Inhibitors of IRAK4 activity

Patent metadata

Field	Value
Publication number	US-9969749-B2
Application number	US-201515515383-A
Country	US
Kind code	B2
Filing date	Sep 25, 2015
Priority date	Sep 30, 2014
Publication date	May 15, 2018
Grant date	May 15, 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 O;
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 heterocycle 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 aryl or heteroaryl each optionally substituted with one or more substituents selected from R b ;
R 6 is absent, halo, or O(C 1 -C 4 )alkyl;
R a is independently selected from: halo, O b (C 1 -C 4 )alkyl, SO 2 (C 1 -C 4 )alkyl, C(O)C 1 -C 4 alkyl, said alkyl optionally substituted with halo or heterocyclyl; and
R b is independently selected from OH, halo, CHF 2 , CF 3 , COOH, SO 2 (C 1 -C 4 )alkyl, C═O(O)C 1 -C 4 alkyl, O b (C 1 -C 4 )alkyl, aryl, heterocyclyl, CN, C(O)N(R c ) 2 , N(R c ) 2 ; said R c and alkyl are optionally substituted with OH, O(C 1 -C 4 )alkyl and heterocyclyl; and
R c is independently H, SO 2 (C 1 -C 4 )alkyl, or C 1 -C 4 alkyl;
or a pharmaceutically acceptable salt or a stereoisomer thereof.

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

wherein:
b is 0 or 1;
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 and piperazinyl, said alkyl, morpholinyl, piperidinyl, azetidinyl and piperaziyle are optionally substituted with one or more substituents selected from R a ;
R 4 is absent or methyl;
R 5 is aryl or heteroaryl each optionally substituted with one or more substituents selected from R b ;
R 6 is absent or F;
R a is independently selected from: F, O b (C 1 -C 4 )alkyl, SO 2 (C 1 -C 4 )alkyl, C(O)C 1 -C 4 alkyl, said alkyl optionally substituted with F or morpholinyl;
R b is independently selected from OH, halo, CHF 2 , CF 3 , COOH, SO 2 (C 1 -C 4 )alkyl, C═O(O)C 1 -C 4 alkyl, O b (C 1 -C 4 )alkyl, aryl, heterocyclyl, CN, C(O)N(R c ) 2 , N(R c ) 2 ; said R c and alkyl are optionally substituted with OH, O(C 1 -C 4 )alkyl and heterocyclyl; and
R c is independently H, SO 2 (C 1 -C 4 )alkyl, or C 1 -C 4 alkyl;
or a pharmaceutically acceptable salt or a stereoisomer thereof.

