Bicyclic heterocycle compounds and their uses in therapy

Patent metadata

Field	Value
Publication number	US-9617248-B2
Application number	US-201314436319-A
Country	US
Kind code	B2
Filing date	Oct 18, 2013
Priority date	Oct 19, 2012
Publication date	Apr 11, 2017
Grant date	Apr 11, 2017

Abstract

The invention relates to new bicyclic heterocycle compounds, to pharmaceutical compositions comprising the compounds and to the use of the compounds in the treatment of diseases, e.g. cancer.

First claim

The invention claimed is:

1. A compound of formula (I):

or a tautomeric or stereochemically isomeric form, N-oxide, pharmaceutically acceptable salt or solvate thereof; wherein
X is CH and Y is CR 9 , or one of X or Y is CR 9 and the other is nitrogen, or X and Y are nitrogen;
W is either absent or selected from CR 6 R 7 , CH 2 —CH 2 , CH 2 —O, O—CH 2 , C═O, SO 2 , O, NR 8 , CH 2 —NR 8 and NR 8 —CH 2 ;
when W is CR 6 R 7 , CH 2 —CH 2 , CH 2 —O, O—CH 2 , C═O, SO 2 , CH 2 —NR 8 or NR 8 —CH 2 ,
then R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a and R 4b are independently selected from hydrogen, halogen, C 1-4 alkyl, carboxyl, hydroxyl, hydroxyC 1-4 alkyl, C 1-4 alkyoxy, C 3-6 cycloalkyl, haloC 1-4 alkyl, methoxymethyl and nitrile,
or R 2a and R 2b , or R 4a and R 4b can together represent ═O,
or R 1a and R 1b , R 2a and R 2b , R 3a and R 3b or R 4a and R 4b can join together to form cyclopropyl or oxetanyl,
or R 1a and R 3a , or R 1a and R 2a , or R 2a and R 3a , or R 2a and R 4a , or R 3a and R 4a , or R 1b and R 3b , or R 1b and R 2b , or R 2b and R 3b , or R 2b and R 4b , or R 3b and R 4b can join together to form a C 1-4 bridged alkyl group,
when W is NR 8 ,
then R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a and R 4b are independently selected from hydrogen, halogen, C 1-4 alkyl, carboxyl, hydroxyl, hydroxyC 1-4 alkyl, C 1-4 alkyoxy, C 3-6 cycloalkyl, haloC 1-4 alkyl, methoxymethyl and nitrile,
or R 2a and R 2b , or R 4a and R 4b can together represent ═O,
or R 1a and R 1b , R 2a and R 2b , R 3a and R 3b or R 4a and R 4b can join together to form cyclopropyl or oxetanyl,
or R 1a and R 3a , or R 1a and R 2a , or R 2a and R 3a , or R 2a and R 4a , or R 3a and R 4a , or R 1b and R 3b , or R 1b and R 2b , or R 2 b and R 3 b, or R 2 b and R 4 b, or R 3b and R 4b can join together to form a C 1-4 bridged alkyl group,
or R 2a/2b or R 4a/4b can join together with the nitrogen atom at W to form a fused heterocyclic group with 5 or 6 ring members which can be optionally substituted by one or more substituents R 10 ,
provided that when X and Y are other than both nitrogen, R 4a and R 4b do not together represent ═O when R 5 is 1,1-difluoroethyl and R 8 is methyl;
when W is O,
then R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a , and R 4b are independently selected from hydrogen, halogen, C 1-4 alkyl, carboxyl, hydroxyl, hydroxyC 1-4 alkyl, C 1-4 alkyoxy, C 3-6 cycloalkyl, haloC 1-4 alkyl, methoxymethyl and nitrile,
or R 2a and R 2b , or R 4a and R 4b can together represent ═O,
or R 1a and R 1b , R 2a and R 2b , R 3a and R 3b or R 4a and R 4b can join together to form cyclopropyl or oxetanyl,
or R 1a and R 3a , or R 1a and R 2a , or R 2a and R 3a , or R 2a and R 4a , or R 3a and R 4a , or R 1b and R 3b , or R 1b and R 2b , or R 2b and R 3b , or R 2b and R 4b , or R 3b and R 4b can join together to form a C 1-4 bridged alkyl group,
provided that when X and Y are other than both nitrogen:
R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a and R 4b are not all hydrogen, or
when one of R 1a or R 1b or R 3a or R 3b is methyl or ethyl the remaining R 1a , R 1b , R 2a , R 2b , R 3a , R 3 b, R 4a and R 4b groups are not all hydrogen, or
when R 2a and R 4a are methyl then R 1a , R 1b , R 2b , R 3a , R 3b and R 4b are not all hydrogen, or
R 1a or R 3b is not methoxymethyl when R 5 is 1,1-difluoropropyl;

