Pyrazolopyrimidine inhibitors of IRAK4 activity

Patent metadata

Field	Value
Publication number	US-10329294-B2
Application number	US-201615557197-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 pyrazolopyrimidine 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 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, cyclopropyl, 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: 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 or CF 3 ; and
R b is independently selected from H and methyl;
or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 which is selected from:
N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-5-piperazin-1-ylpyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-{[(1R,2S)-2-aminocyclohexyl]amino}-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-(cyclohexylamino)-N-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-{[(1R,2R)-2-amino-3,3-difluorocyclohexyl]amino}-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-(cyclohexylamino)-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-[4-(cyclopropylmethyl)piperazin-1-yl]-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-5-(piperidin-4-ylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-(1,4-diazepan-1-yl)-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-5-[(3R)-piperidin-3-ylamino]pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-(4-ethyl-1,4-diazepan-1-yl)-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-(2,5-diazabicyclo[2.2.2]oct-2-yl)-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-(azepan-3-ylamino)-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-(2,5-diazabicyclo[2.2.1]hept-2-yl)-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-(5,8-diazaspiro[2.6]non-5-yl)-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-5-[3-(trifluoromethyl)piperazin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-[3-(difluoromethyl)piperazin-1-yl]-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-(azepan-4-ylamino)-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-(3,6-diazabicyclo[3.1.1]hept-3-yl)-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-{([(1S,2R)-2-hydroxycyclohexyl]amino}-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-[(3 S,5S)-3,5-dihydroxypiperidin-1-yl]-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-[(3S)-3-hydroxypiperidin-1-yl]-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-[(3R)-3-hydroxypiperidin-1-yl]-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]-5-[(3R,5R)-3,5-dihydroxypiperidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]-5-[(3R)-3-hydroxypiperidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]-5-[(3S)-3-hydroxypiperidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-(6-fluoro-1,4-diazepan-1-yl)-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-(3-cyclopropylpiperazin-1-yl)-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-(2-cyclopropylpiperazin-1-yl)-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-(3,3-dimethylpiperazin-1-yl)-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-{([(1R,2S)-2-aminocyclohexyl]amino}-N-[3-(trifluoromethyl)pyridin-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-[(3R)-3-aminopiperidin-1-yl]-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-{([(1S,2R)-2-aminocycloheptyl]amino}-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-(4-methylpiperazin-1-yl)-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-5-(2,2,4-trimethylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-(6,6-difluoro-1,4-diazepan-1-yl)-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-{([(1R,2S)-2-hydroxycyclohexyl]amino}-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-{([(1R,2S)-2-aminocyclohexyl]amino}-N-[2-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-{([(1R,2S)-2-aminocyclohexyl]amino}-N-(4-cyanothiophen-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-(1,4-diazabicyclo[3.2.2]non-4-yl)-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-5-[2-(2,2,2-trifluoroethyl)piperazin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-{([(1R,2S)-2-aminocyclohexyl]amino}-N-(2-cyanothiophen-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-(1,4-diazabicyclo[3.2.1]oct-4-yl)-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-[(3S)-3-aminopiperidin-1-yl]-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-{([(1R,2S)-2-aminocyclohexyl]amino}-N-[2-(trifluoromethyl)furan-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-[1-tert-butyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-5-piperazin-1-ylpyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-[1-tert-butyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-5-(5,8-diazaspiro[2.6]non-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-[1-tert-butyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-5-{[(1R,2S)-2-hydroxycyclohexyl]amino}pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-{([(1R,2R)-2-amino-3,3-difluorocyclohexyl]amino}-N-[1-tert-butyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-[1-tert-butyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-5-(2,5-diazabicyclo[2.2.2]oct-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-(5,8-diazaspiro[2.6]non-5-yl)-N-[1-(1-methylethyl)-3-(tifluoromethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-{([(1R,2S)-2-hydroxycyclohexyl]amino}-N-[1-(1-methylethyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;
5-(2,5-diazabicyclo[2.2.2]oct-2-yl)-N-[1-(1-methylethyl)-3-(trifluoromethyl)-1H-pyrazol-4-y

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

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• A61K45/06

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

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/55

  having seven-membered rings, e.g. azelastine, pentylenetetrazole · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title