Bicyclic heterocycle compounds and their uses in therapy

Patent metadata

Field	Value
Publication number	US-9783538-B2
Application number	US-201415105360-A
Country	US
Kind code	B2
Filing date	Dec 19, 2014
Priority date	Dec 20, 2013
Publication date	Oct 10, 2017
Grant date	Oct 10, 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 a stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof;
wherein
X is CR 4 , N or NR 3 ;
wherein
when X is CR 4 , then U represents nitrogen and R 6 represents oxo; or
when X is N, then U represents carbon and R 6 represents hydroxymethyl or—CH(OR x )CH 2 OR z ; or
when X is NR 3 , then U represents carbon and R 6 represents oxo;

dashed bond ( ) represents a single or double bond wherein at least two of said dashed bonds represent a double bond;
R 1 and R 2 independently represent hydrogen or methyl;
R 3 represents hydrogen, methyl or —NH 2 ;
R 4 represents hydrogen, methyl, hydroxymethyl, —NH 2 or fluorine;
R 5 represents unsubstituted n-butyl or benzyl substituted on the phenyl group by one or two fluorines; and
R x and R z independently represent hydrogen or methyl.

2. A compound as defined in claim 1 , wherein one of R 1 and R 2 represents hydrogen and the other represents methyl or R 1 and R 2 both represent hydrogen, or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof.

3. A compound as defined in claim 1 , wherein R 1 and R 2 both represent hydrogen, or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof.

4. A compound as defined in claim 1 , wherein R 4 represents hydrogen or methyl, or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof.

5. A compound as defined in claim 1 , wherein R 5 represents unsubstituted n-butyl or benzyl substituted by one or two fluorines on the 2, 3 and/or 4 positions of the phenyl group, or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof.

6. A compound as defined in claim 5 , wherein R 5 represents unsubstituted n-butyl, or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof.

7. A compound as defined in claim 5 , wherein R 5 represents
(i) 2-fluorobenzyl, 3-fluorobenzyl or 4-fluorobenzyl; or
(ii) benzyl substituted by one fluorine on the 4 position of the phenyl group; or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof.

8. A compound as defined in claim 5 , wherein R 5 represents
(i) 2,3-difluorobenzyl 3,4-difluorobenzyl or 2,4-difluorobenzyl; or
(ii) benzyl substituted by two fluorines on the 2,4 positions of the phenyl group;
or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof.

9. A compound as defined in claim 5 , wherein R 5 represents unsubstituted n-butyl, 4-fluorobenzyl or 2,4-difluorobenzyl, or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof.

10. A compound as defined in claim 9 , wherein R 5 represents 4-fluorobenzyl, or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof.

11. A compound as defined in claim 1 , wherein one of R x and R z represents hydrogen and the other represents methyl or R x and R z both represent hydrogen, or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof.

12. A compound as defined in claim 11 , wherein R x represents hydrogen or methyl and R z represents hydrogen, or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof.

13. A compound as defined in claim 1 , which is a compound of formula (Ia):

or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof.

14. A compound as defined in claim 1 , which is a compound of formula (Ib):

or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof; wherein R 6 represents hydroxymethyl or —CH(OR x )CH 2 OR z .

15. A compound as defined in claim 1 , which is a compound of formula (Ic):

or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof.

16. A compound as defined in claim 1 , which is a compound of formula (Id):

or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof.

17. A compound as defined in claim 1 , wherein the compound is selected from:

or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof.

18. A compound as defined in claim 1 , wherein the compound is:

or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof.

19. A compound as defined in claim 1 , wherein the compound is a lactate, mesylate or sulfate salt of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one.

20. A compound as defined in claim 1 , wherein the compound is the L-(+)-lactate salt of 1-{6-[(4-Fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one.

21. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 1 , or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof, and a pharmaceutically acceptable excipient.

22. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 1 , or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof, in combination with one or more therapeutic agents.

23. A pharmaceutical composition comprising a compound as defined in claim 18 , or a tautomeric o

Assignees

• Astex Therapeutics Ltd

Inventors

• Chessari Gianni
• Johnson Christopher Norbert
• Howard Steven
• Day James Edward Harvey
• Buck Ildiko Maria
• Griffiths-Jones Charlotte Mary
• Saxty Gordon
• Tamanini Emiliano
• Wilsher Nicola Elisabeth

Classifications

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P37/02

  Immunomodulators · CPC title