IP Library › Granted Patent US 10,329,295
Granted Patent B2
US 10,329,295 · App. 15/557,203 · Granted Jun 25, 2019

Pyrrolotriazine inhibitors of IRAK4 activity

Inventors: Jongwon Lim (Lexington, MA); Michael D. Altman (Needham, MA); Jason D. Brubaker (Cambridge, MA); Craig R. Gibeau (Holliston, MA)
Assignee: Merck Sharp & Dohme Corp.
C07D487/04A61K31/519A61K31/53A61K45/06A61P29/00C07D403/14
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 10,329,295
App. No.
15/557,203
Granted
Jun 25, 2019
Kind
B2
Abstract

The present invention relates to pyrrolotriazine inhibitors of IRAK4 of formula (I) and provides compositions comprising such inhibitors, as well as methods therewith for treating IRAK4-mediated or -associated conditions or diseases.

Claims (196)

1. A compound according to Formula I:

wherein:

Ring A is aryl or heterocyclyl;

n is 0, 1, 2, 3 or 4;

R 1 is independently selected from: (C 1 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl, heterocyclyl, CF 3 , CHF 2 , CN, halo, said alkyl, cycloalkyl and heterocyclyl optionally substituted with halo, OH, CH 3 , and OCH 3 ;

R 2 is H and R 3 is independently selected from: (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, and heterocyclyl each optionally substituted with one or more halo, OH, N(R b ) 2 , or morpholinyl, or R 2 and R 3 can be taken together with the nitrogen to which they are attached to form a heterocyclyl, said heterocyclyl optionally substituted with one or more substituents selected from R a ;

R a is independently selected from (C 1 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl, CF 3 , CHF 2 , OH, halo and NH 2 , said alkyl optionally substituted with (C 3 -C 6 )cycloalkyl and CF 3 ; and

R b is independently selected from H and (C 1 -C 4 )alkyl;

or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 of Formula I:

wherein:

Ring A is pyrazolyl, pyridinyl, thiophenyl, furanyl or phenyl;

n is 0, 1 or 2;

R 1 is independently selected from: (C 1 -C 4 )alkyl, cyclopropyl, oxadiazolyl, pyridinyl, oxazolyl, triazolyl, pyriminidyl, CF 3 , CHF 2 , CN and halo, said alkyl, oxadiazolyl, pyridinyl, oxazolyl, triazolyl and pyriminidyl are optionally substituted with halo, OH, CH 3 , and OCH 3 ;

R 2 is H and R 3 is independently selected from: (C 1 -C 4 )alkyl, cyclohexyl, cycloheptyl, piperidinyl and azepanyl each optionally substituted with one or more F, OH, N(R b ) 2 , or morpholinyl, or R 2 and R 3 can be taken together with the nitrogen to which they are attached to form a heterocyclyl selected from piperazinyl, diazepanyl, diazabicyclooctyl, diazabicycloheptyl, diazaspirononyl, hexahydropyrrolopyrazinyl, piperidinyl, diazabicyclononyl, oxadiazabicyclodecyl and diazatricyclodecyl, said heterocyclyl optionally substituted with one or more substituents selected from R a ;

R a is independently selected from (C 1 -C 4 )alkyl, cyclopropyl, CF 3 , CHF 2 , OH, F and NH 2 , said alkyl optionally substituted with cyclopropyl and CF 3 ; and

R b is independently selected from H and methyl;

or a pharmaceutically acceptable salt thereof.

3. A compound which is selected from:

2-{[(1R,2S)-2-aminocyclohexyl]amino}-N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-{[(1R,2S)-2-aminocyclohexyl]amino}-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-{[(1R,2S)-2-hydroxycyclohexyl]amino}-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-piperazin-1-ylpyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-[(3R)-piperidin-3-ylamino]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-(1,4-diazepan-1-yl)-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-[(3R)-3-aminopiperidin-1-yl]-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-{[(1R,2R)-2-amino-3,3-difluorocyclohexyl]amino}-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-(5,8-diazaspiro[2.6]non-5-yl)-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-(azepan-3-ylamino)-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]-2-piperazin-1-ylpyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