3. A compound which is selected from:
trans-N,N-dimethyl-N′-[6(6-methylpyridazin-4-yl)quinazolin-4-yl]cyclohexane-1,4-diamine;
cis or trans-N,N-dimethyl-N′-(6-phenylquinazolin-4-yl)cyclohexane-1,4-diamine;
cis or trans-N,N-dimethyl-N′-[6-(pyridin-4-yl)quinazolin-4-yl]cyclohexane-1,4-diamine;
cis or trans-N,N-dimethyl-N′-[6-(pyridin-3-yl)quinazolin-4-yl]cyclohexane-1,4-diamine;
cis or trans-N,N-dimethyl-N′-(6-phenylquinazolin-4-yl)cyclohexane-1,4-diamine;
cis or trans-N,N-dimethyl-N′-[6-(pyridin-4-yl)quinazolin-4-yl]cyclohexane-1,4-diamine;
cis or trans-N,N-dimethyl-N′-[6-(pyridin-3-yl)quinazolin-4-yl]cyclohexane-1,4-diamine;
trans-N′-[6-(2-methoxypyridin-4-yl)quinazolin-4-yl]-N,N-dimethylcyclohexane-1,4-diamine;
trans-N,N-dimethyl-N′-[6-(1-methyl-1H-pyrazol-4-yl)quinazolin-4-yl]cyclohexane-1,4-diamine;
cis or trans-N,N-dimethyl-N′-[6-(1H-pyrazol-4-yl)quinazolin-4-yl]cyclohexane-1,4-diamine;
cis or trans-N′-[6-(6-aminopyridin-3-yl)quinazolin-4-yl]-N,N-dimethylcyclohexane-1,4-diamine;
trans-N,N-dimethyl-N′-[6-(1H-pyrazol-3-yl)quinazolin-4-yl]cyclohexane-1,4-diamine;
trans-N,N-dimethyl-N′-{6-[2-(methylamino)pyrimidin-5-yl]quinazolin-4-yl}cyclohexane-1,4-diamine;
trans-N′-{6-[1-(1-ethoxyethyl)-1H-pyrazol-4-yl]quinazolin-4-yl}-N,N-dimethylcyclohexane-1,4-diamine;
trans-N,N-dimethyl-N′-(6-{1-[2-(morpholin-4-yl)ethyl]-1H-pyrazol-4-yl}quinazolin-4-yl)cyclohexane-1,4-diamine;
trans-N,N-dimethyl-N-′-{6-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]quinazolin-4-yl}cyclohexane-1,4-diamine;
trans-N,N-dimethyl-N′-{6-[1-(pyridin-2-ylmethyl)-1H-pyrazol-4-yl]quinazolin-4-yl}cyclohexane-1,4-diamine;
trans-N′-[6-(1-ethyl-1H-pyrazol-4-yl)quinazolin-4-yl]-N,N-dimethylcyclohexane-1,4-diamine;
trans-N,N-dimethyl-N′-{6-[1-(pyridin-4-ylmethyl)-1H-pyrazol-4-yl]quinazolin-4-yl}cyclohexane-1,4-diamine;
4-(4-{[trans-4-(dimethylamino)cyclohexyl]amino}quinazolin-6-yl)pyridine-3-carbonitrile;
trans-N,N-dimethyl-N′-[6-(3-methylpyridin-4-yl)quinazolin-4-yl]cyclohexane-1,4-diamine;
3-(4-{[trans-4-(dimethylamino)cyclohexyl]amino}quinazolin-6-yl)pyridine-4-carbonitrile;
trans-N,N-dimethyl-N′-{6-[5-(morpholin-4-yl)pyridin-3-yl]quinazolin-4-yl}cyclohexane-1,4-diamine;
trans-N′-[6-(3,5-dimethylisoxazol-4-yl)quinazolin-4-yl]-N,N-dimethylcyclohexane-1,4-diamine;
trans-N,N-dimethyl-N′-[6-(pyrimidin-5-yl)quinazolin-4-yl]cyclohexane-1,4-diamine;
trans-N,N-dimethyl-N′-[6-(5-methyl-3-phenylisoxazol-4-yl)quinazolin-4-yl]cyclohexane-1,4-diamine;
5-(4-{[trans-4-(dimethylamino)cyclohexyl]amino}quinazolin-6-yl)pyridine-2-carbonitrile;
5-(4-{[trans-4-(dimethylamino)cyclohexyl]amino}quinazolin-6-yl)pyridin-2-ol;
trans-N′-[6-(2-aminopyrimidin-5-yl)quinazolin-4-yl]-N,N-dimethylcyclohexane-1,4-diamine;
trans-N,N-dimethyl-N′-[6-(6-methylpyridin-3-yl)quinazolin-4-yl]cyclohexane-1,4-diamine;
methyl 5-(4-{[trans-4-(dimethylamino)cyclohexyl]amino}quinazolin-6-yl)pyridine-3-carboxylate;
trans-N′-[6-(isoxazol-4-yl)quinazolin-4-yl]-N,N-dimethylcyclohexane-1,4-diamine;
5-(4-{[trans-4-(dimethylamino)cyclohexyl]amino}quinazolin-6-yl)pyrimidin-2-ol;
trans-N′-[6-(3-fluoropyridin-4-yl)quinazolin-4-yl]-N,N-dimethylcyclohexane-1,4-diamine;
trans-N′-[6-(4-methoxypyridin-3-yl)quinazolin-4-yl]-N,N-dimethylcyclohexane-1,4-diamine;
trans-N,N-dimethyl-N′-{6-[4-(trifluoromethyl)pyridin-3-yl]quinazolin-4-yl}cyclohexane-1,4-diamine;
5-(4-{[trans-4-(dimethylamino)cyclohexyl]amino}quinazolin-6-yl)pyridine-3-carboxylic acid;
trans-N′-[6-(3-methoxypyridin-4-yl)quinazolin-4-yl]-N,N-dimethylcyclohexane-1,4-diamine;
3-(4-{[trans-4-(dimethylamino)cyclohexyl]amino}quinazolin-6-yl)pyridine-2-carbonitrile;
trans-N′-{6-[5-(2-methoxyethoxy)pyridin-3-yl]quinazolin-4-yl}-N,N-dimethylcyclohexane-1,4-diamine;
trans-N,N-dimethyl-N′-{6-[5-(methylsulfonyl)pyridin-3-yl]quinazolin-4-yl}cyclohexane-1,4-diamine;
trans-N′-{6-[2-(cyclopropylamino)pyrimidin-5-yl]quinazolin-4-yl}-N,N-dimethylcyclohexane-1,4-diamine;
2-{[5-(4-{[trans-4-(dimethylamino)cyclohexyl]amino}quinazolin-6-yl)pyrimidin-2-yl]amino}ethanol;
3-(4-{[trans-4-(dimethylamino)cyclohexyl]amino}quinazolin-6-yl)benzonitrile;
trans-N′-[6-(1H-indol-5-yl)quinazolin-4-yl]-N,N-dimethylcyclohexane-1,4-diamine;
N-[trans-4-(morpholin-4-yl)cyclohexyl]-6-(pyridin-3-yl)quinazolin-4-amine;
N-[trans-4-(morpholin-4-yl)cyclohexyl]-6-(pyrimidin-5-yl)quinazolin-4-amine;
N-[trans-4-(morpholin-4-yl)cyclohexyl]-6-(pyridin-4-yl)quinazolin-4-amine;
trans-N′-[6-(2,3-dihydro-1,4-benzodioxin-6-yl)quinazolin-4-yl]-N,N-dimethylcyclohexane-1,4-diamine;
trans-N,N-dimethyl-N′-[6-(pyridazin-4-yl)quinazolin-4-yl]cyclohexane-1,4-diamine;
trans-N′-[6-(5-methoxypyridin-3-yl)quinazolin-4-yl]-N,N-dimethylcyclohexane-1,4-diamine;
trans-N′-[6-(5-fluoro-6-methoxypyridin-3-yl)quinazolin-4-yl]-N,N-dimethylcyclohexane-1,4-diamine;
trans-N′-[6-(5-fluoropyridin-3-yl)quinazolin-4-yl]-N,N-dimethylcyclohexane-1,4-diamine;
5-(4-{[trans-4-(dimethylamino

Assignees

• Merck Sharp & Dohme

Inventors

• Altman Michael D
• Andresen Brian M
• 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
• Torres Luis

Classifications

• A61K31/5383

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

• A61K45/06

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

• C07D401/14

  containing three or more hetero rings · CPC title

• A61K31/517

  ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine · CPC title

• C07D409/04

  directly linked by a ring-member-to-ring-member bond · CPC title