5-[[4-[[morpholin-2-yl]methylamino]-5-(trifluoromethyl)-2 pyridyl]amino]pyrazine-2-carbonitrile and therapeutic uses thereof

Patent metadata

Field	Value
Publication number	US-10259806-B2
Application number	US-201715587270-A
Country	US
Kind code	B2
Filing date	May 4, 2017
Priority date	May 15, 2012
Publication date	Apr 16, 2019
Grant date	Apr 16, 2019

Abstract

The present invention pertains generally to the field of therapeutic compounds. More specifically the present invention pertains to 5-[[4-[[morpholin-2-yl]methylamino]-5-(trifluoromethyl)-2-pyridyl]amino]pyrazine-2-carbonitrile compounds (referred to herein as “TFM compounds”) which, inter alia, inhibit Checkpoint Kinase 1 (CHK1) kinase function. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit CHK1 kinase function, and in the treatment of diseases and conditions that are mediated by CHK1, that are ameliorated by the inhibition of CHK1 kinase function, etc., including proliferative conditions such as cancer, etc., optionally in combination with another agent, for example, (a) a DNA topoisomerase I or II inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or a thymidylate synthase (TS) inhibitor; (d) a microtubule targeted agent; (e) ionizing radiation; (f) an inhibitor of a mitosis regulator or a mitotic checkpoint regulator; (g) an inhibitor of a DNA damage signal transducer; or (h) an inhibitor of a DNA damage repair enzyme.

First claim

The invention claimed is:

1. A compound according to formula II, or a salt thereof:

wherein
R 3 is

where X is an alkyl or alkoxy organic functional group.

2. The compound of claim 1 , wherein X is selected from the group consisting of: methyl (—CH 3 ), benzyloxy (—OCH 2 C 6 H 5 ), t-butoxy (—OC(CH 3 ) 3 ), 2-trimethylsilylethyloxy, and allyloxy.

3. The compound of claim 1 , wherein X is t-butoxy (—OC(CH 3 ) 3 ).

4. A compound of formula III, or a salt thereof:

wherein
R 3 is hydrogen or is

where X is an alkyl or alkoxy organic functional group.

5. The compound of claim 4 , wherein R 3 is hydrogen.

6. The compound of claim 4 , wherein the compound is according to the following structure, or salt thereof:

7. A process for manufacturing a compound according to the following structure, or a salt thereof:

wherein
R 1 is CN;
R 2 is CF 3 ;
R 3 is

where X is an alkyl or alkoxy organic functional group;
the process comprising using cross coupling reaction conditions to couple a compound of the structure:

to a compound of the structure

8. The process of claim 7 , wherein the reaction conditions are as follows:
suspending: the

compound, the

compound, an organic phosphine compound, cesium carbonate, and a palladium(0) compound in an aprotic organic solvent;
and heating the suspension;
wherein R 1 , R 2 and R 3 are as defined in claim 7 .

9. The process of claim 7 , wherein the heating is at about 100° C.

10. The process of claim 7 , wherein the heating lasts for about 24 hours.

11. The process of claim 7 , wherein R 3 is

12. The process of claim 7 , wherein R 3 is

13. The compound of claim 1 , wherein X is methyl (—CH 3 ).

14. The compound of claim 1 , wherein X is benzyloxy (—OCH 2 C 6 H 5 ).

15. The compound of claim 1 , wherein X is 2-trimethylsilylethyloxy.

16. The compound of claim 1 , wherein X is allyloxy.

Assignees

• Cancer Research Tech Ltd

Inventors

• Collins Ian
• Matthews Thomas Peter
• Mchardy Tatiana Faria Da Fonseca
• Osborne James
• Lainchbury Michael
• Walton Michael Ian
• Garrett Michelle Dawn

Classifications

• A61P43/00

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

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D413/14 Primary

  containing three or more hetero rings · CPC title

• A61K31/4745

  condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48) · CPC title