N-(4-cyanothiophen-3-yl)-2-(1,4-diazepan-1-yl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-{[(1R,2S)-2-aminocyclohexyl]amino}-N-(4-cyanothiophen-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-{[(1R,2S)-2-aminocyclohexyl]amino}-N-(4-bromothiophen-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-(1,4-diazepan-1-yl)-N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]-2-[(3R)-piperidin-3-ylamino]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]-2-{[(1R,2S)-2-hydroxycyclohexyl]amino}pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-[(3R)-3-aminopiperidin-1-yl]-N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-(azepan-3-ylamino)-N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-(5,8-diazaspiro[2.6]non-5-yl)-N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-{[(1R,2S)-2-aminocyclohexyl]amino}-N-(2-cyanothiophen-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

N-(2-cyanothiophen-3-yl)-2-(2,5-diazabicyclo[2.2.2]oct-2-yl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

N-(4-bromothiophen-3-yl)-2-(1,4-diazepan-1-yl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

N-(4-bromothiophen-3-yl)-2-(2,5-diazabicyclo[2.2.2]oct-2-yl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-{[(1R,2S)-2-aminocyclohexyl]amino}-N-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

N-(3-chloro-1-methyl-1H-pyrazol-4-yl)-2-(1,4-diazepan-1-yl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-{[(1R,2S)-2-aminocyclohexyl]amino}-N-[2-(trifluoromethyl)phenyl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-(1,4-diazepan-1-yl)-N-[2-(trifluoromethyl)phenyl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-(2,5-diazabicyclo[2.2.2]oct-2-yl)-N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-{[(1R,2S)-2-aminocyclohexyl]amino}-N-(2-chlorothiophen-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

N-(2-chlorothiophen-3-yl)-2-(1,4-diazepan-1-yl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-{[(1R,2S)-2-aminocyclohexyl]amino}-N-(2-bromophenyl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

N-(2-bromophenyl)-2-(1,4-diazepan-1-yl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

N-(3-cyano-1-methyl-1H-pyrazol-4-yl)-2-(1,4-diazepan-1-yl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-{[(1R,2S)-2-aminocyclohexyl]amino}-N-(3-cyano-1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

N-(4-cyanothiophen-3-yl)-2-(2,5-diazabicyclo[2.2.2]oct-2-yl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

N-(2-bromothiophen-3-yl)-2-(1,4-diazepan-1-yl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-{[(1R,2S)-2-aminocyclohexyl]amino}-N-(2-bromothiophen-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

N-(2-chlorophenyl)-2-(1,4-diazepan-1-yl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-{[(1R,2S)-2-aminocyclohexyl]amino}-N-(2-chlorophenyl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-(1,4-diazepan-1-yl)-N-[4-(difluoromethyl)thiophen-3-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-{[(1R,2S)-2-aminocyclohexyl]amino}-N-[4-(difluoromethyl)thiophen-3-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

N-(2-cyanothiophen-3-yl)-2-(1,4-diazepan-1-yl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

N-(3-chloro-1-methyl-1H-pyrazol-4-yl)-2-[(1S,4S)-2,5-diazabicyclo[2.2.2]oct-2-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

N-(3-chloro-1-methyl-1H-pyrazol-4-yl)-2-[(1R,4R)-2,5-diazabicyclo[2.2.2]oct-2-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

N-(3-cyano-1-methyl-1H-pyrazol-4-yl)-2-[(1S,4S)-2,5-diazabicyclo[2.2.2]oct-2-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

N-(3-cyano-1-methyl-1H-pyrazol-4-yl)-2-[(1R,4R)-2,5-diazabicyclo[2.2.2]oct-2-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

N-(2-bromothiophen-3-yl)-2-[(1S,4S)-2,5-diazabicyclo[2.2.2]oct-2-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

N-(2-bromothiophen-3-yl)-2-[(1R,4R)-2,5-diazabicyclo[2.2.2]oct-2-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-{[(1R,2S)-2-aminocyclohexyl]amino}-N-(2-cyanophenyl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-[(3R)-3-aminopiperidin-1-yl]-N-(2-cyanophenyl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

N-(2-cyanophenyl)-2-[(3R)-piperidin-3-ylamino]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

N-(2-chlorothiophen-3-yl)-2-[(1S,4S)-2,5-diazabicyclo[2.2.2]oct-2-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

N-(2-chlorothiophen-3-yl)-2-[(1R,4R)-2,5-diazabicyclo[2.2.2]oct-2-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

N-(2-chlorophenyl)-2-[(1R,4R)-2,5-diazabicyclo[2.2.2]oct-2-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-{[(1R,2S)-2-aminocyclohexyl]amino}-N-[2-(difluoromethyl)phenyl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-(1,4-diazepan-1-yl)-N-[2-(difluoromethyl)phenyl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

