Inhibitors of IRAK4 activity

Patent metadata

Field	Value
Publication number	US-9932350-B2
Application number	US-201515515377-A
Country	US
Kind code	B2
Filing date	Sep 25, 2015
Priority date	Sep 30, 2014
Publication date	Apr 3, 2018
Grant date	Apr 3, 2018

Abstract

The present invention relates to 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:
X is NH or 0;
b is 0 or 1;
n is 0, 1, 2, 3 or 4;
R 1 and R 2 are independently H and (C 1 -C 4 )alkyl, or R 1 and R 2 can be taken together with the nitrogen to which they are attached to form a monocyclic or bicyclic (fused, bridged or spirocyclic) heterocycle containing 3-8 carbon atoms optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said alkyl and heterocycle are optionally substituted with one or more substituents selected from R a ;
R 3 is (C 1 -C 4 )alkyl wherein two adjacent alkyl groups can join together and form a bridged moiety of 3-6 carbon atoms;
R 4 is absent, halo or O b (C 1 -C 4 )alkyl;
R 5 is halo, CN and O(C 1 -C 4 )alkyl, said alkyl optionally substituted with one or more substituents selected from CN and (C═O)NH 2 ;
R 6 is absent, halo, or O(C 1 -C 4 )alkyl;
R a is independently selected from halo, CF 3 , O b (C 1 -C 4 )alkyl, SO 2 (C 1 -C 4 )alkyl, C(O) O b (C 1 -C 6 )alkyl, (C═O) b heterocyclyl, wherein said alkyl can come together with another alkyl to form a bridged moiety and wherein said alkyl and heterocyclyl are optionally substituted with R b ; and

R b is independently selected from OH, halo, SO 2 (C 1 -C 4 )alkyl, O b (C 1 -C 4 )alkyl, and heterocyclyl;
or a pharmaceutically acceptable salt or a stereoisomer thereof.

2. A compound according to claim 1 of Formula I:
wherein:
X is NH or 0;
b is 0 or 1;
n is 0, 1, 2, 3 or 4;
R 1 and R 2 are independently H and (C 1 -C 4 )alkyl, or R 1 and R 2 can be taken together with the nitrogen to which they are attached to form a monocyclic or bicyclic (fused, bridged or spirocyclic) heterocycle containing 3-8 carbon atoms optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said alkyl and heterocycle are optionally substituted with one or more substituents selected from R a ;
R 3 is methyl wherein two adjacent methyl groups can join together and form a bridged moiety of 3-6 carbon atoms;
R 4 is absent or (C 1 -C 4 )alkyl;
R 5 is halo, CN and O(C 1 -C 4 )alkyl, said alkyl optionally substituted with one or more substituents selected from CN and (C═O)NH 2 ;
R 6 is absent, halo, or O(C 1 -C 4 )alkyl;
R a is independently selected from halo, CF 3 , O b (C 1 -C 4 )alkyl, SO 2 (C 1 -C 4 )alkyl, C(O) O b (C 1 -C 6 )alkyl, heterocyclyl, C═O-tetrahydrofuranyl, wherein said alkyl can come together with another alkyl for form a bridged moiety and wherein said alkyl and heterocyclyl are optionally substituted with R b ; and

R b is independently selected from OH, halo, SO 2 (C 1 -C 4 )alkyl, O b (C 1 -C 4 )alkyl, morpholinyl and oxetanyl;
or a pharmaceutically acceptable salt or a stereoisomer thereof.

3. A compound according to claim 1 of Formula I:
wherein:
X is NH or O;
b is 0 or 1;
n is 0, 1 or 2;
R 1 and R 2 are independently H and (C 1 -C 4 )alkyl, or R 1 and R 2 can be taken together with the nitrogen to which they are attached to form morpholinyl, piperidinyl, azetidinyl, piperazinyl, pyrrolinyl, pyrhexahydrocyclopentaoxazinyl, hexahydropyranopyridinyl, hexahydrofuropyrrolyl, azabicyclooctyl, oxaazabicyclooctyl and azapanyl, said alkyl, morpholinyl, piperidinyl, azetidinyl, piperazinyl, pyrrolinyl, pyrhexahydrocyclopentaoxazinyl, hexahydropyranopyridinyl, hexahydrofuropyrrolyl, azabicyclooctyl, oxaazabicyclooctyl and azapanyl are optionally substituted with one or more substituents selected from R a ;
R 3 is methyl wherein two adjacent methyl groups can come together and form a bridged moiety;
R 4 is absent or methyl;
R 5 is selected from: Br, F, Cl, CN and O(C 1 -C 4 )alkyl, said alkyl optionally substituted with one or more substituents selected from CN and (C═O)NH 2 ;
R 6 is absent, halo, or CH 3 ;
R a is independently selected from F, CF 3 , O b (C 1 -C 4 )alkyl, SO 2 (C 1 -C 4 )alkyl, C(O) O b (C 1 -C 6 )alkyl, heterocyclyl, C═O-tetrahydrofuran, wherein said alkyl can come together with another alkyl for form a bridged moiety and wherein said alkyl and heterocyclyl are optionally substituted with R b ; and

R b is independently selected from OH, halo, SO 2 (C 1 -C 4 )alkyl, O b (C 1 -C 4 )alkyl, morpholinyl and oxetanyl;
or a pharmaceutically acceptable salt or a stereoisomer thereof.

