[1,2,4]triazolo[4,3-B]pyridazines for use in the treatment of proliferative diseases

Patent metadata

Field	Value
Publication number	US-10407432-B2
Application number	US-201815950443-A
Country	US
Kind code	B2
Filing date	Apr 11, 2018
Priority date	Jul 28, 2014
Publication date	Sep 10, 2019
Grant date	Sep 10, 2019

Abstract

The invention concerns compounds of Formula (I)

or pharmaceutically-acceptable salts thereof, wherein R 1 , R 2 and n have any of the meanings defined hereinbefore in the description; processes for their preparation, pharmaceutical compositions containing them and their use as anti-proliferative and/or cell-killing agents.

First claim

The invention claimed is:

1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof

wherein: —
R 1 is the group

or the group

and - - - - denotes the point of attachment;
R 2 is a C 1 -C 4 alkyl; and
n is 2 or 3.

2. A compound as claimed in claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is the group

where - - - denotes the point of attachment;
R 2 is C 1 -C 4 alkyl; and
n is 2 or 3.

3. A compound as claimed in claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is the group

where - - - - denotes the point of attachment;
R 2 is C 1 -C 4 alkyl; and
n is 2 or 3.

4. A compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is the group

where - - - - denotes the point of attachment;
R 2 is C 1 -C 4 alkyl; and
n is 2.

5. A compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof, which compound is selected from:
4-(2-(4-(1-(3-methoxy-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)ethyl)-1,3-dimethylpiperazin-2-one;
1-(4-(2-(4-(1-(3-methoxy-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)ethyl)-3,5-dimethylpiperazin-1-yl)ethanone;
4-(3-(4-(1-(3-methoxy-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)propyl)-1,3-dimethylpiperazin-2-one; and
1-(4-(3-(4-(1-(3-methoxy- [1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)propyl)-3,5-dimethylpiperazin-1-yl)ethanone.

6. A compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof, which compound is selected from:
(R)-4-(2-(4-(1-(3-methoxy-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)ethyl)-1,3-dimethylpiperazin-2-one;
1-((3S,5R)-4-(2-(4-(1-(3-methoxy-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)ethyl)-3,5-dimethylpiperazin-1-yl)ethanone;
(R)-4-(3-(4-(1-(3-methoxy-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)propyl)-1,3-dimethylpiperazin-2-one; and
1-((3R,5S)-4-(3-(4-(1-(3-methoxy-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)propyl)-3,5-dimethylpiperazin-1-yl)ethanone.

7. A method for the treatment of cancer in a warm blooded animal in need of such treatment which comprises administering to said animal an effective amount of (R)-4-(2-(4-(1-(3-methoxy-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)ethyl)-1,3-dimethylpiperazin-2-one or a pharmaceutically acceptable salt thereof; and the cancer is acute myeloid and mixed lineage leukemia (AML).

8. A method for the treatment of cancer in a warm blooded animal in need of such treatment which comprises administering to said animal an effective amount of a co-crystal of (R)-4-(2-(4-(1-(3-methoxy-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)ethyl)-1,3-dimethylpiperazin-2-one and the co-former molecule 6-hydroxy-2-naphthoic acid; and the cancer is acute myeloid and mixed lineage leukemia (AML).

Assignees

• Astrazeneca Ab

Inventors

• Bradbury Robert Hugh
• Rabow Alfred Arthur
• Waring Michael James
• Mccabe James Francis
• Glossop Steven Christopher
• Mahmood Arshed
• Cotter Zoe Ann

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07C65/11

  with carboxyl groups on a condensed ring system containing two rings · CPC title

• E21B7/062

  the tool shaft rotating inside a non-rotating guide travelling with the shaft (E21B7/067 and E21B7/068 take precedence) · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title