N-(2-cyanophenyl)-2-piperazin-1-ylpyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

N-(2-cyanophenyl)-2-(1,4-diazepan-1-yl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-[(3S)-azepan-3-ylamino]-N-(2-cyanophenyl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-[(1S,4S)-2,5-diazabicyclo[2.2.2]oct-2-yl]-N-[2-(difluoromethyl)phenyl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-[(1R,4R)-2,5-diazabicyclo[2.2.2.2]oct-2-yl]-N-[2-(difluoromethyl)phenyl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

N-(3-bromo-1-methyl-1H-pyrazol-4-yl)-2-[(1S,4S)-2,5-diazabicyclo[2.2.2]oct-2-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

N-(3-bromo-1-methyl-1H-pyrazol-4-yl)-2-[(1R,4R)-2,5-diazabicyclo[2.2.2]oct-2-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

N-(2-chlorophenyl)-2-[(1S,4S)-2,5-diazabicyclo[2.2.2]oct-2-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-{[(1R,2S)-2-aminocyclohexyl]amino}-N-(3-bromo-1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

N-(3-bromo-1-methyl-1H-pyrazol-4-yl)-2-(1,4-diazepan-1-yl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-[(1R,4R)-2,5-diazabicyclo[2.2.2]oct-2-yl]-N-[2-(trifluoromethyl)phenyl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-[(3S)-azepan-3-ylamino]-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-{[(1R,2S)-2-aminocyclohexyl]amino}-N-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

N-(2-cyanophenyl)-2-{[(1R,2S)-2-hydroxycyclohexyl]amino}pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-[(3R)-azepan-3-ylamino]-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-[(3R)-azepan-3-ylamino]-N-(2-cyanophenyl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

N-(2-cyanophenyl)-2-[(1S,4S)-2,5-diazabicyclo[2.2.2]oct-2-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

N-(2-cyanophenyl)-2-[(1R,4R)-2,5-diazabicyclo[2.2.2]oct-2-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

N-(2-cyanophenyl)-2-(5,8-diazaspiro[2.6]non-5-yl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

N-(2-bromophenyl)-2-[(1R,4R)-2,5-diazabicyclo[2.2.2]oct-2-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-[(1S,4S)-2,5-diazabicyclo[2.2.2]oct-2-yl]-N-[2-(trifluoromethyl)phenyl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-{[(1R,2R)-2-amino-3,3-difluorocyclohexyl]amino}-N-(3-chloro-1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-[(1S,4S)-2,5-diazabicyclo[2.2.2]oct-2-yl]-N-[4-(difluoromethyl)thiophen-3-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-[(1R,4R)-2,5-diazabicyclo[2.2.2]oct-2-yl]-N-[4-(difluoromethyl)thiophen-3-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-(3,8-diazabicyclo[3.2.1]oct-3-yl)-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-(3,8-diazabicyclo[3.2.1]oct-3-yl)-N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

N-(2-bromophenyl)-2-[(1S,4S)-2,5-diazabicyclo[2.2.2]oct-2-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-(1,4-diazepan-1-yl)-N-[2-(trifluoromethyl)thiophen-3-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-[(1S,4S)-2,5-diazabicyclo[2.2.2]oct-2-yl]-N-[2-(trifluoromethyl)thiophen-3-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-[(1R,4R)-2,5-diazabicyclo[2.2.2]oct-2-yl]-N-[2-(trifluoromethyl)thiophen-3-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-{[(1R,2S)-2-aminocyclohexyl]amino}-N-[2-(trifluoromethyl)thiophen-3-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-{[(1R,2R)-2-amino-3,3-difluorocyclohexyl]amino}-N-(3-bromo-1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-[(3R)-azepan-3-ylamino]-N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-[(3S)-azepan-3-ylamino]-N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-{[(1R,2R)-2-amino-3,3-difluorocyclohexyl]amino}-N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-{[(1R,2R)-2-amino-3,3-difluorocyclohexyl]amino}-N-[4-(difluoromethyl)thiophen-3-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-{[(1R,2R)-2-amino-3,3-difluorocyclohexyl]amino}-N-(2-bromothiophen-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-{[(1R,2R)-2-amino-3,3-difluorocyclohexyl]amino}-N-[2-(trifluoromethyl)thiophen-3-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-(3,8-diazabicyclo[3.2.1]oct-8-yl)-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-{[(1R,2R)-2-amino-3,3-difluorocyclohexyl]amino}-N-(2-chlorothiophen-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-{[(1R,2R)-2-amino-3,3-difluorocyclohexyl]amino}-N-(3-cyano-1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-(3,6-diazabicyclo[3.2.1]oct-3-yl)-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-[(1S,5S)-3,6-diazabicyclo[3.2.1]oct-3-yl]-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-[(1R,5R)-3,6-diazabicyclo[3.2.1]oct-3-yl]-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-(3,6-diazabicyclo[3.2.1]oct-3-yl)-N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-[(1S,5S)-3,6-diazabicyclo[3.2.1]oct-3-yl]-N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-[(1R,5R)-3,6-diazabicyclo[3.2.1]oct-3-yl]-N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

