Bicyclic heterocycle compounds and their uses in therapy

Patent metadata

Field	Value
Publication number	US-9663512-B2
Application number	US-201314436364-A
Country	US
Kind code	B2
Filing date	Oct 18, 2013
Priority date	Oct 19, 2012
Publication date	May 30, 2017
Grant date	May 30, 2017

Abstract

The invention relates to new bicyclic heterocycle compounds, to pharmaceutical compositions comprising said compounds and to the use of said 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 3 , or one of X or Y is CR 3 and the other is nitrogen or X and Y are nitrogen;
R 1 is selected from
(i) N-linked pyrazolyl which is substituted on any of the carbon atoms with two substituents independently selected from C 1-4 alkyl, hydroxyl, hydroxyC 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkyl, methoxymethyl, ═O and nitrile,
(ii) C-linked pyrazolyl which is optionally substituted on a nitrogen atom with a substituent selected from C 1-4 alkyl, hydroxyC 1-4 alkyl and haloC 1-4 alkyl, and further optionally substituted on the carbon atoms with one or two substituents independently selected from C 1-4 alkyl, hydroxyl, hydroxyC 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkyl, methoxymethyl, ═O and nitrile,
(iii) imidazolyl which is optionally substituted with one or two substituents independently selected from halogen, C 1-4 alkyl, hydroxyl, hydroxyC 1-4 alkyl, C 1-4 alkyoxy, haloC 1-4 alkyl, methoxymethyl, ═O and nitrile,
(iv) pyridinyl which is substituted with two substituents independently selected from halogen, C 1-4 alkyl, hydroxyl, hydroxyC 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkyl, methoxymethyl, ═O and nitrile, and
(v) triazolyl substituted with one substituent selected from halogen, C 1-4 alkyl, hydroxyl, hydroxyC 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkyl, ═O and nitrile or two substituents independently selected from halogen, hydroxyl, hydroxyC 1-4 alkyl, C 1-4 alkyoxy, haloC 1-4 alkyl, methoxymethyl, ═O and nitrile;
R 2 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; and
R 3 is selected from hydrogen and nitrile.

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

5. A compound as defined in claim 1 , wherein R 1 is selected from:
(i) C-linked pyrazolyl which is optionally substituted on a nitrogen atom with a substituent selected from C 1-4 alkyl, hydroxyC 1-4 alkyl and haloC 1-4 alkyl, and further optionally substituted on the carbon atoms with one or two substituents independently selected from C 1-4 alkyl, hydroxyl, hydroxyC 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkyl, methoxymethyl, ═O and nitrile;
(ii) C-linked imidazolyl which is optionally substituted with one or two substituents independently selected from halogen, C 1-4 alkyl, hydroxyl, hydroxyC 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkyl, methoxymethyl, ═O and nitrile;
(iii) C-linked pyridinyl which is substituted with one or two substituents independently selected from halogen, C 1-4 alkyl, hydroxyl, hydroxyC 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkyl, methoxymethyl, ═O and nitrile; and
(iv) C-linked triazolyl substituted with one substituent selected from halogen, C 1-4 alkyl, hydroxyl, hydroxyC 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkyl, ═O and nitrile or two substituents independently selected from halogen, hydroxyl, hydroxyC 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkyl, methoxymethyl, ═O and nitrile,
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 1 is selected from:
(i) N-linked pyrazolyl which is substituted on any of the carbon atoms with two substituents independently selected from methyl, ethyl, isopropyl, hydroxyl, hydroxymethyl, methoxy, monofluoromethyl, trifluoromethyl, ═O and nitrile;
(iii) N-linked imidazolyl which is optionally substituted with one or two substituents independently selected from fluorine, chlorine, methyl, ethyl, isopropyl, hydroxyl, hydroxymethyl, methoxy, monofluoromethyl, trifluoromethyl, ═O and nitrile; and
(iv) N-linked pyridinyl which is substituted with two substituents independently selected from fluorine, chlorine, methyl, ethyl, isopropyl, hydroxyl, hydroxymethyl, methoxy, monofluoromethyl, trifluoromethyl, ═O and nitrile,
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 1 is selected from:
(i) N-linked pyrazolyl which is substituted on two of the carbon atoms with a methyl substituent;
(iii) N-linked imidazolyl which is optionally substituted with one or two substituents independently selected from chlorine, methyl, ethyl, hydroxymethyl, trifluoromethyl and nitrile; and
(iv) N-linked pyridinyl which is substituted with two substituents selected from methyl and ═O,
or a tautomeric or stereochemically isomeric form, N-oxide, pharmaceutically acceptable salt or solvate thereof.

8. A compound as defined in claim 1 , wherein R 1 is selected from:
(i) N-linked pyrazolyl which is substituted on two of the carbon atoms with a methyl substituent;
(iii) N-linked imidazolyl which is substituted with one or two substituents independently selected from chlorine, methyl, ethyl, hydroxymethyl, trifluoromethyl and nitrile; and
(iv) N-linked pyridinyl which is substituted with two substituents selected from methyl and ═O,
or a tautomeric or stereochemically isomeric form, N-oxide, pharmaceutically acceptable salt or solvate thereof.

9. A compound as defined in claim 5 , wherein R 1 is a C-linked pyrazolyl which is optionally substituted on a nitrogen atom with a substituent selected from C 1-4 alkyl, hydroxyC 1-4 alkyl and haloC 1-4 alkyl, and further optionally substituted on the carbon atoms with one or two substituents independently selected from C 1-4 alkyl, hydroxyl, hydroxyC 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkyl, methoxymethyl, ═O and nitrile,
or a tautomeric or stereochemically isomeric form, N-oxide, pharmaceutically acceptable salt or solvate thereof.

10. A compound as defined in claim 9 , wherein when R 1 represents a C-linked pyrazolyl which is substituted on a nitrogen atom with a substituent, said substituent is selected from C 1-4 alkyl, hydroxyC 1-4 alkyl and haloC 1-4 alkyl, and further optionally substituted on the carbon atoms with one or two substituents independently selected from C 1-4 alkyl, hydroxyl, hydroxyC 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkyl, methoxymethyl, ═O and nitrile,
or a tautomeric or stereochemically isomeric form, N-oxide, pharmaceutically acceptable salt or solvate thereof.

11. A compound as defined in claim 10 , wherein when R 1 represents a C-linked pyrazolyl, said pyrazolyl is substituted on one nitrogen atom by a C 1-4 alkyl substituent and optionally substituted on one carbon atom by a C 1-4 alkyl substituent,
or a tautomeric or stereochemically isomeric form, N-oxide, pharmaceutically acceptable salt or solvate thereof.

12. A compound as defined in clai

Assignees

• Astex Therapeutics Ltd

Inventors

• Chessari Gianni
• Johnson Christopher Norbert
• Page Lee William
• Millemaggi Alessia
• Howard Steven
• Saxty Gordon
• Heightman Thomas Daniel

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07D487/04

  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

• C07D403/14 Primary

  containing three or more hetero rings · CPC title