 6 membered saturated ring containing one oxygen atom;
R 11 phenyl, pyridinyl or pyrazolyl; wherein each phenyl, pyridinyl or pyrazolyl can be 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 12 is C 1 -C 6 alkyl or C 3 -C 7 cycloalkyl; wherein each C 1 -C 6 alkyl or C 3 -C 7 cycloalkyl is substituted with one or more substituents each independently selected from the group consisting of: CF 3 , CH 3 , OCH 3 , OCF 3 , and halogen;
each Z independently is C or N, provided that at least two Z are C;
Q and V each independently represent C═O, SO 2 or CR 20 R 21 ;
p and s independently represent an integer from 0 to 3, wherein the sum of p and s minimally should be 2, and when p=0 or s=0 then the carbon atom marked with * is directly bound to W;
R 20 and R 21 are each independently selected from the group consisting of: hydrogen, hydroxyl, C 1 -C 3 alkyl, C 3 -C 7 cycloalkyl, CF 3 , OCH 3 , OCF 3 , and halogen;
R 22 is selected from the group consisting of: hydrogen, hydroxyl, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, CF 3 , OCH 3 , OCF 3 , and halogen;
W is selected from the group consisting of: SO, SO 2 , S, C, O, and N, wherein such C or N is optionally substituted with one or more R 23 ;
R 23 is selected from the group consisting of: hydrogen, hydroxyl, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl-R 24 , SO 2 R 24 SO 2 N(R 24 ) 2 , aryl, heteroaryl, C(═O)OR 24 , OR 24 , C(═O)R 24 , C(═O)N(R 24 ) 2 , OC(═O)N(R 24 ) 2 , P(═O)—(O—C 1 -C 6 -alkyl) 2 , N(R 24 ) 2 , NR 25 C(═O)OR 24 , NR 25 C(═O)N(R 24 ) 2 , NR 25 SO 2 R 24 , and a 4 to 6 membered saturated ring containing one oxygen atom, wherein any of such C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, aryl or heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of: halogen, OH, CN, and OCH 3 ;
R 24 is selected from the group of: hydrogen, OH, halogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C(═O) C 1 -C 6 alkyl, C(═O) C 3 -C 7 cycloalkyl, aryl, heteroaryl, benzyl, and a 4 to 6 membered saturated ring containing one oxygen atom; wherein any of such C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C(═O) C 1 -C 6 alkyl, C(═O) C 3 -C 7 cycloalkyl, aryl, heteroaryl, and benzyl is optionally substituted with one or more substituents each independently selected from the group consisting of: halogen, CF 3 , OH, CN, OCH 3 , OC(═O)CH 3 ), and C 1 -C 3 alkyl substituted with at least one CN;
R 25 is selected from the group consisting of hydrogen and C 1 -C 3 alkyl;
aryl represents phenyl or naphthalenyl;
heteroaryl 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;
or a pharmaceutically acceptable addition salt or a solvate thereof.

2. The compound according to claim 1 , wherein for Formula (b′) and (d′), one X is N.

3. A compound according to claim 1 , wherein each of R 1a , R 1b , R 1c or R 1d is independently selected from the group consisting of: chloro, bromo and fluoro.

4. A compound according to claim 1 , wherein each of R 1a , R 1b , R 1c or R 1d is chloro.

5. A compound according to claim 1 , wherein R 2 is —(CR 8 R 9 ) m —R 10 ; m is an integer from 1 to 4; and each of R 8 and R 9 is independently selected from: H or C 1 -C 6 alkyl.

6. A compound according to claim 1 , wherein R 2 is C 1 -C 6 alkyl-R 10 .

7. A compound according to claim 6 , wherein R 10 is selected from the group consisting of: C 1 -C 3 alkyl, H, OH, CN, F, CF 2 H, CF 3 , SO 2 —C 1 -C 3 alkyl, and SO 2 C 3 -C 6 cycloalkyl.

8. A compound according to claim 1 , wherein the compound has the Formula selected from the group consisting of: RII, RIII, RIV, RV, RVI and RVII:

or any stereoisomeric form thereof.

9. The compound as claimed in claim 8 wherein R 23 is selected from the group consisting of hydrogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 3 alkyl-R 24 , SO 2 R 24 , O—R 24 , phenyl, pyridinyl pyrimidyl, pyrazolyl, C(═O)OR 24 , and C(═O)R 24 , wherein any of such C 1 -C 6 alkyl, phenyl, pyridinyl, pyrimidyl, and pyrazolyl is optionally substituted with one or more members each independently selected from the group consisting of: OCH 3 , halogen, OH and CN.

10. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, and as active ingredient a compound as claimed in claim 1 .

11. A method for treating viral RSV infections comprising administering to a subject in need thereof, a therapeutically effective amount of a compound as claimed in claim 1 .

12. A method for treating viral RSV infections comprising administering to a subject in need thereof, a therapeutically effective amount of a composition as claimed in claim 10 .

13. The compound selected from the group consisting of:
tert-butyl 1′-({5-chloro-1-[3-(methylsulfonyl)propyl]-1H-indol-2-yl}methyl)-2′-oxo-1′,2′-dihydro-1H-spiro[piperidine-4,3′-pyrrolo[2,3-c]pyridine]-1-carboxylate;
1′-({5-chloro-1-[3-(methylsulfonyl)propyl]-1H-indol-2-yl}methyl)spiro[piperidine-4,3′-pyrrolo[2,3-c]pyridin]-2′(1′H)-one;
1′-({5-chloro-1-[3-(methylsulfonyl)propyl]-1H-indol-2-yl}methyl)spiro[piperidine-4,3′-pyrrolo[2,3-c]pyridin]-2′(1′H)-one;
tert-butyl 1′-({5-chloro-1-[3-(methylsulfonyl)propyl]-1H-benzimidazol-2-yl}methyl)-2′-oxo-1′,2′-dihydro-1H-spiro[azetidine-3,3′-indole]-1-carboxylate;
1′-({5-chloro-1-[3-(methylsulfonyl)propyl]-1H-benzimidazol-2-yl}methyl)spiro[azetidine-3,3′-indol]-2′(1′H)-one;
1′-({5-chloro-1-[3-(methylsulfonyl)propyl]-1H-benzimidazol-2-yl}methyl)-1-(2-hydroxy-2-methylpropanoyl)spiro[azetidine-3,3′-indol]-2′(1′H)-one;
1′-({5-chloro-1-[3-(methylsulfonyl)propyl]-1H-benzimidazol-2-yl}methyl)-1-(pyridin-3-yl)spiro[azetidine-3,3′-indol]-2′(1′H)-one;
1′-({5-chloro-1-[3-

Assignees

• Janssen R&D Ireland
• Janssen Sciences Ireland Uc

Inventors

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

Classifications

• A61P31/14

  for RNA viruses · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title

• A61P31/12

  Antivirals · CPC title

• C07D491/20

  Spiro-condensed systems · CPC title

• C07D491/107

  with only one oxygen atom as ring hetero atom in the oxygen-containing ring · CPC title