N-(4-chlorothiophen-3-yl)-2-(1,4-diazepan-1-yl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-{[(1R,2R)-2-amino-3,3-difluorocyclohexyl]amino}-N-(2-bromophenyl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

N-(4-chlorothiophen-3-yl)-2-[(1S,4S)-2,5-diazabicyclo[2.2.2]oct-2-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

N-(4-chlorothiophen-3-yl)-2-[(1R,4R)-2,5-diazabicyclo[2.2.2]oct-2-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-{[(1R,2S)-2-aminocyclohexyl]amino}-N-(4-chlorothiophen-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

N-(3-cyano-1-methyl-1H-pyrazol-4-yl)-2-(3,8-diazabicyclo[3.2.1]oct-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

N-(3-cyano-1-methyl-1H-pyrazol-4-yl)-2-(3,8-diazabicyclo[3.2.1]oct-8-yl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

N-(3-cyano-1-methyl-1H-pyrazol-4-yl)-2-(3,6-diazabicyclo[3.2.1]oct-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

N-(3-cyano-1-methyl-1H-pyrazol-4-yl)-2-[(1S,5S)-3,6-diazabicyclo[3.2.1]oct-3-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

N-(3-cyano-1-methyl-1H-pyrazol-4-yl)-2-[(1R,5R)-3,6-diazabicyclo[3.2.1]oct-3-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-(3,6-diazabicyclo[3.2.1]oct-6-yl)-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-[(1S,5R)-3,6-diazabicyclo[3.2.1]oct-6-yl]-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-[(1R,5S)-3,6-diazabicyclo[3.2.1]oct-6-yl]-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-(3,6-diazabicyclo[3.2.1]oct-6-yl)-N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-[(1S,5R)-3,6-diazabicyclo[3.2.1]oct-6-yl]-N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-[(1R,5S)-3,6-diazabicyclo[3.2.1]oct-6-yl]-N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-(3,8-diazabicyclo[3.2.1]oct-8-yl)-N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

N-(3-cyano-1-methyl-1H-pyrazol-4-yl)-2-{[(1R,2S)-2-hydroxycyclohexyl]amino}pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-[(3S)-3-aminopiperidin-1-yl]-N-(3-cyano-1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

N-(3-cyano-1-methyl-1H-pyrazol-4-yl)-2-[(3R)-piperidin-3-ylamino]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-[(3R)-3-aminopiperidin-1-yl]-N-(3-cyano-1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-{[(1R,2R)-2-amino-3,3-difluorocyclohexyl]amino}-N-(4-chlorothiophen-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-{[(1S,2R)-2-amino-5,5-difluorocyclohexyl]amino}-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-{[(1S,2R)-2-amino-4,4-difluorocyclohexyl]amino}-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-{[(1S,2R)-2-amino-4,4-difluorocyclohexyl]amino}-N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-{[(1S,2R)-2-amino-5,5-difluorocyclohexyl]amino}-N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-{[(1S,2R)-2-amino-5,5-difluorocyclohexyl]amino}-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-{[(1S,2R)-2-amino-4,4-difluorocyclohexyl]amino}-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

N-(3-cyano-1-methyl-1H-pyrazol-4-yl)-2-(3,6-diazabicyclo[3.2.1]oct-6-yl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

N-(3-cyano-1-methyl-1H-pyrazol-4-yl)-2-(3,6-diazabicyclo[3.2.1]oct-6-yl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

