Inhibitors of IRAK4 activity

Patent metadata

Field	Value
Publication number	US-9943516-B2
Application number	US-201515515388-A
Country	US
Kind code	B2
Filing date	Sep 25, 2015
Priority date	Sep 30, 2014
Publication date	Apr 17, 2018
Grant date	Apr 17, 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 or (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 hydrogen, halo or O b (C 1 -C 4 )alkyl;
R 5 is a non-aromatic cyclic moiety optionally substituted with one or more substituents selected from R b ;
R 6 is hydrogen, 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, COOH, CN, 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 II:

wherein:
R 1 and R 2 are independently H or (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 morpholine ring;
R 4 is hydrogen or methyl;
R 5 is a non-aromatic cyclic moiety optionally substituted with one or more substituents selected from R b ;
R 6 is hydrogen or F; and
R b is independently selected from OH, halo, COOH, (C 1 -C 4 )alkyl, and CN;
or a pharmaceutically acceptable salt or a stereoisomer thereof.

3. A compound according to claim 2 of Formula II:
wherein:
R 1 and R 2 are methyl, or R 1 and R 2 can be taken together with the nitrogen to which they are attached to form a morpholine ring;
R 4 is hydrogen or methyl;
R 5 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl, each optionally substituted with one or more substituents selected from R b ;
R 6 is hydrogen or F; and
R b is independently selected from OH, F, COOH, methyl, and CN;
or a pharmaceutically acceptable salt or a stereoisomer thereof.

4. A compound which is selected from:
6-Cyclopropyl-5-methyl-N-(trans-4-morpholinocyclohexyl)quinazolin-4-amine;
N′-(6-cyclopropylquinazolin-4-yl)-N,N-dimethylcyclohexane-1,4-diamine;
6-cyclopropyl-N-(trans-4-morpholin-4-ylcyclohexyl)quinazolin-4-amine;
6-cyclopropyl-7-fluoro-N-(trans-4-morpholin-4-ylcyclohexyl)quinazolin-4-amine;
6-(1-methylcyclopropyl)-N-(trans-4-morpholin-4-ylcyclohexyl)quinazolin-4-amine;
6-cyclobutyl-N-(trans-4-morpholin-4-ylcyclohexyl)quinazolin-4-amine;
6-cyclopentyl-N-(trans-4-morpholin-4-ylcyclohexyl)quinazolin-4-amine;
6-cyclohexyl-N-(trans-4-morpholin-4-ylcyclohexyl)quinazolin-4-amine;
N-((trans)-4-morpholinocyclohexyl)-6-(oxetan-3-yl)quinazolin-4-amine;
N-(trans-4-morpholin-4-ylcyclohexyl)-6-(tetrahydrofuran-3-yl)quinazolin-4-amine;
N-((trans)-4-morpholinocyclohexyl)-6-(tetrahydrofuran-2-yl)quinazolin-4-amine;
4-{4-[(trans-4-morpholin-4-ylcyclohexyl)amino]quinazolin-6-yl}cyclohexanecarbonitrile;
6-(4,4-difluorocyclohexyl)-N-(trans-4-morpholin-4-ylcyclohexyl)quinazolin-4-amine;
N-(trans-4-morpholin-4-ylcyclohexyl)-6-(tetrahydro-2H-pyran-4-yl)quinazolin-4-amine;
N-(trans-4-morpholin-4-ylcyclohexyl)-6-(tetrahydro-2H-pyran-3-yl)quinazolin-4-amine;
4-{4-[(trans-4-morpholin-4-ylcyclohexyl)amino]quinazolin-6-yl}cyclohexanecarboxylic acid;
3-(4-(((trans)-4-Morpholinocyclohexyl)amino)quinazolin-6-yl)cyclohexanol;
3-(4-(((trans)-4-Morpholinocyclohexyl)amino)quinazolin-6-yl)cyclohexanol; and
3-(4-(((trans)-4-Morpholinocyclohexyl)amino)quinazolin-6-yl)cyclohexanol;
or a pharmaceutically acceptable salt or stereoisomer thereof.

5. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of claim 1 .

6. A method for treating rheumatoid arthritis or inflammatory bowel disease which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 1 .

7. A method of treating rheumatoid arthritis or inflammatory bowel disease which comprises administering a therapeutically effective amount of a compound of claim 1 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.

Assignees

• Merck Sharp & Dohme

Inventors

• Altman Michael D
• Andresen Brian M
• Brubaker Jason D
• Donofrio Anthony
• Fischmann Thierry
• Gibeau Craig R
• Lesburg Charles A
• Lim Jongwon
• Maclean John K F
• Mansoor Umar F
• Northrup Alan B
• Sanders John M
• Smith Graham F
• Torres Luis

Classifications

• C07D405/04

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

• A61K45/06

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

• C07D239/94

  Nitrogen atoms · CPC title

• A61K31/517 Primary

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

• A61P29/00

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