Pyrrolotriazine inhibitors of IRAK4 activity

Patent metadata

Field	Value
Publication number	US-10329295-B2
Application number	US-201615557203-A
Country	US
Kind code	B2
Filing date	Mar 7, 2016
Priority date	Mar 12, 2015
Publication date	Jun 25, 2019
Grant date	Jun 25, 2019

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.

First claim

What is claimed is:

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-carboxami

Assignees

• Merck Sharp & Dohme
• Lim Jongwon
• Altman Michael D
• Brubaker Jason D
• Gibeau Craig R

Inventors

• Lim Jongwon
• Altman Michael D
• Brubaker Jason D
• Gibeau Craig R

Classifications

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• C07D403/14

  containing three or more hetero rings · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K31/53

  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