N-(3-cyano-1-methyl-1H-pyrazol-4-yl)-2-(3,6-diazabicyclo[3.2.1]oct-6-yl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-{[(1R,2R)-2-amino-3,3-difluorocyclohexyl]amino}-N-(2-cyanophenyl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-{[(1R,2R)-2-amino-3,3-difluorocyclohexyl]amino}-N-[2-(trifluoromethyl)phenyl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-{[(1R,2R)-2-amino-3,3-difluorocyclohexyl]amino}-N-(2-chlorophenyl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-{[(1S,2R)-2-amino-4,4-difluorocyclohexyl]amino}-N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-{[(1S,2R)-2-amino-5,5-difluorocyclohexyl]amino}-N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-[(3R)-3-aminopiperidin-1-yl]-N-(2-cyanothiophen-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

N-(4-cyanothiophen-3-yl)-2-{[(1R,2S)-2-hydroxycyclohexyl]amino}pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-[(3S)-3-aminopiperidin-1-yl]-N-(4-cyanothiophen-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-[(3R)-3-aminopiperidin-1-yl]-N-(4-cyanothiophen-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

N-(4-cyanothiophen-3-yl)-2-[(3R)-piperidin-3-ylamino]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

N-(2-cyanothiophen-3-yl)-2-[(3R)-piperidin-3-ylamino]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

N-(2-cyanothiophen-3-yl)-2-{[(1R,2S)-2-hydroxycyclohexyl]amino}pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-[(3S,5R)-3-amino-5-fluoropiperidin-1-yl]-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-[(3R,5R)-3-amino-5-fluoropiperidin-1-yl]-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-[(3S,5S)-3-amino-5-fluoropiperidin-1-yl]-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-[(3S,5R)-3-amino-5-fluoropiperidin-1-yl]-N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-[(3S)-3-aminopiperidin-1-yl]-N-(2-cyanothiophen-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-{[(1R,2R)-2-amino-3,3-difluorocyclohexyl]amino}-N-(4-cyanothiophen-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-{[(3S,5R)-5-fluoropiperidin-3-yl]amino}-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]-2-{[(3S,5R)-5-fluoropiperidin-3-yl]amino}pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-[(3R,5R)-3-amino-5-fluoropiperidin-1-yl]-N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-[(3S,5S)-3-amino-5-fluoropiperidin-1-yl]-N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-{[(1R,2R)-2-amino-3,3-difluorocyclohexyl]amino}-N-(2-cyanothiophen-3-yl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]-2-{[(3R,5S)-5-fluoropiperidin-3-yl]amino}pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-{[(3R,5S)-5-fluoropiperidin-3-yl]amino}-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-{[(3S,5S)-5-fluoropiperidin-3-yl]amino}-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-{[(3R,5R)-5-fluoropiperidin-3-yl]amino}-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-[(3R,5S)-3-amino-5-fluoropiperidin-1-yl]-N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]-2-{[(3S,5S)-5-fluoropiperidin-3-yl]amino}pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]-2-{[(3R,5R)-5-fluoropiperidin-3-yl]amino}pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-{[(1R,2S)-2-aminocyclohexyl]amino}-N-(1-ethyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-{[(1R,2S)-2-aminocyclohexyl]amino}-N-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-{[(1R,2S)-2-aminocyclohexyl]amino}-N-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-{[(1R,2S)-2-aminocyclohexyl]amino}-N-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

2-[(1S,4S)-2,5-diazabicyclo[2.2.2]oct-2-yl]-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide; and

2-[(1R,4R)-2,5-diazabicyclo[2.2.2]oct-2-yl]-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;

or a pharmaceutically acceptable salt thereof.

4. A pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of claim 1 .

5. A method for treating an inflammatory disease which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

6. The method according to claim 5 wherein the inflammatory disease is selected from rheumatoid arthritis, inflammatory bowel disease and cancer.

7. A method of treating an inflammatory disease which comprises administering a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, in combination with a second therapeutic agent.

8. The method of claim 7 wherein the second therapeutic agent is selected from an anti-cancer agent and an anti-inflammatory agent.

Assignments (2)
MERGER Recorded Aug 8, 2022
From: MERCK SHARP & DOHME CORP.
To: MERCK SHARP & DOHME LLC
Reel/Frame 061102/0145 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 20, 2017
From: LIM, JONGWON; ALTMAN, MICHAEL D.; BRUBAKER, JASON D.; GIBEAU, CRAIG R.
To: MERCK SHARP & DOHME CORP.
Reel/Frame 043640/0672 →
Continuity (2)
Provisional Application 62132202 · Mar 12, 2015
Related Publication 20180051030A1 · Feb 22, 2018