Substituted pyrimidinyl-pyrroles active as kinase inhibitors

Patent metadata

Field	Value
Publication number	US-9283224-B2
Application number	US-201214112559-A
Country	US
Kind code	B2
Filing date	Apr 5, 2012
Priority date	Apr 19, 2011
Publication date	Mar 15, 2016
Grant date	Mar 15, 2016

Abstract

The present invention relates to substituted pyrimidinyl-pyrrole compounds of formula (I) which modulate the activity of protein kinases and are therefore useful in treating diseases caused by dysregulated protein kinase activity, in particular Janus kinases. The present invention also provides methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and methods of treating diseases utilizing such compounds or the pharmaceutical compositions containing them.

First claim

The invention claimed is:

1. A compound of formula (I):

wherein:
R1 is selected from the group consisting of a halogen and a straight or branched C 1 -C 6 alkyl and
R2 is selected from the group consisting of a halogen and a substituted C 1 -C 6 alkyl;
R3 is NR8R9 wherein:
R8 and R9 are independently hydrogen or an optionally substituted group selected from straight or branched C 1 -C 6 alkyl, straight or branched C 2 -C 6 alkenyl, straight or branched C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, cycloalkyl-alkyl, aryl, arylalkyl, heterocyclyl and heterocyclyl-alkyl, or R8 and R9, taken together with the nitrogen atom to which they are bonded, may form an optionally substituted 5 to 6 membered heteroaryl or heterocyclyl group optionally containing one additional heteroatom selected from N, O and S;

R4 is hydrogen, an optionally substituted straight or branched C 1 -C 6 alkyl or NR10R11, wherein:
R10 and R11 are independently hydrogen or an optionally substituted group selected from straight or branched C 1 -C 6 alkyl, straight or branched C 2 -C 6 alkenyl, straight or branched C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, cycloalkyl-alkyl, aryl, arylalkyl, heterocyclyl and heterocyclyl-alkyl, or R10 and R11, taken together with the nitrogen atom to which they are bonded, may form an optionally substituted 5 to 6 membered heteroaryl or heterocyclyl group optionally containing one additional heteroatom selected from N, O and S;

R12 is hydrogen or an optionally substituted straight or branched C 1 -C 6 alkyl;
or a pharmaceutically acceptable salt thereof, with the proviso that the following compounds are excluded:
5-(2-amino-pyrimidin-4-yl)-2-(5-fluoro-2-methyl-phenyl)-1H-pyrrole-3-carboxamide,
5-(2-amino-pyrimidin-4-yl)-2-(2,5-difluoro-phenyl)-1H-pyrrole-3-carboxamide,
5-(2-amino-pyrimidin-4-yl)-2-(5-chloro-2-methyl-phenyl)-1H-pyrrole-3-carboxamide,
5-(2-amino-pyrimidin-4-yl)-2-(5-chloro-2-fluoro-phenyl)-1H-pyrrole-3-carboxamide and
5-(2-amino-pyrimidin-4-yl)-2-(2-chloro-5-fluoro-phenyl)-1H-pyrrole-3-carboxamide.

2. A compound of formula (I) as defined in claim 1 wherein:
R4 is NR10R11, wherein R10 and R11 are independently hydrogen or an optionally substituted straight or branched C 1 -C 6 alkyl.

3. A compound of formula (I) as defined in claim 1 wherein:
R3 is NR8R9, wherein R8 and R9 are independently hydrogen or an optionally substituted straight or branched C 1 -C 6 alkyl.

4. A compound of formula (I) as defined in claim 1 wherein:
R12 is hydrogen.

5. A compound or a pharmaceutically acceptable salt thereof which is selected from the group consisting of:
5-(2-Aminopyrimidin-4-yl)-2-[2-chloro-5-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(2,5-dichlorophenyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methoxyphenyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(2-chloro-5-ethylphenyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-ethylphenyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(2-chloro-5-methylphenyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(2-chloro-5-cyanophenyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-bromo-2-methoxyphenyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-bromo-2-fluorophenyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-[2-chloro-5-(hydroxymethyl)phenyl]-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(2-chloro-5-methoxyphenyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-[2-chloro-5-(trifluoromethoxy)phenyl]-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-[2-methyl-5-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-[5-chloro-2-(propan-2-yl)phenyl]-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-[2,5-bis(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-[2-ethyl-5-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-[5-chloro-2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-cyano-2-methylphenyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-N-methyl-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-N-ethyl-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-N-(2-hydroxyethyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-N-[2-(piperidin-1-yl)ethyl]-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-N-(1-methylpiperidin-4-yl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-N-phenyl-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-N-(furan-2-ylmethyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-N-(3-hydroxypropyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-N-(2-methoxyethyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-N-(2-fluoroethyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-N,N-dimethyl-1H-pyrrole-3-carboxamide,
N-(2-Aminoethyl)-5-(2-aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-N-[2-(methylamino)ethyl]-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-N-benzyl-2-(5-chloro-2-methylphenyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-N-(2-methylpropyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-N-(2,2-dimethylpropyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-ethylphenyl)-N-methyl-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-ethylphenyl)-N-ethyl-1H-pyrrole-3-carboxamide,
5-(2-aminopyrimidin-4-yl)-2-(5-chloro-2-ethylphenyl)-N-(2-hydroxyethyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-ethylphenyl)-N,N-dimethyl-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-[2-chloro-5-(trifluoromethyl)phenyl]-N-methyl-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-hydroxyphenyl)-1H-pyrrole-3-carboxamide,
2-(5-chloro-2-methylphenyl)-5-[2-(methylamino)pyrimidin-4-yl]-1H-pyrrole-3-carboxamide,
5-(Pyrimidin-4-yl)-2-(5-chloro-2-methyl-phenyl)-1H-pyrrole-3-carboxamide,
2-(5-Chloro-2-methylphenyl)-5-(2-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-ethylphenyl)-1-methyl-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-1-methyl-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-1-ethyl-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-1-(2-hydroxyethyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-N-methyl-2-[2-methyl-5-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide and
5-(2-Aminopyrimidin-4-yl)-2-[2-ethyl-5-(trifluoromethyl)phenyl]-N-methyl-1H-pyrrole-3-carboxamide.

6. A process for preparing a compound of formula (I) as defined in claim 1 or the pharmaceutically acceptable salts thereof, characterized in that the process comprises the following steps:
Step 1: metal-catalyzed coupling reaction of a halo derivative of formula (II)

with a substituted a

Assignees

• Brasca Maria Gabriella
• Bandiera Tiziano
• Bertrand Jay Aaron
• Gnocchi Paola
• Mirizzi Danilo
• Nesi Marcella
• Panzeri Achille
• Nerviano Medical Sciences Srl

Inventors

• Brasca Maria Gabriella
• Bandiera Tiziano
• Bertrand Jay Aaron
• Gnocchi Paola
• Mirizzi Danilo
• Nesi Marcella
• Panzeri Achille

Classifications

• C07D403/04 Primary

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

• C07F5/025

  Boronic and borinic acid compounds · CPC title

• A61K31/506 Primary

  not condensed and containing further heterocyclic rings · CPC title

• C07F5/02

  Boron compounds · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title