when W is absent,
then R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a and R 4b are independently selected from hydrogen, halogen, C 1-4 alkyl, carboxyl, hydroxyl, hydroxyC 1-4 alkyl, C 1-4 alkyoxy, C 3-6 cycloalkyl, haloC 1-4 alkyl, methoxymethyl and nitrile,
or R 2a and R 2b , or R 4a and R 4b can together represent ═O,
or R 1a and R 1b , R 2a and R 2b , R 3a and R 3b or R 4a and R 4b can join together to form cyclopropyl or oxetanyl,
or R 1a and R 3a , or R 1a and R 2a , or R 2a and R 3a , or R 2a and R 4a , or R 3a and R 4a , or R 1b and R 3b , or R 1b and R 2b , or R 2b and R 3b , or R 2b and R 4b , or R 3b and R 4b can join together to form a C 1-4 bridged alkyl group,
or R 2a/2b and R 4a/4b can join together to form a fused phenyl or pyridinyl group which can be optionally substituted by one or more substituents R 10 ,
provided that when X and Y are other than both nitrogen:
R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a and R 4b are not all hydrogen, or
when one of R 2a or R 2b or R 4a or R 4b is fluorine the remaining R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a and R 4b groups are not all hydrogen, or
when R 2a and R 2b , or R 4a and R 4b join to form ═O then the remaining R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a and R 4b groups are not all hydrogen, or
R 2a and R 2b , or R 4a and R 4b are not both fluorine when R 5 is 2,4-difluorobenzyl;

R 5 is selected from: benzyl optionally substituted on the phenyl group by one or two substituents selected from fluorine and nitrile, and optionally substituted on the methylene by hydroxyl; and
C 2-4 alkyl substituted by one or two substituents selected from fluorine and hydroxyl;
R 6 and R 7 are independently selected from hydrogen, hydroxyl and fluorine;
R 8 is selected from hydrogen, C 1-4 alkyl, —SO 2 -C 1-4 alkyl, —SO 2 —NH(C 1-4 alkyl), —SO 2 —N(C 1-4 alkyl) 2 , —C(═O)—NH—SO 2 -C 1-4 alkyl, —C(═O)—NH—SO 2 -phenyl, —C(═O)—N(C 1-4 alkyl) 2 , pyrimidinyl, —C(═O)-phenyl, —C(═O)—C 3-6 cycloalkyl and —C(═O)—C 1-4 alkyl, wherein the alkyl or cyclic groups can be optionally substituted by one or more R 10 ;
R 9 is selected from hydrogen and nitrile; and
R 10 is independently selected from hydrogen, halogen, C 1-4 alkyl, carboxyl, hydroxyl, hydroxyC 1-4 alkyl, C 1-4 alkyoxy, C 3-6 cycloalkyl, haloC 1-4 alkyl, methoxymethyl and nitrile.

2. A compound as defined in claim 1 , wherein X and Y are both nitrogen; X is nitrogen and Y is CR 9 ; or X is CR 9 and Y is nitrogen,
or a tautomeric or stereochemically isomeric form, N-oxide, pharmaceutically acceptable salt or solvate thereof.

3. A compound as defined in claim 2 , wherein X is nitrogen and Y is CH,
or a tautomeric or stereochemically isomeric form, N-oxide, pharmaceutically acceptable salt or solvate thereof.

4. A compound as defined in claim 1 , wherein W is either absent or is selected from CR 6 R 7 , CH 2 —O, C═O, SO 2 , O, NR 8 and CH 2 —NR 8 ,
or a tautomeric or stereochemically isomeric form, N-oxide, pharmaceutically acceptable salt or solvate thereof.

5. A compound as defined in claim 1 , wherein W represents O,
or a tautomeric or stereochemically isomeric form, N-oxide, pharmaceutically acceptable salt or solvate thereof.

6. A compound as defined in claim 1 , wherein R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a and R 4b independently represent hydrogen or C 1-4 alkyl,
or a tautomeric or stereochemically isomeric form, N-oxide, pharmaceutically acceptable salt or solvate thereof.

7. A compound as defined in claim 1 , wherein R 1a and R 3b both represents methyl and R 1b , R 2a , R 2b , R 3a , R 4a and R 4b each represent hydrogen,
or a tautomeric or stereochemically isomeric form, N-oxide, pharmaceutically acceptable salt or solvate thereof.

8. A compound as defined in claim 1 , wherein when W represents NR 8 :
R 1a and R 1b both represent hydrogen or

Assignees

• Astex Therapeutics Ltd

Inventors

• Chessari Gianni
• Johnson Christopher Norbert
• Page Lee William
• Buck Ildiko Maria
• Day James Edward Harvey
• Howard Steven
• Saxty Gordon
• Murray Christopher William

Classifications

• C07D471/04

  Ortho-condensed systems · 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

• A61P35/00

  Antineoplastic agents · CPC title

• C07D403/14 Primary

  containing three or more hetero rings · CPC title

• C07D413/14 Primary

  containing three or more hetero rings · CPC title