Bicyclic heterocycle compounds and their uses in therapy

Patent metadata

Field	Value
Publication number	US-9980973-B2
Application number	US-201715411463-A
Country	US
Kind code	B2
Filing date	Jan 20, 2017
Priority date	Oct 19, 2012
Publication date	May 29, 2018
Grant date	May 29, 2018

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 method of treating a disease state or condition mediated by inhibitor of apoptosis protein (IAP), the method comprising administering to a subject in need thereof 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 method according to claim 1 , wherein X and Y are both nitrogen; X is nitrogen and Y is CH; or X is CH and Y is nitrogen.

3. A method according to claim 2 , wherein X is nitrogen and Y is CH.

4. A method according to claim 2 , wherein X is CH and Y is nitrogen.

5. A method according to 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.

6. A method according to 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.

7. A method according to 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.

8. A method according to 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.

9. A method according to 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.

10. A method according to 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.

11. A method according to 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.

12. A method according to claim 11 , wherein when R 1 represents a C-linked pyrazolyl, said pyrazolyl is substituted on one nitrogen atom by a methyl substituent and substituted on one carbon atom by a methyl substituent.

13. A method according to claim 12 , wherein when R 1 represents a C-linked pyrazolyl, said R 1 group is 1,3-dimethyl-1H-pyrazol-5-yl.

14. A method according to claim 1 , wherein R 2 is selected from 4-fluorobenzyl, 2,4-difluorobenzyl, 2-cyano-4-fluorobenzyl, 1,1-difluoropropyl and 1,1-difluorobutyl.

15. A method according to claim 1 , wherein the compound is a compound of formula (Ie):

or a tautomeric or stereochemically isomeric form, N-oxide, pharmaceutically acceptable salt or solvate thereof;
wherein R 4 is independently selected from C 1-4 alkyl, hydroxyC 1-4 alkyl and haloC 1-4 alkyl when on an nitrogen atom and selected from C 1-

Assignees

• Astex Therapeutics Ltd

Inventors

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

Classifications

• A61K31/553 Primary

  having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine · CPC title

• A61K31/5025

  ortho- or peri-condensed with heterocyclic ring systems · CPC title

• A61K31/541

  Non-condensed thiazines containing further heterocyclic rings · CPC title

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title

• A61K31/5375

  1,4-Oxazines, e.g. morpholine · CPC title