Pyrrolotriazines as alk inhibitors

Patent metadata

Field	Value
Publication number	US-2016068535-A1
Application number	US-201514944668-A
Country	US
Kind code	A1
Filing date	Nov 18, 2015
Priority date	May 29, 2013
Publication date	Mar 10, 2016
Grant date	—

Abstract

This application provides compounds of the general formula (I)

and/or a salt thereof, where X, R 1 and R 2 are as defined herein. Compositions and therapeutic uses are also described.

First claim

1 . A compound of the general formula (I)

and/or a salt thereof, wherein:
X is CH or N;
R 1 is chosen from H or C 1 -C 6 alkyl optionally substituted with at least one R 3 ;
at least one R 2 is halogen and the other R 2 is chosen from hydrogen or halogen;
each R 3 is independently chosen from hydroxyl, C 1 -C 6 alkoxy, CON(R 4 ) 2 , and OCOR 4 ; and
each R 4 is independently chosen from hydrogen, C 1 -C 6 alkyl, and phenyl substituted with at least one halogen.

2 . The compound according to claim 1 wherein the other R 2 is halogen.

3 . The compound according to claim 1 wherein the other R 2 is hydrogen.

4 . The compound according to claim 1 wherein at least one R 2 is fluorine.

5 . The compound according to claim 2 wherein the other R 2 is fluorine.

6 . The compound according to claim 1 wherein X is CH.

7 . The compound according to claim 1 wherein X is N.

8 . The compound according to claim 1 wherein R 1 is H.

9 . The compound according to claim 1 wherein R 1 is C 1 -C 6 alkyl optionally substituted with at least one R 3 .

10 . The compound according to claim 9 wherein the at least one R 3 is hydroxyl.

11 . The compound according to claim 9 wherein the at least one R 3 is C 1 -C 6 alkoxy.

12 . The compound according to claim 9 wherein the at least one R 3 is CON(R 4 ) 2 .

13 . The compound according to claim 9 wherein the at least one R 3 is OCOR 4 .

14 . The compound according to claim 1 wherein R 4 is hydrogen.

15 . The compound according to claim 1 wherein R 4 is C 1 -C 6 alkyl.

16 . The compound according to claim 1 wherein R 4 is phenyl substituted with at least one halogen.

17 . The compound according to claim 16 wherein R 4 is phenyl substituted with at least one bromine.

18 . A compound that is a single enantiomer selected from the group consisting of:

and/or a salt thereof.

19 . The single enantiomer according to claim 18 that is (3R,4R)-1-(2-Hydroxy-ethyl)-4-{3-methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-3-ol, and/or a salt thereof.

20 . A compound selected from the group consisting of:
(±)-3,4-cis-1-(2-Methoxy-ethyl)-4-{3-methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-3-ol; (±)-3,4-cis-1-(2-Hydroxy-ethyl)-4-{3-methoxy-4-[7-(2-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-3-ol; (±)-2-(3,4-trans-3-Fluoro-4-{3-methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-ethanol; (±)-3,4-cis-4-{3-Methoxy-4-[7-(2-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-3-ol; (±)-[4-(3,4-trans-3-Fluoro-piperidin-4-yl)-2-methoxy-phenyl]-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-amine; (±)-2-(3,4-trans-3-fluoro-4-{3-methoxy-4-[7-(2-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-ethanol; (±)-2-(3,3-Difluoro-4-{3-methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-ethanol; (±)-1-(3,4-trans-3-Fluoro-4-{3-methoxy-4-[7-(2-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-2-methyl-propan-2-ol; (±)-2-(3,3-Difluoro-4-{3-methoxy-4-[7-(2-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-ethanol; (±)-[4-(3,3-Difluoro-piperidin-4-yl)-2-methoxy-phenyl]-[7-(2-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-amine; (±)-[4-(3,4-trans-3-Fluoro-piperidin-4-yl)-2-methoxy-phenyl]-[7-(2-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-amine; (3R,4S)-1-(2-Hydroxy-ethyl)-4-{3-methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-3-ol; (3S,4R)-1-(2-Hydroxy-ethyl)-4-{3-methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-3-ol; 2-((3S,4S)-3-Fluoro-4-{3-methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-ethanol; 2-((3R,4R)-3-Fluoro-4-{3-methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-ethanol; (3S,4S)-1-(2-Hydroxy-ethyl)-4-{3-methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-3-ol; (3R,4R)-1-(2-Hydroxy-ethyl)-4-{3-methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-3-ol; 4-Bromo-benzoic acid 2-((3R,4R)-3-hydroxy-4-{3-methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-ethyl ester; 2-(4-{3-Methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-ethanol; and a salt thereof.

21 . A pharmaceutical composition comprising a compound according to claim 1 , and/or a salt thereof, and a pharmaceutically acceptable excipient.

22 . A method of inhibiting ALK kinase in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to claim 1 , and/or a salt thereof.

23 . A method of treating a ALK-positive disease/disorder in a patient in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to claim 1 , and/or a salt thereof.

24 . A method of treating proliferative disease in a patient in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to claim 1 , and/or a salt thereof.

Assignees

• Cephalon Inc

Inventors

• Haltiwanger Ralph C
• Mesaros Eugen F
• Ott Gregory R

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/53 Primary

  having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine (melarsoprol A61K31/555 {; with four nitrogen atoms A61K31/495}) · CPC title

• A61P35/02

  specific for leukemia · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61P43/00

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