4. A compound which is selected from:
4-[(trans-4-aminocyclohexyl)amino]quinazoline-6-carbonitrile;
trans-N-(6-bromoquinazolin-4-yl)cyclohexane-1,4-diamine;
6-bromo-4-{[trans-4-(morpholin-4-yl)cyclohexyl]oxy}quinazoline;
6-bromo-N-[trans-4-(morpholin-4-yl)cyclohexyl]quinazolin-4-amine;
trans-N′-(6,7-dimethoxyquinazolin-4-yl)-N,N-dimethylcyclohexane-1,4-diamine;
trans-N′-(6,7-difluoroquinazolin-4-yl)-N,N-dimethylcyclohexane-1,4-diamine;
4-{[trans-4-(dimethylamino)cyclohexyl]amino}quinazoline-6-carbonitrile;
trans-N′-(6-bromoquinazolin-4-yl)-N,N-dimethylcyclohexane-1,4-diamine;
4-{[trans-4-(morpholin-4-yl)cyclohexyl]amino}quinazoline-6-carbonitrile;
6-methoxy-N-[trans-4-(morpholin-4-yl)cyclohexyl]quinazolin-4-amine;
6-fluoro-N-[trans-4-(morpholin-4-yl)cyclohexyl]quinazolin-4-amine;
N-[trans-4-(morpholin-4-yl)cyclohexyl]-6-(propan-2-yloxy)quinazolin-4-amine;
6-bromo-7-fluoro-N-[trans-4-(morpholin-4-yl)cyclohexyl]quinazolin-4-amine;
7-fluoro-6-methoxy-N-[trans-4-(morpholin-4-yl)cyclohexyl]quinazolin-4-amine;
6-chloro-N-[trans-4-(morpholin-4-yl)cyclohexyl]quinazolin-4-amine;
trans-N′-(6-methoxyquinazolin-4-yl)-N,N-dimethylcyclohexane-1,4-diamine;
[(4-{[trans-4-(dimethylamino)cyclohexyl]amino}quinazolin-6-yl)oxy]acetonitrile;
4-[(4-{[trans-4-(dimethylamino)cyclohexyl]amino}quinazolin-6-yl)oxy]butanenitrile;
2-[(4-{[trans-4-(dimethylamino)cyclohexyl]amino}quinazolin-6-yl)oxy]acetamide;
4-{[(1S,6R)-5-(morpholin-4-yl)bicyclo[4.1.0]hept-2-yl]amino}quinazoline-6-carbonitrile;
4-{[trans-4-(azetidin-1-yl)cyclohexyl]amino}quinazoline-6-carbonitrile;
4-({cis or trans-4-[(3R or S)-3-(trifluoromethyl)piperidin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile;
4-({cis or trans-4-[(3R or S)-3-(trifluoromethyl)piperidin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile;
4-({cis or trans-4-[(3R or S)-3-(trifluoromethyl)piperidin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile;
4-({cis or trans-4-[(3R or S)-3-(trifluoromethyl)piperidin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile;
4-{[cis-4-(azetidin-1-yl)cyclohexyl]amino}quinazoline-6-carbonitrile;
4-{[trans-4-(2,3-dimethylmorpholin-4-yl)cyclohexyl]amino}quinazoline-6-carbonitrile;
4-{[cis-4-(2,3-dimethylmorpholin-4-yl)cyclohexyl]amino}quinazoline-6-carbonitrile;
4-({trans-4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]cyclohexyl}amino)quinazoline-6-carbonitrile;
4-({trans-4-[4-(methyl sulfonyl)piperidin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile;
4-({trans-4-[(2R or 2S)-2-(hydroxymethyl)morpholin-4-yl]cyclohexyl}amino)quinazoline-6-carbonitrile;
4-({trans-4-[(2R or 2S)-2-(hydroxymethyl)morpholin-4-yl]cyclohexyl}amino)quinazoline-6-carbonitrile;
4-({trans-4-[3-(methyl sulfonyl)pyrrolidin-1-yl]cyclohexyl}amino)quinazoline-6-carbonitrile;
4-({trans-4-[(2S,6S or 2R,6R)-2,6-dimethylmorpholin-4-yl]cyclohexyl}amino)quinazoline-6-carbonitrile;
4-({trans-4-[(2S,6S or 2R,6R)-2,6-dimethylmorpholin-4-yl]cyclohexyl}amino)quinazoline-6-carbonitrile;
4-({trans-4-[(2S or 2R)-2-methylmorpholin-4-yl]cyclohexyl}amino)quinazoline-6-carbonitrile;
4-({trans-4-[(2S or 2R)-2-methylmorpholin-4-yl]cyclohexyl}amino)quinazoline-6-carbonitrile;
4-({trans-4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]cyclohexyl}amino)quinazoline-6-carbonitrile;
4-{[trans-4-(4-

Assignees

• Merck Sharp & Dohme
• Gibeau Craig R
• Kattar Solomon D
• Lesburg Charles A
• Lim Jongwon
• Maclean John K F
• Mansoor Umar F
• Northrup Alan B
• Sanders John M
• Smith Graham F

Inventors

• Altman Michael D
• Brubaker Jason D
• Childers Matthew L
• Donofrio Anthony
• Fischmann Thierry
• Gibeau Craig R
• Kattar Solomon D
• Lesburg Charles A
• Lim Jongwon
• Maclean John K F
• Mansoor Umar F
• Northrup Alan B
• Sanders John M
• Smith Graham F

Classifications

• A61K31/538

  ortho- or peri-condensed with carbocyclic ring systems · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• C07D491/08 Primary

  Bridged systems · CPC title

• A61K45/06

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

• C07D498/08

  Bridged systems · CPC title